thromboplastin and Disseminated-Intravascular-Coagulation

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.

Topics: COVID-19; Cytokine Release Syndrome; Disseminated Intravascular Coagulation; Extracellular Traps; Gene Expression Regulation; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Neutrophils; Pulmonary Embolism; Respiratory Insufficiency; SARS-CoV-2; Signal Transduction; Thromboplastin

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.

Topics: Anticoagulants; Biomarkers; Blood Viscosity; Disease Management; Disseminated Intravascular Coagulation; Endothelium, Vascular; Female; Fibrinolysis; Humans; Male; Neoplasms; Platelet Activation; Pregnancy; Pregnancy Complications, Hematologic; Prevalence; Prognosis; Sepsis; Severity of Illness Index; Thrombin; Thromboembolism; Thromboplastin

SARS-CoV-2 attaches to the angiotensin-converting enzyme 2 (ACE-2) receptor on human cells. The virus causes hypercytokinemia, capillary leak, pulmonary edema, acute respiratory distress syndrome, acute cardiac injury, and leads to death. Mesenchymal stem cells (MSCs) are ACE-2 negative cells; therefore, can escape from SARS-CoV-2. MSCs prevent hypercytokinemia and help the resolution of the pulmonary edema and other damages occurred during the course of COVID-19. In addition, MSCs enhance the regeneration of the lung and other tissues affected by SARS-CoV-2. The case series reported beneficial effect of MSCs in COVID-19 treatment. However, there are some concerns about the safety of MSCs, particularly referring to the increased risk of disseminated intravascular coagulation, and thromboembolism due to the expression of TF/CD142. Prospective, randomized, large scale studies are needed to reveal the optimum dose, administration way, time, efficacy, and safety of MSCs in the COVID-19 treatment.

Topics: COVID-19; Disseminated Intravascular Coagulation; Humans; Lung; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Peptidyl-Dipeptidase A; Prospective Studies; Regeneration; Risk Factors; SARS-CoV-2; Thromboembolism; Thromboplastin

Several clinical conditions, in particular those associated with a systemic inflammatory response, can cause some degree of activation of coagulation but when the procoagulant stimulus is sufficiently severe and overcomes the natural anticoagulant mechanisms of coagulation, disseminated intravascular coagulation (DIC) may occur. The clinical manifestations of DIC encompass multiorgan dysfunction caused by fibrin-platelet clots in the microcirculation, and bleeding caused by consumption of platelets and coagulation factors. Molecular mechanisms that play a role in inflammation-induced effects on coagulation have been recognized in much detail. Exposure of blood to tissue factor is the most common trigger, whereas the intravascular coagulation is propagated due to loss of function of physiological anticoagulants and impaired fibrinolysis. In patients with DIC, various abnormalities in routine coagulation parameters may be observed, including thrombocytopenia, prolonged global coagulation assays, or high levels of fibrin split products. In addition, more sophisticated tests for activation of individual factors or pathways of coagulation may point to specific involvement of these components in the pathogenesis of the disorder. A combination of readily available tests is usually sufficient in establishing the diagnosis of DIC, and for this purpose, several scoring algorithms have been developed. Some specific clinical situations may elicit coagulation responses that can be distinguished from DIC or may occur in combination with DIC, including dilutional coagulopathy, liver failure-related coagulation derangement, and thrombotic microangiopathies.

Topics: Algorithms; Blood Coagulation Disorders; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Humans; Thromboplastin

Filoviruses are responsible for highly lethal infections. Those viruses are found in intertropical areas of Africa and Asia where they circulate in their supposed natural reservoir, fruit bats. During filovirus outbreaks and depending on the strains, various modifications in hemostasis have been observed in patients. The disseminated intravascular coagulation identified in these infections is multicausal and involves both viral factors and abnormal physiological responses. In this review we will describe the mechanisms responsible for these disturbances and we will highlight some aspects of the basis of filovirus high pathogenicity.

Topics: Adrenal Cortex; Animals; Chiroptera; Communicable Diseases, Emerging; Cytokines; Disease Reservoirs; Disseminated Intravascular Coagulation; Endothelial Cells; Filoviridae; Filoviridae Infections; Haplorhini; Hepatocytes; Host-Pathogen Interactions; Humans; Necrosis; Recombinant Proteins; Thromboplastin; Viral Load; Viral Proteins

Coagulopathy is common in acute sepsis and may range from subclinical activation of blood coagulation (hypercoagulability), which may contribute to venous thromboembolism, to acute disseminated intravascular coagulation, characterized by widespread microvascular thrombosis and consumption of platelets and coagulation proteins, eventually causing bleeding. The key event underlying this life-threatening complication is the overwhelming inflammatory host response to the pathogen leading to the overexpression of inflammatory mediators. The latter, along with the microorganism and its derivatives drive the major changes responsible for massive thrombin formation and fibrin deposition: (1) aberrant expression of tissue factor mainly by monocytes-macrophages, (2) impairment of anticoagulant pathways, orchestrated by dysfunctional endothelial cells (ECs), and (3) suppression of fibrinolysis because of the overproduction of plasminogen activator inhibitor-1 by ECs and thrombin-mediated activation of thrombin-activatable fibrinolysis inhibitor. Neutrophils and other cells, upon activation or death, release nuclear materials (neutrophil extracellular traps and/or their components such as histones, DNA, lysosomal enzymes, and High Mobility Group Box-1), which have toxic, proinflammatory and prothrombotic properties thus contributing to clotting dysregulation. The ensuing microvascular thrombosis-ischemia significantly contributes to tissue injury and multiple organ dysfunction syndromes. These insights into the pathogenesis of sepsis-associated coagulopathy may have implications for the development of new diagnostic and therapeutic tools.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelium, Vascular; Endotoxemia; Extracellular Traps; Fibrinolysis; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Macrophages; Models, Biological; Monocytes; Multiple Organ Failure; Neutrophils; Protein C; Sepsis; Thrombophilia; Thromboplastin; Thrombotic Microangiopathies

Microparticles (MP) are small extracellular vesicles (30-1,000 nm) that are released from activated cells or platelets. Exposure of negatively charged phospholipids and tissue factor (TF) renders MP procoagulant. Normal plasma levels of intravascular TF-exposing MP (TFMP) are low, but their number may rise in pathological conditions, including cancer and infectious disease. Emerging evidence indicates an important role for these circulating TFMP in the pathogenesis of thrombotic complications such as venous thromboembolism and disseminated intravascular coagulation, whereas their contribution to arterial thrombosis is less studied. Despite serious limitations of the currently available assays for measuring TFMP levels or the procoagulant activity associated with TFMP with respect to sensitivity and specificity, the scientific interest in TFMP is rapidly growing because their application as prognostic biomarkers for thrombotic complications is promising. Future advances in detection methods will likely provide more insight into TFMP and eventually improve their clinical utility.

Topics: Animals; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Humans; Thromboplastin; Venous Thrombosis

Thrombocytopenia-associated multiple organ failure (TAMOF) is a clinical phenotype that encompasses a spectrum of syndromes associated with disseminated microvascular thromboses, such as the thrombotic microangiopathies thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) and disseminated intravascular coagulation (DIC). Autopsies findings in TTP, HUS, or DIC reveal specific findings that can differentiate these 3 entities. Von Willebrand factor and ADAMTS-13 play a central role in TTP. Shiga toxins and the complement pathway are vital in the development of HUS. Tissue factor is the major protease that drives the pathology of DIC. Acute kidney injury (AKI) is a common feature in patients with TAMOF.

Topics: Acute Kidney Injury; ADAM Proteins; ADAMTS13 Protein; Antibodies, Monoclonal, Humanized; Complement Inactivating Agents; Complement System Proteins; Disseminated Intravascular Coagulation; Hemolytic-Uremic Syndrome; Humans; Multiple Organ Failure; Purpura, Thrombotic Thrombocytopenic; Shiga Toxins; Thromboplastin; von Willebrand Factor

Coagulopathy is a unique component of the pathology of acute promyelocytic leukaemia (APL). Though many causative factors have been elucidated, therapies to rectify the coagulopathy are far from being realised. Thrombotic and bleeding complications remain the major causes of early deaths. In this chapter, the known causes of abnormalities in haemostatic function, namely the coagulopathy and changes in the fibrinolytic system, will be reviewed. Major risk factors for these complications are identified. Current available measures for correction of the coagulopathy and their effectiveness are critically examined. Unless the coagulopathy can be effectively controlled, bleeding complications will remain an obstacle to achieving a cure for this disease. The issues that need to be addressed in next phase of investigations are also discussed.

Topics: Annexin A2; Anticoagulants; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Blood Coagulation Tests; Carboxypeptidase B2; Disseminated Intravascular Coagulation; Fibrinolysis; Forecasting; Granulocyte Precursor Cells; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recombinant Proteins; Risk Factors; S100 Proteins; Thrombomodulin; Thrombophilia; Thromboplastin; Tretinoin; Urokinase-Type Plasminogen Activator

Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation, leading to a widespread deposition of fibrin in the circulation. There is ample experimental and pathological evidence that the fibrin deposition contributes to multiple organ failure. The massive and ongoing activation of coagulation may result in depletion of platelets and coagulation factors, which may cause bleeding (consumption coagulopathy). The syndrome of DIC is well known in the medical literature for centuries, although a more precise description of the underlying mechanisms had to await the 20th century. Initial ideas on a role of the contact activation system as the primary trigger for the systemic activation of coagulation as well as a presumed hyperfibrinolytic response in DIC have been found to be misconceptions. Experimental and clinical evidence now indicate that the initiation of coagulation in DIC is caused by tissue factor expression, which in combination with downregulated physiological anticoagulant pathways and impaired fibrinolysis leads to widespread fibrin deposition. In addition, an extensive bidirectional interaction between coagulation and inflammation may further contribute to the pathogenesis of DIC.

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; History, 20th Century; History, 21st Century; Humans; Thromboplastin; Thrombosis

Acute promyelocytic leukemia (APL) has evolved from being a deadly to a highly curable disease, due to targeted molecular therapy with all-trans retinoic acid (ATRA). As a result, the incidence of early hemorrhagic deaths for which APL is notorious has reduced to 5-10% as reported in clinical trials. These results are not replicated outside of clinical trials as is evident from recent population-based registries. High incidence of early hemorrhagic deaths remains the greatest contributor to treatment failure in this otherwise curable leukemia. Additionally, thrombosis is now being increasingly recognized in APL patients and may be associated with ATRA usage.

Topics: Antifibrinolytic Agents; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Tests; Clinical Trials as Topic; Combined Modality Therapy; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor VIIa; Factor VIII; Fibrinogen; Fibrinolysis; Hemorrhage; Heparin; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Neoplasm Proteins; Oxides; Plasma; Platelet Count; Platelet Transfusion; Recombinant Proteins; Thromboplastin; Thrombosis; Treatment Failure; Tretinoin

Tissue factor (TF) is a major initiator of extrinsic pathway of blood coagulation. A dual role of TF in the extensive crosstalk between blood coagulation and inflammation has recently become apparent. The majority of the cases of systemic inflammatory response syndrome, disseminated intravascular coagulation, and sepsis are accompanied by hyperactivation of TF in circulating monocytes and damaged tissue. Systemic Gram-negative infection induces expression of TF by vascular cells. In addition to extrinsic coagulation pathway, TF induces proinflammatory signaling cascade originating from activation of protease-activated receptors. Because TF-activated proteolytic cascade is placed in a nexus between coagulation and inflammation, early modulation of TF activity presently becomes a tempting experimental therapeutic strategy in systemic inflammatory response syndrome patients.

Topics: Anti-Bacterial Agents; Blood Coagulation; Disseminated Intravascular Coagulation; Gram-Negative Bacteria; Humans; Lipopolysaccharides; Monocytes; Sepsis; Signal Transduction; Systemic Inflammatory Response Syndrome; Thromboplastin

Topics: Antineoplastic Agents; Blood Coagulation; Cysteine Endopeptidases; Cytokines; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasms; Thromboplastin; Tretinoin

Thrombosis, or complications from thrombosis, currently occupies the top three positions in the cardiovascular causes of morbidity and mortality in the developed world. There are a limited number of safe and effective drugs to prevent and treat thrombosis. Animal models of thrombosis are necessary to better understand the complex components and interactions involved in the formation of a clot. Tissue factor (TF) is required for the initiation of blood coagulation and likely plays a key role in both arterial and venous thrombosis. Understanding the role of TF in thrombosis may permit the development of new antithrombotic drugs. This review will focus on the role of TF in in vivo models of thrombosis.

Topics: Animals; Arterial Occlusive Diseases; Blood Coagulation; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Humans; Microcirculation; Thromboplastin; Thrombosis; Venous Thrombosis

Topics: Anticoagulants; Blood Coagulation Factors; Cysteine Endopeptidases; Cytokines; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; Neoplasm Proteins; Neoplasms; Thromboplastin; Venous Thromboembolism

As activation of the coagulation pathway is a physiological response to injury, the development of disseminated intravascular coagulation (DIC) is a warning signal to the clinician that the primary pathological disease state is decompensating. In pregnancy, DIC can occur in several settings, which include emergencies such as placental abruption and amniotic fluid embolism as well as complications such as pre-eclampsia. Whilst the acuteness of the event and the proportionality in the coagulant and fibrinolytic responses may vary between these different conditions, a common theme for pregnancy-associated DIC is the pivotal role played by the placenta. Removal of the placenta is the linchpin to treatment in most cases but appropriate blood product support is also key to management. This is necessary because DIC itself can have pathological consequences that translate clinically into a worse prognosis for affected patients. This article will describe how pregnancy-associated DIC can be diagnosed promptly and how treatment should be managed strategically. It also discusses the latest developments in our understanding of haemostatic mechanisms within the placenta and how these may have relevance to new diagnostic approaches as well as novel therapeutic modalities.

Topics: Anticoagulants; Blood Coagulation Factors; Blood Component Transfusion; Disseminated Intravascular Coagulation; Factor VIIa; Female; Humans; Obstetric Labor Complications; Placenta; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Thromboplastin

Sepsis is often associated with systemic intravascular activation of coagulation, potentially leading to widespread microvascular deposits of fibrin, and thereby contributing to multiple organ dysfunction. A complex interaction exists between activation of inflammatory systems and the initiating and regulating pathways of coagulation. A diagnosis of sepsis-associated disseminated intravascular coagulation can be made by a combination of routinely available laboratory tests, for which simple diagnostic algorithms have become available. Strategies to inhibit coagulation activation may theoretically be justified and are being evaluated in clinical studies.

Topics: Anticoagulants; Antithrombin III; Disseminated Intravascular Coagulation; Glycocalyx; Humans; Multiple Organ Failure; Plasma; Platelet Transfusion; Protein C; Sepsis; Thromboplastin

Malaria remains a highly prevalent disease in more than 90 countries and accounts for at least 1 million deaths every year. Plasmodium falciparum infection is often associated with a procoagulant tonus characterized by thrombocytopenia and activation of the coagulation cascade and fibrinolytic system; however, bleeding and hemorrhage are uncommon events, suggesting that a compensated state of blood coagulation activation occurs in malaria. This article (i) reviews the literature related to blood coagulation and malaria in a historic perspective, (ii) describes basic mechanisms of coagulation, anticoagulation, and fibrinolysis, (iii) explains the laboratory changes in acute and compensated disseminated intravascular coagulation (DIC), (iv) discusses the implications of tissue factor (TF) expression in the endothelium of P. falciparum infected patients, and (v) emphasizes the procoagulant role of parasitized red blood cells (RBCs) and activated platelets in the pathogenesis of malaria. This article also presents the Tissue Factor Model (TFM) for malaria pathogenesis, which places TF as the interface between sequestration, endothelial cell (EC) activation, blood coagulation disorder, and inflammation often associated with the disease. The relevance of the coagulation-inflammation cycle for the multiorgan dysfunction and coma is discussed in the context of malaria pathogenesis.

Topics: Animals; Blood Platelets; Coma; Disseminated Intravascular Coagulation; Endothelium, Vascular; Erythrocytes; Fibrinolysis; Humans; Inflammation; Malaria, Falciparum; Plasmodium falciparum; Platelet Activation; Thrombocytopenia; Thromboplastin

Tissue factor (TF) performs an essential role in the blood clotting system by activating the extrinsic coagulation pathway following vascular injury. In addition to this physiological hemostatic role for wound repair, TF also plays pivotal roles in organ dysfunction in trauma patients by triggering pathological disseminated thrombosis and inflammation. Constitutively expressed TF in subendothelial cells is released into the circulation following trauma and can be detected as slightly elevated TF levels in the plasma. Liberation of constitutive TF into the blood and inducible tissue factor expression on monocytes and the other cells may synergistically increase plasma TF levels to higher values at the early stage of posttrauma, especially in patients with disseminated intravascular coagulation (DIC) in association with sustained systemic inflammatory response syndrome. Marked TF generation not adequately balanced by physiological coagulation inhibitors such as tissue factor pathway inhibitor in posttrauma DIC patients has been observed. Based on these pieces of evidence, it has now been accepted that combined activation of TF-dependent coagulation inadequately regulated by anticoagulant mechanisms and inflammation may synergistically play important roles in the pathogenesis of posttrauma multiple organ dysfunction syndrome.

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Gene Expression Regulation; Humans; Inflammation; Multiple Organ Failure; Thromboplastin; Wounds and Injuries

Tissue factor plays an essential role in the initiation of coagulation in vivo. In severe conditions, including sepsis and acute lung injury, increased expression of tissue factor may induce disseminated intravascular coagulation and fibrin deposition in organs, which are believed to have a determining impact on patient outcome. Tissue factor also acts as a signaling receptor and is involved in the systemic inflammatory response, as in cancer progression and atherosclerosis. Interventions aiming at limiting tissue factor activities have been evaluated in multiple experimental studies and the observed results have supported the potential benefits for coagulation disorders, inflammation, and survival. The effects of the main physiological inhibitor of tissue factor, tissue factor pathway inhibitor, have been evaluated in two large clinical trials in sepsis. Even though they are not associated with an improved outcome, the observed data support further clinical studies.

Topics: Animals; Blood Coagulation; Clinical Trials as Topic; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Humans; Inflammation; Lipoproteins; Lung; Lung Injury; Sepsis; Signal Transduction; Thromboplastin

The incidence of severe complications, such as disseminated intravascular coagulation (DIC) in malignant lymphoma, differs between clinical stages and histological types of the disease, but they occur frequently in stage IV or natural killer (NK) cell lymphoma. Patients with stage IV or NK cell lymphoma exhibit abnormal thrombotic and hemostatic states. One of the mechanisms in DIC might involve elevated cytokine expression by lymphoma cells stimulating the expression of tissue factor (TF) in blood cells or surrounding tissue. During chemotherapy for lymphoma, the white blood cell count was significantly reduced at days 1 and 3, but significantly increased at days 7 and 9. At day 7 of chemotherapy, leukocyte TF mRNA levels were significantly increased. Plasma concentrations of granulocyte elastase derived-XDP (GEXDP) levels correlated with D-dimer levels, suggesting that almost all elevated D-dimer is GE-XDP. C-reactive protein (CRP), GE-XDP and D-dimer were significantly elevated in patients with infection, DIC or acute respiratory distress syndrome (ARDS). Analysis of patients with DIC or ARDS revealed that TF mRNA correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes during chemotherapy.

Topics: C-Reactive Protein; Cytokines; Disseminated Intravascular Coagulation; Humans; Infections; Leukocyte Elastase; Lymphoma, Non-Hodgkin; RNA, Messenger; Thromboplastin

Tissue factor (TF) is a transmembrane protein that, in complex with factor VIIa (FVIIa), initiates coagulation. It also influences various other physiological and pathological events, such as inflammation, and negatively influences survival during sepsis. TF resembles a conserved class of pro-inflammatory cytokine receptors and activates a set of pro-inflammatory intracellular signal transduction routes. Interestingly, whereas the homology of TF to the class II cytokine receptors is reflected in a similar type of signal transduction, the mechanism by which the signal is transduced across the membrane differs greatly. This review discusses the role of TF and its ligand FVIIa in inflammation, sepsis, and signal transduction, and describes the way in which these processes interact.

Topics: Animals; Cattle; Disseminated Intravascular Coagulation; Factor VIIa; Gene Expression Regulation; Guinea Pigs; Humans; Inflammation; Mice; Protein-Tyrosine Kinases; Rabbits; Rats; Receptors, Cytokine; Sepsis; Sequence Homology; Signal Transduction; Thromboplastin; Trans-Activators

Thrombosis and disseminated intravascular coagulation (DIC) are common complications in cancer. Patients with malignancy have a prothrombotic state due to the ability of almost all type of cancer cells to activate the coagulation system. However, none of the haemostatic markers of coagulation has any predictive value for the occurrence of the thrombotic events in one individual patient. The pathogenesis of the prothrombotic state in cancer is complex and, probably, multifactorial. Prothrombotic factors in malignancy include the tumour production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant (CP)) and inflammatory cytokines, and the interaction between tumour cells and blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other mechanisms of thrombus promotion include some general responses of the host to the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of inhibitors of coagulation, and impaired fibrinolysis. In addition, the prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all of the mechanisms allowing the prothrombotic state of cancer are entirely understood. Therefore, it is presently difficult to rank the relative weight of these multiple interactions on the basis of the well-recognised clinical evidences of enhanced thrombotic episodes in patients with cancer. In this review we attempt to describe the current proposed mechanisms for the pathogenesis of the prothrombotic state in cancer patient. A better understanding of these mechanisms could help clinicians in the developments of more targeted treatment to prevent thromboembolic complications in cancer patient.

Topics: Biomarkers; Blood Cells; Blood Coagulation; Cysteine Endopeptidases; Cytokines; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Thromboplastin; Thrombosis

The transmembrane glycoprotein tissue factor (TF) is the initiator of the coagulation cascade in vivo. When TF is exposed to blood, it forms a high-affinity complex with the coagulation factors factor VII/activated factor VIIa (FVII/VIIa), activating factor IX and factor X, and ultimately leading to the formation of an insoluble fibrin clot. TF plays an essential role in hemostasis by restraining hemorrhage after vessel wall injury. An overview of biological and physiological aspects of TF, covering aspects consequential for thrombosis and hemostasis such as TF cell biology and biochemistry, blood-borne (circulating) TF, TF associated with microparticles, TF encryption-decryption, and regulation of TF activity and expression is presented. However, the emerging role of TF in the pathogenesis of diseases such as sepsis, atherosclerosis, certain cancers and diseases characterized by pathological fibrin deposition such as disseminated intravascular coagulation and thrombosis, has directed attention to the development of novel inhibitors of tissue factor for use as antithrombotic drugs. The main advantage of inhibitors of the TF*FVIIa pathway is that such inhibitors have the potential of inhibiting the coagulation cascade at its earliest stage. Thus, such therapeutics exert minimal disturbance of systemic hemostasis since they act locally at the site of vascular injury.

Topics: Animals; Arteriosclerosis; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Vessels; Disseminated Intravascular Coagulation; Fibrin; Gene Expression Regulation; Humans; Neoplasms; Sepsis; Thromboplastin; Thrombosis

Topics: Biomarkers; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Humans; Leukemia; Lipoproteins; Neoplasms; Specimen Handling; Thromboplastin

To review the role of tissue factor-dependent coagulation in acute lung injury. To interpret preclinical and clinical data on therapeutic intervention of the coagulation cascade, focusing on the principles of proteolytic cell signaling of the coagulant and anticoagulant pathways.. This review is based on published original research and relevant review articles on cell signaling by coagulation proteases and on experimental models that implicate the tissue factor-initiated coagulation cascade in acute lung injury and systemic inflammation.. The coagulation cascade signals via protease activated receptors in the tissue factor-initiation phase and downstream via the effector protease, thrombin. Bleomycin-induced acute lung injury is an example of thrombin signaling-dependent pathology. Frequently, thrombin signaling is a major contributor to inflammation in the extravascular space but intravascular thrombin signaling is a threshold-regulated event. At low concentrations, intravascular thrombin activates the protein C pathway by converting protein C (bound to endothelial cell protein C receptor) to activated protein C and this generates antiinflammatory signals along the activated protein C-endothelial cell protein C receptor-protease activated receptor 1 pathway on endothelial cells. Direct thrombin signaling only occurs when intravascular thrombin concentrations exceed a coagulant threshold. In systemic bacterial toxin-mediated inflammation, inhibition of thrombin is not sufficient to limit inflammation, whereas tissue factor inhibition interrupts a self-sustaining inflammatory escalation in acute lung injury. Therefore, in the vasculature, inflammatory signaling by the tissue factor initiation complex is favored over thrombin signaling.

Topics: Disseminated Intravascular Coagulation; Humans; Receptors, Thrombin; Respiratory Distress Syndrome; Signal Transduction; Thromboplastin

In the pathogenesis of disseminated intravascular coagulation, dysfunctional natural anticoagulant pathways appear to play a pivotal role. In this article, we will address the mechanisms that contribute to this defect in the regulation of coagulation activation. Furthermore, we will explore the experimental and clinical evidence that restoration of these anticoagulant pathways results in clinical improvement.. We have searched and reviewed published articles on experimental studies of disseminated intravascular coagulation models in animals and clinical studies in patients with disseminated intravascular coagulation.. All three major anticoagulant pathways, that is, the antithrombin pathway, the protein C system, and tissue factor pathway inhibitor, are defective in sepsis and disseminated intravascular coagulation. Several mechanisms contribute to this defect. Restoration of these pathways, in principle, by administration of coagulation inhibitor concentrates or recombinant anticoagulant factors, appears to ameliorate the coagulation disorder and, more important, result in improvement of clinically relevant outcomes, such as a reduction of organ failure and mortality.. Restoration of disrupted physiologic anticoagulant pathways in disseminated intravascular coagulation is not only a logical point of impact in patients with sepsis and an activated coagulation system, but also is associated with an improved outcome in experimental and (initial) clinical studies.

Topics: Animals; Anticoagulants; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Humans; Multiple Organ Failure; Protein C; Sepsis; Thrombin; Thromboplastin; Treatment Outcome

In most instances, tissue factor (TF) exposed to the circulation is the sole culprit underlying the initiation of disseminated intravascular coagulation (DIC), although notable exceptions because of a more direct activation of the coagulation system, by snake venoms, for example, do occur. Peripheral monocytes and subendothelial structures are the potential sources of such TF; in the former, TF emerges on the cell surface on synthesis induction and in the latter it becomes available subsequent to permeability changes or damage to the endothelium. Subendothelial TF is constitutively present in fibroblasts, pericytes, and macrophages and at a higher than normal level in tumor-associated macrophages. This scenario of coagulation activation probably describes the principal events underlying emerging acute DIC states under pathophysiological conditions such as abruptio placentae, septic abortion, amniotic fluid embolization, and pregnancy toxemia. Under disease conditions associated with DIC, the continuous exposure to excess TF typically exhausts the available tissue factor pathway inhibitor (TFPI), leading to rampant thrombin generation, persistent feedback activation of factor XI (FXI) by the generated thrombin, and hence virtually uncheckable ongoing fibrin generation (DIC). Recently, it was shown that patients subject to meningococcal sepsis had comparatively large amounts of mainly monocyte-derived circulating TF-containing microparticles. Because phosphatidylserine (PS) is exposed on such particles, in addition to TF, they probably contribute crucially to DIC during meningococcal sepsis. Although endothelial cells (EC) have been shown to express large amounts of TF in vitro, this observation hardly relates to the situation in vivo, where, in contrast, synthesis and exposure of EC TF is very limited and not likely to be of any significance in emerging and ongoing DIC.

Topics: Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Humans; Pregnancy; Signal Transduction; Thromboplastin

Tissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.

Topics: Animals; Arteriosclerosis; Blood Coagulation; Calcium Signaling; Cytokines; Disseminated Intravascular Coagulation; Factor VIIa; Fibroblasts; Gene Expression Regulation; GTP Phosphohydrolases; Humans; Inflammation; Lipoproteins; Lipoproteins, LDL; MAP Kinase Signaling System; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Neoplasm Metastasis; Neoplasms; Neovascularization, Physiologic; Papio; Phagocytes; Sepsis; Signal Transduction; src-Family Kinases; Thromboplastin

An occlusive thrombus in the coronary arteries is the critical pathological event that immediately precedes most cases of myocardial infarction. Often the thrombus originates with a bleed from a fissured atheroma. Atheroma formation, therefore, creates risk of thrombosis; asymptomatic episodes of thrombosis and healing contribute to the pathogenesis of atherosclerosis and the development of atherosclerotic plaques. Based largely on in vitro and animal model evidence, infectious agents and their products can activate the coagulation cascade enzymatically or by up-regulating tissue factor. By initiating a procoagulant response, infectious agents can indirectly trigger a prothrombotic response. Alternatively, some microbes can directly trigger platelet aggregation in vitro and in animal models, suggesting direct prothrombotic potential in human cardiovascular disease. Activation of coagulation and thrombosis characterizes the pathological response to infectious agents in human disseminated intravascular coagulation and infective endocarditis. Given the underlying biological plausibility, the cumulative lifetime burden of chronic pathogens may be expected to create risk of atherosclerosis and thrombosis, and, indirectly, signs of cardiovascular disease.

Topics: Animals; Antigens, Bacterial; Bacteremia; Bacterial Proteins; Blood Coagulation; Cardiovascular Diseases; Collagen; Coronary Artery Disease; Coronary Thrombosis; Disease Models, Animal; Disseminated Intravascular Coagulation; Endocarditis, Bacterial; Humans; Platelet Aggregation; Risk Factors; Thromboplastin; Thrombosis

Tissue factor mediated pathways leading to microvascular thromboses and endothelial activation appear to play an important role in the development of multiple organ failure associated with severe sepsis. Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of tissue factor associated coagulation cascades. In experimental models of severe sepsis, treatment with TFPI results in significant reduction in mortality. Similarly, a recently completed Phase II 210-patient study comparing placebo and infusions of TFPI showed trends toward a relative reduction in day 28 all-cause mortality in TFPI treated patients. These data suggest that coagulation cascades involving tissue factor contribute to organ dysfunction in critically ill septic patients. TFPI may be a useful therapy in improving outcome of severe sepsis.

Topics: Animals; Clinical Trials as Topic; Disseminated Intravascular Coagulation; Lipoproteins; Recombinant Proteins; Sepsis; Thromboplastin

Topics: Cholecalciferol; Disseminated Intravascular Coagulation; Humans; Retinoids; Thrombomodulin; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Humans; Thromboplastin

There is considerable evidence that the hemostatic system is involved in the growth and spread of malignant disease. There is an increased incidence of thromboembolic disease in patients with cancers and hemostatic abnormalities are extremely common in such patients. Antihemostatic agents have been successfully used to treat a variety of experimental tumors, and several clinical trials in humans have been initiated. Although metastasis is undoubtedly multifactorial, intravascular coagulation activation and peritumor fibrin deposition seem to be important. The mechanisms by which hemostatic activation facilitates the malignant process remain to be completely elucidated. Of central importance may be the presence on malignant cells of tissue factor and urokinase receptor. Recent studies have suggested that these proteins, and others, may be involved at several stages of metastasis, including the key event of neovascularization. Tissue factor, the principal initiator of coagulation, may have additional roles, outside of fibrin formation, that are central to the biology of some solid tumors.

Topics: Animals; Anticoagulants; Antineoplastic Agents; Biomarkers; Blood Coagulation Tests; Cell Adhesion; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor Xa; Fibrin; Fibrinolysis; Hemostasis; Heparin; Humans; Monocytes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Platelet Activation; Platelet Aggregation Inhibitors; Receptors, Thrombin; Thrombophilia; Thrombophlebitis; Thromboplastin; Vitamin K

Disseminated intravascular coagulation (DIC) can be caused by a variety of diseases. Experimental models of DIC have provided substantial insight into the pathogenesis of this disorder, which may ultimately result in improved treatment. Disseminated coagulation is the result of a complex imbalance of coagulation and fibrinolysis. Simultaneously occurring tissue factor-dependent activation of coagulation, depression of natural anticoagulant pathways and shutdown of endogenous fibrinolysis all contribute to the clinical picture of widespread thrombotic deposition in the microvasculature and subsequent multiple organ failure. Cornerstone for the treatment of DIC is the optimal management of the underlying disorder. At present, specific treatment of the coagulation disorders themselves is not based on firm evidence from controlled clinical trials. Plasma and platelet transfusion are used in patients with bleeding or at risk for bleeding and low levels of coagulation factors or thrombocytopenia. The role of heparin and low molecular weight heparin is controversial, but their use may be justified in patients with active DIC and clinical signs of extensive fibrin deposition such as those with meningococcal sepsis. There is some evidence to indicate that low molecular weight heparin is as effective as unfractionated heparin but may be associated with a decreased bleeding risk. Antithrombin III (AT III) replacement appears to be effective in decreasing the signs of DIC if high doses are administered, but effects on survival or other clinically significant parameters are at best uncertain. If AT III supplementation is used, the dosage should be selected to achieve normal or supranormal plasma levels of 100% or higher. Results of studies on protein C concentrate, thrombomodulin or inhibitors of tissue factor are promising, but the efficacy and safety of these novel strategies remains to be established in appropriate clinical trials.

Topics: Anticoagulants; Blood Coagulation; Blood Component Transfusion; Disseminated Intravascular Coagulation; Fibrinolysis; Fibrinolytic Agents; Humans; Platelet Transfusion; Serine Proteinase Inhibitors; Thromboplastin

Over the last years numerous studies have focussed on the in vivo expression of tissue factor (TF) in health and disease. The selective perivascular distribution of TF and the lethal effects of TF knockouts have added strong support to the widely accepted view that TF plays a pivotal role in the initiation of blood coagulation during physiological hemostasis. Inappropriate in vivo expression of TF, particularly by cells that do not express this protein under normal conditions (mainly monocyte-macrophages and endothelial cells), has been documented and is likely responsible for fibrin deposition in a variety of pathological conditions, among which sepsis-associated disseminated intravascular coagulation (DIC) and thromboembolic disease. In malignancy, in vivo expression of TF by tumor cells and/or by host cells has been implicated not only in intratumoral and systemic activation of blood coagulation but also in tumor growth and dissemination.

Topics: Arteriosclerosis; Disseminated Intravascular Coagulation; Humans; Neoplasms; Reference Values; Thrombophlebitis; Thromboplastin; Thrombosis

Topics: Bleeding Time; Blood Coagulation; Blood Coagulation Disorders; Clinical Laboratory Techniques; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; Mass Screening; Partial Thromboplastin Time; Risk Factors; Thromboplastin; Transfusion Reaction; Vitamin K

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Cell Membrane; Cytokines; Disseminated Intravascular Coagulation; Endothelium, Vascular; Endotoxins; Gene Expression Regulation; Growth Substances; Humans; Mice; Neoplasms; Organ Specificity; Protein Processing, Post-Translational; Sepsis; Thromboplastin

The early stage of the state in which coagulation or fibrinolytic pathway is activated has been difficult to estimate. It has become possible to detect disseminated intravascular coagulation (DIC) at an early stage due to the development of highly sensitive methods which quantitate so called "molecular markers". Herein, to evaluate the clinical usefulness of plasmin-alpha 2-plasmin inhibitor complex (PIC) and tissue factor activity in plasma were examined. The first time, monitoring the plasma levels of PIC might be useful for the diagnosis of a pre-DIC condition and for effective control of therapy. We believed that combination assay for both PIC and D dimer will be adequate to differentiate whether the hemostatic abnormalities are induced mainly by DIC or hepatic insufficiency. Recently, new clinical usefulness of PIC has been reported. The PIC/thrombin-antithrombin III complex ratio was lower in patients with poor prognosis than in those with good prognosis, and it was also lower in those with organ failure than in those without it. The tissue factor is a major activator of the coagulation cascade and may play a role in initiating thrombosis. A simple chromogenic substrate assay for the quantitation of tissue factor activity in plasma samples was developed. Abnormally high levels were found in 80% of the patients with DIC, predominantly in patients with non-hematological solid tumors and acute leukemia. Serial determinations of plasma tissue factor demonstrated that plasma tissue factor changes immediately with the course of DIC. Plasma tissue factor did not correlate with hemostatic markers of DIC such as thrombin-antithrombin III complex, PIC, FDP D-dimer. Tissue factor activity correlated well with membrane anchoring region of tissue factor protein levels. Tissue factor activity correlate with tumor necrosis factor alpha levels in patients with non-hematological solid tumors without hepatocellular carcinoma. These findings suggest that the plasma tissue factor is potentially valuable for monitoring the progress of DIC in a limited population of patients.

Topics: alpha-2-Antiplasmin; Antifibrinolytic Agents; Biomarkers; Disseminated Intravascular Coagulation; Fibrinolysin; Humans; Thromboplastin

Anti-tissue factor antibody and active site-inhibited factor VIIa inhibit both the disseminated intravascular coagulant response to LD100 Escherichia coli and its lethal inflammatory effects. In contrast, active site inhibited factor Xa while completely inhibiting disseminated intravascular coagulant does not protect baboons from LD100 E. coli. This review examines the role of tissue factor and factor VIIa in initiating the disseminated intravascular coagulant response and in amplifying the inflammatory response.

Topics: Amino Acid Sequence; Animals; Binding Sites; Disseminated Intravascular Coagulation; Escherichia coli; Factor VIIa; Factor Xa Inhibitors; Molecular Sequence Data; Papio; Thromboplastin

Plasma tissue factor (TF) antigen can be detected in healthy volunteers and may be significantly increased in patients with disseminated intravascular coagulation (DIC). Plasma TF antigen level in patients with DIC was significantly reduced after therapy. The TF activity of human umbilical vein endothelial cells (HUVEC) cultured with lipopolysaccharide (LPS), cytokines and the medium of cultured mononuclear cells (MNC) was significantly increased. TF expression was induced in HUVEC and MNC by incubation with lipoproteins, suggesting that hyperlipidaemia is a direct risk factor in thrombotic disease. TF activity in HUVEC was significantly increased in the presence of plasma and this activation was higher in patients with thrombotic thrombocytopenic purpura (TTP) and DIC. Enhanced TF production by endothelial cells may be important in the pathogenesis of thrombotic diseases.

Topics: Cells, Cultured; Disseminated Intravascular Coagulation; Endothelium, Vascular; Humans; Lipopolysaccharides; Purpura, Thrombocytopenic; Thromboplastin; Umbilical Veins

Tissue factor (TF) is now considered to be the primary physiologic activator of the blood coagulation system. Coupled with recent advances in our understanding of the biochemistry of TF this has heightened interest in measuring aspects of TF activity in disease states. Expression of TF by blood monocytes in various diseases is an established trigger for intravascular coagulation and there is now a considerable body of experience with its measurement. This has considerable clinical potential although more widespread application awaits a consensus on the most appropriate methodologic approach to its measurement. TF can be detected in urine and may reflect the activation state of renal macrophages. Urinary TF is increased in cancer and could have diagnostic and prognostic value in a variety of malignant diseases. Finally, it is now possible to measure soluble TF in plasma. One such assay is commercially available and is technically simple to perform. The clinical value of such assays, however, must await better understanding of the source and function of soluble TF in plasma.

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Humans; Monocytes; Thromboplastin

This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis. Activation of the contact system induces activation of the classical complement pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis. Physiologic inhibition depends on the C1-inhibitor (C1-Inh.). Septic patients exhibit a relative deficiency of biologically active C1-Inh. Substitution with concentrations of C1-Inh has been safely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septic shock. The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIC. Endothelial and monocyte generation of tissue factor (TF) is activated by bacterial products and endotoxin. Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPI). The potential for TFPI substitution to inhibit the activation of the coagulation cascade in sepsis requires further study. Thrombin generation is inhibited by antithrombin III (AT III) and the protein C-protein S system. During sepsis, AT III is consumed and degraded by elastase. Animal studies have shown that DIC and death were prevented by high doses of AT III concentrates. Although a significant reduction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of AT III substitution in human sepsis is still debated. None of the studies was able to document a statistically significant reduction in mortality. Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa. The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory protein. During sepsis, protein C activity is significantly reduced, either by acute consumption or by thrombomodulin down-regulation, and increased levels of plasma C4bBP inhibit protein S. Infusion of activated protein C and protein S substitution both protect animals from the lethal effects of bacteria. Combining these different coagulation inhibitors should be carefully studied before its use in septic patients is recommended.

Topics: Animals; Antithrombin III; Blood Coagulation; Complement C1 Inactivator Proteins; Complement Pathway, Classical; Disseminated Intravascular Coagulation; Humans; Protein C; Protein S; Sepsis; Thromboplastin

The baboon model of E. coli sepsis illustrates three concepts with respect to the host response and vascular endothelium. First, the endothelium is the primary target. E. coli sepsis is an acute inflammatory disease of the vascular endothelium. Second, the endothelium is not a passive target. Initially it regulates both the inflammatory and coagulopathic aspects of E. coli sepsis through membrane associated regulatory receptor/plasma protein assemblies including protein C/thrombomodulin, activated protein C/protein S, C4bBP/protein S, tissue factor pathway inhibitor/Xa, antithrombin III/glycosaminoglycans. Third, when overridden by inflammatory events, the endothelium can change its anticoagulant phenotype and mount a massive procoagulant fibrinolytic counter-attack on its luminal side through the expression of tissue factor and release of tissue plasminogen activator. Fourth, again when overridden by inflammatory events, the endothelium can change its antioxidant phenotype and produce a "distal" tissue hypoxia on its abluminal side through induction of free radical generation and peroxidation of mitochondrial lipid membranes of those tissues with high metabolic rates. It has become increasingly clear that the so-called anticoagulant systems which act on the proximal factors of the clotting cascade (protein C, TFPI, AT-III, PGI2) also attenuate the amplification of the inflammatory response. Aspects of the mechanism by which this occurs are coming to light. This includes the attenuation of Il-6 response by TFPI and the attenuation of the complement effects by C4bBP/PS. The specifics of these observations in the E. coli sepsis model will be reviewed.

Topics: Animals; Antibodies; Anticoagulants; Carrier Proteins; Complement Inactivator Proteins; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelium, Vascular; Escherichia coli Infections; Glycoproteins; Interleukin-6; Lipoproteins; Papio; Protein C; Protein S; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Animals; Blood Coagulation; Cytokines; Disseminated Intravascular Coagulation; Endotoxins; Factor VIIa; Fibrinolysis; Humans; Thromboplastin; Toxemia

Inflammation and the cytokines clearly affect the coagulation system. Less clear are the specific influences of the coagulation system on inflammation. In this chapter only some of the coagulation systems affected by the cytokines are discussed, and the influences on the fibrinolytic system, which is also downregulated by selected cytokines are not mentioned; see Schneiderman and Loskutoff (1991) for a brief review. The major focus is on possible models by which inflammation and coagulation are linked, and examples where in vitro studies have led to correct in vivo predictions and where the results remain ambiguous. Finally, this chapter is clearly a biased perspective with the primary emphasis on the components and pathways with which the author has personal experience.

Topics: Animals; Blood Coagulation Factors; Cell Adhesion Molecules; Cells, Cultured; Cytokines; Disseminated Intravascular Coagulation; Endothelium, Vascular; Humans; Inflammation; Models, Biological; Neoplasms; Papio; Protein C; Shock, Septic; Thrombomodulin; Thromboplastin; Thrombosis

Cells of monocyte lineage serve as effector cells in the cellular immune response. In addition, they respond to LPS and cytokines with activation and expression of inflammatory effector gene products similar to those elicited by the antigen driven response. The response to antigen proceeds at the T helper cell level through two independent forms of cellular collaboration, contact and lymphokine. We review the control of expression of the Tissue Factor (TF) gene and the function of the TF protein. The enhanced initiation of transcription of the TF gene appears to require engagement of a 56 bp LPS Response Element, an enhancer that is engaged by both AP-1 type heterodimeric complexes as well as NF kappa B like heterodimeric complexes. Dissociation of NF kappa B from Ig kappa B by cytokine and LPS stimulation, and possibly activated T cells, may represent a common pathway to induction of the TF and other inflammatory genes. Enhancement of expression of TF is observed upon adhesion of Mo to endothelial cells and extracellular matrix proteins, as well as upon engagement of leukocyte integrins. The biological effects that follow from expression of TF by vascular cells have been resolved by analysis of function aided by the use of recombinant full length TF and truncated surface domain of TF. The rules of assembly of the cognate ligands of TF, namely the zymogen plasma factors VII and the serine protease factor VIIa, with the soluble surface domain of TF in free solution, in the presence of phospholipid surfaces and cell surface and of the anchored TF molecule have been described. It is evident that assembly of the surface domain of TF with VIIa to form the binary TF.VIIa complex induces a significant increase in the Kcat of the catalytic domain of VIIa for small peptidyl substrates and more profoundly for protein substrate. This provides substantial evidence for an allosteric effect on the catalytic cleft of VIIa that is imparted by binding to TF, its cognate catalytic cofactor. It is also evident that the TF.VIIa complex is proteolytically active and can activate the zymogen plasma factor X to the serine protease Xa in free solution, inferring that extended substrate recognition by induced structural loci of the TF.VIIa complex are created from either or both proteins to constitute a new recognition structure. It is also evident that association of X with charged phospholipid surfaces enhances the proteolytic activation of this zymogen by increasing recognitio

Topics: Animals; Blood Coagulation; CD4-Positive T-Lymphocytes; Cytokines; Disseminated Intravascular Coagulation; Endothelium, Vascular; Enzyme Activation; Factor VII; Factor VIIa; Gene Expression Regulation; Humans; Immunity, Cellular; Lipid Bilayers; Lipopolysaccharides; Lymphocyte Activation; Membrane Lipids; Mice; Monocytes; NF-kappa B; Shock, Septic; Thromboplastin; Transcription, Genetic

Extrinsic pathway inhibitor (EPI) is a Kunitz type serine protease inhibitor. EPI is a potent inhibitor of the factor VIIa/thromboplastin (TP) complex in the presence of factor Xa and is also a direct inhibitor of factor Xa. The inhibitory mechanism is complex and is currently thought to involve, in a first step, the formation of a EPI-factor Xa complex, and, in a second step, the formation a quaternary EPI-factor Xa-factor VIIa-TP complex. In the blood vessels, EPI is confined to three different pools. A major pool of EPI is bound to the endothelial surface, and this fraction may be released by heparin. Plasma contains a second, but smaller pool of EPI (approximately 10-50% of the endothelial surface pool) at a concentration of 50-100 ng/ml. This pool consists mostly of EPI-lipoprotein complexes and only less than 10% is carrier-free EPI. A third pool of EPI is confined to platelets (less than 10% of the plasma pool). The biological role of these pools has not yet been clarified, but some evidence suggest that the carrier-free EPI is biologically most active. In patients, disseminated intravascular coagulation may continue despite normal or even elevated EPI levels. However, evidence has now been provided to indicate that EPI can inhibit factor VIIa/TP complexes formed in vivo to prevent the effect of limited amounts of TP. Taken together, the present knowledge of EPI indicates that EPI functions as a key inhibitor to feedback control of blood coagulation initiated by TP.

Topics: Blood Coagulation; Blood Platelets; Disseminated Intravascular Coagulation; Endothelium, Vascular; Factor VII; Factor VIIa; Factor Xa Inhibitors; Feedback; Heparin; Humans; Lipoproteins; Liver Diseases; Neoplasms; Recombinant Proteins; Reference Values; Sepsis; Thromboplastin

Topics: Amino Acid Sequence; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Factor VII; Hemophilia A; Humans; Lipoproteins; Molecular Sequence Data; Thromboplastin

Topics: Animals; Bacteremia; Biomarkers; Disseminated Intravascular Coagulation; Dogs; Edema; Escherichia coli Infections; Inflammation; Papio; Protein C; Rats; Shock, Septic; Thromboplastin; Tumor Necrosis Factor-alpha

Tissue factor is the initiator of the extrinsic coagulation pathway and is an important regulator of haemostasis. Tissue factor is constitutively expressed in numerous cells and tissues, and can be induced in monocytes and endothelial cells by different inflammatory agents. Lymphocytes and serum factors can modulate the expression of tissue factor in monocytes. The regulation of tissue factor expression in monocytes appears to be different from that in endothelial cells. Phorbol myristate acetate can inhibit as well as induce tissue factor activity in monocytes, whereas phorbol myristate acetate only induces the expression of tissue factor in endothelial cells. Tissue factor expression in monocytes from patients with infections is not always associated with DIC. The extrinsic pathway inhibitor may play a role in the development of DIC in patients with sepsis. Deposition of extravascular fibrin may be an important determinant of tissue injury.

Topics: Amino Acid Sequence; Blood Coagulation; Disseminated Intravascular Coagulation; Endothelium; Endotoxins; Gene Expression Regulation; Humans; Leukocytes, Mononuclear; Molecular Sequence Data; Organ Specificity; Tetradecanoylphorbol Acetate; Thromboplastin

Topics: Antifibrinolytic Agents; Diagnosis, Differential; Disseminated Intravascular Coagulation; Heparin; Humans; Thromboplastin; Thrombosis

Topics: Disseminated Intravascular Coagulation; Fibrinogen; Humans; Thromboplastin; Thrombosis

Reversible acute disseminated intravascular coagulation (DIC) has been induced in dogs by intravenous injection of homologous tissue thromboplastin. There was no measurable consumption of antithrombin III and heparin cofactor II even if fibrinogen was reduced during DIC by more than 80% of its baseline. The prothrombin level remained practically constant. These data correspond to the generation of a few nanomoles of thrombin in vivo with subsequent pseudo-first order inactivation by the major thrombin inhibitors. An ex vivo measure of the pseudo-first order rate constant (dynamic thrombin inhibitory capacity, DTIC) was a sensitive probe of circulating heparin. There was no change of DTIC during DIC in the absence of exogenous heparin suggesting that heparin-like endogenous glycosaminoglycans were not released in substantial amounts. Pretreatment with heparin efficiently inhibited the development of tissue thromboplastin induced DIC. This animal model may serve as a tool for the study of glycosaminoglycan anticoagulants in vivo.

Topics: Animals; Antithrombin III; Disease Models, Animal; Disseminated Intravascular Coagulation; Dogs; Female; Fibrinogen; Glycoproteins; Glycosaminoglycans; Heparin; Heparin Cofactor II; Male; Thrombin; Thromboplastin

Mononuclear phagocytes, a specialized cell lineage comprising bone-marrow precursors, blood monocytes and tissue macrophages, can interact with blood coagulation mechanisms with resulting thrombus formation or extravascular fibrin accumulation. Such procoagulant activity is usually activation dependent and requires interaction of the cells with immune or nonimmune stimuli. In the former case (e.g., alloantigens, soluble protein antigens) collaboration of mononuclear phagocytes with T lymphocytes is necessary and is mediated by cell-to-cell contact or lymphokines. Prototype of a direct acting stimulus is bacterial lipopolysaccharide. Mononuclear phagocyte procoagulant activity is expressed in the form of cell membrane-bound or released factors which display molecular heterogeneity. They include the initiator of the extrinsic clotting pathway, tissue factor, known clotting proteases such as factors V and VII, and novel proteolytic enzymes including prothrombinase and a factor X activator. Mononuclear phagocyte procoagulants are pathogenetically involved in generalized disorders with intravascular coagulation and thromboembolic phenomena. These disorders, exemplified by the Shwartzman reaction and possibly by paraneoplastic thromboembolism, are initiated by blood monocytes. Extravascular fibrin deposition can be initiated by tissue-infiltrating monocytes and macrophages in disease states such as acute renal allograft failure and solid tumours.

Topics: Animals; Blood Coagulation Factors; Cell Communication; Disseminated Intravascular Coagulation; Graft Rejection; Humans; Hypersensitivity, Delayed; Inflammation; Macrophages; Neoplasms; T-Lymphocytes; Thromboplastin

The author analyses the reported data and his own findings concerned with the involvement of mononuclear phagocytes in the regulation of hemostasis and in the pathogenesis of a number of frequently occurring forms of the hemostatic system pathology. The content of monocytic thromboplastin was measured in 56 patients with the intravascular blood coagulation syndrome of varying etiology. Production of monocytic thromboplastin reached the highest degree in patients with purulent conditions whereas in patients presenting with the terminal stage of sepsis, it did not exceed normal or even dropped down, which may be connected with depletion of monocytes because of their preliminary hyperactivation.

Topics: Blood Platelets; Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Humans; Macrophages; Monocytes; Thromboplastin

Topics: Acute Disease; Animals; Disseminated Intravascular Coagulation; Hematologic Diseases; Heparin; Humans; Leukemia; Rabbits; Thromboplastin

Topics: Disseminated Intravascular Coagulation; Humans; Neoplasms; Thromboplastin

Topics: Adult; Aged; Blood Platelets; Disseminated Intravascular Coagulation; Female; Humans; Leukocytes; Male; Middle Aged; Platelet Aggregation; Prostaglandins; Thromboplastin; Thrombosis; Thromboxane A2

Complement appears to be an important system for cell activation in circulating blood. It is established that granulocytes may be stimulated through complement activation. In the present paper we propose also a central role of complement in the induction of thromboplastin synthesis in blood monocytes and endothelial cells.

Topics: Antigen-Antibody Reactions; Complement Activation; Complement System Proteins; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Endothelium; Endotoxins; Humans; Monocytes; Sepsis; Thromboplastin

The importance of the blood coagulation sequence as an integral part in the pathogenesis of diseases inside as well as outside the blood vessels is becoming increasingly apparent. Mononuclear phagocytes have important functions in initiation of coagulation by producing several procoagulant substances, including thromboplastin, the potent trigger of the extrinsic pathway. Increasing evidence demonstrates the clinical importance of monocyte and macrophage thromboplastin synthesis in the pathogenesis of a variety of diseases. This review surveys the role of monocyte/macrophage thromboplastin in relation to inflammatory diseases, cancer, disseminated intravascular coagulation and diseases of the blood vessels, thrombosis and atherosclerosis.

Topics: Arteriosclerosis; Arthritis, Rheumatoid; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Endopeptidases; Glomerulonephritis; Graft Rejection; Humans; Hypersensitivity, Delayed; Kidney Transplantation; Membrane Proteins; Monocytes; Neoplasm Proteins; Pulmonary Embolism; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Platelets; Disseminated Intravascular Coagulation; Factor X; Fibrin; Fibrinolysis; Humans; Neoplasms; Neovascularization, Pathologic; Thrombophlebitis; Thromboplastin

Topics: Animals; Antigen-Antibody Complex; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Chromatography, Gel; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Humans; Partial Thromboplastin Time; Peptide Hydrolases; Platelet Count; Prothrombin Time; Rabbits; Shwartzman Phenomenon; Thrombin; Thromboplastin

Topics: Blood Coagulation Factors; Cells, Cultured; Disseminated Intravascular Coagulation; Hemophilia A; Humans; Saliva; Thromboplastin; Trypsin; Trypsin Inhibitors; Vitamin K

Disseminated intravascular coagulation (DIC) of blood develops as a result of a sharp increase in the release of thromboplastic substances. The mechanism of disseminated thrombosis is switched in at the level of the microcirculatory bed with defibrination of the peripheral blood and subsequent hemorrhages and bleedings. The causes of DIC development may include complications of pregnancy and delivery, different kinds of shock including endotoxin shock, hemorrhage, hemolysis. Histomorphological findings in DIC are as follows: hemorrhagic syndrome, fibrin thrombi in capillaries, arterioles and venules of the skin, kidneys, adrenals, hypophysis, gastrointestinal tract, lungs and other organs followed by necroses and hemorrhages in these organs. Clinically, DIC is manifested by symptoms of insufficiency of the affected organs (acute renal insufficiency, Waterhouse-Fridericksen syndrome, etc).

Topics: Disseminated Intravascular Coagulation; Female; Hemolysis; Hemorrhage; Humans; Kidney; Male; Microcirculation; Necrosis; Obstetric Labor Complications; Pregnancy; Pregnancy Complications, Hematologic; Shock; Surgical Procedures, Operative; Thromboplastin; Thrombosis

Tissue factor is an ubiquitous phospholipid-protein complex, which triggers blood coagulation through the so-called extrinsic pathway. Reactions initiated by tissue factor bypass many of the early stages of coagulation (contact phase) and involve factors VII, X, V, II and fibrinogen but also factor IX (and VIII) as it was recently demonstrated. So, it appears that tissue factor has a key-role in the haemostasic process as it has been suggested by the mildness or the absence of haemorrhagic syndrome in contact factors deficiencies. Tissue factor activity has been found in many types of cells, especially in white bloods cells. Experimental studies have demonstrated the presence of tissue factor activity in polymorphonuclears, lymphocytes, monocytes (or macrophages). This activity is enhanced by gram-negative endotoxin stimulation, inflammation, cell mediated immunologic phenomena or malignancy. These data are in good agreement with a wild range of features observed in human pathology: fibrin deposits in inflammatory lesions, disseminated intravascular coagulation (DIC) during the course of gram-negative septicemias or acute promyelocytic leukemias, local thrombi at the early phase of graft rejection. The protective effect of a phospholipase C against DIC induced in rats by tissue factor infusion suggests in the future, a specific therapy would be possible in man that, in the frequent clinical conditions involving clotting activation through tissue factor pathway.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Fibrin; Graft Rejection; Humans; Inflammation; Leukemia; Leukocytes; Rabbits; Sepsis; Thromboplastin

Topics: Afibrinogenemia; Blood Coagulation; Blood Coagulation Tests; Diagnosis, Differential; Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Humans; Models, Biological; Syndrome; Thromboplastin; Toxemia

Topics: Anticoagulants; Disseminated Intravascular Coagulation; Fetal Blood; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Infant, Newborn; Kidney Diseases; Neoplasms; Thromboembolism; Thromboplastin

Topics: Afibrinogenemia; Anti-Infective Agents; Antigens; Blood Coagulation Disorders; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Hemagglutination Inhibition Tests; Heparin; Humans; Prothrombin Time; Radioimmunoassay; Thrombin; Thrombocytopenia; Thromboplastin

Topics: Blood; Blood Coagulation; Blood Coagulation Tests; Calcium; Disseminated Intravascular Coagulation; Factor V; Factor VII; Factor VIII; Female; Fibrinogen; Fibrinolysis; Humans; Pregnancy; Pregnancy Complications, Hematologic; Prothrombin; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Factor IX; Factor VII; Factor X; Factor XI; Factor XII; Fibrin; Fibrinolysis; Humans; Prothrombin; Thrombin; Thromboplastin

Topics: Blood Coagulation Factors; Blood Platelet Disorders; Disseminated Intravascular Coagulation; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Factor XII; Factor XIII; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; Plasminogen; Prothrombin; Thrombin; Thromboplastin

Topics: Anemia, Hemolytic; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Factor XII; Fibrinogen; Fibrinolysis; Heparin; Humans; Liver Diseases; Meningitis, Meningococcal; Phospholipids; Thrombin; Thromboplastin

Topics: Adenocarcinoma; Anemia, Hemolytic; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Erythrocyte Aging; Erythrocytes, Abnormal; Fibrinogen; Hemolytic-Uremic Syndrome; Heparin; Humans; Hypertension, Malignant; Iodine Radioisotopes; Kidney Transplantation; Liver Transplantation; Purpura, Thrombotic Thrombocytopenic; Rabbits; Thromboplastin; Transplantation, Homologous; Venoms

Topics: Animals; Blood Cell Count; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Complement System Proteins; Disseminated Intravascular Coagulation; Fibrinogen; Fibrinolysis; Humans; Immunoassay; Leukocytes; Plasminogen; Postoperative Complications; Prothrombin Time; Thrombophlebitis; Thromboplastin

Topics: Animals; Antifibrinolytic Agents; Blood Coagulation; Blood Coagulation Factors; Diagnosis, Differential; Disseminated Intravascular Coagulation; Dogs; Fibrinolysis; Heparin; Humans; Liver; Platelet Adhesiveness; Shock; Thrombin; Thromboplastin; Thrombosis

Topics: Adolescent; Adult; Blood Coagulation; Blood Coagulation Disorders; Child; Disseminated Intravascular Coagulation; Embolism, Fat; Endotoxins; Fatty Acids; Female; Fibrinolysis; Heart Defects, Congenital; Hemangioma; Hemolysis; Humans; Leukemia; Male; Middle Aged; Mononuclear Phagocyte System; Neoplasms; Pregnancy; Pregnancy Complications; Purpura, Thrombocytopenic; Skin Neoplasms; Thromboplastin

Topics: Abruptio Placentae; Disseminated Intravascular Coagulation; Embolism; Female; Fibrinogen; Fibrinolysis; Humans; Pregnancy; Thromboplastin; Thrombosis

The CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has been widely proved effective on relapsed and refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Meanwhile, CAR-T therapy-related toxicities, including cytokine release syndrome (CRS) and neurological toxicities, are drawing researchers' attention. In addition, our research team notices that coagulopathy and even disseminated intravascular coagulation (DIC) are common problems during CAR-T therapy. In our phase 1/2 clinical trial (NCT02965092), 53 r/r B-ALL patients underwent leukapheresis on day - 11 and received lymphodepleting chemotherapy on day - 7 to day - 5. Finally, they received split infusions of anti-CD19 CAR-T cells on day 0 to day 2. Plasma concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1) were also measured to identify the mechanism of coagulation disorders. The overall 1-month remission rate of the 53 patients was 88.7%. During the treatment course, 19 patients experienced grade 3-4 CRS, 8 patients developed grade 2-3 neurological toxicities. Beyond that, 30 patients (30/53, 56.6%) suffered from coagulation disorders, and half of them should be diagnosed as DIC. Benefiting from replacement and anticoagulant therapy, 14 patients successfully got out of the conditions of DIC. Remarkably, the severity of coagulopathy was positively correlated with CRS grade. What is more, plasma TF and PECAM-1 levels indicated that vascular endothelial factors played key roles in the process of CRS-related coagulopathy. To conclude, coagulation disorders frequently happen during CAR-T therapy. TF and PECAM-1 are of great importance in the etiology and pathogenesis of coagulation problems. Early and proper interventions targeted at CRS-related coagulopathy contribute a lot to the control of side effects in CAR-T therapy.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Disease-Free Survival; Disseminated Intravascular Coagulation; Female; Humans; Immunotherapy, Adoptive; Infant; Infant, Newborn; Male; Middle Aged; Neoplasm Proteins; Platelet Endothelial Cell Adhesion Molecule-1; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Safety; Survival Rate; Thromboplastin; Vascular Endothelial Growth Factor A

Cancer and stroke, which are known to be associated with one another, are the most common causes of death in the elderly. However, the pathomechanisms that lead to stroke in cancer patients are not well known. Circulating extracellular vesicles (EVs) play a role in cancer-associated thrombosis and tumor progression. Therefore, we hypothesized that cancer cell-derived EVs cause cancer-related coagulopathy resulting in ischemic stroke.. Serum levels of D-dimer and EVs expressing markers for cancer cells (epithelial cell adhesion molecule [CD326]), tissue factor (TF [CD142]), endothelial cells (CD31+CD42b-), and platelets (CD62P) were measured using flow cytometry in (a) 155 patients with ischemic stroke and active cancer (116 - cancer-related, 39 - conventional stroke mechanisms), (b) 25 patients with ischemic stroke without cancer, (c) 32 cancer patients without stroke, and (d) 101 healthy subjects.. The levels of cancer cell-derived EVs correlated with the levels of D-dimer and TF+ EVs. The levels of cancer cell-derived EVs (CD326+ and CD326+CD142+) were higher in cancer-related stroke than in other groups (P<0.05 in all the cases). Path analysis showed that cancer cell-derived EVs are related to stroke via coagulopathy as measured by D-dimer levels. Poor correlation was observed between TF+ EV and D-dimer, and path analysis demonstrated that cancer cell-derived EVs may cause cancer-related coagulopathy independent of the levels of TF+ EVs.. Our findings suggest that cancer cell-derived EVs mediate coagulopathy resulting in ischemic stroke via TF-independent mechanisms.

Topics: Aged; Disseminated Intravascular Coagulation; Extracellular Vesicles; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Neoplasms; Stroke; Thromboplastin

Septic shock-induced disseminated intravascular coagulopathy (DIC) contributes to multiple organ failure. Mechanisms governing vascular responses to open occurrence of DIC have not yet been established. Circulating plasma microparticles (MPs), released upon cell stress, constitute a catalytic procoagulant surface and are surrogates of vascular cell activation/injury. Herein, MPs were assessed as possible markers of haemostatic and vascular dysfunction in the DIC time course.. One hundred patients with septic shock from three ICUs were enrolled and their haemostatic status evaluated at admission (D1), D2, D3 and D7. Circulating procoagulant MPs were isolated, quantified by prothrombinase assay and their cellular origin determined. DIC diagnosis was made according to the JAAM 2006 score.. Ninety-two patients were analysed and 40 had DIC during the first 24 h. Routine clotting times and factor/inhibitor activity did not allow assessing vascular cell involvement. At admission, thrombin generation and fibrinolysis were observed in both groups while impaired fibrin polymerisation was evidenced only in DIC patients. Sustained thrombin generation persisted over time in both groups at D7. While total microparticle concentrations were in the same range regardless of DIC diagnosis, specific phenotypes were already detected at admission in DIC patients. Endothelial- and leucocyte-derived MPs were higher in DIC while an increased soluble glycoprotein V/platelet ratio was delayed, underscoring the first involvement of endothelial cells and leucocytes whereas platelet activation was delayed. Endothelium-derived CD105-MPs (OR 6.55) and CD31-MPs (OR 0.49) were strongly associated with early DIC in multivariate analysis.. Endothelial-derived microparticles are relevant biomarkers of septic shock-induced DIC and could be used to evaluate early vascular injury.

Topics: Biomarkers; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Endothelial Cells; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Shock, Septic; Thromboplastin; Young Adult

To evaluate the pathogenetic role of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and neutrophil elastase in acute respiratory distress syndrome (ARDS), as well as to test the hypothesis that TFPI levels modified by neutrophil activation are not sufficient to prevent TF-dependent intravascular coagulation, leading to sustained systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), which determine the prognosis of these patients.. The study subjects consisted of 55 patients with trauma and sepsis who were divided into three groups according to the Lung Injury Score. Ten normal healthy volunteers served as control. Plasma levels of TF, TFPI, and neutrophil elastase were measured on the day of injury or the day of diagnosis of sepsis (day 0) and days 1 through 4. The number of SIRS criteria that the patient met and the disseminated intravascular coagulation (DIC) score is determined daily.. Patients (15) developed ARDS, 23 were at risk for but did not develop the syndrome, and 17 patients were without risk for ARDS. TF and neutrophil elastase levels in ARDS patients were persistently higher than those in other two groups and control subjects. However, the TFPI levels showed no difference among the three groups, which retained normal or slightly elevated levels compared to the control subjects. DIC scores did not improve and SIRS continued during the study period in patients with ARDS. The ARDS patients showed higher numbers of dysfunctioning organs and associated with poorer outcome than the other two groups.. Systemic activation of the TF-dependent pathway not adequately balanced by TFPI is one of the aggravating factors of ARDS. High levels of neutrophil elastase released from activated neutrophils may explain the imbalance of TF and TFPI. Persistent DIC and sustained SIRS contribute to MODS, determining the prognosis of ARDS patients.

Topics: Disseminated Intravascular Coagulation; Female; Humans; Leukocyte Elastase; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Respiratory Distress Syndrome; Risk Assessment; Statistics as Topic; Systemic Inflammatory Response Syndrome; Thromboplastin

Tissue factor (TF), the main trigger of coagulation is important in the propagation of cardiovascular diseases. Based on an in vitro study, we hypothesised that enalapril may blunt the endotoxin-induced, TF-triggered coagulation in humans.. In a randomised, controlled trial, 30 healthy male volunteers received 2 ng/kg of lipopolysaccharide (LPS) after pre-treatment with placebo or enalapril for 5 days or with enalapril 2 h before LPS infusion.. Infusion of LPS increased interleukin-6 levels 400 fold, and induced a 10-fold increase in prothrombin fragment, a fourfold increase in D-dimer, and a fivefold increase in plasmin-antiplasmin complexes. However, pre-treatment with enalapril did not blunt LPS-induced coagulation.. Our trial provides evidence against a modulatory role of angiotensin converting enzyme in LPS-induced, TF-triggered coagulation.

Topics: Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Disseminated Intravascular Coagulation; Enalapril; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Humans; Infusions, Intravenous; Interleukin-6; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Prothrombin; Statistics, Nonparametric; Thromboplastin

During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)

Topics: Adult; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Proteins; Depression, Chemical; Disseminated Intravascular Coagulation; Double-Blind Method; Endotoxemia; Endotoxins; Feedback; Fibrin Fibrinogen Degradation Products; Hirudin Therapy; Hirudins; Humans; Lipoproteins; Male; Monocytes; Partial Thromboplastin Time; Recombinant Proteins; Thrombin; Thromboplastin; Treatment Outcome

The contact system activation can play a role in microthrombus formation of disseminated intravascular coagulation (DIC). This study investigated whether the activity of prekallikrein and high-molecular-weight kininogen (HMWK) correlated DIC progression. Contact system factors (prekallikrein, HMWK, activated factor XII), coagulation factors (IX, XI, XII) and tissue factor were measured in 140 patients who clinically suspected of having DIC. Prekallikrein and HMWK activity levels showed significant linear relationships with DIC score and antithrombin level, whereas prekallikrein and HMWK antigen levels did not. The activated factor XII, factor XII, factor XI and tissue factor were significant risk factors of overt-DIC. This finding suggests that consumption of prekallikrein and HMWK contributes to microvascular thrombosis in DIC. Measurements of prekallikrein and HMWK activity could be used as potential diagnostic markers for overt-DIC.

Topics: Disseminated Intravascular Coagulation; Factor XIIa; Humans; Kininogen, High-Molecular-Weight; Kininogens; Prekallikrein; Risk Factors; Thromboplastin; Thrombosis

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.

Topics: Animals; Disseminated Intravascular Coagulation; Histones; Inflammasomes; Mice; Pyroptosis; Thromboplastin

Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated cofactor V (FVa), and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragment 1 (F1) and fragment 2 (F2) specifically to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa, which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin F1 + F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit patients with sepsis (n = 144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in factor VIII (FVIII)- and FIX-deficient plasma, as well as in FVIII-deficient mice. In summary, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation and correcting coagulation factor deficiency.

Topics: Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Factor V; Factor X; Factor Xa; Histones; Humans; Mice; Mice, Inbred C57BL; Thromboplastin

Lipopolysaccharide (LPS) and tissue factor (TF) have frequently been used to induce disseminated intravascular coagulation (DIC) in experimental animal models. We have previously reported that the pathophysiology of DIC differs according to the inducing agents. However, inflammatory status and bleeding symptoms have not been fully compared between rat models of the two forms of DIC. We attempted to evaluate detailed characteristic features of LPS- and TF-induced DIC models, especially in regard to inflammatory status and bleeding symptoms, in addition to selected hemostatic parameters and pathologic findings in the kidneys. The degree of hemostatic activation in both types of experimental DIC was identical, based on the results of thrombin-antithrombin complex levels. Markedly elevated tumor necrosis factor, interleukin-6, and high-mobility group box-1 concentrations were observed with severe organ dysfunction and marked fibrin deposition in the kidney on administration of LPS, whereas markedly elevated D-dimer concentration and bleeding symptoms were observed with TF administration. Pathophysiology such as fibrinolytic activity, organ dysfunction, inflammation status, and bleeding symptom differed markedly between LPS- and TF-induced DIC models in rats. We, therefore, recommend that these disease models be assessed carefully as distinct entities to determine the implications of their experimental and clinical use.

Topics: Animals; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Disease Models, Animal; Disease Susceptibility; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Lipopolysaccharides; Male; Prognosis; Rats; Thromboplastin

Sepsis-induced disseminated intravascular coagulation (DIC) is a common life-threatening terminal-stage disease with high mortality. This study aimed to identify effective miRNAs as therapeutic targets for DIC. Bioinformatics and luciferase reporter gene analyses were performed to predict miR-19a-3p and validate that it targets tissue factor (TF). Quantitative real-time PCR was used to detect the expression of miR-19a-3p and TF, and TF procoagulant activity was determined using the chromogenic substrate method. Western blotting was used to detect the protein levels of TF, AKT serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK), nuclear factor kappa B (NF-κB) P65, NFKB inhibitor alpha (IκB-a) and their phosphorylated counterparts in cell experiments. Furthermore, a rat model was established to explore the potential of miR-19a-3p in DIC treatment. As a result, a human clinical study revealed that miR-19a-3p was downregulated and that TF was upregulated in neonates with sepsis-induced DIC compared with those in the control group. The luciferase reporter assay showed that TF was a direct target of miR-19a-3p. Cell experiments verified that the mRNA and protein levels of TF, and the p-AKT/AKT, p-Erk/Erk, p-P65/P65, p-IκB-a/IκB-a ratios, and TF procoagulant activity were significantly decreased in lipopolysaccharide (LPS) -induced human peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) inhibited by overexpression of miR-19a-3p, and that miR-19a-3p regulating TF was dependent on the NF-kB and AKT pathways. In vivo, miR-19a-3p injection into DIC rats suppressed the mRNA expression of TF; more importantly, significant improvements in coagulation function indicators and in histopathologies of lung and kidney were observed. In conclusion, miR-19a-3p may suppress DIC by targeting TF and might be a potential therapeutic target in treating sepsis-induced DIC.

Topics: Animals; Cells, Cultured; Disseminated Intravascular Coagulation; Down-Regulation; Female; Human Umbilical Vein Endothelial Cells; Humans; Infant, Newborn; Lipopolysaccharides; Male; MicroRNAs; Rats; Rats, Sprague-Dawley; Sepsis; Thromboplastin

Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS). Patients with HFRS have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine whether circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients.. Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n = 27) and those who did not (n = 61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and platelets.. Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity were significantly associated with plasma tPA and PAI-1, suggesting that endothelial cells could be a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared with those who did not, even after adjustment for sex and age. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with area under the curve = 0.63 (95% confidence interval, 0.51-0.76) and P = .046.. Plasma EVTF activity during HFRS is associated with intravascular coagulation.

Topics: Adult; Biomarkers; Blood Coagulation; Disseminated Intravascular Coagulation; Extracellular Vesicles; Female; Fibrinolysis; Hemorrhagic Fever with Renal Syndrome; Humans; Kinetics; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Puumala virus; Sensitivity and Specificity; Thromboplastin; Tissue Plasminogen Activator; Venous Thromboembolism

Microparticle (MP)-associated tissue factor (TF) activity in plasma might play a role in human disseminated intravascular coagulation (DIC). The aim of this study was to compare MP-TF activity between non-DIC and DIC groups. Ten clinically healthy beagles and 26 diseased dogs were enrolled. The proportion of dogs with increased MP-TF activity was significantly higher in the DIC group than the non-DIC group (P=0.014). MP-TF activity in the DIC group was significantly higher than the non-DIC group (P=0.021). MP-TF activity positively correlated with plasma D-dimer concentration (r=0.42, P=0.034). Moreover, MP-TF activity was decreased by the time of recovery in some dogs with DIC. Larger prospective studies are warranted to assess its value as a diagnostic and prognostic biomarker in DIC.

Topics: Animals; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Dog Diseases; Dogs; Female; Male; Retrospective Studies; Thromboplastin

Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.

Topics: Animals; Blood Coagulation; Caspases, Initiator; Cell Line, Tumor; Disseminated Intravascular Coagulation; Endotoxemia; Enzyme Activation; HeLa Cells; HT29 Cells; Humans; Interleukin-1alpha; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphate-Binding Proteins; Phosphatidylserines; Pyroptosis; Signal Transduction; Thromboplastin

Embolization of amniotic fluid (AF) into the blood circulation leads to disseminated intravascular coagulation (DIC). Procoagulant phosphatidylserine (PS)- and tissue factor (TF)-exposing extracellular vesicles (EVs) might play an important role in AF embolism-induced DIC. It was the aim of the present study to perform analyses of the procoagulant properties of AF with a panel of functional coagulation assays and flow cytometry. We applied a prothrombinase assay (that quantifies PS exposure on EVs), an EV-associated TF activity assay, a fibrin generation assay, a thrombin generation assay, a whole blood clotting model, and flow cytometry in AF and control plasma. We found that PS exposure on EVs was 21-fold increased in AF compared with plasma. Also, EV-associated TF activity was highly increased in AF compared with plasma. AF-derived EVs activated the blood coagulation cascade via PS and TF in the fibrin and thrombin generation assays. In a whole blood clotting model, AF-derived EVs significantly shortened the clotting time from 734 ± 139 seconds in the presence to 232 ± 139 seconds in the absence of an anti-TF antibody. The contact activation pathway via factor XII (FXII) was not affected. Applying flow cytometry, a subpopulation of PS

Topics: Amniotic Fluid; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Extracellular Vesicles; Female; Fibrin; Flow Cytometry; Humans; Phosphatidylserines; Pregnancy; Thrombin; Thromboplastin; Thrombosis

Sepsis-induced disseminated intravascular coagulation (DIC) is a major cause of death in patients admitted to intensive care units. Endothelial injury with microparticle production is reported in the pathogenesis of sepsis. Endothelial microparticles (EMPs) present several cell-specific surface antigens with different bioactivities, for example, tissue factor (TF), thrombomodulin (TM), and endothelial protein C receptor (EPCR). We investigated associations between these three different surface antigen-positive EMPs and sepsis-induced DIC. This cross-sectional study composed of 24 patients with sepsis and 23 healthy controls was conducted from November 2012 to September 2013. Blood samples were collected from patients within 24 h of diagnosis of severe sepsis and from healthy controls. Numbers of TF-positive EMPs (TF EMPs), TM-positive EMPs (TM EMPs), and EPCR-positive EMPs (EPCR EMPs) were measured by flow cytometry immediately thereafter. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were assessed in the severe sepsis patients at enrollment. We assessed DIC with the International Society of Thrombosis and Haemostasis (ISTH) overt DIC diagnostic criteria algorithm. Numbers of antigen-positive EMPs were increased significantly in both severe sepsis patients and controls and with the increase in ISTH DIC score. Numbers of TF EMPs and EPCR EMPs correlated significantly with Sequential Organ Failure Assessment score, and numbers of EPCR EMPs correlated significantly with Acute Physiology and Chronic Health Evaluation II score. Numbers of the three antigen-positive EMPs were increased significantly in severe sepsis patients versus those in healthy controls and with the increase of ISTH DIC score, suggesting that the specific bioactivity of each antigen-positive EMP may play a role in the progression of sepsis-induced DIC.

Topics: Adult; Aged; Algorithms; Antigens, CD; Antigens, Surface; Case-Control Studies; Cell-Derived Microparticles; Cross-Sectional Studies; Disease Progression; Disseminated Intravascular Coagulation; Endothelial Protein C Receptor; Endothelium; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Flow Cytometry; Gene Expression Regulation; Humans; Intensive Care Units; Interleukin-6; Male; Middle Aged; Receptors, Cell Surface; Sepsis; Surface Properties; Thrombomodulin; Thromboplastin; Time Factors

To investigate the protective effect of hydrogen sulfide (H2S) on tissue factor-induced disseminated intravascular coagulation (DIC) in rabbits and its mechanism.. Thirty-two healthy rabbits were randomly divided into four groups: normal control group, NaHS control group, DIC model group, NaHS pretreatment group (each, n = 8). Ten minutes before model reproduction, rabbits in NaHS control and pretreatment groups were given 3.4 mg/kg NaHS (dissolved in normal saline to 5 mL) via ear vein, while rabbits in normal control and DIC model groups were given an equivalent volume of normal saline. Ten minutes later, rabbits in DIC model and NaHS pretreatment groups were intravenously given tissue factor (TF) 2 mL/kg (dissolved in normal saline to 30 mL, at the speed of 1 mL/min for 5 minutes, 2 mL/min for 5 minutes, and 3 mL/min for 5 minutes), and rabbits in normal control and NaHS control groups were given normal saline. 3 mL of blood was collected 10 minutes before TF injection, and 3, 5, 8, 10, 13, 15, 45, 85, 135 minutes after TF injection for determination of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen content (FIB), fibrin degradation products (FDP), and platelet count (PLT). Microcirculation in the mesentery was also observed under microscope.. Compared with normal control group, PT and APTT became shorter at 5 minutes after TF injection, and the rate of their change was increased [PT: -8.3 (-11.7 to -5.3)% vs. 1.3 (-2.5 to 3.8)%, P < 0.01; APTT: -19.1 (-30.4 to -9.4)% vs. -2.6 (-6.2 to 3.0)%, P < 0.05]. PT and APTT were prolonged 15 minutes after TF injection, and their changes were more significant [PT: 31.0 (25.0 to 36.9)% vs. -1.3 (-6.3 to 5.0)%, APTT: 61.3 (50.0 to 72.9)% vs. 0.0 (-10.0 to 10.0)%, both P < 0.01] in DIC model group. TT was gradually reduced after TF injection, FIB and PLT were gradually decreased, and their changes were more obvious at 15 minutes in DIC model group compared with those in normal control group [TT: -9.5 (-12.0 to -6.2)% vs. -2.0 (-4.0 to 0.7)%, FIB: -4.3 (-9.9 to -2.2)% vs. -1.0 (-5.8 to 4.3)%, PLT: -90.0 (-93.4 to -86.5)% vs. -1.0 (-3.9 to 2.6), all P < 0.01]. After TF injection, it appeared latex-like particles in FDP test board, and it was gradually increased within 3-15 minutes, and then it gradually became less marked. The rate of blood flow in mesenteric capillaries was decreased obviously within 10 minutes, and it became faster accompanying with obvious hemorrhage. PT and APTT in NaHS pretreatment group became shortened 5 minutes after TF injection, and their rate of change was significantly decreased compared with that of DIC model group [PT: -6.3 (-8.6 to 0.0)% vs. -8.3 (-11.7 to -5.3)%, APTT: -13.6 (-24.2 to -2.3)% vs. -19.1 (-30.4 to -9.4)%, both P < 0.05], and prolonged at 15 minutes, and their rate of change was significantly decreased compared with that of DIC model group [PT: 10.1 (3.8 to 15.2)% vs. 31.0 (25.0 to 36.9)%, P < 0.01; APTT: 27.8 (-15.8 to 39.7)% vs. 61.3 (50.0 to 72.9)%, P < 0.05]. TT, FIB, and PLT were reduced at 15 minutes in NaHS pretreatment group, and their rate of change was markedly decreased compared with that of DIC model group [TT: -4.5 (-7.8 to -1.3)% vs. -9.5 (-12.0 to -6.2)%, P < 0.01; FIB: -3.3 (-8.0 to 1.9)% vs. -4.3 (-9.9 to -2.2)%, P < 0.05; PLT: -58.8 (-53.0 to 64.0)% vs. -90.0 (-93.4 to -86.5)%, P < 0.01]. The rate of agglutination of latex particles in NaHS pretreatment group was decreased significantly at each time point compared with DIC model group; mesenteric capillary blood flow slowed down gradually within 10 minutes, but it was faster as compared with the DIC model group. It became faster later, but bleeding was obviously less.. These results show that H2S protects against TF-induced DIC by inhibiting the activity of coagulation system and platelet aggregation.

Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Hydrogen Sulfide; Partial Thromboplastin Time; Platelet Aggregation; Platelet Count; Rabbits; Sulfides; Thromboplastin

Topics: Adult; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Thromboplastin; Thrombosis

Topics: Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Thromboplastin

Trauma-induced tissue factor (TF) release into the systemic circulation is considered to play an important role in the development of disseminated intravascular coagulation (DIC) immediately after severe trauma. However, the relationship between TF and hyperfibrinolysis, especially fibrinogenolysis, has been unclear. A total of 18 rats were divided into three groups: (a) the control group was infused with normal saline; (b) the low-dose group was infused with 4 U/kg TF; and (c) the high-dose group was infused with 16 U/kg TF. Arterial blood was drawn immediately and 2 and 4 h after the start of TF infusion. At each sampling point, arterial blood gases, platelet counts, and coagulation variables were measured. The fibrinogen degradation products were evaluated by a Western blot analysis. Hypotension, hypoxemia, and lactic acidosis were not observed in any of the three groups. In proportion to the doses of TF, the platelet counts, coagulation, and fibrinolysis variables deteriorated in line with DIC. The α2-plasmin inhibitor levels significantly decreased in the high-dose group compared with the other groups. The amounts of fibrinogen degradation products increased in proportion to the doses of TF. The plasmin-α2-plasmin inhibitor complex level in the high-dose group increased more than that of the other groups. In conclusion, TF can induce DIC associated with fibrinolysis and fibrinogenolysis without tissue hypoperfusion. The decrease in the α2-plasmin inhibitor level and the significant increase in the plasmin level may be the two main factors underlying the pathogenesis of hyperfibrin(ogen)olysis after TF administration.

Topics: alpha-2-Antiplasmin; Animals; Blood Coagulation; Blood Pressure; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysis; Hemoglobins; Male; Oxygen; Partial Pressure; Platelet Count; Rats; Rats, Wistar; Thromboplastin

We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC.. We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction.. Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients.. Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed.

Topics: Acute Disease; Adult; Antithrombins; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Peptide Fragments; Prospective Studies; Prothrombin; Shock, Traumatic; Thrombin; Thromboplastin

Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC.. To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P ≤ .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P ≤ .05 for all comparisons except for PAI level).. DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET.

Topics: Animals; Anthrax; Antigens, Bacterial; Antithrombin III; Bacillus anthracis; Bacterial Toxins; Blood Coagulation; Cell Wall; Disseminated Intravascular Coagulation; Fibrinogen; Nitric Oxide; Partial Thromboplastin Time; Peptide Hydrolases; Peptidoglycan; Plasminogen Inactivators; Protein C; Prothrombin; Rats; Rats, Sprague-Dawley; Thromboplastin

Sepsis, a leading cause of death worldwide, involves widespread activation of inflammation, massive activation of coagulation, and lymphocyte apoptosis. Calpains, calcium-activated cysteine proteases, have been shown to increase inflammatory reactions and lymphocyte apoptosis. Moreover, calpain plays an essential role in microparticle release.. We investigated the contribution of calpain in eliciting tissue damage during sepsis.. To test our hypothesis, we induced polymicrobial sepsis by cecal ligation and puncture in wild-type (WT) mice and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor.. In WT mice, calpain activity increased transiently peaking at 6 hours after cecal ligation and puncture surgery. Calpastatin overexpression improved survival, organ dysfunction (including lung, kidney, and liver damage), and lymphocyte apoptosis. It decreased the sepsis-induced systemic proinflammatory response and disseminated intravascular coagulation, by reducing the number of procoagulant circulating microparticles and therefore delaying thrombin generation. The deleterious effect of microparticles in this model was confirmed by transferring microparticles from septic WT to septic transgenic mice, worsening their survival and coagulopathy.. These results demonstrate an important role of the calpain/calpastatin system in coagulation/inflammation pathways during sepsis, because calpain inhibition is associated with less severe disseminated intravascular coagulation and better overall outcomes in sepsis.

Topics: Animals; Apoptosis; Calcium-Binding Proteins; Calpain; Cell-Derived Microparticles; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple Organ Failure; NF-kappa B; Sepsis; Thromboplastin

Recombinant human soluble thrombomodulin (TM-α) was recently developed as an anticoagulant for patients with disseminated intravascular coagulation (DIC). However, the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment have not yet been elucidated. We investigated the pharmacokinetics and pharmacodynamics of TM-α in DIC patients with severe renal impairment. Eleven DIC patients with severe renal impairment (creatinine clearance <30 mL/min) and 10 DIC patients without severe renal impairment (creatinine clearance ≥30 mL/min) were included in this study. In all patients, a dose of 380 U/kg of TM-α was administered during a 30-min infusion. Blood samples were taken before the start of the first TM-α administration, and at 0.5, 2, 4, 8, and 24 h after the start of administration. Although the clearance of TM-α in the patients with renal impairment was 80% of that in the patients without renal impairment, none of the pharmacokinetic values were significantly different between the groups. In the pharmacokinetic simulation, however, the trough levels of TM-α increased gradually in the patients with renal impairment when the same dose of TM-α was repeatedly administered. After the administration of TM-α, the prothrombinase activities in the patients in both groups were sufficiently inhibited during the observation period. Although the pharmacokinetic values in DIC patients with severe renal impairment were only slightly different from those in DIC patients without severe renal impairment, we need to pay attention to the elevation of the trough levels of TM-α when the same dose of TM-α is repeatedly administered.

Topics: Aged; Anticoagulants; Disseminated Intravascular Coagulation; Female; Humans; Kidney Diseases; Male; Recombinant Proteins; Thrombomodulin; Thromboplastin

Upregulation of tissue factor (TF) expression on activated donor endothelial cells (ECs) triggered by the immune response (IR) has been considered the main initiator of consumptive coagulopathy (CC). In this study, we aimed to identify potential factors in the development of thrombocytopenia and CC after genetically engineered pig liver transplantation in baboons. Baboons received a liver from either an α1,3-galactosyltransferase gene-knockout (GTKO) pig (n = 1) or a GTKO pig transgenic for CD46 (n = 5) with immunosuppressive therapy. TF exposure on recipient platelets and peripheral blood mononuclear cell (PBMCs), activation of donor ECs, platelet and EC microparticles, and the IR were monitored. Profound thrombocytopenia and thrombin formation occurred within minutes of liver reperfusion. Within 2 h, circulating platelets and PBMCs expressed functional TF, with evidence of aggregation in the graft. Porcine ECs were negative for expression of P- and E-selectin, CD106, and TF. The measurable IR was minimal, and the severity and rapidity of thrombocytopenia were not alleviated by prior manipulation of the IR. We suggest that the development of thrombocytopenia/CC may be associated with TF exposure on recipient platelets and PBMCs (but possibly not with activation of donor ECs). Recipient TF appears to initiate thrombocytopenia/CC by a mechanism that may be independent of the IR.

Topics: Animals; Animals, Genetically Modified; Cell-Derived Microparticles; Disseminated Intravascular Coagulation; Galactosyltransferases; Papio; Sus scrofa; Thrombocytopenia; Thromboplastin; Transplantation, Heterologous

Inflammation is a major cause of disseminated intravascular coagulation (DIC) in dogs, but underlying mechanisms for its initiation are unknown. We hypothesized that pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, induce tissue factor (TF) expression on canine monocyte surfaces, which may contribute to DIC initiation.. The objectives of this study were to determine if (1) IL-6 and IL-8 would induce TF activity on canine monocytes, (2) fetal bovine serum or autologous plasma was required for IL-6- or IL-8-induced TF responses in canine monocytes, and (3) these pro-inflammatory cytokines would enhance TF activity on canine monocytes in response to low concentrations of lipopolysaccharide (LPS).. Canine monocytes were isolated from EDTA-anticoagulated blood as peripheral blood mononuclear cells (PBMC) by double-density gradient centrifugation and adhesion to plastic. Adherent cells were stimulated for 4 hours with recombinant canine (rc)-IL-6 or rc-IL-8 (10-5000 pg/mL) with or without 10% heat-inactivated (HI) fetal bovine serum, untreated autologous canine plasma (ACP), or HI-ACP. Lipopolysaccharide (100 ng/mL) served as a positive control. Cells were also costimulated with either cytokine (100 pg/mL) or low concentrations of LPS (0.1 and 1 ng/mL). Monocytes immunopurified from PBMC with anti-CD14 antibodies were also stimulated with both cytokines (100 and 5000 pg/mL). TF activity on cell surfaces was measured by a 2-stage amidolytic assay, based on activated factor X generation.. Neither rc-IL-6 nor rc-IL-8 consistently stimulated TF procoagulant activity in canine PBMC or purified monocytes after 4 hours. Serum, plasma, or low concentrations of LPS did not enhance the TF response to these cytokines.. IL-6 or IL-8 at evaluated concentrations may not play major roles in coagulation activation by induction of TF expression on monocytes in dogs with inflammation.

Topics: Animals; Disseminated Intravascular Coagulation; Dogs; Female; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Monocytes; Neutrophils; Recombinant Proteins; Thromboplastin; Up-Regulation

Thrombomodulin, which is expressed solely on monocytes, along with tissue factor (TF), takes part in coagulation and inflammation. Circulating blood monocytes can be divided into 3 major subtypes on the basis of their receptor phenotype: classical (CD14brightCD16negative, CMs), inflammatory (CD14brightCD16positive; IMs), and dendritic cell-like (CD14dimCD16positive DMs). Monocyte subtype is strongly regulated, and the balance may influence the clinical outcomes of disseminated intravascular coagulation (DIC). Therefore, we investigated the phenotypic difference in thrombomodulin and TF expression between different monocyte subtypes in coagulopathy severity and prognosis in patients suspected of having DIC.. In total, 98 patients suspected of having DIC were enrolled. The subtypes of circulating monocytes were identified using CD14 and CD16 and the thrombomodulin and TF expression in each subtype, expressed as mean fluorescence intensity, was measured by flow cytometry. Plasma level of tissue factor was measured by ELISA. In cultures of microbead-selected, CD14-positive peripheral monocytes, lipopolysaccharide (LPS)- or interleukin-10-induced expression profiles were analyzed, using flow cytometry.. The proportion of monocyte subtypes did not significantly differ between the overt and non-overt DIC groups. The IM thrombomodulin expression level was prominent in the overt DIC group and was well correlated with other coagulation markers. Of note, IM thrombomodulin expression was found to be an independent prognostic marker in multivariate Cox regression analysis. In addition, in vitro culture of peripheral monocytes showed that LPS stimulation upregulated thrombomodulin expression and TF expression in distinct populations of monocytes.. These findings suggest that the IM thrombomodulin phenotype is a potential independent prognostic marker for DIC, and that thrombomodulin-induced upregulation of monocytes is a vestige of the physiological defense mechanism against hypercoagulopathy.

Topics: Adult; Aged; Biomarkers; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Monocytes; Phenotype; Prognosis; Retrospective Studies; Thrombomodulin; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Humans; Mice; Rats; Thromboplastin

A high mortality occurs in dogs with idiopathic immune-mediated haemolytic anaemia (IMHA) during the first 2 weeks after the diagnosis. The aim of this study was to investigate the inflammatory response and coagulation abnormalities in dogs with IMHA in relation to the prognosis and to establish the contribution of whole blood tissue factor (TF) and IL-8 gene expressions. Gene expressions in dogs with IMHA were compared to healthy dogs, dogs with DIC, dogs with sepsis, and in two groups of dogs that underwent intensive care treatment but had no evidence for either DIC or sepsis. The whole blood TF and IL-8 expressions were up regulated in all non-IMHA groups. Similarly, the TF expression in IMHA dogs was high, but the intravascular IL-8 expression was not increased. The dogs with IMHA had a pronounced inflammatory response that included a high WBC, left shift and monocytosis in comparison to the other disease groups. Coagulation factor activities in IMHA dogs were decreased fitting consumptive coagulopathy and the acute phase proteins FVIII and fibrinogen were increased. The platelet parameters suggested platelet activation and high platelet turnover in IMHA dogs. The model that best explained mortality contained monocytosis, increased activated partial thromboplastin time and elevated creatinine. Whole blood TF gene expression is up regulated and may contribute to consumptive coagulopathy in dogs with IMHA. Increased TF expression by activated platelets is an alternative explanation and should be investigated.

Topics: Anemia, Hemolytic, Autoimmune; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Dog Diseases; Dogs; Female; Inflammation; Interleukin-8; Male; Prognosis; Real-Time Polymerase Chain Reaction; Sepsis; Thromboplastin

The objective of this study is to report the use of thromboelastography as a diagnostic tool for the hyperfibrinolytic phase of disseminated intravascular coagulopathy in a dog with metastatic haemangiosarcoma. We established a cytological (i.e. fine needle aspirate) and histopathological (i.e. excisional surgical biopsy) diagnosis of haemangiosarcoma in a 10-year-old male castrated Bichon Frise with multiple dark purple dermoepidermal nodules on the ventral abdomen and medial stifle areas, multiple small pulmonary nodules and a solitary liver mass. The dog was treated with chemotherapy (AC protocol). Forty-nine days after completion of four treatment cycles, the dog was presented for recheck. Complete blood count revealed anaemia and mild thrombocytopenia. Chemistry profile showed no significant abnormalities. Analysis of haemostasis consisted of prolonged clotting times (prothrombin time, activated partial thromboplastin time), mild hypofibrinogenaemia and increased D-dimers. A presumptive diagnosis of disseminated intravascular coagulopathy was made. A re-calcified thromboelastography was simultaneously done to confirm the coagulopathy. Thromboelastographic tracings correlated with the plasma-based test results showing hypocoagulability (prolonged clotting times and prolonged thromboelastography clot kinetics; weaker clot with decreased fibrinogen levels, platelet count and lower thromboelastography tracing amplitude) and hyperfibrinolysis (increased D-dimers and increased D-dimers and increased thromboelastography lysis parameters). Based on these results, the dog was considered to be in the hyperfibrinolytic phase of disseminated intravascular coagulopathy. Results of the conventional haemostasis tests supported those obtained on thromboelastography. Humane euthanasia was performed because of poor prognosis and progressive disease, making further follow-up unavailable. As demonstrated in this case report, thromboelastography was found to be a helpful diagnostic tool for the diagnosis and monitoring of the hyperfibrinolytic phases of disseminated intravascular coagulopathy.

Topics: Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Dog Diseases; Dogs; Fatal Outcome; Hemangiosarcoma; Male; Thrombelastography; Thrombin; Thromboplastin

Venom-induced consumption coagulopathy occurs in snake envenoming worldwide but the interaction between procoagulant snake venoms and human coagulation remains poorly understood. We aimed to evaluate an assay using endogenous thrombin potential (ETP) to investigate the procoagulant properties of a range of Australian whole venoms in human plasma and compared this to traditional clotting and prothrombinase activity studies. We developed a novel modification of ETP using procoagulant snake venoms to trigger thrombin production. This was used to characterise the relative potency, calcium and clotting factor requirements of five important Australian snake venoms and efficacy of commercial antivenom, and compared this to prothrombinase activity and clotting assays. All five venoms initiated thrombin generation in the absence and presence of calcium. Pseudonaja textilis (Brown snake; p<0.0001), Hoplocephalus stephensii (Stephen's-banded snake; p<0.0001) and Notechis scutatus (tiger snake; p=0.0073) all had statistically significant increases in ETP with calcium. Venom potency varied between assays, with ETP ranging from least potent with Oxyuranus scutellatus (Taipan) venom to intermediate with N. scutatus and H. stephensii venoms to most potent with P. textilis and Tropidechis carinatus (Rough-scale snake) venoms. ETPs for N. scutatus, T. carinatus and H. stephensii venoms were severely reduced with factor V deficient plasma. Antivenom neutralized the thrombin generating capacity but not prothrombin substrate cleaving ability of the venoms. Contrary to previous studies using clotting tests and factor Xa substrates, these venoms differ in calcium requirement. ETP is a useful assay to investigate mechanisms of other procoagulant venoms and is a robust method of assessing antivenom efficacy.

Topics: Anticoagulants; Antivenins; Australia; Blood Coagulation; Calcium; Coagulants; Disseminated Intravascular Coagulation; Drug Dosage Calculations; Elapid Venoms; Enzyme Activation; Humans; Kinetics; Prothrombin; Reptilian Proteins; Serine Endopeptidases; Snake Bites; Snake Venoms; Substrate Specificity; Thromboplastin

Tissue factor (TF) is the primary activator of the coagulation cascade. During endotoxemia, TF expression leads to disseminated intravascular coagulation. However, the relative contribution of TF expression by different cell types to the activation of coagulation has not been defined. In this study, we investigated the effect of either a selective inhibition of TF expression or cell type-specific deletion of the TF gene (F3) on activation of coagulation in a mouse model of endotoxemia. We found that inhibition of TF on either hematopoietic or nonhematopoietic cells reduced plasma thrombin-antithrombin (TAT) levels 8 hours after administration of bacterial lipopolysaccharide (LPS). In addition, plasma TAT levels were significantly reduced in endotoxemic mice lacking the TF gene in either myeloid cells (TF(flox/flox),LysM(Cre) mice) or in both endothelial cells (ECs) and hematopoietic cells (TF(flox/flox),Tie-2(Cre) mice). However, deletion of the TF gene in ECs alone had no effect on LPS-induced plasma TAT levels. Similar results were observed in mice lacking TF in vascular smooth muscle cells. Finally, we found that mouse platelets do not express TF pre-mRNA or mRNA. Our data demonstrate that in a mouse model of endotoxemia activation of the coagulation cascade is initiated by TF expressed by myeloid cells and an unidentified nonhematopoietic cell type(s).

Topics: Animals; Antithrombin III; Blood Coagulation; Blood Platelets; Cells, Cultured; Disseminated Intravascular Coagulation; Endothelial Cells; Endotoxemia; Gene Deletion; Leukocytes; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Myeloid Cells; Peptide Hydrolases; Radiation Chimera; RNA Precursors; RNA, Messenger; Species Specificity; Thromboplastin

Elevated levels of circulating procoagulants like tissue factor may increase the risk of systemic coagulation activation, thrombin generation, and consumptive coagulopathy. I measured procoagulant activity in plasma by using a clot-based assay that incorporated normal plasma to replace missing factors, corn trypsin inhibitor to block contact activation, factor VIIa to improve sensitivity to tissue factor activity, and anti-tissue factor antibodies to measure tissue factor-specific activity. Procoagulant activity was evaluated in 58 trauma patients. Trauma patients without coagulopathy (n = 50) showed 5-fold higher procoagulant activity than did control subjects (P < .001), whereas trauma patients with coagulopathy (n = 8) showed 10-fold higher activity than control subjects (P < .001) and 2-fold higher activity than trauma patients without coagulopathy (P = .03). In control subjects, tissue factor activity was below the detection limit of the assay. Tissue factor activity was 3- to 4-fold higher in trauma patients with coagulopathy vs patients without coagulopathy (P = .002). Trauma patients with coagulopathy have increased circulating tissue factor activity.

Topics: Anticoagulants; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Thromboplastin; Wounds and Injuries

Thromboelastography (TEM) yields a multitude of data that are complicated to analyze. We evaluated its value in identification of global coagulopathy in overt disseminated intravascular coagulation (DIC). We studied 21 patients, each with International Society for Haemostasis and Thrombosis scores of 5 or more (compatible with overt DIC) and less than 5 (suggestive of nonovert DIC), who underwent whole blood nonadditive TEM. A TEM score based on the reaction and kappa times, alpha angle, and maximum amplitude was defined as the total number of TEM parameters deranged in the direction of hypocoagulability. The TEM score at a cutoff of 2 or more achieved sensitivity of 95.2%, specificity of 81.0%, and the highest receiver operating characteristic area under the curve of all parameters of 0.957 for identifying overt DIC. Individual TEM parameters correlated variably with conventional tests. Their combination into a cohesive TEM score possibly better captured the multiple hemostatic derangements occurring in DIC. The TEM score may bring objectivity to the analysis of TEM data.

Topics: Algorithms; Blood Coagulation; Disseminated Intravascular Coagulation; Hospitals, University; Humans; Partial Thromboplastin Time; Point-of-Care Systems; Predictive Value of Tests; Prospective Studies; Prothrombin Time; ROC Curve; Thrombelastography; Thrombin; Thromboplastin

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, and we have previously established a rabbit model of non-overt DIC based on the ISTH classification of non-overt DIC. In this rabbit model, we used purified rabbit brain thromboplastin to induce DIC and test applicability of ISTH classifications of overt human DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered a 2.5 mg thromboplastin/kg bolus and a 15 minutes 1.25 mg thromboplastin/kg infusion, were determined at four time points over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH classifications of overt DIC. Despite the fact that injection of purified thromboplastin resulted in decreased platelet count, increased prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes and fibrin degradation products, and pulmonary micro-thrombosis, none of the rabbits were diagnosed as having overt DIC according to ISTH classification. We conclude that purified thromboplastin causes haemostatic abnormalities in the rabbit but this experimental model was not diagnosed as overt DIC.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemostasis; Humans; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Rabbits; Thrombelastography; Thromboplastin

Consumptive coagulopathy (CC) remains a challenge in pig-to-primate organ xenotransplantation (Tx). This study investigated the role of tissue factor (TF) expression on circulating platelets and peripheral blood mononuclear cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs that were either wild-type (n = 2), alpha1,3-galactosyltransferase gene-knockout (GT-KO; n = 1) or GT-KO and transgenic for the complement-regulatory protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed TF within 4 h of Tx. In the remaining baboons, TF was detected on platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation developed with formation of thrombin. In the six baboons with CC, TF was not detected on baboon PBMCs until CC was beginning to develop. Graft histopathology showed fibrin deposition and platelet aggregation (n = 6), but with only minor or no features indicating a humoral immune response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation of platelets to express TF was associated with the initiation of CC, whereas TF expression on PBMCs was concomitant with the onset of CC, often in the relative absence of features of acute humoral xenograft rejection. Prevention of recipient platelet activation may be crucial for successful pig-to-primate kidney Tx.

Topics: Animals; Antibodies, Monoclonal; Antilymphocyte Serum; CD40 Ligand; Disseminated Intravascular Coagulation; Famotidine; Galactosyltransferases; Gene Knockout Techniques; Graft Rejection; Histamine H2 Antagonists; Immunosuppressive Agents; Kidney Transplantation; Papio; Platelet Activation; Platelet Aggregation; Swine; Thrombin; Thromboplastin; Transplantation, Heterologous

Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)-dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.

Topics: Animals; beta-Alanine; Capillary Leak Syndrome; Capillary Permeability; Disseminated Intravascular Coagulation; Endothelial Protein C Receptor; Endothelium, Vascular; Endotoxins; Enzyme Activation; Glycoproteins; Hirudins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Protein C; Receptor, PAR-1; Receptors, Cell Surface; Receptors, Lysosphingolipid; Signal Transduction; Specific Pathogen-Free Organisms; Sphingosine-1-Phosphate Receptors; Systemic Inflammatory Response Syndrome; Thiophenes; Thrombin; Thromboplastin

A rare case is described of acute disseminated intravascular coagulation (DIC) following isolated mild head injury with acute subdural haematoma, coagulopathy onset preceding craniotomy. Surgical treatment of the cause followed by swift diagnosis and treatment soon after surgery enabled a good outcome. Post-operative recollection of subdural and extadural blood was treated by further surgery. DIC following isolated mild head injury without axonal damage is rare, but fatal if missed. Thrombocytopaenia in head injured patients should be investigated expediently. Post-operative interim imaging (if not standard practice) should also be considered to exclude haemorrhagic recollection requiring further surgery.

Topics: Adult; Brain; Craniotomy; Decompression, Surgical; Disseminated Intravascular Coagulation; Early Diagnosis; Emergency Medical Services; Head Injuries, Closed; Hematoma, Epidural, Cranial; Hematoma, Subdural, Acute; Humans; Male; Partial Thromboplastin Time; Plasma; Platelet Transfusion; Subdural Space; Thrombocytopenia; Thromboplastin; Tomography, X-Ray Computed; Treatment Outcome; Violence

Topics: Amniotic Fluid; Anticoagulants; Blood Coagulation; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Factor Xa; Female; Heparin; Humans; Phosphatidylserines; Pregnancy; Prothrombin; Thromboplastin

Amniotic fluid (AF) may induce disseminated intravascular coagulation (DIC) when it enters maternal circulation by breaching the placental-maternal circulation barrier. The precise mechanism of the procoagulant activity of AF is unclear, but tissue factor (TF) has been proposed to be the main cause. As one constituent of AF, AF cells accumulate and undergo apoptosis continuously. Therefore, we speculate that AF cells have procoagulant activity due to the externalisation of phosphatidylserine (PS). The present study aims to demonstrate that, in addition to TF, the PS that is externalised on AF cells is important for the procoagulant activity of AF. Ten AF samples from parturient women were analysed using lactadherin as the probe for PS. Anti-TF antibody also was used to identify TF and its associated coagulation functions in AF cells. Normal platelets, neutrophils, and lymphocytes were harvested as controls. Confocal microscopy and flow cytometry was used to assess PS expression on AF cells. The procoagulant activity of AF cells was demonstrated by a plasma coagulation assay and further confirmed by factor Xase/prothrombinase assays. PS and TF were present on most AF cells, providing substantial procoagulant activity. Furthermore, factor Xase and prothrombinase assays showed that AF cells substantially enforced the activation of factor X and prothrombin. PS on AF cells is an important procoagulant source for AF. Lactadherin is an ideal anticoagulant for inhibiting the procoagulant activity of AF cells.

Topics: Adult; Amniotic Fluid; Blood Coagulation; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Factor Xa; Female; Flow Cytometry; Humans; Microscopy, Confocal; Phosphatidylserines; Pregnancy; Prothrombin; Thromboplastin

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, but the scoring systems have rarely been applied to animal models of DIC. In this study, we use rabbit brain thromboplastin (thromboplastin) to induce DIC in a rabbit model and test the applicability of the ISTH criteria for standardized diagnosis of DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered 0.625, 1.25, 2.5 or 5 mg thromboplastin/kg as a single bolus, were collected at four timepoints over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH diagnostic criteria for non-overt DIC. Injection of 5 mg thromboplastin/kg was lethal. For the remaining groups, a dose dependent decrease in blood pressure, platelet count and fibrinogen level together with a dose dependent increase in prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes, fibrin degradation products and number of thrombi in lung vasculature was seen. The administration of a bolus of 1.25 - 2.5 mg thromboplastin/kg to rabbits induced a reproducible dose dependent model of non-overt DIC according to the ISTH diagnostic criteria. We conclude that the non-overt ISTH score can be applied to evaluate severity and progression of DIC in a standardized manner in this thromboplastin induced rabbit model.

Topics: Animals; Blood Pressure; Disease Models, Animal; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Female; Fibrinogen; Platelet Count; Prothrombin Time; Rabbits; Thromboplastin; Time Factors

Trauma patients are at risk of developing an acute coagulopathy of trauma (ACT) related to tissue injury, shock, and hemodilution. ACT is incompletely understood, but is similar to disseminated intravascular coagulation (DIC) and is associated with poor outcome.. Thrombin generation assays were used to evaluate plasma hemostasis in 42 trauma patients, 25 normal subjects, and 45 patients on warfarin and in laboratory-prepared factor reduced plasma.. Prolonged prothrombin time (PT), more than 18 seconds, or an international normalized ratio of greater than 1.5 was present in 15 trauma patients indicating possible ACT. Native thrombin generation (no activator added, contact activation blocked) showed that Trauma with ACT patients had lag times 68% shorter and peak thrombin generation threefold higher than normal patients indicating the presence of circulating procoagulants capable of initiating coagulation systemically. Trauma patients had lower platelet counts and fibrinogen and Factor (F)II levels putting them at increased risk of bleeding. In laboratory-prepared isolated factor-reduced samples and in patients with vitamin K-dependent factor deficiency due to warfarin, thrombin generation decreased in direct proportion to FII levels. In contrast, in diluted plasma and in trauma patients with reduced factor levels, thrombin generation was increased and associated with slower inhibition of thrombin generation (prolonged termination time) and decreased antithrombin levels (43% of normal in Trauma with ACT).. Thrombin generation studies indicate that Trauma with ACT patients show dysregulated hemostasis characterized by excessive non-wound-related thrombin generation due to a combination of circulating procoagulants capable of activating coagulation systemically and reduced inhibitor levels allowing systemic thrombin generation to continue once started.

Topics: Adult; Anticoagulants; Antithrombins; Disseminated Intravascular Coagulation; Female; Hemostasis; Humans; Male; Middle Aged; Plasma; Prothrombin; Prothrombin Time; Thrombin; Thromboplastin; Vitamin K; Warfarin; Wounds and Injuries

Topics: Disseminated Intravascular Coagulation; Heat Stroke; Humans; Inflammation; Thromboplastin

Tissue factor (TF) expressed on sub-cellular membrane vesicles, so-called plasma microparticles (MPs), has recently emerged as a potential key player in intravascular coagulation activation in various disease states. In this report, we demonstrate significantly increased levels of TF-specific procoagulant activity (PCA) of plasma MPs in five patients presenting with overt disseminated intravascular coagulation (DIC) due to an underlying malignancy, including non-small-cell lung cancer (n = 1), melanoma (n = 1), prostate cancer (n = 2), and acute promyelocytic leukemia (n = 1). Clotting experiments on available tumor cell samples suggested that cancer cells were a potential source of circulating TF-positive MPs at least in three of the five patients. Furthermore, follow-up plasma samples from two surviving patients revealed that response of their malignancies to specific anti-cancer therapy was paralleled by resolution of overt DIC and a significant decline in MP-associated TF PCA. Levels of plasma TF antigen, as assessed by an enzyme-linked immunosorbent assay, were also increased at presentation albeit to a lesser extent compared to MP-associated TF PCA, likely due to insufficient solubilization of the phospholipid-incorporated full-length TF molecule by the detergent. In summary, our findings suggest that MP-associated TF PCA may play an important pathogenic role in the evolution of overt DIC in various types of malignancy.

Topics: Aged; Aged, 80 and over; Antithrombin III; Antithrombins; Disseminated Intravascular Coagulation; Factor V; Factor XIII; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Neoplasms; Peptide Hydrolases; Platelet Count; Thromboplastin; Triazines

Severe heatstroke is a leading cause of morbidity and mortality during heat waves. The pathogenesis of tissue injury, organ failure, and death in heatstroke is not well understood.. We investigated the pathways of heatstroke-induced tissue injury and cell death in anesthetized baboons (Papio hamadyras) subjected to environmental heat stress until core temperature attained 42.5 degrees C (moderate heatstroke; n = 3) or onset of severe heatstroke (n = 4) signaled by a fall in systolic blood pressure to < 90 mm Hg and rise in core temperature to 43.1+/-0.1 degrees C. Three sham-heated animals served as controls. Light and electron microscopy revealed widespread hemorrhage and thrombosis, transmural migration of leukocytes, and microvascular endothelium injury in severe heatstroke. Immunohistology and ultrastructural analysis demonstrated increased staining of endothelial von Willebrand factor (vWF), tissue factor (TF), and endothelial leukocyte-platelet interaction. Extensive apoptosis was noted in spleen, gut, and lung, and in hematopoeitic cells populating these organs. Double-labeling studies colocalized active caspase-3 and TF with apoptotic cells. Findings in sham-heated animals were unremarkable.. These data suggested that microvascular injury, thrombosis, inflammation, and apoptosis may play an important role in the pathogenesis of heatstroke injury.

Topics: Animals; Apoptosis; Blood Pressure; Body Temperature; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelium, Vascular; Heat Stress Disorders; Heat Stroke; Inflammation; Papio hamadryas; Thromboplastin; Thrombosis; von Willebrand Factor

Plasma-derived human antithrombin (pAT) is used for the treatments of disseminated intravascular coagulation (DIC) and hereditary antithrombin deficiencies. We expressed recombinant human antithrombin (rAT) in Chinese hamster ovary (CHO) cells. The purified rAT is composed of 55% alpha-isoform and 45% beta-isoform. The structure of the N-linked oligosaccharides of rAT is the same biantennary complex type as previously found in pAT with less sialylated on the non-reducing ends. Most of the oligosaccharides of rAT are fucosylated at the reducing ends of N-acetylglucosamine, while those of pAT are not fucosylated. Despite of the difference in sialylation and fucosylation of the oligosaccharide units, rAT and pAT showed indistinguishable heparin cofactor and progressive activities, and they bound to thrombin in a one-to-one stoichiometric manner. In lipopolysaccharide (LPS)-induced and thromboplastin-induced DIC rat models, rAT reduced fibrinogen and platelet consumption to a similar extent with pAT. In LPS-induced DIC model, both ATs similarly restrained the increase of alanine aminotransferase and aspartate aminotransferase activities. Finally, pharmacokinetic analysis showed that both ATs had similar half-lives in the circulation of normal rats. Together, the present study demonstrated that rAT prepared in CHO cells has potential for a substitute of pAT in therapeutic use.

Topics: Alanine Transaminase; Animals; Antithrombin III Deficiency; Antithrombins; Aspartate Aminotransferases; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrinogen; Glycosylation; Humans; Lipopolysaccharides; Male; Oligosaccharides; Protein Isoforms; Rats; Rats, Wistar; Recombinant Proteins; Stereoisomerism; Thromboplastin; Time Factors

Sepsis is a life-threatening disorder resulting from systemic inflammatory and coagulatory responses to infection. High-mobility group box 1 protein (HMGB1), an abundant intranuclear protein, was recently identified as a potent lethal mediator of sepsis. However, the precise mechanisms by which HMGB1 exerts its lethal effects in sepsis have yet to be confirmed. We recently reported that plasma HMGB1 levels correlated with disseminated intravascular coagulation (DIC) score, indicating that HMGB1 might play an important role in the pathogenesis of DIC.. To investigate the mechanisms responsible for the lethal effects of HMGB1, and more specifically, to explore the effects of HMGB1 on the coagulation system.. Rats were exposed to thrombin with or without HMGB1, and a survival analysis, pathologic analyses and blood tests were conducted. The effects of HMGB1 on the coagulation cascade, anticoagulant pathways and surface expression of procoagulant or anticoagulant molecules were examined in vitro.. Compared to thrombin alone, combined administration of thrombin and HMGB1 resulted in excessive fibrin deposition in glomeruli, prolonged plasma clotting times, and increased mortality. In vitro, HMGB1 did not affect clotting times, but inhibited the anticoagulant protein C pathway mediated by the thrombin-thrombomodulin complex, and stimulated tissue factor expression on monocytes.. These findings demonstrate the procoagulant role of HMGB1 in vivo and in vitro. During sepsis, massive accumulation of HMGB1 in the systemic circulation would promote the development of DIC.

Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Cells, Cultured; Coagulants; Cytokines; Disease Models, Animal; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Hemolysis; High Mobility Group Proteins; HMGB1 Protein; Humans; Inflammation; Kidney; Lung; Male; Monocytes; Protein C; Rats; Rats, Sprague-Dawley; Repressor Proteins; Thrombin; Thromboplastin; Thrombosis

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that activates and directs the migration of leukocytes that have CXCR4, which is the unique receptor for SDF-1. Although SDF-1/CXCR4 interaction has been implicated in various inflammatory conditions, its role in modulating coagulation has not been determined. We studied the plasma SDF-1 levels in 90 patients with suspected disseminated intravascular coagulation (DIC) and we found that circulating SDF-1 was significantly increased in the overt DIC patients and was also increased in overt DIC patients who have a poor outcome. We then tested in vitro whether SDF-1 can affect the expression of monocyte tissue factor (TF) and endothelial thrombomodulin (TM), and both of these play important roles in coagulopathy. SDF-1 did not affect the expression of surface TF protein and its function and the TF mRNA level in both monocytes and the monocytic leukemia cell line THP-1. SDF-1 also did not change the surface TM expression of endothelial cells. SDF-1 could enhance low-dose ADP induced platelet aggregation, although it failed by itself to induce aggregation. These findings suggest that plasma SDF-1 might be closely associated with hypercoagulability though its action as a platelet activator.

Topics: Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Disseminated Intravascular Coagulation; Endothelial Cells; Humans; Monocytes; Platelet Function Tests; Prognosis; Thrombomodulin; Thrombophilia; Thromboplastin

Tissue factor (TF) is involved in cancer growth and metastasis, and haemostatic abnormalities are found in most patients with advanced malignancies, including prostate cancer (PC). Because anti-haemostatic agents are increasingly screened for their potential to prolong survival in tumor patients, a detailed characterization of haemostatic markers in selected cancer subtypes and clinical stages is warranted. In this study, we measured preoperative plasma TF antigen in a large cohort of patients with localized PC and correlated its levels with markers of coagulation and platelet activation, prostate-specific antigen (PSA), and histopathological findings to explore its potential as a prognostic marker in this tumor entity. Out of 140 patients, 19% and 23% had plasma TF antigen levels of <40 pg/ml (low-TF) and >200 pg/ml (high-TF), respectively, which was substantially higher than in 42 healthy male controls. Patients also had low-grade systemic coagulation activation as evidenced by elevated D-dimer, F1 + 2, and PAP plasma levels. Furthermore, similar to sP-selectin and sCD40L antigen, flow cytometric analysis of platelet-derived microparticles in plasma revealed significantly increased numbers in high-TF as compared to low-TF patients and controls. Whereas elevated D-dimer was associated with larger and less differentiated tumors, preoperative plasma TF antigen levels (median [IQR]) were higher in patients with (161 pg/ml [100-236]) than in those without recurrent PC (105 pg/ml [52-182]), as indicated by a serum PSA of >0.1 ng/ml during ambulatory follow-up. In patients with localized PC, preoperative plasma TF antigen levels correlate with platelet activation in vivo and may indicate an increased risk for recurrent disease.

Topics: alpha-2-Antiplasmin; Antigens, Neoplasm; Biomarkers, Tumor; Blood Coagulation; CD40 Ligand; Cell Differentiation; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Flow Cytometry; Follow-Up Studies; Hemostasis; Humans; Male; Middle Aged; Neoplasm Invasiveness; P-Selectin; Peptide Fragments; Platelet Activation; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Prothrombin; Recurrence; Risk Assessment; Thromboplastin; Time Factors

Topics: Antifibrinolytic Agents; Brain Injuries; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Thromboplastin

Hemostatic parameters were examined before and during 102 courses of chemotherapy in 42 patients with malignant lymphoma with high risk for infection. The white blood cell count was significantly reduced in all patients at days 1 and 3, but significantly increased at days 7 and 9, compared to before chemotherapy. At day 7 of chemotherapy, tissue factor (TF) mRNA levels in leukocytes were significantly increased in all patients, especially those with infection. Plasma concentrations of granulocyte elastase derived-XDP (GE-XDP) levels correlated with D-dimer levels during chemotherapy in patients with malignant lymphoma, suggesting that the elevated D-dimer is fibrin products degraded by granulocyte elastase. GE-XDP, C-reactive protein (CRP), GE-XDP and D-dimer were significantly higher in patients with infection, disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS) than those without. In patients with DIC or ARDS, TF mRNA correlated with D-dimer, and GE-XDP correlated with leukocyte count, CRP and D-dimer, suggesting that inflammatory changes due to thrombosis may cause the activation of leukocytes in patients with malignant lymphoma during chemotherapy. Activated leukocytes and granulocyte elastase may elicit a hypercoagulable state and ARDS in patients with malignant lymphoma during chemotherapy.

Topics: Aged; Antineoplastic Agents; C-Reactive Protein; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemostasis; Humans; Infections; Leukocyte Count; Leukocyte Elastase; Leukocytes; Lymphoma; Male; Middle Aged; Prospective Studies; Respiratory Distress Syndrome; RNA, Messenger; Thromboplastin; Time Factors

Severe hemorrhage at multiple organs is frequently observed in chickens infected with highly pathogenic avian influenza (HPAI) A viruses. In this study we examined whether HPAI virus infection leads to coagulation disorder in chickens. Pathological examinations showed that the fibrin thrombi were formed in arterioles at the lung, associated with the viral antigens in endothelial cells of chickens infected intravenously with HPAI virus. Hematological analyses of peripheral blood collected from the chickens revealed that coagulopathy was initiated at early stage of infection when viral antigens were detected only in the endothelial cells and monocytes/macrophages. Furthermore, gene expression of the tissue factor, the main initiator of blood coagulation, was upregulated in the spleen, lung, and brain of HPAI virus-infected chickens. These results suggest that dysfunction of endothelial cells and monocytes/macrophages upon HPAI virus infection may induce hemostasis abnormalities represented by the excessive blood coagulation and consumptive coagulopathy in chickens.

Topics: Animals; Arterioles; Brain; Chickens; Disseminated Intravascular Coagulation; Endothelial Cells; Gene Expression; Influenza A Virus, H5N1 Subtype; Influenza in Birds; Lung; Platelet Count; Prothrombin Time; RNA, Messenger; Spleen; Thromboplastin; Thrombosis

Tissue factor (TF) plays a central role during disseminated intravascular coagulation (DIC) in sepsis. We hypothesized that a frequent D/I polymorphism, at nucleotide position -1208 in the promoter region, could influence TF-mRNA and downstream coagulation.. Basal- and lipopolysaccharide (LPS)-induced TF-mRNA expression, microparticle-associated TF-procoagulant activity and coagulation were determined in healthy men (n = 74) before and after endotoxin (LPS) infusion (2 ng kg(-1)). Basal values of TF-mRNA ranged between 34 and > 37.5 cycles.. Baseline TF-mRNA levels significantly differed between genotypes: I/I carriers had almost 2-fold higher TF-mRNA levels compared to D/D carriers at baseline (P < 0.01). In accordance, higher levels of microparticle-associated TF-procoagulant activity could be seen in I/I carriers. However, the genotype did not affect basal or LPS-induced levels of prothrombin fragment F1+2, D-dimer or cytokines including tumor necrosis factor and interleukin-6.. The TF-1208 polymorphism is functional in that it regulates basal TF-mRNA in circulating monocytes and circulating microparticle-associated TF-procoagulant activity in vivo, but does not influence the relative increase in TF-mRNA or coagulation activation during low-grade endotoxemia.

Topics: Disseminated Intravascular Coagulation; Endotoxemia; Endotoxins; Genotype; Humans; Interleukin-6; Leukocytes; Male; Monocytes; Polymorphism, Genetic; RNA, Messenger; Thromboplastin; Tumor Necrosis Factor-alpha

Pathologic disseminated intravascular coagulation (PDIC) is a serious complication in sepsis. In an in-vitro system consisting of incubation of fresh citrated blood with lipopolysaccharides (LPS) or glucans and subsequent plasma recalcification plasmatic thrombin was quantified. Five hundred microliters of freshly drawn citrated blood of healthy donors were incubated with up to 800 ng/mL LPS (Escherichia coli) or up to 80 microg/mL Zymosan A (ZyA; Candida albicans) for 30 minutes at room temperature (RT). The samples were centrifuged, and 30 microL plasma were recalcified with 1 volume or less of CaCl(2) (25 micromoles Ca(2+)/mL plasma). After 0 to 12 minutes (37 degrees C), 20 microL 2.5 M arginine, pH 8.6, were added. Thirty microliters 0.9 mM HD-CHG-Ala-Arg-pNA in 2.3 M arginine were added, and the absorbance increase at 405 nm was determined. Fifty microliters plasma were also incubated with 5 microL 250 mM CaCl2 for 5, 10, or 15 minutes (37 degrees C). Fifty microliters 2.5 M arginine stops coagulation, and 50 microL 0.77 mM HD-CHG-Ala-Arg-pNA in 2.3 M arginine starts the thrombin detection. The standard was 1 IU/mL thrombin in 7% human albumin instead of plasma. Arginine was also added in the endotoxin exposure time (EET) or in the plasma coagulation reaction time (CRT). Tissue factor (TF)-antigen and soluble CD14 were determined. LPS at blood concentrations greater than 10 ng/mL or ZyA at greater than 1 microg/mL severalfold enhance thrombin generation, when the respective plasmas are recalcified. After 30 minutes EET at RT, the thrombin activity at 12 minutes CRT generated by the addition of 200 ng/mL LPS or 20 microg/mL ZyA is approximately 200 mIU/mL compared to approximately 20 mIU/mL without addition of endotoxin, or compared to about 7 mIU/mL thrombin at 0 minutes CRT. Arginine added to blood or to plasma inhibits thrombin generation; the inhibitory concentration 50% (IC 50) is approximately 15 mM plasma concentration. Endotoxin incubation of blood increases neither TF nor sCD14. This assay allows the study of the hemostasis alteration in PDIC, particularly in PDIC by sepsis. The thrombin generated by blood plus endotoxin incubation and plasma recalcification suggests that the contact phase of coagulation; e.g., triggered by cell components of (phospholipase-) lysed cells such as monocyte or endothelium DNA or phospholipid-vesicles (microparticles), is of primary pathologic importance in sepsis-PDIC. Arginine at plasma concentrations of 10 to

Topics: Arginine; Blood; Blood Coagulation Tests; Cells, Cultured; Disseminated Intravascular Coagulation; Endotoxins; Humans; Lipopolysaccharide Receptors; Lipopolysaccharides; Models, Cardiovascular; Sepsis; Thrombin; Thromboplastin; Zymosan

Previous reports have suggested an interplay between the pathways mediating coagulation and inflammation in endotoxemia and sepsis. The present study was designed to examine whether cross-signaling between the pathways mediating coagulation and inflammation occurs, as suggested by the pattern of cytokine production observed following tissue-factor (TF)-induced disseminated intravascular coagulation (DIC).. Prospective, comparative, experimental study.. Laboratory at a university hospital.. Male Wistar rats, aged 6-7 wks, and weighing 160-170 g.. Male Wistar rats were administered TF (3.75 units/kg every 4 hrs), TF, and tranexamic acid (TA; 50 mg/kg every 4.5 hrs) or lipopolysaccharide (30 mg/kg every 4 hrs) via the tail vein, and blood was sampled at 0, 4, 8 and 12 hrs.. Subsequent alterations in thrombin-antithrombin complex and fibrinogen levels, as well as platelet counts, indicated that the severity of both types of experimental DIC (TF-induced and lipopolysaccharide-induced) was similar with respect to hemostatic activation and development of consumption coagulopathy. In lipopolysaccharide-induced DIC, a sharp increase in plasma tumor necrosis factor levels was observed at 4 hrs, after which a sharp decline was noted. Plasma levels of interleukin-6 were markedly increased at 4 hrs, after which a sustained elevation was observed for the duration of the experimental period (tumor necrosis factor, 1270 +/- 280, 180 +/- 40, and 120 +/- 30 pg/mL at 4, 8 and 12 hrs, respectively; interleukin-6, 5810 +/- 1320, 4850 +/- 730, and 5230 +/- 1280 pg/mL at 4, 8 and 12 hrs, respectively). On the other hand, tumor necrosis factor and interleukin-6 were not detected following TF-induced DIC (0 +/- 0 at 4, 8, and 12 hrs for both tumor necrosis factor and interleukin-6). In the TF+TA group, significant increases in tumor necrosis factor and interleukin-6 were observed, compared with the TF group.. There is no overt interplay between the pathways mediating coagulation and inflammation in TF-induced DIC, as observed in lipopolysaccharide-induced DIC.

Topics: Animals; Antifibrinolytic Agents; Cytokines; Disseminated Intravascular Coagulation; Hemostatics; Interleukin-10; Interleukin-6; Lipopolysaccharides; Male; Prospective Studies; Rats; Rats, Wistar; Receptor Cross-Talk; Signal Transduction; Thromboplastin; Tranexamic Acid; Tumor Necrosis Factor-alpha

A 70-year-old woman developed disseminated intravascular coagulation (DIC) during a craniotomy for a parasagittal anaplastic/malignant meningioma. This was successfully treated with rapid resection of the tumour and haematological replacement, but a poor neurological outcome resulted. The tumour was demonstrated to express tissue factor, an important causative factor in other tumour associated DIC and previously shown to be expressed by malignant meningiomas. A link between the two is suggested.

Topics: Aged; Brain Neoplasms; Craniotomy; Disseminated Intravascular Coagulation; Female; Humans; Intraoperative Complications; Meningioma; Neoplasm Proteins; Thromboplastin

The aim of this study was to test the efficacy of different dosages of low molecular weight heparin (LMWH) in acute DIC which was induced in anaesthetised dogs by 4 h infusions of a canine lung thromboplastin extract. In all animals during the first 2 h, development of acute DIC was characterised by decreasing fibrinogen concentrations, platelet numbers, factor V- and antithrombin activities. Two hours after starting the thromboplastin infusion, intravenous LMWH treatment in different dosages started in groups 2 and 3 to achieve plasma levels between 0.27+/-0.01 and 0.36+/-0.02 anti-FXaUml(-1) or 0.62+/-0.08 and 0.90+/-0.07 antiFXaUml(-1) (mean+/-SD), respectively, during the time period of parallel administration of thromboplastin and LMWH (group 1=control; 4 dogs/group). In this time period, changes in factor V activity and fibrinogen concentration did not differ between group 2 and the control group. This was in contrast to group 3. The results of this study indicate that an efficacious interruption of the consumption reaction in cases of severe canine DIC requires high plasma heparin levels.

Topics: Animals; Anticoagulants; Disseminated Intravascular Coagulation; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Female; Heparin, Low-Molecular-Weight; Male; Thromboplastin

Tissue factor (TF) mRNA levels in leukocyte and TF antigen in plasma were examined in patients with deep vein thrombosis (DVT). Although TF mRNA levels in leukocytes were higher in patients with DVT than in healthy volunteers, they were lower in patients with DVT than in those with solid cancer and those with disseminated intravascular coagulation (DIC). On the other hand, the plasma levels of TF antigens were markedly high in patients with DVT/pulmonary embolism (PE). Analysis of the role of underlying disease of DVT showed no significant difference in TF mRNA levels and TF antigens among patients with solid cancer, post-surgical, other diseases and those free of underlying diseases. In patients with VTE, plasma levels of D-dimer, soluble fibrin, GE-XDP and plasminogen activator inhibitor-1 did not correlate with TF mRNA or TF antigen. In analysis of 18 patients with PE with and without DVT, TF mRNA levels in leukocytes correlated with the plasma levels of D-dimer. These findings suggest that TF in leukocytes is more likely to be involved in the development of thrombosis in PE than DVT.

Topics: Adult; Aged; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Humans; Leukocytes; Male; Middle Aged; Neoplasms; Pulmonary Embolism; RNA, Messenger; Thromboplastin; Up-Regulation; Venous Thrombosis

While the adenosine 5'-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagen-adhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y12 and P2Y1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectron-microscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y1-deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus.

Topics: Adult; Animals; Blood Coagulation; Blood Platelets; Clopidogrel; Collagen; Disease Models, Animal; Disseminated Intravascular Coagulation; Factor Xa; Humans; Leukocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Immunoelectron; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Reference Values; Thrombin; Thromboplastin; Thrombosis; Ticlopidine

The biphasic waveform that can predict for disseminated intravascular coagulation (DIC) is due to the formation of a calcium-dependent complex between C reactive protein (CRP) and very low density lipoprotein (VLDL). As thrombin generation is pivotal to DIC, this aspect has been specifically investigated and the VLDL component has been found to increase prothrombinase activity via both quantitative and qualitative changes. The specific prothrombinase activity of VLDL from patients manifesting the biphasic waveform was 2.5 times that of normal individuals or critically ill patients without the biphasic waveform. This activity was due to an increase in anionic phospholipid surfaces that could be inhibited with excess annexin V and which was dependent on structurally intact apolipoprotein B. The qualitative change appeared to be due to a deficiency of phosphatidylethanolamine in VLDL from patients with the biphasic waveform. The functional consequence of this enhanced prothrombinase activity was an increased procoagulant effect in plasma. Using a modified activated partial thromboplastin time assay, the mean normal clot time decreased significantly when VLDL from patients with biphasic waveforms was substituted. These results indicate that VLDL derived from patients with the biphasic waveform can enhance thrombin procoagulant activity. As the CRP-VLDL complex exists in vivo, it could have a pathogenic role in disseminating the process of intravascular coagulation.

Topics: Adsorption; Annexin A5; Apolipoproteins B; Blood Coagulation Tests; C-Reactive Protein; Cell Separation; Cerebrosides; Chromatography, Thin Layer; Coagulants; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Immunosorbent Techniques; Lipoproteins; Lipoproteins, VLDL; Partial Thromboplastin Time; Phosphatidylethanolamines; Protein Binding; Sepsis; Thrombin; Thromboplastin; Time Factors; Triglycerides

Disseminated intra-vascular coagulation (DIC) is a serious and frequently fatal condition associated with gross abnormalities of thrombosis, haemostasis, vascular function and inflammation. We measured serial levels of plasma soluble E selectin (marking endothelia damage), interleukin 6 (IL-6, a marker if inflammation) and tissue factor (involved in coagulation) in two young adults with bacterially-induced DIC. Soluble E selectin and IL-6 were grossly elevated on presentation and increased as the DIC progressed. Tissue factor was normal on admission but also increased with the DIC. However, levels remained high in one of the patients who subsequently died, whilst levels resolved in the patient who survived. We suggest that both admission and evolving sE-selectin and IL-6 levels may be useful in predicting outcome, and that measurement of TF has little extra to offer.

Topics: Adult; Biomarkers; Disease Progression; Disseminated Intravascular Coagulation; E-Selectin; Endothelium, Vascular; Female; Humans; Interleukin-6; Male; Meningitis, Meningococcal; Meningococcal Infections; Prognosis; Sepsis; Shock, Septic; Thromboplastin

We clarified the role of fibrinolysis in tissue-factor (TF)-induced rat disseminated intravascular coagulation (DIC) using tranexamic acid (TA). TA suppressed the elevation in D-dimer levels normally observed following TF-induced DIC, and an increase in organ dysfunction was seen. Enhanced fibrinolysis plays an important role in preventing the development of organ failure in TF-induced DIC.

Topics: Animals; Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Male; Rats; Rats, Wistar; Thromboplastin; Tranexamic Acid

We compared the levels of tissue factor (TF) mRNA in leukocytes with plasma TF antigens of patients in hypercoagulable state caused by various diseases. Flow cytometric analysis showed absence of TF antigen expression on neutrophils and monocytes in healthy subjects but strong expression in both cell types of patients with infections.TF mRNA levels in leukocytes were low in healthy subjects but they were significantly elevated in patients with underlying diseases of disseminated intravascular coagulation (DIC), especially in acute myeloid leukaemia (AML) and infections.TF mRNA levels in leukocytes were significantly high in patients with all diseases except those with thrombosis, and plasma TF antigen levels were significantly high in all diseases. TF mRNA in leukocytes and plasma TF antigen levels were significantly high in patients with overt-DIC, and TF mRNA/antigen ratio was significantly high in patients with overt-DIC. In patients with solid cancers, TF mRNA and TF mRNA/antigen ratio were significantly higher in patients with metastases than those without. TF mRNA levels in leukocytes and plasma levels of TF antigen did not correlate in normal subjects and all patients, but they tended to be correlated in patients with AML, infections or overt-DIC. Our analysis suggests that TF expression in leukocytes plays an important role in various diseases but the expression level does not always correlate with plasma levels of TF antigen.

Topics: Adult; Aged; Base Sequence; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; DNA, Complementary; Female; Humans; Infections; Leukocytes; Male; Middle Aged; Monocytes; Neoplasms; Neutrophils; RNA, Messenger; Thromboplastin

6,7-Dihydroxy-3-phenylcoumarin (DHPC) was tested to determine whether it had any effect on vitamin K inhibition, by investigating the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level and platelet count. The anticoagulant and antithrombotic effects of DHPC were compared with those of warfarin by conducting a 4 h acute trial on thromboplastin-induced disseminated intravascular coagulation (DIC), investigating various haemostatic and antioxidant system parameters and performing a haemogram. Of most significance was that in the 5-d DHPC trial on healthy controls, PT, APTT, fibrinogen, platelet count remained within normal levels. In the 4-h DIC trial, both DHPC (0.025 mg/kg, i.v.) and warfarin (0.25 mg/kg, i.v.) significantly inhibited DIC, by reducing the PT, APTT, and fibrin degradation products and increasing fibrinogen levels and platelet count. In the DIC drug groups, lipid peroxidation significantly increased only in the warfarin group and glutathione significantly increased only in the DHPC group. However leucocyte count was significantly higher in the DHPC than the warfarin group. Further investigation is required for why DHPC is effective on the parameters investigated, at doses one-tenth of those of warfarin.

Topics: Animals; Anticoagulants; Coumarins; Depression, Chemical; Disseminated Intravascular Coagulation; Female; Fibrinogen; Lipid Peroxidation; Models, Animal; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboplastin; Warfarin

We investigated the relationship between endothelin, a potent vasoconstrictor peptide, and the pathophysiology of disseminated intravascular coagulation (DIC), using two models of DIC. Experimental DIC was induced by sustained infusion of 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin, for 4 h via the rat tail vein. The effect of administration of a non-selective endothelin receptor antagonist (TAK-044) (2, 10, or 50 mg/kg, from -0.5 to 4 h) on thromboplastin-induced DIC was not significant. However, LPS-induced elevation of alanine aminotransferase, creatinine and glomerular fibrin deposition was significantly suppressed by co-administration of TAK-044 in a dose-dependent manner, although no effect of TAK-044 was observed on the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of D-dimer, which reflect the grade of fibrinolysis of cross-linked fibrin, were significantly increased by co-administration of each dose of TAK-044 in the LPS-induced DIC model in rats. Our results suggest that vasoconstriction, as well as depressed fibrinolysis, contribute to severe organ dysfunction in LPS-induced, but not thromboplastin-induced, DIC, and that endothelin plays a role in the development of organ injury in LPS-induced DIC in rats.

Topics: Alanine Transaminase; Animals; Creatinine; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Fibrin; Hemostatics; Lipopolysaccharides; Male; Peptides, Cyclic; Rats; Rats, Wistar; Thromboplastin

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.

Topics: Adult; Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Antithrombin III; Biomarkers; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Hematologic Neoplasms; Hemorrhage; Humans; Infections; Interleukin-1; Interleukin-6; International Normalized Ratio; Male; Middle Aged; Multiple Organ Failure; Neoplasms; Peptide Hydrolases; Plasminogen; Plasminogen Activator Inhibitor 1; Platelet Count; Prognosis; Thrombomodulin; Thromboplastin; Thrombosis; Tissue Plasminogen Activator

To study the altering rule of coagulation function at molecular level in patients with secondary brain injury (SBI).. Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) were studied in 32 patients 1, 2, 3 and 7 days after craniocerebral injury. Repeated cranial CT scans and platelet counts were made simultaneously. Same measurements were done in 30 normal adults except CT scan.. No obvious difference was found in age, sex and platelet count between the injured and the normal groups. TFPI/TF decreased markedly in the first week after injury in patients with SBI, but only decreased on the 7th day in the patients without obvious SBI. For the patients who developed delayed intracranial hematoma (DIH) or hematoma enlargement, TF rose only 1 and 2 days after injury, but TFPI had a tendency to rise again after a fall on the 3rd day. For those patients who developed no DIH, TF rose all the time within the 1st week.. Decrease of TFPI/TF for a long time, especially within 3 days after injury, may be one of the most important reasons for SBI. High expression of TF for a relative short time and increase of TFPI after a fall within 3 days may be one of the important reasons for DIH or hematoma enlargement.

Topics: Adolescent; Adult; Anticoagulants; Craniocerebral Trauma; Disseminated Intravascular Coagulation; Female; Humans; Lipoproteins; Male; Middle Aged; Platelet Count; Thromboplastin; Tomography, X-Ray Computed

In a preliminary study, we have demonstrated that tissue factor (TF) is immunohistochemically stained in monocytes from patients with disseminated intravascular coagulation (DIC) but not from healthy volunteers, and that leukocytes from DIC patients induce enhanced activated factor X (FXa) generation in the presence of a mixture of FVIIa, FX and Ca(2+). Then, TF mRNA levels in leukocytes were measured to evaluate the role of TF in the pathophysiology of various diseases. TF mRNA levels in leukocytes were low in healthy volunteers but they were significantly increased in various diseases, especially in patients with infectious diseases, solid cancer, and hematopoietic tumors. TF mRNA levels in leukocytes were significantly higher in patients with high levels of C reactive protein (CRP) than in those with low CRP. TF mRNA levels were significantly higher in patients with DIC than in those without DIC. TF mRNA levels were well correlated with TF antigens in plasma and leukocytes. These findings suggest that the expression of TF mRNA in leukocytes is increased in various diseases and that this may play an important role in hypercoagulability or DIC.

Topics: Adult; Aged; C-Reactive Protein; Calcium; Disseminated Intravascular Coagulation; Factor VIIa; Factor X; Factor Xa; Female; Humans; Immunohistochemistry; Leukocytes; Male; Middle Aged; RNA, Messenger; Thrombophilia; Thromboplastin; Time Factors

Tissue factor (TF) and lipopolysaccharide (LPS) are frequently used to induce disseminated intravascular coagulation (DIC) in experimental animal models. Although the pathophysiology of DIC may differ depending on which agent is used for induction, previous studies on models of DIC have not distinguished which DIC-inducing agent was used. In the present paper, we evaluate the characteristics of TF-induced and LPS-induced DIC using two types of DIC models, with special reference to selected hemostatic parameters and pathological findings within the kidney. Male Wistar rats were administered TF (3.75 U/kg; sustained infusion for 4 h) or LPS (30 mg/kg; sustained infusion for 4 h) via the tail vein, and blood sampling was performed at 0, 1, 3, 4, 5, 7, 9, 11, and 28 h. Judging from changes in the levels of thrombin-antithrombin complex, fibrinogen levels, and platelet counts, it is reasonable to conclude that the severity of both types of experimental DIC is similar with regard to hemostatic activation and consumption coagulopathy. A marked elevation in the level of D-dimer was noted without any organ dysfunction or much fibrin deposition in the kidney upon administration of TF. However, a markedly prolonged period of elevation in plasminogen activator inhibitor activity, a prolonged depression in antithrombin III activity, severe organ failure, and a markedly prolonged period of fibrin deposition in the kidney was observed following LPS administration. A modest number of the rats from the TF-induced DIC model died during the experimental period, whereas a large number of rats died during LPS-induced DIC, especially after 9 h. Since the time course of the pathophysiology differed remarkably among the TF-induced and LPS-induced DIC models in rats, we recommend that TF-induced and LPS-induced DIC be approached as distinct models in order to determine the implications of their experimental and clinical use.

Topics: Animals; Biomarkers; Blood Coagulation Factor Inhibitors; Blood Coagulation Factors; Disease Models, Animal; Disease Progression; Disseminated Intravascular Coagulation; Hemostasis; Kidney; Kinetics; Lipopolysaccharides; Male; Rats; Rats, Wistar; Thromboplastin

Topics: Disseminated Intravascular Coagulation; Drug Delivery Systems; Humans; Lipoproteins; Neoplasms; Protein C; Thromboplastin

Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor (TF) plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood-cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1-48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever.

Topics: Animals; Disseminated Intravascular Coagulation; Fibrin; Hemorrhagic Fever, Ebola; Macaca fascicularis; Macaca mulatta; Macrophages; Male; Monocytes; RNA, Messenger; Thromboplastin

To determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death.. Prospective, cohort study.. General intensive care unit of tertiary care emergency department.. Thirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors. Ten normal, healthy volunteers served as controls.. None.. Tissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1-4 after diagnosis. The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously. The results of these measurements were compared between the survivors and the nonsurvivors. In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects. However, the TFPI values showed no difference between the two groups. No correlation was found between the peak concentrations of tissue factor and TFPI. Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period. The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors.. We systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock. Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death. High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis.

Topics: Adult; Anticoagulants; Cohort Studies; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Japan; Leukocyte Elastase; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Platelet Count; Prognosis; Prospective Studies; Respiratory Distress Syndrome; Sepsis; Serine Proteinase Inhibitors; Survival Analysis; Thromboplastin; Treatment Outcome

Systemic activation of coagulation leading to disseminated intra-vascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. The efficacy of these agents in attenuating the activation of coagulation and formation of microvascular thrombosis in sepsis may depend on the mechanism of inhibition. Here we demonstrate the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits the tissue factor/factor VIIa complex by a novel mechanism, in a model of endotoxin-induced coagulation activation in chimpanzees. Administration of a low dose of Gram-negative endotoxin induced marked increases of thrombin generation as measured by plasma levels of prothrombin activation fragment F(1+2) and thrombin-antithrombin complexes, which were completely blocked by rNAPc2. In chimpanzees receiving rNAPc2 alone, there was a significant reduction in the activation of factor X but not factor IX, compared to animals receiving placebo. In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin. In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Disease Models, Animal; Disseminated Intravascular Coagulation; Endotoxemia; Endotoxins; Factor VIIa; Helminth Proteins; Pan troglodytes; Protein Binding; Recombinant Proteins; Thrombin; Thromboplastin

We have investigated the role of two vasoactive substances, nitric oxide (NO)and endothelin (ET), in the pathophysiology of disseminated intravascular coagulation (DIC), using two types of DIC models. Experimental DIC was induced by sustained infusion of 0.1, 1, 10, or 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin (TF), for 4 h via the rat tail vein. Plasma levels of both NOX (metabolites of NO) and ET were significantly increased following infusion of 0.1 mg/kg or greater of LPS in the LPS-induced DIC rat model. In contrast, although a marked increase in the plasma levels of NOX was observed, only a slight increase in plasma ET levels was seen in the TF-induced DIC rat model. No significant differences in the plasma levels of platelets or thrombin-ATIII complex were observed among the TF-induced and LPS (50 mg/dl)-induced DIC models. However, plasma NOX levels rose significantly higher in the TF-induced model, relative to the LPS-induced model (p <0.01). Conversely, plasma ET levels were significantly greater after LPS-induction, compared to TF-induction, of DIC (p <0.01). Vasoconstriction, as well as depressed fibrinolytic activity, may be additional factors leading to severe organ dysfunction in the LPS-induced DIC rat model. Moreover, vasodilatation, as well as enhanced fibrinolytic activity, may help to prevent rats from severe organ dysfunction in the TF-induced DIC model. Our results suggest that modulator of vasoactive substances should be examined in the treatment of DIC.

Topics: Animals; Antithrombin III; Disease Models, Animal; Disseminated Intravascular Coagulation; Endothelins; Hemostasis; Lipopolysaccharides; Male; Nitric Oxide; Peptide Hydrolases; Platelet Count; Rats; Rats, Wistar; Thromboplastin; Up-Regulation; Vasoconstriction; Vasodilation

Sepsis and septic shock are very complex and dynamic clinical syndromes. A systemic response to an infection or other triggers can induce a cascade consisting of toxins--leukocytes--cytokines--mediators of inflammation--endothelial cell dysfunction--activation of blood coagulation--intravascular fibrin deposition--alteration of microcirculation, resulting in a damage of organs. Multi organ failure and sepsis are therefore tightly connected. The associated disturbances of blood coagulation range between a simple activation of coagulation with a transient increase of activation markers (i.e. D-dimer), similar to an acute-phase reaction and full blown disseminated intravascular coagulation with consumption coagulopathy. This article summarizes these pathophysiological mechanisms, shows available diagnostic tools and differential diagnoses, and discusses therapeutic options for sepsis and multi organ failure.

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Endothelium, Vascular; Fibrinolysis; Humans; Inflammation Mediators; Multiple Organ Failure; Platelet Activation; Shock, Septic; Systemic Inflammatory Response Syndrome; Thromboplastin

Tissue factor and lipopolysaccharide frequently have been used to induce disseminated intravascular coagulation in experimental animal models. Although the pathophysiology of disseminated intravascular coagulation may differ according to the agents used to induce it, these previous models have not distinguished between the use of different disseminated intravascular coagulation-inducing agents. In this study, we attempted to evaluate the characteristic features of these agents in two types of disseminated intravascular coagulation models, with special reference to selected hemostatic parameters and pathologic findings in the kidney.. Prospective, comparative, experimental study.. Laboratory at a university hospital.. Twenty-seven male Wistar rats, age 6-7 wks, weighing 160-170 g.. Three groups of animals were studied: a control group (n = 8) receiving physiologic saline, a tissue factor-treated group (n = 11) receiving tissue factor 3.75 units/kg, and a lipopolysaccharide-treated group (n = 8) receiving lipopolysaccharide 30 mg/kg; each group sustained infusion for 4 hrs via the tail vein.. The degree of hemostatic activation in both types of experimental disseminated intravascular coagulation was identical, based on the results of thrombin-antithrombin III complex levels. Markedly elevated D-dimer concentrations were observed without organ dysfunction or fibrin deposition in the kidney on administration of tissue factor, whereas markedly elevated plasminogen activator inhibitor activity, decreased antithrombin III activity, severe organ failure, and marked fibrin deposition in the kidney were observed for lipopolysaccharide administration.. Because pathophysiology differed remarkably between the tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats, we recommend that they be assessed carefully as distinct entities to determine implications of their experimental and clinical use.

Topics: Animals; Antithrombin III; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostasis; Kidney; Lipopolysaccharides; Male; Peptide Hydrolases; Prospective Studies; Rats; Rats, Wistar; Thromboplastin

We examined whether JTV-803, a specific activated factor X inhibitor independent of antithrombin III (ATIII), is effective against disseminated intravascular coagulation (DIC) in rat models induced by tissue factor (TF) or lipopolysaccharides (LPS). In male Wistar rats, DIC was induced by a 4 h infusion of thromboplastin (3.75 U/kg) or LPS (50 mg/kg). The rats were given JTV-803 (0.3 or 3 mg/kg, bolus intravenously) (JTV-803 groups) or low molecular weight heparin (LMWH groups) (200 U/kg, bolus intravenously) prior to an injection of TF or LPS. The results showed that JTV-803 was dose-dependently effective against DIC in both TF-induced and LPS-induced rat models. This anti-DIC effect of JTV-803 at higher doses was almost equivalent to that of LMWH in both types of DIC. Plasma ATIII activity was more prominent in the group treated with JTV-803 than in that treated with LMWH. None of rats died in the TF-induced DIC model with or without drug administration. On the contrary, seven of 22 rats died (mortality rate, 31.8%) in the LPS-induced DIC model without drug administration. Although the mortality rate of rats induced with LPS and treated with LMWH was quite high (6/16, 37.5%), none of the LPS-induced rats treated with JTV-803 died. These findings suggested that JTV-803 can treat both TF-induced and LPS-induced DIC models, and that this drug has greater potential in preserving ATIII and in improving the prognosis of DIC.

Topics: Animals; Anticoagulants; Antithrombin III; Biomarkers; Blood Proteins; Dalteparin; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Factor X; Hemostasis; Isoquinolines; Kidney Glomerulus; Lipopolysaccharides; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Tetrahydroisoquinolines; Thromboplastin

Tissue factor (TF) plays an important role in the pathogenesis of atherosclerotic, sepsis and disseminated intravascular coagulation (DIC). TF pathway is therefore an attractive therapeutic target in a number of disease states. Here two TF mutants were developed and named MCsTF and MFsTF, in which the amino acids of active sites were mutated. Both of them were expressed in E.coli and used to inhibit TF pathway through competitive FVII/VIIa binding with TF. The results indicated that rMCsTF almost lost all activities of FX activation and procoagulation, and rMFsTF lost 90% activity. The specific catalytic constant ( k ( cat )/ K (m)) of FX activation by the complex formed by FVIIa with rMCsTF or rMFsTF were 2.0% and 3.7%, respectively, compared to that of rsTF. The inhibition effects of the mutants were studied in vitro, and it appeared that the prothrombin time were prolonged in a dose-dependent manner. Therefore, these mutants of TF may become new kind of specific inhibitors of TF pathway, as a promising drug for the treatment of patients with over-expression of TF.

Topics: Arteriosclerosis; Cloning, Molecular; Disseminated Intravascular Coagulation; DNA, Complementary; Escherichia coli; Gene Expression; Humans; Mutation; Thromboplastin

To determine the precise relationship between tissue factor and tissue factor pathway inhibitor (TFPI) after trauma, as well as to test the hypothesis that low TFPI levels are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome (MODS).. Prospective, observational cohort study.. Emergency room and intensive care unit in a university hospital.. Thirty-three trauma patients, 18 with disseminated intravascular coagulation (DIC) and 15 without DIC were studied. Ten normal, healthy volunteers served as control subjects.. None.. Antigen concentration of tissue factor and TFPI, and global parameters of coagulation and fibrinolysis were measured on the day of admission, and on days 1-4 after admission. The number of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined, simultaneously. The results of these measurements, incidence of MODS, and outcome were compared between the DIC patients and those without DIC. In the DIC patients, significantly higher tissue factor levels (p =.0049) and lower platelet counts (p =.0016) were found compared with the non-DIC patients and control subjects. However, the TFPI values remained at normal levels during the study period. No correlation was found between the peak levels of tissue factor and TFPI. The mean duration of SIRS and the maximum number of the SIRS criteria being met by the patients in the DIC group were statistically longer and higher than those in the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the DIC patients compared with those in the non-DIC patients, and the DIC patients had a poor outcome.. We systematically elucidated the relationship between tissue factor and TFPI in post-trauma patients. Highly activated tissue factor-dependent coagulation pathway is not sufficiently prevented by the normal TFPI levels in patients with DIC. The DIC associated with thrombotic and inflammatory responses causes MODS, and leads to poor outcome in post-trauma patients.

Topics: Analysis of Variance; APACHE; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Inflammation; Lipoproteins; Male; Middle Aged; Multiple Organ Failure; Multiple Trauma; Platelet Count; Prognosis; Prospective Studies; Systemic Inflammatory Response Syndrome; Thromboplastin; Time Factors; Treatment Outcome

1Alpha,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; i.v.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug's efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.

Topics: Administration, Oral; Animals; Anticoagulants; Cholecalciferol; Coagulants; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Heparin; Kidney Diseases; Kidney Glomerulus; Lipopolysaccharides; Male; Rats; Rats, Wistar; Sepsis; Thromboplastin; Thrombosis

All-trans retinoic acid (ATRA) has been introduced to the management of acute promyelocytic leukemia (APL) as a differentiation treatment. This drug not only causes complete remission, but also improves disseminated intravascular coagulation (DIC) without adding anticoagulants in APL. We have attempted to determine whether ATRA is effective against DIC in rat models induced by tissue factor (TF) or lipopolysaccharide (LPS), because the anticoagulant effect of ATRA has been considered to induce thrombomodulin upregulation and TF downregulation on endothelial cells as well as on APL cells. In male Wistar rats, DIC was induced by a 4-h infusion of thromboplastin (3.75 U/kg) or lipopolysaccharide (30 mg/kg). The rats were given ATRA orally each day at a dose of 100 mg/kg per day for 1 week before the injection of TF or LPS in ATRA treatment groups, or given low molecular weight heparin (LMWH) 10 min before the injection of TF or LPS (200 U/kg, bolus intravenously) in LMWH treatment groups. No significant changes in hemostatic parameters or markers of organ dysfunction were caused by the ATRA administration, while DIC was significantly improved by LMWH in the TF-induced model. DIC was significantly improved by both ATRA and LMWH in the LPS-induced model. These findings suggested that ATRA was useful for treating DIC only in the LPS-induced model, and that drug efficacy should be carefully assessed because the agents used to induce DIC considerably influenced the outcome.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Keratolytic Agents; Lipopolysaccharides; Male; Rats; Rats, Wistar; Thromboplastin; Tretinoin

Danaparoid and heparin, on the basis of anti-activated factor X (anti-FXa) activity, were equipotent in accelerating the rate of interaction of FXa and antithrombin III. In rat tissue factor-induced disseminated intravascular coagulation (DIC) models, an intravenous administration of danaparoid inhibited the decrease in plasma fibrinogen and platelet counts and the increase in serum fibrinogen degradation products. Expressed on the basis of anti-FXa activity, these effects were comparable with those of dalteparin and heparin. In rat mesenteric small artery and vein, less bleeding was observed after intravenous administration of danaparoid than after dalteparin or heparin. Danaparoid did not affect adenosine diphosphate- or collagen-induced platelet aggregation, and showed weaker inhibitory effects on aggregation induced by thrombin, or collagen + thrombin, than did dalteparin or heparin. These findings suggest that danaparoid may be useful for the prevention of DIC and has less tendency to cause bleeding than dalteparin or heparin, probably as a result of its weaker ability to inhibit platelet aggregation.

Topics: Animals; Anticoagulants; Antithrombin III; Bleeding Time; Chondroitin Sulfates; Dalteparin; Dermatan Sulfate; Disease Models, Animal; Disseminated Intravascular Coagulation; Drug Combinations; Drug Evaluation, Preclinical; Enzyme Inhibitors; Factor Xa; Factor Xa Inhibitors; Heparin; Heparitin Sulfate; Kinetics; Male; Platelet Aggregation; Rats; Rats, Wistar; Risk Assessment; Thromboplastin

A 54-year-old man was diagnosed as having pancreatic cancer and disseminated intravascular coagulation. His plasma tissue factor level on the 11th hospital day was 996 pg/ml (normal range, 120-270 pg/ml). He was treated with gabexate mesilate, antithrombin III, and low-molecular-weight heparin. However, he died of multiple organ failure on the 17th hospital day. The histological finding was poorly differentiated ductal adenocarcinoma of the pancreas, and the production of tissue factor in this lesion was revealed. Tissue factor is a factor that initiates blood coagulation; thus, its expression in pancreatic cancer is one of the causes of coagulation abnormalities in this disease. Although one report has demonstrated immunoreactivity for tissue factor in pancreatic cancer, the patient's detailed clinical course was not mentioned in that report. This is the first report to prove that pancreatic cancer produced tissue factor in a patient with disseminated intravascular coagulation.

Topics: Adenocarcinoma; Disseminated Intravascular Coagulation; Humans; Male; Middle Aged; Pancreatic Neoplasms; Radiography; Thromboplastin

Disseminated intravascular coagulation in humans is frequently associated with Gram-negative bacterial sepsis. Therefore, to examine the role and time frame of the in vivo induction of tissue factor (TF) by bacterial endotoxin, a reverse transcription polymerase chain reaction and a solid-phase ELISA assay were developed to monitor the in vivo production in rabbits, of TF mRNA and TF antigen by peripheral blood leukocytes (PBL).. : Healthy rabbits were injected intravenously with either 1, 10 or 50 microg/kg of Salmonella endotoxin. Blood samples were obtained both before endotoxin administration and at various time points thereafter, up to 24 h. Some experiments were also done to determine whether all-trans retinoic acid would ameliorate the signs of the endotoxin-induced disseminated intravascular coagulation.. PBL counts dropped significantly within 2 h of rabbits receiving the endotoxin, recovering to baseline levels by 24 h. Platelet counts decreased gradually over this same time frame. Fibrin deposition was noted in renal glomerular capillaries at 24 h. An increase (P<0.001) in PBL-associated TF mRNA levels was observed 2 h post-endotoxin (10 microg/kg, n = 8), followed by a gradual decline over the subsequent 24 h. The average increase in TF mRNA at 2 h was approximately 4.6-fold (P<0.001) over that seen at time 0. The amount of mononuclear cell associated TF antigen demonstrated a peak at 2 h post-endotoxin (10 microg/kg, n = 13), with levels approximately 9.6-fold greater than (P<0.001) baseline. Pre-treatment of rabbits with all-trans retinoic acid significantly (P<0.001) ameliorated the PBL-associated increase in TF mRNA and TF antigen levels.. These results suggest that low dose endotoxin (10 microg/kg) faithfully reproduces the non-overt activation of coagulation observed in primates and human volunteers, supporting the hypothesis that TF expression is involved in the in vivo initiation and propagation of disseminated intravascular coagulation. Moreover, all-trans retinoic acid may be effective in modulating in vivo the TF transcription induced by endotoxin.

Topics: Animals; Antithrombin III; Blood Cell Count; Disseminated Intravascular Coagulation; Drug Evaluation, Preclinical; Endotoxemia; Fibrin; Fibrinogen; Gene Expression Regulation; Kidney Glomerulus; Leukocytes; Lipopolysaccharides; Male; Rabbits; RNA, Messenger; Thrombocytopenia; Thromboplastin; Tretinoin

Topics: Annexin A2; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Thromboplastin

Patients with meningococcal sepsis generally suffer from disseminated intravascular coagulation (DIC). The aim of this study was to address whether these patients have elevated numbers of circulating microparticles that contribute to the development of DIC. Plasma samples from 5 survivors, 2 nonsurvivors, and 5 healthy volunteers were analyzed for the presence of microparticles by flow cytometry. Ongoing coagulation activation in vivo was quantified by enzyme-linked immunosorbent assay of plasma prothrombin fragment F(1 + 2), and procoagulant properties of microparticles in vitro were estimated by thrombin-generation assay. On admission, all patients had increased numbers of microparticles originating from platelets or granulocytes when compared with controls (P =.004 and P =.008, respectively). Patients had elevated levels of F(1 + 2) (P =.004), and their microparticles supported thrombin generation more strongly in vitro (P =.003) than those of controls. Plasma from the patient with the most fulminant disease course and severe DIC contained microparticles that expressed both CD14 and tissue factor, and these microparticles demonstrated extreme thrombin generation in vitro. We conclude that patients with meningococcal sepsis have elevated numbers of circulating microparticles that are procoagulant. These findings may suggest a novel therapeutic approach to combat clinical conditions with excessive coagulation activation.

Topics: Adolescent; Adult; Biomarkers; Blood Coagulation Factors; Blood Platelets; Child; Child, Preschool; Disseminated Intravascular Coagulation; Female; Granulocytes; Humans; Infant; Lipopolysaccharide Receptors; Male; Meningococcal Infections; Particle Size; Sepsis; Survivors; Thrombin; Thrombophilia; Thromboplastin

Tissue factor (TF) antigen and activity were measured in leukemic cell homogenates. In leukemic cell homogenate, especially that of acute promyelocytic leukemia (APL), both TF antigen and activity were significantly higher than these levels in the mononuclear cells obtained from healthy volunteers. Both TF antigen and activity were significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. In leukemic cell homogenates, there was a close correlation between TF antigen and TF activity. The TF activity/TF antigen ratio was significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. As the TF activity was not increased in lymphocytic leukemia cell homogenates to which were added phospholipids, the decrease in TF activity in lymphocytic leukemia might not be due to phospholipid in the leukemic cell membrane. Values for TF activity, TF antigen, and the TF activity/TF antigen ratio in leukemic cell homogenate from patients with disseminated intravascular coagulation (DIC) were significantly higher than those in patients without DIC. Therefore, the measurement of TF antigen and activity in leukemic cells could be useful for the prediction of DIC.

Topics: Antigens, Neoplasm; Disseminated Intravascular Coagulation; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Monocytic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Leukemia, T-Cell; Leukocytes, Mononuclear; Neoplasm Proteins; Thromboplastin

Topics: Acute Disease; Animals; Antithrombin III; Blood Coagulation Disorders; Complement Activation; Cytokines; Disseminated Intravascular Coagulation; Endotoxemia; Fibrin; Gene Expression Regulation; Hemorrhage; Humans; Lipoproteins; Lung Injury; Primates; Protein C; Reactive Oxygen Species; Respiratory Distress Syndrome; Sepsis; Thromboplastin; Transcription, Genetic; Tumor Necrosis Factor-alpha

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.

Topics: Acetylcysteine; Animals; Antioxidants; Blood Coagulation Disorders; Bronchoalveolar Lavage Fluid; Capillary Leak Syndrome; Disseminated Intravascular Coagulation; Fibrin; Fibrinolysis; Gene Expression Regulation; Lipopolysaccharides; Lipoproteins; Macrophage Activation; Macrophages, Alveolar; Male; Models, Biological; Neutrophils; NF-kappa B; Oxidative Stress; Plasminogen Activator Inhibitor 1; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Respiratory Distress Syndrome; Shock, Hemorrhagic; Shock, Septic; Thromboplastin; Transcription, Genetic; Tumor Necrosis Factor-alpha

To determine the duration of vascular blood vessel dysfunction and coagulation abnormalities after administration of endotoxin in a nonlethal septic rabbit model.. Randomized, controlled, interventional trial.. University animal laboratory.. A total of 30 male New Zealand White rabbits, randomly assigned to one of two groups.. Male New Zealand White rabbits were randomly divided into control or lipopolysaccharide (LPS) (0.5 mg/kg iv bolus Escherichia coli endotoxin)-treated groups. Metabolic acidosis and coagulation activation confirmed the presence of septic shock. The abdominal aorta was removed at 24 hrs (day 1), day 5, or day 21 after LPS injection. Immunohistochemical staining for an endothelial cell marker (PECAM-1/CD31) was performed to assess endothelial injury. Endothelium-dependent vascular relaxation was analyzed by in vitro vascular reactivity studies. Responses to acetylcholine, to calcium ionophore (A-23187), and to sodium nitroprusside were studied. In addition, arterial blood samples were collected on day 1, day 5, and day 21 for measurement of clotting factors and tissue factor activity.. LPS injection resulted in endothelial injury, with loss of approximately 25% of the endothelial area on day 5, which disappeared on day 21. LPS injection also caused a significantly reduced relaxation response to acetylcholine (44.9% +/-9.9% vs. 76.5%+/-5.4% for the control group; p < .005), which was restored on day 21. In contrast, vascular relaxation in response to A-23187 and sodium nitroprusside was not altered. A significant decrease in the platelet count was observed on day 1, associated with a decrease in factors II and V. On day 5, platelet count and factors II and V were corrected in conjunction with an elevated monocyte tissue factor activity in LPS-injected rabbits. On day 21, coagulation abnormalities were corrected.. A single endotoxin injection in the rabbit was responsible for prolonged aortic endothelial cell dysfunction, as well as a prolonged procoagulant state. The latter is a potential trigger for disseminated intravascular coagulation. Importantly, these features are associated with normalization of conventional biological evidence of septic shock.

Topics: Animals; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Endothelium, Vascular; Endotoxins; Escherichia coli; Male; Rabbits; Shock, Septic; Thrombophilia; Thromboplastin; Vascular Resistance

Platelets contribute to hemostasis by forming a platelet plug and by providing a procoagulant surface for the assembly and activation of the coagulation factors. The contribution of platelets to prothrombotic disorders has been difficult to analyze. Recently an assay was reported that measured the procoagulant activity of test platelets by making the platelet lipid surface the limiting factor in the production of thrombin. In this report we describe a novel technique, based on this assay, that we used to study patient serum factors that activate control platelets and in turn initiate measurable procoagulant activity. Using this assay we investigated a group of patients with prothrombotic disorders. The patient test serum was incubated with normal platelets in the presence of activated factor Xa. The resultant thrombin was measured in a chromogenic assay. The rate-limiting step was the presence of any potential platelet-activating factors, such as antibodies in the heat-treated test serum, that would allow the Xa to bind to the platelet phospholipid surface. Serum samples from patients with heparin-induced thrombocytopenia (HIT) and the anti-phospholipid antibody syndrome enhanced platelet procoagulant activity, while samples from patients with idiopathic thrombocytopenic purpura and disseminated intravascular coagulation (DIC) did not. HIT serum samples also induced platelet activation, as measured by platelet microparticle shedding, carbon 14-labeled serotonin release, and platelet aggregation. The measurement of serum-induced platelet procoagulant activity provides a method for the investigation of circulating platelet agonists in prothrombotic disorders.

Topics: Antiphospholipid Syndrome; Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Factor Xa; Heparin; Humans; Platelet Activation; Platelet Aggregation; Prothrombin; Purpura, Thrombocytopenic, Idiopathic; Serotonin; Thrombin; Thromboplastin

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Humans; Lipoproteins; Papio; Thromboplastin

Extravascular coagulation and fibrin deposition coupled with perturbations of intravascular coagulation occurs in association with acute respiratory distress syndrome (ARDS). To evaluate the pathogenetic role of an extrinsic coagulation pathway in the intravascular coagulation of ARDS patients and to explore the time course of the changes of tissue factor levels, platelet counts, and disseminated intravascular coagulation (DIC), we performed a prospective cohort study.. The study subjects consisted of 113 patients: 27 patients with ARDS, 31 patients at risk for but not developing the syndrome, and 55 patients without ARDS. According to the underlying disease, the patients were further subdivided into two groups: patients with trauma (n = 76) and patients with sepsis (n = 37). Ten normal healthy volunteers served as control subjects. Plasma tissue factor antigen (tissue factor) levels and platelet counts were measured on the day of admission and on days 1 through 4 after admission. Simultaneously, the DIC scores were determined.. The values of tissue factor in the patients with ARDS were significantly more elevated than those measured in the other two groups (p < 0.001) and control subjects (p < 0.001) on the day of admission. The values continued to be markedly high up to day 4 of admission. On the day of admission, the platelet counts in the ARDS patients showed significantly lower values (p < 0.05) than those in the other two groups. The incidence of DIC and the DIC scores in ARDS patients were significantly higher than those in the other two groups. The tissue factor levels (r(s) = 0.428, p < 0.0001) and DIC scores (r(s) = 0.357, p < 0.0002) correlated significantly with Lung Injury Score. When the patients were subdivided into two subgroups, i.e., trauma and sepsis, some differences of the tissue factor levels were noted between the two groups.. We demonstrated that tissue-factor dependent coagulation pathway of plasma is extensively activated in patients with ARDS, followed by intravascular coagulation and platelet consumption. We further provide precise information on the time course of tissue factor levels and DIC in patients with ARDS and those at risk for developing this syndrome.

Topics: Analysis of Variance; APACHE; Blood Coagulation; Case-Control Studies; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Humans; Male; Middle Aged; Multiple Trauma; Platelet Count; Prospective Studies; Prothrombin Time; Respiratory Distress Syndrome; Risk Factors; Sepsis; Thromboplastin; Time Factors

Induction of tissue factor (TF) activity by endotoxin and cytokines is an important mechanism for initiation of disseminated intravascular coagulation (DIC) seen in patients with gram-negative sepsis. Based on data from an in vitro study in which dithiocarbamates abrogated endothelial cell TF activity by inhibition of the NF-kappaB pathway, we investigated whether dithiocarbamates had in vivo activity in an animal model of DIC. Dithiocarbamates ameliorated the adverse clinical and histological effects of endotoxin-induced DIC, including morbidity, hypofibrinogenemia, and target organ damage, especially in the liver and kidney, even when given up to 1 hour after administration of endotoxin. This pilot study confirms the key role of the nuclear factor-kappa beta (NF-kappaB) pathway in induction of TF activity in initiating sepsis-associated DIC and suggests that dithiocarbamates may be useful in treatment of DIC associated with excessive TF expression because of gram-negative sepsis. Additional studies of dithiocarbamates in DIC models are warranted.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Endotoxins; Female; Fibrinogen; NF-kappa B; Rabbits; Thiocarbamates; Thromboplastin; Transcription, Genetic

We investigated antithrombin III (ATIII)-dependency of the anticoagulant effects of human urinary soluble thrombomodulin (UTM) both in vivo and in vitro, in comparison with those of heparins. For neutralization of rat plasma ATIII activity, we used F(ab')2 fragment of anti-rat ATIII antibody and could establish an appropriate in vivo model to evaluate the ATIII-dependency of antithrombotic agents. The efficacy of UTM on thromboplastin-induced disseminated intravascular coagulation produced in ATIII-decreased rats was almost the same as that in normal rats, whereas unfractionated (UF)-heparin remarkably diminished its effect in ATIII-decreased rats. The prolongation effect of UTM on activated partial thromboplastin time or prothrombin time in plasma in vitro was unchanged in both normal and ATIII-decreased rats, but the effect of UF-heparin remarkably diminished in ATIII-decreased rat plasma. Such ATIII-independence in the anticoagulant effect of UTM was also observed in human plasma. Thus, differing from heparins, since the anticoagulant effect of UTM does not depend on plasma ATIII activity, UTM is expected to be a useful antithrombotic agent for the treatment of thromboembolic diseases, even in the case with low plasma ATIII activity.

Topics: Animals; Anticoagulants; Antithrombin III; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Heparin; Humans; Immunoglobulin Fab Fragments; Male; Rats; Rats, Wistar; Solubility; Thrombomodulin; Thromboplastin; Urine; Whole Blood Coagulation Time

Thrombomodulin (TM) is a thrombin receptor on the endothelial cell surface, effective as an anticoagulant by changing procoagulant thrombin to an anticoagulant one. As rabbit TM with glycosaminoglycan (GAG) has a more potent anticoagulant activity than that without GAG, we expressed recombinant GAG-modified urinary thrombomodulin (GAG-UTM) in C-127 cells. The effect of an additional GAG chain on anticoagulant activity was investigated in comparison with unmodified recombinant UTM (r-UTM). In vitro, the activity of cleavage of fibrinogen by thrombin or prothrombinase activity was more potently depressed by GAG-UTM than by r-UTM, and the generation of activated protein C by TM-thrombin complex was accelerated by GAG modification. The acceleration of antithrombin III-dependent anticoagulant activity was shown only by GAG-UTM. Parameters like thrombin time, prothrombin time and activated partial thromboplastin time in human plasma were prolonged by GAG-UTM more than by r-UTM. In vivo, the effect of GAG-UTM and r-UTM in endotoxin-induced disseminated intravascular coagulation (DIC) rats was investigated using hematological parameters. GAG-UTM and r-UTM significantly reduced the decrease in fibrinogen and platelet number induced by endotoxin at the dosage of 0.1 and 1.0 mg/kg/h, respectively, suggesting that the antithrombotic effect of GAG-UTM in endotoxin-induced DIC rats was 10-fold as potent as that of r-UTM. GAG-UTM reduced the prolongation of the bleeding time induced by endotoxin, while r-UTM accelerated it. These results suggest that the addition of a GAG chain may increase availability as an anticoagulant.

Topics: Angiotensin III; Animals; Anticoagulants; Blood Cell Count; Blood Coagulation; Disseminated Intravascular Coagulation; DNA; Enzyme Inhibitors; Glycosaminoglycans; Humans; Kinetics; Male; Polymerase Chain Reaction; Protein C; Rabbits; Rats; Rats, Wistar; Recombinant Proteins; Thrombomodulin; Thromboplastin

To determine the role of plasma tissue factor on disseminated intravascular coagulation (DIC) in trauma and septic patients, and also to investigate the relationships between tissue factor and various thrombin markers, we made a prospective cohort study. Forty trauma patients and 20 patients with sepsis were classified into subgroups according to the complication of DIC. Plasma tissue factor antigen concentration (tissue factor), prothrombin fragment F1+2 (PF1+2), thrombin antithrombin complex (TAT), fibrinopeptide A (FPA), and D-dimer were measured on the day of admission (day 0), and on days 1, 2, 3, and 4 after admission. The levels of plasma tissue factor in the DIC group were more elevated than those of the non-DIC group in both the trauma and the septic patients. In patients with sepsis, tissue factor levels on days 0 through 4 in the non-DIC group showed markedly higher values than those in the control patients (135 +/- 8 pg/ml). Significant correlations between tissue factor and PF1+2, TAT, FPA, and D-dimer were observed in the DIC patients, however, no such correlations were found in the non-DIC patients. These results suggest that elevated plasma tissue factor in patients with trauma and sepsis gives rise to thrombin generation, followed by intravascular coagulation.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; APACHE; Biomarkers; Disseminated Intravascular Coagulation; Endothelium, Vascular; Female; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Male; Middle Aged; Monocytes; Peptide Fragments; Peptide Hydrolases; Prospective Studies; Prothrombin; Sepsis; Thrombin; Thromboplastin; Wounds and Injuries

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Disseminated Intravascular Coagulation; Female; Flow Cytometry; Gene Expression Regulation; Humans; Macrophage-1 Antigen; Male; Middle Aged; Monocytes; NF-kappa B; Sepsis; Thromboplastin; Time Factors

We examined tissue factor expression on lipopolysaccharide-stimulated endothelial cells and their small vesicles by using specific antibodies and flow cytometry. Tissue factor functional activity was also assessed by activation of factor X. Endothelial cells were stimulated with 10 microg/ml of lipopolysaccharide in M-199/bovine serum albumin. Flow cytometry showed that expression of tissue factor on endothelial cells reached a maximum at 6 hours after stimulation, whereas that on small vesicles reached a maximum after 12 hours. Factor X activation mediated by factor VIIa and tissue factor was observed over a similar time course and was inhibited by the addition of antitissue factor antibody. Immunoelectron microscopy suggested that small vesicles with expression of some tissue factor were produced from the surface of endothelial cells. Our findings thus showed that tissue factor on endothelial cells produced by lipopolysaccharide stimulation was partly released to small vesicles. This may cause disseminated intravascular coagulation and related coagulation disorders.

Topics: Cells, Cultured; Disseminated Intravascular Coagulation; Endothelium, Vascular; Enzyme Activation; Factor X; Factor Xa; Gene Expression Regulation; Humans; Lipopolysaccharides; Microscopy, Immunoelectron; Thromboplastin; Umbilical Veins

In healthy volunteers, the plasma total tissue factor pathway inhibitor (TFPI) level was 68.7+/-14.1 ng/ml; the plasma free TFPI level, 17.7+/-5.4 ng/ml; the lipoprotein-associated TFPI (LP-TFPI), 51.1+/-12.0 ng/ml; the free TFPI/total TFPI ratio 0.26+/-0.07; and the plasma tissue factor levels were 149+/-46 pg/ml. Plasma tissue factor levels in patients with disseminated intravascular coagulation (DIC) were significantly higher than those in pre-DIC patients or in non-DIC patients. Plasma total-TFPI, free-TFPI and LP-TFPI levels were significantly higher in DIC patients than those in pre-DIC patients or in non-DIC patients. Before the onset of DIC, the plasma levels of tissue factor gradually increased, and 3 days before the onset of DIC they were significantly higher than those in non-DIC patients. The plasma levels of tissue factor reached their highest level 1 day before the onset of DIC and gradually decreased after the onset of DIC. Plasma levels of total-TFPI, free-TFPI, and LP-TFPI gradually increased before the onset of DIC, and the total-TFPI and LP-TFPI reached their highest levels at the onset of DIC. Plasma free-TFPI reached highest level one day after the onset of DIC. During the clinical course of DIC, the plasma level of tissue factor was the first to increase, then that of LP-TFPI and finally the free-TFPI plasma levels. These differences in the peak plasma levels of tissue factor, free-TFPI, and LP-TFPI might be related to the clinical course of DIC.

Topics: Disseminated Intravascular Coagulation; Female; Humans; Lipoproteins; Male; Reference Values; Retrospective Studies; Serine Proteinase Inhibitors; Thromboplastin

This study was conducted in order to examine possible anticoagulant properties of the lungs during tissue thromboplastin-induced intravascular coagulation. Rabbit brain tissue thromboplastin (n = 17) or saline (n = 6 + 3) was infused above the right atrium (n = 11 + 3) of the heart or in the arcus aorta (n = 6) for a period of 120 min in non-pregnant New Zealand rabbits. Rabbits infused with tissue thromboplastin responded with significantly (p < 0.05) more excessive changes in a number of haemodynamic variables (heart rate, PaO2,PaCO2, blood pH etc.) compared with rabbits infused with saline. Similarly, the prothrombin time (p < 0.05) and the activated partial thromboplastin time (p < 0.05) were significantly more prolonged in rabbits receiving tissue thromboplastin compared with control animals. Also the concentration of blood platelets (p < 0.05), plasma fibrinogen (p < 0.05), antithrombin (p < 0.05), and protein C (p < 0.05) decreased significantly in thromboplastin-treated animals compared with control animals. In all these haemostatic variables there was a common trend that animals infused with tissue thromboplastin in the arcus aorta responded more excessively than animals infused in the right atrium of the heart, and these deviations were statistically significant for fibrinogen (p < 0.05) and prothrombin time (p < 0.05). Similarly, animals infused with tissue thromboplastin in the arcus aorta had an increased number of microthrombi in the lungs and kidneys compared with animals receiving tissue thromboplastin above the right atrium. As the lungs are the first pass organ when you infuse above the right atrium the results from this study suggest that the lungs play a key role in protecting the organism against excessive tissue thromboplastin-induced activation of coagulation.

Topics: Animals; Anticoagulants; Disseminated Intravascular Coagulation; Female; Fibrin; Hematocrit; Hemodynamics; Lung; Partial Thromboplastin Time; Prothrombin Time; Rabbits; Thromboplastin; Thrombosis

We measured the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. Plasma TF (273 +/- 90 pg/ml) and TFPI (252 +/- 125 ng/ml) levels were significantly increased in patients with DIC compared with non-DIC patients. Plasma TF antigen level was significantly increased in pre-DIC patients (285 +/- 85 pg/ml), while the plasma TFPI level (152 +/- 54 ng/ml) was not markedly increased in such a state. The plasma TF/TFPI ratio was high in the pre-DIC patients (2.10 +/- 0.90), and low in the DIC patients (1.40 +/- 0.87) and healthy volunteers (0.84 +/- 0.26). There was no significant difference between the DIC patients with a good outcome and those with a poor outcome in terms of plasma TF levels, although the plasma TFPI level in the DIC patients with a good outcome (289 +/- 133 ng/ml) was significantly higher than those with a poor outcome (187 +/- 75 ng/ml). During the clinical course of DIC, plasma TF antigen was increased first, and an increase of the plasma TFPI level followed the increase in plasma TF level. These findings suggest that plasma TFPI is released from vascular endothelial cells and it may reflect vascular endothelial cell injury. It is conceivable that TF and TFPI may play an important role in the onset of DIC.

Topics: Anticoagulants; Disseminated Intravascular Coagulation; Endothelium, Vascular; Humans; Lipoproteins; Prognosis; Thromboplastin

Topics: Disseminated Intravascular Coagulation; Humans; Systemic Inflammatory Response Syndrome; Thrombin; Thromboplastin

To determine the roles of tissue factor and thrombin on the systemic inflammatory response syndrome (SIRS) in posttrauma patients, as well as to investigate the relationship between SIRS and sepsis.. Prospective, cohort study.. General intensive care unit of a tertiary care emergency department.. Forty trauma patients were classified into subgroups, according to the duration of SIRS: non-SIRS patients (n = 9); patients with SIRS for < 2 days (n = 15); and patients with SIRS for > 3 days (n = 16).. None.. Tissue factor antigen concentration, prothrombin fragment F1+2, thrombin antithrombin complex, fibrinopeptide A, and cross-linked fibrin degradation products (D-dimer) were measured on the day of admission, and on days 1 through 4 after admission. Simultaneously, the number of SIRS criteria that the patients met and the disseminated intravascular coagulation score were determined. The results of these measurements, frequency of acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome, sepsis, and outcome were compared among the groups. The values of all five hemostatic molecular markers in the patients with SIRS for > 3 days were significantly more increased than those molecular marker values measured in the other groups on the day of admission. These values continued to be markedly high up to day 4 of admission. The occurrence rates of disseminated intravascular coagulation in these patient groups were significantly higher than those rates in the other two groups (p = .0001), and the disseminated intravascular coagulation scores did not improve during the study period. The occurrence rates of ARDS (p < .05) and multiple organ dysfunction syndrome (p < .01) were higher in patients with SIRS for > 3 days compared with those rates in the other groups, and the patients with SIRS for > 3 days had a poor outcome. No significant difference was noted in the frequency of sepsis among the groups.. Sustained SIRS is the main determinant for ARDS, multiple organ dysfunction syndrome, and outcome in posttrauma patients. Disseminated intravascular coagulation associated with massive thrombin generation and its activation is involved in the pathogenesis of sustained SIRS. Sepsis has a small role in early posttrauma multiple organ dysfunction syndrome.

Topics: Abbreviated Injury Scale; Adult; Analysis of Variance; Anticoagulants; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Respiratory Distress Syndrome; Systemic Inflammatory Response Syndrome; Thrombin; Thromboplastin; Wounds and Injuries

Disseminated intravascular coagulation (DIC) is a frequent complication of endotoxin shock, and modulation of endothelial cell hemostatic properties has been proposed to play an important role in its onset. We examined the in vivo expression of tissue factor (TF) and TF pathway inhibitor (TFPI) in rat lungs of a lipopolysaccharide (LPS)-induced DIC model. Light and electron microscopic studies showed that fibrin-rich thrombi were present in the pulmonary microvasculature 3 hours after intraperitoneal injection of LPS (7.5 mg/kg) and increased in number at 6 hours. In an immunohistochemical study, an increase in number of monocytes in the microvasculature was observed after LPS injection, and many of these cells (> 90%) were positive for TF antigen. However, no TF expression in endothelial cells was detected. Pulmonary endothelial cells showed positive reaction for TFPI antigen before LPS injection, but TFPI-positive endothelial cells markedly decreased in number after LPS injection. mRNA expression of TF increased and that of TFPI decreased in the lung tissue 3 and 6 hours after LPS injection. High values of TF activity were detected in the lung tissue and plasma, whereas TFPI activities decreased after LPS injection. These results indicate that imbalance between TF and TFPI, overexpression of TF, and underexpression of TFPI in the lung may contribute to thrombus formation in this LPS-induced DIC model.

Topics: Animals; Disseminated Intravascular Coagulation; Immunohistochemistry; Lipopolysaccharides; Lipoproteins; Lung; Male; Microscopy, Electron; Rats; Rats, Inbred F344; Thromboplastin

The procoagulant activity of mononuclear cells (MNCs) may play an important role in the disseminated intravascular coagulation seen in septic shock. This study compares the capacity of Escherichia coli (E. coli) and recombinant human TNF-alpha (rhTNF-alpha) to induce procoagulant activity by baboon MNCs. In vivo studies showed that MNC procoagulant activity was significantly increased at T + 120 min after LD100 E. coli infusion into baboons. Most of this procoagulant activity was attributable to tissue factor. In contrast, a bolus infusion of rhTNF-alpha (150 micrograms/kg) and a monoclonal antibody to activated protein C (2 mg/kg) did not induce any increase of MNC procoagulant activity at T + 120 min even though the plasma TNF-alpha level was 10 times higher than that seen following infusion of E. coli. In vitro studies showed that E. coli at concentrations comparable to that observed in the vivo study and LPS at a concentration of 2.5 ng/mL induced more intense tissue factor expression by both human and baboon monocytes than rhTNF-alpha in the concentrations ranging from 10 to 1,000 ng/mL. These results suggest that TNF-alpha alone is not sufficient to induced noticeable MNC procoagulant activity, at least, in the early stage of this septic shock model.

Topics: Animals; Blood Pressure; Coagulants; Disseminated Intravascular Coagulation; Escherichia coli; Escherichia coli Infections; Fibrinogen; Humans; Lethal Dose 50; Leukocytes; Leukocytes, Mononuclear; Lipopolysaccharides; Papio; Platelet Count; Recombinant Proteins; Shock, Septic; Thromboplastin; Tumor Necrosis Factor-alpha

We measured the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. Plasma TF (273 +/- 90 pg/ml) and TFPI (252 +/- 125 ng/ml) levels were significantly increased in patients with DIC compared with non-DIC patients. Plasma TF antigen level was significantly increased in pre-DIC patients (285 +/- 85 pg/ml), while the plasma TFPI level (152 +/- 54 ng/ml) was not markedly increased in such a state. The plasma TF/TFPI ratio was high in the pre-DIC patients (2.10 +/- 0.90), and low in the DIC patients (1.40 +/- 0.87) and healthy volunteers (0.84 +/- 0.26). There was no significant difference between the DIC patients with a good outcome and those with a poor outcome in terms of plasma TF levels, although the plasma TFPI level in the DIC patients with a good outcome (289 +/- 133 ng/ml) was significantly higher than that in those with a poor outcome (187 +/- 75 ng/ml). During the clinical course of DIC, plasma TF antigen was increased first, and an increase of the plasma TFPI level followed the increase in plasma TF level. These findings suggest that plasma TFPI is released from vascular endothelial cells and it may reflect vascular endothelial cell injury. It is conceivable that TF and TFPI may play an important role in the onset of DIC.

Topics: Anticoagulants; Disseminated Intravascular Coagulation; Humans; Lipoproteins; Reference Values; Thromboplastin; Treatment Outcome

We investigated the protective effects of DX-9065a, an orally active, newly synthesized, and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation (DIC) in rats. Experimental DIC was induced by a 4 hour sustained infusion of thromboplastin at a dose of 2.5 mg/kg. The rats were orally administered DX-9065a at 10, 30, 100 mg/kg 30 minutes before thromboplastin injection. In this DIC model, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin(ogen) degradation products, fibrinogen level, thrombin-antithrombin III complex level, prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administered at 100 mg/kg without thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggested that the new oral anti-Xa drug, DX-9065a, has a protective effect against thromboplastin-induced DIC model with little risk of bleeding.

Topics: Administration, Oral; Animals; Anticoagulants; Disease Models, Animal; Disseminated Intravascular Coagulation; Factor X; Factor Xa Inhibitors; Male; Naphthalenes; Propionates; Rats; Rats, Wistar; Thromboplastin

The very early anticoagulant response was analysed in non-pregnant female New Zealand rabbits infused with rabbit brain tissue thromboplastin for a period of 10 min (n = 6), 20 min (n = 6), and 30 min (n = 6). The rabbits infused with thromboplastin responded with a significant drop in mean arterial pressure (P < 0.05), an increase in blood PaO2 (P < 0.05) and a decrease in PaCO2 (P < 0.05), while control animals remained stable with respect to these variables. The thromboplastin-treated animals had an immediate drop in platelet count (P < 0.05), plasma fibrinogen (P < 0.05) and a prolongation in prothrombin time (P < 0.05) and activated partial thromboplastin time (P < 0.05). The concentrations in a number of proteins involved in the anticoagulant response (antithrombin, plasminogen, antiplasmin) as well as global fibrinolytic activity did not change significantly following 10, 20 and 30 min infusion of thromboplastin, while the concentration of protein C decreased continuously during the infusion periods (P < 0.05) to reach the lowest level (approximately 60%) in animals infused with thromboplastin for 30 min. The animals infused with tissue thromboplastin had microthrombi in 1-6% of the renal glomeruli, but the number of microthrombi did not differ significantly between animals infused for 10, 20 and 30 min. It is concluded that the protein C system may play a key role during the initial phase of intravascular coagulation and immediate activation of protein C may protect against excessive deposition of fibrin.

Topics: alpha-2-Antiplasmin; Animals; Disseminated Intravascular Coagulation; Female; Fibrinogen; Partial Thromboplastin Time; Plasminogen; Platelet Count; Protein C; Prothrombin Time; Rabbits; Thromboplastin

We measured plasma levels of tissue factor (TF), total tissue factor pathway inhibitor (TFPI) and free TFPI antigen in patients with diabetes mellitus (DM), hyperlipidemia and disseminated intravascular coagulation (DIC). The mean TF, total TFPI and free TFPI antigen concentrations were significantly higher in patients with DM than in controls and the plasma TF concentration was significantly higher in patients with retinopathy or nephropathy than in DM with no complications. The mean TF, total TFPI and free TFPI antigen concentrations were significantly higher in patients with hyperlipidemia than in controls. There was a significant positive correlation between levels of total TFPI and total cholesterol. In patients with hyperlipidemia, the level of total TFPI was significantly decreased compared to base line level by cholesterol lowering drug, however, free TFPI concentration did not change by cholesterol lowering drug. The TF and total TFPI concentrations were significantly higher in patients with DIC than in controls.

Topics: Anticoagulants; Antigens; Biomarkers; Cholesterol; Diabetes Mellitus; Disseminated Intravascular Coagulation; Humans; Hyperlipidemias; Lipoproteins; Thromboplastin

Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.

Topics: Animals; Anticoagulants; Carrageenan; Disease Models, Animal; Disseminated Intravascular Coagulation; Fibrin; Humans; Immunohistochemistry; Lipoproteins; Male; Rats; Rats, Wistar; Recombinant Proteins; Shock, Septic; Survival Rate; Thromboplastin; Thrombosis; Tissue Distribution

Microvascular thrombosis with intravascular fibrin deposition is a characteristic pathologic alteration during endotoxic shock. This effect is predominantly mediated by expression of the cellular procoagulant tissue factor by endothelial cells and cells of monocyte or macrophage lineage, resulting in acceleration of the coagulation cascade and fibrin deposition.. To determine whether modulation of this response by treatment with an antitissue factor antibody might have beneficial effects.. A polyclonal antibody to murine tissue factor was prepared by injecting rabbits with a synthesized peptide sequence of murine tissue factor. To determine the activity of the antibody, elicited murine peritoneal macrophages were treated for 4 hours with 10-micrograms/mL lipopolysaccharide (LPS), and procoagulant activity was determined via a clotting assay (milliunits of activity per 10(6) macrophages).. The tissue factor antibody abrogated LPS-induced macrophage procoagulant activity, confirming activity of the antibody (macrophages, 236 +/- 28 mU/10(6) macrophages; macrophages/LPS, 3801 +/- 190* mU/10(6) macrophages; macrophages/LPS/alpha-tissue factor, 753 +/- 92* mU/10(6) macrophages; n = 3; the asterisk indicates P < .05 by an analysis of variance). Additionally, antibody-protein affinity was confirmed by Western blot analysis. Having determined the activity of the antibody in vitro, we tested its efficacy in vivo in a lethal endotoxemia model. Mice were immunized with 200 microL of antiserum intraperitoneally 2 hours before injection with 250 micrograms of LPS intraperitoneally and 24 hours later. Control animals received 200 microL of saline solution. All animals initially exhibited lethargy and piloerection, characteristic of the predicted response to LPS. However, immunized animals had a significantly (P < .05) reduced mortality compared with control animals. Fibrinogen levels were significantly (P < .05) higher in the immunized mice, suggesting decreased consumption of coagulation factors, a finding consistent with an antitissue factor effect. Further, plasma tumor necrosis factor levels 90 minutes after LPS injection were similar in both groups, suggesting normal induction of the cytokine cascade.. Modulation of microvascular fibrin deposition by abrogating tissue factor-mediated coagulation significantly (P < .05) improved survival in this model without attenuating the initiation of the cytokine cascade. These findings suggest a pathogenic role for coagulation in the induction of acute organ injury during sepsis.

Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Disseminated Intravascular Coagulation; Female; Immunization; Mice; Molecular Sequence Data; Shock, Septic; Thromboplastin; Thrombosis

We measured plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. TF antigen was detected in the plasma of healthy volunteers, and the levels were significantly increased in the patients with DIC, but decreased slightly in those with TTP. Plasma TFPI levels were significantly decreased in patients with TTP compared with those in healthy volunteers. The concentration of plasma thrombomodulin (TM) antigen was significantly higher in those with TTP than in normal volunteers. One month after treatment, TTP patients showed a significant decrease in plasma TM levels, and a significant increase in plasma TFPI levels, but plasma levels of TF antigen were not significantly increased. As plasma TFPI/TF ratio was significantly increased after treatment, the hypercoagulable state was therefore improved after treatment. There was no significant difference in plasma TF and TFPI levels between those who achieved complete remission (CR) and those who died. However, plasma TM levels were significantly higher in those who died than in those who achieved CR. Plasma TFPI levels might reflect injury of vascular endothelial cells as do plasma TM levels, and decreased plasma TFPI/TF ratio and vascular endothelial cell injuries might play causative roles in TTP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic; Combined Modality Therapy; Disseminated Intravascular Coagulation; Endothelium, Vascular; Female; Humans; Lipoproteins; Male; Middle Aged; Mitomycin; Plasma Exchange; Platelet Aggregation Inhibitors; Purpura, Thrombotic Thrombocytopenic; Remission Induction; Thrombomodulin; Thromboplastin; Treatment Outcome

Topics: Disseminated Intravascular Coagulation; Factor VII; Humans; Lipoproteins; Thromboplastin

Induction of tissue factor (TF) expression on monocytes and endothelial cells is central to the development of septic coagulopathy. Serum concentrations of endotoxin in septic patients who develop disseminated intravascular coagulation (DIC) do not, however, reach the levels that would directly stimulate TF expression on either monocytes or endothelium. We show, using an in vitro coculture system, that the interaction of monocytes with endothelium induces the expression of significant levels of TF. Unstimulated cocultures of monocytes (2 x 10(4)/well) and endothelial cells (2 x 10(4)/well) produced 35.3 +/- 8.5 mU of PCA/well, representing a 5-fold increase over the combined PCA of each cell type cultured alone (7.1 +/- 1.5 mU, n = 6, P < 0.001). Significant enhancement was also found in the presence of low concentrations of LPS. Induction of TF protein was confirmed by Western blotting. Fixation of monocytes with paraformaldehyde completely abolished TF induction in cocultures, whereas fixation of endothelium had no effect, suggesting that TF induction occurred in monocytes rather than endothelial cells. Induction of TF in cocultures could be further augmented by preincubating the endothelial cells with IFN-gamma. When endothelium was prestimulated with 500 U/ml IFN-gamma there was 142 +/- 11% increase over unstimulated cocultures (n = 5, P < 0.01). TF induction was inhibited by 32 +/- 6% in the presence of anti-ICAM-1 mAb (n = 5, P < 0.01). Our results suggest that monocyte interactions with vascular endothelium, regulated by inflammatory cytokines, and mediated by adhesive ligand binding, leads to the induction of functional monocyte TF protein, which may be responsible for the initiation of DIC in sepsis.

Topics: Antibodies, Monoclonal; Blotting, Western; Cell Adhesion; Cell Communication; Coculture Techniques; Disseminated Intravascular Coagulation; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Interferon-gamma; Monocytes; Thromboplastin

Filovirus infections in humans and primates cause intrinsic activation of the clotting cascade. Tissue factor, the normal activator of the clotting cascade, is released into the bloodstream from activated leukocytes and viral budding from infected cells. This release of tissue factor, a trans-membrane protein found in large amounts in cells preferred by filoviruses for replication, initiates the hemorrhagic complications characteristic of filovirus infection. These complications contribute to the high mortality rates of filovirus infections. Directing chemotheraputic measures at the release of tissue factor, which causes the hemorrhagic complications, will result in significant reductions of mortality rates in man and primates.

Topics: Animals; Antibodies, Monoclonal; Cells; Disseminated Intravascular Coagulation; Filoviridae; Filoviridae Infections; Humans; Leukocytes, Mononuclear; Pentoxifylline; Primate Diseases; Primates; Thromboplastin; Viral Envelope Proteins; Virus Replication

We examined plasma antigen levels of tissue factor (TF) in 95 cases of disseminated intravascular coagulation (DIC), to investigate the role of TF in DIC. A significant elevation of plasma antigen levels of TF was observed in cases of DIC associated with cancer. However, no such significant elevation was observed in cases of DIC associated with acute promyelocytic leukemia (APL), acute leukemia except APL, blastic crisis of chronic myelogenous leukemia, non-Hodgkin lymphoma (NHL), sepsis or fulminant hepatitis. No significant elevation of TF was observed in patients without DIC, except 4 cases of cancer who developed DIC thereafter. Plasma antigen levels of TF were higher in both cases of DIC with renal failure and chronic renal failure without DIC than its levels in those without renal failure. Therefore, plasma antigen levels of TF in DIC patients with renal failure were considered to be carefully estimated. The levels of TF were decreased with the clinical improvement in some cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. Thus, plasma antigen levels of TF is an important marker to predict the development and/or prognosis of DIC, especially in patients with cancer.

Topics: Adult; Disseminated Intravascular Coagulation; Female; Humans; Male; Neoplasms; Prognosis; Renal Insufficiency; Thromboplastin

We evaluated the antithrombotic effects of DX-9065a, a specific factor Xa inhibitor, using tissue thromboplastin-induced DIC (TP-DIC) and the arterio-venous shunt (AV shunt) in rats. Intravenous TP injection reduced the platelet counts and fibrinogen concentrations in blood. In the TP-DIC model, an intravenous dose of DX-9065a 0.23 mg/kg 1 min before TP injection suppressed the consumption of platelets and fibrinogen to 57% and 66%, respectively, and the production of FDP almost completely. In the AV shunt model, DX-9065a inhibited thrombus formation to 51% on intravenous administration of 0.23 mg/kg and to 60% when given orally at 23.3 mg/kg. Intravenous administration of 2.33 mg/kg of DX-9065a did not affect the bleeding time. These results suggest that Xa inhibition may be an appropriate approach for suppressing thrombosis without impairing haemostasis.

Topics: Animals; Anticoagulants; Arteriovenous Shunt, Surgical; Bleeding Time; Blood Coagulation; Disseminated Intravascular Coagulation; Factor Xa Inhibitors; Fibrin Fibrinogen Degradation Products; Fibrinogen; Male; Naphthalenes; Platelet Count; Propionates; Rats; Rats, Wistar; Thromboplastin

In order to assess the clinical implication of tissue factor pathway inhibitor (TFPI) in disseminated intravascular coagulation (DIC), plasma concentrations of TFPI were measured together with plasma tissue factor (TF) in 30 healthy subjects and 49 patients with DIC associated with a variety of underlying diseases. The mean TFPI concentration was elevated in patients with DIC at presentation (205.8 +/- SD 79.1 ng/ml) as compared with healthy subjects (97.3 +/- 22.2 ng/ml, P < 0.001). The mean plasma TF concentration in patients with DIC (412.7 +/- 445.7 pg/ml) was also higher than that in healthy subjects (137.5 +/- 50.6 pg/ml, P < 0.001). Elevated TF levels were found predominantly in patients with DIC caused by cancer and leukemia, whereas TFPI was elevated in all underlying disease categories. Plasma TFPI concentration did not correlate with plasma TF. In addition, hemostatic markers of DIC such as thrombin-antithrombin complex, prothrombin fragment 1 + 2, plasmin-plasmin inhibitor complex, FDP or fibrinogen did not correlate with TFPI. Serial determinations of plasma TFPI in each patient demonstrated that the behavior of TFPI was independent of the changes in plasma TF and other hemostatic parameters. These findings indicate that plasma TFPI does not decrease in DIC and is not valuable for monitoring the progress of DIC.

Topics: Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Humans; Lipoproteins; Thromboplastin

Thrombus formation and the sequential expression of tissue factor (TF), interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1 ra) in several organs were examined immunohistochemically and morphometrically in a novel model of disseminated intravascular coagulation (DIC) developed by modifying the generalized Shwartzman reaction (GSR) in rabbits. The new model [carrageenan (CA)-lipopolysaccharide (LPS)] was induced by the administration of a priming dose of intraperitoneal CA, 10 mg/kg, followed 24 h later by a provocative dose of LPS 25 micrograms/kg, while GSR was induced by the intravenous injection of two doses of LPS 25 micrograms/kg. CA was detected predominantly within macrophages in the spleen and liver. Fibrin thrombi were formed as early as 1 h after the second LPS treatment in all examined organs reaching a peak at 3-9 h and their prevalence was higher in the CA-LPS group (p < 0.05). The sequential expressions of TF and IL-1 beta correlated well with each other in both groups reaching a peak at 3-9 h with the CA-LPS group showing a more pronounced expression than the GSR group. Macrophages in the liver, spleen and lungs, and Bowman's epithelial cells expressed both proteins, while IL-1 beta was also expressed by endothelial and epithelial cells. IL-1 ra was expressed by the same cells expressing IL-1 beta, however, its expression continued to increase gradually over 24 h. The mortality rate was lower (p < 0.05) and neutrophilic sequestration less prominent in the CA-LPS group than in the GSR group. These findings indicate that CA efficiently replaced the priming LPS treatment and the consequently enhanced production of IL-1 beta may have resulted in the upregulation of TF expression leading to the high level of thrombi in this new model which may provide a tool for further studies on the role of cytokines in DIC.

Topics: Animals; Carrageenan; Disease Models, Animal; Disseminated Intravascular Coagulation; Female; Immunohistochemistry; Injections, Intraperitoneal; Injections, Intravenous; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Kidney; Lipopolysaccharides; Liver; Lung; Rabbits; Shwartzman Phenomenon; Sialoglycoproteins; Spleen; Thromboplastin; Thrombosis; Time Factors; Tissue Distribution

Reciprocal interactions between elements of the acute inflammatory response and the coagulation system play important roles in host defense homeostasis during Gram-negative bacterial sepsis. However, derangements in the regulation of the inflammatory-coagulant axis in this setting may result in progressive tissue damage and disseminated intravascular coagulation. In this article, the integrated responses in the baboon model of Escherichia coli sepsis are analyzed as a basis of understanding these response interactions in the critically ill. In particular, three topics will be reviewed. First, the role of tissue factor in mediating the coagulant response to inflammation and the role of tumor necrosis factor (TNF) in initiating and amplifying this coagulant response into a full-blown consumptive coagulopathy are defined. A second and parallel topic concerns the role played by tissue factor pathway inhibitor and other anticoagulant systems in not only regulating this coagulant response, but also in attenuating the initial inflammatory response. The third topic concerns the use of assays of enzyme inhibitor complexes composed of components of these regulatory anticoagulant systems to help define the hypercoagulable state and possibly to make an early, specific diagnosis of sepsis prior to overt failure of the hemostatic system.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Endothelium, Vascular; Escherichia coli Infections; Fibrin; Inflammation; Lipoproteins; Papio; Sepsis; Thromboplastin; Tumor Necrosis Factor-alpha

We investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin-induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection. In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed.

Topics: Administration, Oral; Animals; Anticoagulants; Disseminated Intravascular Coagulation; Drug Evaluation, Preclinical; Endotoxins; Factor Xa Inhibitors; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Kidney Glomerulus; Male; Naphthalenes; Partial Thromboplastin Time; Platelet Count; Propionates; Prothrombin Time; Rats; Rats, Wistar; Thromboplastin

Protein C (PC) is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating thrombosis and fibrinolysis by inhibiting not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). In the present study we examined the effects of human APC on tissue thromboplastin-induced disseminated intravascular coagulation (DIC) in rabbits and compared them with those of heparin. Both APC (300-3000 U/kg) and heparin (100-300 IU/kg) inhibited the decreases in platelet count and fibrinogen level equally. APC improved the prolonged bleeding time, but heparin aggravated bleeding with potent prolongation of activated partial thromboplastin time (APTT). Furthermore, in APC-treated animals, fibrin deposition in glomeruli was less than in heparin-treated animals. This result that APC accelerated local fibrinolysis by neutralizing PAI-1. From our findings, we concluded that APC can improve both coagulation and fibrinolysis in a DIC model and should be useful for the clinical remedy of DIC without having an adverse side effect like a bleeding tendency.

Topics: Animals; Bleeding Time; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Heparin; Humans; Kidney Glomerulus; Male; Partial Thromboplastin Time; Plasminogen Activator Inhibitor 1; Platelet Count; Protein C; Rabbits; Thrombolytic Therapy; Thromboplastin

To investigate the clinical significance of determination of plasma tissue factor (TF) antigen, we have developed a highly sensitive enzyme-linked immunosorbent assay (ELISA) for plasma TF, using two different monoclonal antibodies against TF apoprotein, 6B4 (catching antibody) and 5G9 (detecting antibody), and tetramethyl benzidine/H2O2 as substrates. Titration curves of recombinant human TF in buffer containing Triton X-100 were linear within the range from 50 to 2000 pg/ml. The total assay time was 3 h. Ultracentrifugation and immunoblot analysis indicated that human plasma and urine contained 50,000 g sedimentable and non-sedimentable forms of TF, both of which were detected by our ELISA method. Plasma and urine concentrations of TF in healthy subjects and patients with various diseases were measured by the ELISA method. In healthy subjects, plasma and urinary TF levels were found to be 149 +/- 72 pg/ml (n = 30) and 175 +/- 60 pg TF/urine creatinine mg (n = 95), respectively. TF was increased in plasma of patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, vasculitis associated with collagen diseases, diabetic microangiopathy and chronic renal failure receiving haemodialysis, but not in the plasma of endotoxaemic patients without DIC. The plasma TF/serum creatinine ratio did not show a positive correlation. Measurement of TF antigen in plasma may be useful for evaluating the endothelial damage and cell destruction in TF-containing tissues.

Topics: Adult; Aged; Blood Coagulation Disorders; Diabetes Mellitus; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Female; Hematologic Diseases; Humans; Immunoblotting; Male; Middle Aged; Purpura, Thrombotic Thrombocytopenic; Reference Standards; Thromboplastin; Ultracentrifugation; Vasculitis

The recent introduction of thromboplastin reagents with low international sensitivity index (ISI) values into the US market for the purpose of generating a more precise international normalized ratio than high ISI thromboplastins could has necessitated an evaluation of the impact of the low ISI reagents on prothrombin time (PT) testing in general. In this study, PT testing with three thromboplastin reagents, one of which (presently used in our laboratory) has an ISI of 2.10 and the other two ISI values of 0.92 and 1.06, respectively, was performed on normal individuals, on quality control reference plasma specimens and single-factor-deficient plasma specimens, and on patients with liver disease, intravascular coagulation, and receiving oral anticoagulant therapy. We found that PTs of normal individuals determined by all three thromboplastins were virtually identical. The thromboplastins with a low ISI generated much longer PTs on abnormal reference plasma specimens than did the high ISI product. Low ISI reagents also produced longer PTs in all three groups of patients. However, the degree of prolongation was far greater for patients receiving warfarin than for the other two groups of patients. Conversion of the PT to an international normalized ratio minimized the discrepancy seen in the PT ratio in patients receiving oral anticoagulants. The two low ISI thromboplastins did not produce near-identical values of PT, PT ratio, or international normalized ratio on plasma specimens obtained from patients who received warfarin therapy. The critical value set for PT with a high ISI thromboplastin would not be adequate if the reagent is to be replaced with a low ISI product.

Topics: Administration, Oral; Disseminated Intravascular Coagulation; Humans; Liver Diseases; Prothrombin Time; Quality Control; Reference Standards; Regression Analysis; Sensitivity and Specificity; Thromboplastin; Warfarin

Nafamostat mesilate (NM), a synthetic protease inhibitor, is frequently used for the treatment of disseminated intravascular coagulation (DIC) in Japan. NM inhibits several proteases which may be importantly involved in the pathophysiology of DIC. Since tissue factor (TF) plays a critical role in DIC associated with septicemia, inhibition of the extrinsic pathway of coagulation by coagulation inhibitors may be useful for the treatment of DIC. NM inhibited extrinsic pathway activity (TF-F.VIIa mediated-F.Xa generation) in a concentration dependent manner; the IC50 was 1.0 x 10(-7) M. F.Xa was not inhibited by NM at the concentrations used in the experiment, suggesting that NM might inhibit TF-F.VIIa complex activity. When incubated with TF-F.VIIa complex, NM inhibited the complex activity with an IC50 of 1.5 x 10(-7) M, the same value that found for inhibition of extrinsic pathway activity. A Lineweaver-Bulk's plot of the inhibition demonstrated that NM inhibited TF-F.VIIa complex in a competitive fashion, with an inhibition constant (Ki) of 2.0 x 10(-7) M. These findings suggested that NM may be a potent inhibitor of TF-F.VIIa complex and the therapeutic effect of NM in DIC patients could be partly explained by inhibition of the extrinsic pathway of the coagulation system.

Topics: Amino Acid Sequence; Benzamidines; Blood Coagulation; Disseminated Intravascular Coagulation; Factor VIIa; Guanidines; Humans; Molecular Sequence Data; Protease Inhibitors; Sepsis; Thromboplastin

Recently it has been shown that tissue factor (TF), an important trigger for initiating blood coagulation, is present in the circulating plasma. In order to assess the clinical implications of TF in plasma, plasma concentration of TF was quantitated in 65 patients with disseminated intravascular coagulation (DIC). The mean concentration of plasma TF was elevated in patients with DIC at presentation as compared with healthy subjects (446 +/- SD 536 pg/ml vs. 138 +/- 51 pg/ml, P < 0.001). Abnormally high levels were found only in 46.2% of the patients, predominantly in patients with non-hematological solid tumors and acute leukemia. Plasma TF did not correlate with hemostatic markers of DIC such as thrombin-antithrombin III complex, prothrombin fragment 1 + 2, plasma-alpha 2-plasmin inhibitor complex, FDP, D-dimer, or fibrinogen. Serial determinations of plasma TF demonstrated that plasma TF changes roughly in parallel with the course of DIC in most patients with elevated TF at presentation of DIC. These findings suggest that plasma TF is potentially valuable for monitoring the progress of DIC in a limited population of patients.

Topics: Disseminated Intravascular Coagulation; Female; Hemostasis; Humans; Middle Aged; Osmolar Concentration; Thromboplastin

We reported that recombinant human soluble thrombomodulin (rhs-TM) is effective for disseminated intravascular coagulation (DIC) in vivo, in mice and rats. In the present work, we investigated the effects of decreased plasma antithrombin III (ATIII) levels on anticoagulant effects of rhs-TM, as compared to findings with heparin, of which effect is lowered by the decreased plasma ATIII levels in patients with DIC. Rat plasma ATIII levels decreased when we mixed plasma with anti-rat ATIII antibody and the potential of heparin to prolong APTT or PT was markedly diminished. The potential of rhs-TM to prolong APTT and PT was not affected. In rats injected with anti-rat ATIII antibody, plasma ATIII levels decreased immediately. When the rats were infused with tissue factor (TF), DIC was induced. At doses of rhs-TM and heparin which were equally effective at inhibiting the decrease in platelet count and fibrinogen level in control rats treated with TF, only rhs-TM remained effective in preventing DIC in rats with reduced ATIII levels. Heparin was not effective when administered to these rats with reduced ATIII levels. Therefore, rhs-TM effectively inhibits coagulation independent of ATIII levels, in contrast to heparin, which depends on the ATIII level.

Topics: Animals; Anticoagulants; Antithrombin III; Antithrombin III Deficiency; Disseminated Intravascular Coagulation; Heparin; Humans; Immune Sera; Male; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thrombomodulin; Thromboplastin

In 43 patients with leukemia, we determined the increase of tissue factor (TF) activity production by leukemic cells that was induced by incubation with endotoxin at the time of admission. Definite disseminated intravascular coagulation (DIC) developed in 8 patients on admission (Group III) and in 8 patients just after the initiation of treatment (Group II), but not in the remaining 27 patients (Group I). TF activity before incubation (TF1) was 0.70 U/10(8) cells or more in 6 patients of Group III, while it was less in all the patients of Group II and 25 of the 27 patients of Group I. On the other hand, TF activity after incubation with endotoxin (TF2) increased to more than 1.11 U/10(8) cells in all the patients of Groups II and III, while it remained less in all the patients of Group I. These results suggest that the leukemic cells in Group II might not have expressed sufficient TF activity to cause DIC until chemotherapy was begun, and that 1.11 U/10(8) cells or more of TF2 might strongly indicate the development of DIC during treatment for leukemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cell Count; Disseminated Intravascular Coagulation; Endotoxins; Female; Humans; In Vitro Techniques; Leukemia; Male; Middle Aged; Risk Factors; Thromboplastin

This study demonstrated that intravenous infusion of recombinant human soluble thrombomodulin (rhs-TM) could inhibit disseminated intravascular coagulation (DIC) caused by 4 hr infusion of tissue factor (TF) in rats. Extended infusion of TF reduced fibrinogen and platelet counts and elevated serum FDP level. Pretreatment and coinfusion of rhs-TM could block changes of these DIC-parameters without prolongation of APTT. Heparin, which is a potent anti-DIC drug, could also inhibit these changes with extra prolongation of APTT and PT. Thus, these results suggest thrombomodulin prevent DIC less bleeding tendency than heparin.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Female; Fibronectins; Heparin; Infusions, Intravenous; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thrombomodulin; Thromboplastin

The plasma tissue factor (TF) antigen level was measured in patients with disseminated intravascular coagulation (DIC). The plasma TF antigen was detected in normal volunteers, and it was significantly higher in DIC patients than in non-DIC patients. However, in some patients with DIC, the plasma TF antigen level was within the normal range. The plasma TF antigen level in patients with DIC significantly decreased after therapy, but it was not correlated with organ failure or outcome. The plasma TF antigen level in patients with DIC was not correlated with other hemostatic markers. The plasma TF antigen level tended to be higher in DIC patients with nonlymphoid leukemia than in those with lymphoid tumor. TF might be implicated in the occurrence and progression of DIC.

Topics: Antigens; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Humans; Reference Values; Thromboplastin

We have evaluated the contribution of depression of individual procoagulant vitamin K-dependent clotting factors to the ability of warfarin to protect rabbits against tissue factor-induced coagulation. Mean activities of individual procoagulant factors were determined, in assays with rabbit substrates, for a group of rabbits achieving a protective degree of anticoagulation with warfarin. Values were: factor VII, 12%; factor IX, 7%; factor X, 14%, and prothrombin, 13%. The effect upon tissue factor-induced coagulation of selective immunodepletion of each factor to a comparable level was then evaluated. Immunodepletion of plasma factor X or prothrombin, but not of factor VII or factor IX, protected otherwise normal rabbits against tissue factor-induced coagulation. Next, we determined the effect upon the protection in warfarin-treated rabbits of selectively restoring factor X or prothrombin before infusing tissue factor. When either factor was selectively restored, warfarin's protective effect was abolished. Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Factor IX; Factor VII; Factor X; Female; Infusions, Intravenous; Protein Precursors; Prothrombin; Rabbits; Thromboplastin; Vitamin K; Warfarin

The possible involvement of platelet activating factor (PAF) in the pathogenesis of endotoxin-induced disseminated intravascular coagulation (DIC) was investigated in rats using a novel potent PAF antagonist, TCV-309. TCV-309 (> 1 mg/kg, i.v.) showed beneficial effects in rats with experimental DIC induced by a 4-hour sustained infusion of endotoxin (1 mg/kg) in a dose-dependent manner. TCV-309 (1 mg/kg) significantly ameliorated the decrease in platelet count and plasma fibrinogen, the prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) and the increase in fibrin and fibrinogen degradation products (FDP) and inhibited glomerular fibrin deposition. Furthermore, plasma tissue factor (TF) activity was greatly increased in the DIC rats, and this was also significantly decreased by TCV-309 (1 mg/kg). TCV-309 (1 mg/kg) did not affect these parameters in normal rats. A 4-hour sustained infusion of PAF (60 micrograms/kg) caused mild but significant changes in some DIC parameters such as PT, fibrinogen and FDP concentration and increased the plasma TF activity. TCV-309 (1 mg/kg) inhibited all these PAF-induced changes. TCV-309 (0.1 mM) itself had no direct in vitro effects on the blood coagulation system including TF activity. These results strongly suggest that PAF plays a role in the pathogenesis of endotoxin-induced DIC via the generation of TF. Prophylactic use of PAF antagonists may therefore be useful for the treatment of DIC with sepsis.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Isoquinolines; Male; Platelet Activating Factor; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Thromboplastin

Tissue factor activity of intact cell and cell lysate, and the presence of tissue factor antigen on cell surface, were examined in leukemic cells from patients with acute myelogenous leukemia (AML, M1-M5) or acute lymphoblastic leukemia (ALL-L1), and in mononuclear cells from normal donors. Leukemic cells from AML or ALL had significantly more tissue factor activity not only on intact cells but also in cell lysate than mononuclear cells from normal donors (p < 0.001). Tissue factor activities of the intact leukemic cells and lysate from AML patients with DIC were significantly higher than those without DIC (p < 0.001). The relationship between the percent of positive cells for tissue factor and the presence of DIC at the time of diagnosis of acute leukemia was observed. The patients with DIC showed the higher percentage of tissue factor-positive cells than those without (p < 0.01). The development of DIC following chemotherapy was recognized in 2 out of 7 AML-MI patients and 2 out of 4 ALL-L1 patients who had relatively high tissue factor activities of cell lysate. The release of tissue factor from cytoplasm induced by chemotherapy would be another mechanism for the development of DIC. The report suggests the possibility of the prediction for DIC by the flowcytometric assay of tissue factor antigen.

Topics: Antigens, Surface; Disseminated Intravascular Coagulation; Flow Cytometry; Humans; Leukemia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thromboplastin

Previous studies on recombinant human soluble thrombomodulin (rsTM) from Chinese hamster ovary cells revealed that rsTM was expressed as two proteins that differed functionally in vitro due to the presence (rsTM beta) or absence (rsTM alpha) of chondroitin-4-sulfate. The current study evaluates the in vivo behavior of rsTM in rats and in a rat model of tissue factor-induced disseminated intravascular coagulation (DIC). rsTM beta was more potent than rsTM alpha for prolongation of the activated partial thromboplastin time (APTT) and their in vivo half-lives determined by ELISA were 20 min for rsTM beta and 5.0 h for rsTM alpha. Injection of a tissue factor suspension (5 mg/kg) resulted in DIC as judged by decreased platelet counts and fibrinogen concentrations, prolonged APTT, and increased fibrin and fibrinogen degradation products (FDP) levels. A bolus injection of either rsTM (0.2 mg/kg) 1 min before induction of DIC essentially neutralized effects on platelets, fibrinogen, and FDP levels, and had only a moderate effect on APTT prolongation. The dose of anticoagulant to inhibit the drop in platelet counts by 50% (ED50) was 0.2 mg/kg rsTM alpha, 0.07 mg/kg rsTM beta, and 7 U/kg heparin. The effect of increasing concentrations of rsTM and heparin on bleeding times were compared in experiments involving incision of the rat tail. Doubling of the bleeding times occurred at 5 mg/kg rsTM alpha, 3 mg/kg rsTM beta or 90 U/kg heparin. These values represent a 25-fold increase over the ED50 for rsTM alpha, 43-fold for rsTM beta and 13-fold for heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Enzyme-Linked Immunosorbent Assay; Fibrinogen; Fibrinolysis; Glycosaminoglycans; Hemorrhage; Heparin; Male; Platelet Count; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Thrombin; Recombinant Proteins; Solubility; Thromboplastin

Tissue factor-like activity was measured in the plasma of 30 patients with disseminated intravascular coagulation(DIC) and 22 patients without DIC using a chromogenic substrate. Twenty-three of the 30 patients with DIC (77%) exhibited tissue factor-like activity levels above normal range (greater than 3.0 U/L), and in eleven of these patients, the levels were more than 10 U/L. Of the 22 patients without DIC, seven patients had elevated levels (3-10 U/L), and had a possibility to be developing DIC. So, we considered them to be in a pre-DIC state. No correlation was found between tissue factor-like activity and alpha 2 plasmin inhibitor-plasmin complex or FDP-D dimer. In a patient with acute monocytic leukemia, the elevated tissue factor-like activity (84.4 U/L) rapidly decreased after the initiation of chemotherapy, whereas in a patient with pancreatic cancer, the level remained elevated (67.4-79.2 U/L). These results suggested that the plasma tissue factor-like activity is differ from the other parameters reflecting the process of DIC and is a useful indicator of the presence of an initiating factor of blood coagulation in some selected patients with DIC or pre-DIC.

Topics: Adult; alpha-2-Antiplasmin; Antifibrinolytic Agents; Cerebral Infarction; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Humans; Leukemia, Monocytic, Acute; Male; Middle Aged; Pancreatic Neoplasms; Thromboplastin

Although in vitro experiments have established that extrinsic pathway inhibitor (EPI) is the only known plasma inhibitor of factor VIIa-tissue factor (TF) catalytic activity of potential physiologic significance, evidence of its function in vivo has been lacking. TF-induced intravascular coagulation may occur in patients despite normal plasma levels of EPI and, in our earlier studies, normal plasma EPI levels did not protect rabbits from intravascular coagulation induced by an infusion of purified TF (1 microgram/kg). Studies have now been carried out in which plasma EPI levels were reduced in rabbits to below 20% of the initial level by injection of anti-rabbit EPI IgG. Infusion into such animals of purified rabbit TF apoprotein (0.25 microgram/kg) reconstituted into phospholipid vesicles induced substantial disseminated intravascular coagulation. Infusion of control saline or phospholipid vesicles not containing TF was without significant effect as was infusion of TF (0.25 microgram/kg) into animals injected with nonimmune goat IgG. These data establish that EPI can dampen TF-induced intravascular coagulation in rabbits. They support the hypothesis that EPI plays a significant role in regulating coagulation resulting from the exposure of blood to trace concentrations of TF during the illnesses and minor injuries of normal existence.

Topics: Animals; Disseminated Intravascular Coagulation; Factor V; Factor VII; Factor VIII; Female; Fibrinogen; Immunoglobulin G; Kinetics; Lipoproteins; Protease Inhibitors; Rabbits; Thromboplastin

We have reported earlier that immunodepletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation (DIC) induced by infusing a low concentration of tissue factor (TF). We now describe the effect of immunodepletion of EPI in rabbits administered endotoxin. Cortisone-treated rabbits were administered anti-rabbit EPI immunoglobulin (IgG) or Fab fragments or were administered control nonimmune material before an injection of endotoxin. In four of seven rabbits administered anti-EPI, plasma EPI activity levels were reduced by 70% to 80% of initial levels for 6 to 8 hours. In these rabbits the endotoxin induced extensive DIC, as evidenced by substantial decreases in fibrinogen, factor V, factor VIII, and platelets, and gross hemorrhagic necrosis of the kidneys due to massive deposition of fibrin in the glomerular microcirculation (the generalized Shwartzman reaction). In three rabbits administered anti-EPI, plasma EPI levels were only transiently reduced. In these rabbits and in four rabbits administered nonimmune IgG or Fab, endotoxin induced minimal to moderate intravascular clotting and deposits of fibrin were not found in the glomerular capillaries. Because it is believed that TF expressed on monocytes triggers endotoxin-induced coagulation, these data are taken as evidence that EPI functions as a natural anticoagulant that can regulate factor VIIa/TF activity expressed on cell surfaces in vivo. They support a hypothesis that EPI prevents thrombotic complications that might otherwise result from exposure of blood to cytokine-induced generation of small amounts of TF on cell surfaces in many inflammatory and infectious disease states.

Topics: Animals; Disseminated Intravascular Coagulation; Endotoxins; Factor V; Factor VII; Factor VIII; Fibrinogen; Kidney; Lipoproteins; Necrosis; Rabbits; Thromboplastin

Using clotting assay and radioimmunoassay (RIA), tissue factor activity (TFA) and TF related antigen (TFR:AG) were determined in an extracellular culture medium of HL-60 cells. After 12 h incubation, TFA and TFR:AG in the medium with endotoxin (EDX: 1 microgram/ml) reached maximums which were 1.8 and 2.1 times greater than those in the medium without EDX, respectively. In the leukemic cells of 10 patients with acute nonlymphoid leukemia (ANLL), TFR:AG showed a significant correlation with TFA (p less than 0.01). On day 1 of the induction chemotherapy, TFR:AG in the 7 patients with DIC significantly increased to 288.9 +/- 153.1 ng/ml (p less than 0.01), whereas no increase in TFR:AG was recognized in the 3 patients without DIC. These results suggest that TF may be released from leukemic cells into the culture medium or blood stream, and that this may correlate with the development of DIC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Endotoxins; Humans; Leukemia, Myeloid, Acute; Mercaptopurine; Prednisolone; Thromboplastin; Tumor Cells, Cultured

Topics: Adult; Aged; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Neoplasms; Thromboplastin

Rabbits were given polyclonal anti-tissue factor (TF) immunoglobulin G (IgG) before an injection of endotoxin to test the hypothesis that TF triggers disseminated intravascular coagulation (DIC) after endotoxin. The rabbits had been prepared with cortisone to develop DIC after one injection of endotoxin. Anti-TF IgG substantially reduced the falls in fibrinogen, factors V and VIII, and platelets noted in control rabbits given preimmune IgG before endotoxin. At autopsy 24 hours later, fibrin was present in glomerular capillaries of 4 of 5 control rabbits, but in none of 11 rabbits given anti-TF IgG. DIC was also induced in a second group of rabbits by the infusion, over 4 hours, of 1 microgram/kg of purified, reconstituted rabbit brain TF. This resulted in striking falls in plasma fibrinogen, factors V, and VIII that were diminished, but not prevented by prior treatment with anti-TF IgG. Circulating activated factor VII, induced by either TF infusion or endotoxin, could not be detected after DIC. Mean plasma extrinsic pathway inhibitor (EPI) activity did not fall significantly after endotoxin, and only to about 65% of the preinfusion after infusion of TF. Thus, DIC induced by both agents proceeded despite nearly normal plasma EPI levels. Because EPI neutralizes factor VIIa/TF in vitro only after a short lag period, the DIC that persisted for up to 6 hours after injection of endotoxin suggests that TF activity continued to be generated during this period on cells to which the circulating blood was exposed. All animals given endotoxin became ill with cyanosis, tachypnea, cold ears, and diarrhea, regardless of whether they had received anti-TF IgG to attenuate DIC. Infusion of TF caused some animals to die acutely with pulmonary arterial thromboses, but surviving animals did not appear ill. The findings support the hypothesis that exposure of blood to TF triggers DIC after endotoxin, but is not important for the pathogenesis of endotoxin-induced shock.

Topics: Animals; Antibodies; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Endotoxins; Factor VII; Female; Fibrinogen; Immunoglobulin G; Kinetics; Lipoproteins; Protease Inhibitors; Rabbits; Thromboplastin; Time Factors

Tissue factor activity (TFA) of leukemic cells (1 x 10(8) cells/mL) was measured in 44 patients with acute nonlymphoid leukemia (ANLL) by the one-stage assay using factor-IX deficient plasma (OSA-dIX) and two-stage assay (TSA). According to the preventative heparin dose schedule based on the TFA measured by the TSA, all disseminated intravascular coagulation (DIC) was controlled successfully. The procedure of the TSA was too complicated for clinical use, and its minimal measurable value was 125 units (U)/L of TFA. The OSA-dIX was simpler in its procedure and sensitive enough to measure accurately a TFA quantity as small as 30 U/L with high reproducibility. In 20 ANLL patients with 125 U/L or more of TFA measured by both assays, there was a significant relationship between their logarithms of TFA (r = 0.93, P less than 0.01). These results suggested that DIC complication in ANLL patients would be controlled successfully by the administration of heparin dosage based on the TFA measured by the OSA-dIX.

Topics: Adult; Blood Coagulation; Blood Coagulation Tests; Bone Marrow; Disseminated Intravascular Coagulation; Factor IX; Female; Humans; Leukemia, Myeloid, Acute; Leukocytes; Male; Middle Aged; Reproducibility of Results; Thromboplastin; Tumor Cells, Cultured

A case is reported of a 60 year-old patient with chronic disseminated intravascular coagulation (DIC) which was increased by the therapeutic embolization of a renal tumour. The patient had 2 primary carcinomas (renal and prostatic) with vertebral metastases, severe chronic anaemia (due to haematuria), and chronic DIC, with thrombocytopaenia, soluble complexes, and fibrinogen and fibrin degradation products. Therapeutic embolization of the renal artery was carried out with fragments of dura mater. Although the result was anatomically very satisfactory, the patient's condition worsened, with continuing haematuria, and development of an haematoma in the lumbar fossa. Coagulation factors and antithrombin III (AT III) concentrations decreased, whereas the activated partial thromboplastin, thrombin and reptilase times increased. The patient also suffered from acute renal failure (creatinine: 690 mumol.l-1). Treatment consisted in fluid replacement, red blood cell and platelet transfusions, 150 IU.kg-1.d-1 heparin and 20 IU.kg-1.d-1 AT III. Haematological tests returned to pre-embolization values on the ninth day. The sudden worsening in the patient's condition was probably due to the sudden massive release of tissue thromboplastins related to the renal necrosis induced by the therapeutic embolization. The use of heparin AT III in the management of this patient is discussed.

Topics: Antithrombin III; Blood Coagulation Factors; Blood Platelets; Blood Transfusion; Chronic Disease; Disseminated Intravascular Coagulation; Embolization, Therapeutic; Hematuria; Heparin; Humans; Kidney Neoplasms; Male; Middle Aged; Renal Artery; Thromboplastin

Topics: Animals; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Protein C; Rats; Thromboplastin

Antithrombotic potency of recombinant hirudins rHV2, rHV2-Lys47 and rHV2-Arg47 was studied in a model of experimental thrombosis induced by tissue factor in the rat. Venous thrombosis was induced by i.v. injection of 25 mg/kg tissue factor followed by stasis of the inferior vena cava. In this model natural recombinant hirudins, rHV2 and rHV2-Lys47 injected 5 min before thrombo-plastin totally inhibited thrombosis in the same micrograms range as heparin or natural hirudin extracted from leeches. However, the mutant variant rHV2-Arg47 gave a maximal 60% inhibition of thrombosis. Variants rHV2-Lys47 (30 micrograms/kg) and rHV2-Arg47 (157 micrograms/kg) injected 5 min before thromboplastin prevented by 90 to 100% the drop in platelet count observed during the disseminated intravascular coagulation induced by thromboplastin injection. Recombinant hirudins were less anticoagulant than heparin as measured by an APTT on rat plasma. After rat tail transection, rHV2-Lys47 caused a 2-fold smaller prolongation of the bleeding time than an equivalent antithrombotic dose of heparin. Plasmatic elimination of rHV2-Lys47 from rat plasma after i.v. injection had a fast distribution phase with a half-life of 3 min during which 90% of injected rHV2-Lys47 was lost and was followed by a slower elimination phase. Thus recombinant hirudin rHV2-Lys47 appears as a promising potent antithrombotic agent for the prevention of thrombin-dependent venous thrombosis and disseminated intravascular coagulation.

Topics: Animals; Bleeding Time; Disseminated Intravascular Coagulation; Hirudin Therapy; Hirudins; Iodine Radioisotopes; Male; Rats; Rats, Inbred Strains; Recombinant Proteins; Thrombophlebitis; Thromboplastin

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Endotoxins; Escherichia coli; Humans; Lipopolysaccharides; Lymphocytes; Monocytes; Thromboplastin

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.

Topics: Antithrombin III; Disseminated Intravascular Coagulation; Endotoxins; Factor VII; Fibrinogen; Fibrinopeptide A; Humans; Lipopolysaccharides; Lipoproteins; Meningitis, Meningococcal; Meningococcal Infections; Multiple Organ Failure; Neisseria meningitidis; Protein C; Sepsis; Thromboplastin

Topics: Biological Assay; Disseminated Intravascular Coagulation; Humans; Kidney Diseases; Radioimmunoassay; Reference Values; Specimen Handling; Spectrophotometry; Thromboplastin

Topics: Chromogenic Compounds; Disseminated Intravascular Coagulation; Humans; Methods; Serum Globulins; Thromboplastin

This is a method for measuring tissue factor (TF, Factor III, tissue thromboplastin) activity in plasma by using a chromogenic substrate. As pretreatment, the euglobulin fraction of plasma was prepared by removing endogenous inhibitors and heated at 60 degrees C for 3 min to remove fibrinogen. This allowed us to measure the low TF activity in plasma that could not otherwise be measured. Neither phospholipids nor coagulation factors VII, IX, X, or Xa in the samples interfere. Within-run and day-to-day reproducibility were both good. The mean value obtained by this method for normal persons was 1.02 (SD 0.91) arbitrary units/L. A markedly high plasma TF activity of 20 arb. units/L or more was observed in patients with some types of disseminated intravascular coagulation.

Topics: Disseminated Intravascular Coagulation; Fibrinogen; Humans; Hydrogen-Ion Concentration; Oligopeptides; Specimen Handling; Thromboplastin

Plasma or serum extrinsic pathway inhibitor (EPI) activity was measured in 24 patients with disseminated intravascular coagulation (DIC) and in 23 patients with severe hepatocellular disease. EPI was measured as activity in a test sample that inhibited factor VIIa/tissue factor (TF)-catalyzed activation of 3H-factor IX (activation peptide release) in the presence of factor X. Of the 24 patients with DIC, 13 had sepsis and five had metastatic carcinoma, disorders in which tissue factor is believed to initiate DIC. EPI activity ranged from 68% to 300% (mean 134% +/- 50%). Serial measurements in nine patients failed to show depletion of EPI activity coincident with worsening DIC. DIC induced by tissue factor or other activating materials may progress despite normal EPI levels. In the patients with liver disease, of whom 15 had decompensated chronic hepatocellular disease (two fatal cases) and eight had acute fulminant liver failure (seven fatal cases), plasma or serum EPI activity varied from less than 20% to 194%. Values were distributed in a bimodal fashion. EPI activity could not be correlated with either the etiology of the liver disease or the degree of prolongation of the prothrombin time. Patients with chronic hepatocellular disease who survived had normal or elevated EPI activity. Patients with fatal hepatic dysfunction had low, normal, or high values for EPI activity. This must mean that secretion of EPI from cells other than hepatocytes can maintain normal plasma EPI levels.

Topics: Acinetobacter Infections; Adult; Chronic Disease; Disseminated Intravascular Coagulation; Factor VII; Factor VIIa; Female; Humans; Liver Diseases; Male; Mediastinitis; Middle Aged; Stomach Neoplasms; Thromboplastin

Topics: Androgen Antagonists; Disseminated Intravascular Coagulation; Humans; Male; Prostatic Neoplasms; Thromboplastin

Topics: Aged; Disseminated Intravascular Coagulation; Humans; Male; Stomach Neoplasms; Thromboplastin

Inhibition of Factor VIIa-tissue factor activity by a plasma component(s) that requires factor Xa has been described recently. In this communication, we have developed a specific radiometric assay (which utilizes 3H-Factor IX and is sensitive to less than 1% of plasma level) for this inhibitor and have measured its activity in various disease states. Strikingly, the levels of this inhibitor were found to be normal in patients with advanced chronic hepatocellular disease but low in patients with disseminated intravascular coagulation (DIC). When endotoxin was used to induce DIC in rabbits, the levels of this inhibitor fell by 25-90%. Human umbilical vein endothelial cells (HUVE), bovine pulmonary artery endothelial cells, and a human hepatoma cell line (HepG2) all synthesized and secreted this inhibitor, whereas a promyelocytic cell line (HL-60) did not and a monocytic cell line (U937) appears to synthesize only small amounts. When ammonium sulfate-fractionated human plasma and serum-free conditioned media from both HUVE and HepG2 cells were electrophoresed on sodium dodecyl sulfate acrylamide gels, two activity peaks corresponding to Mr approximately 45,000 and Mr approximately 33,000 were eluted in each case. These observations suggest that (a) the inhibitor is consumed in DIC and that (b) endothelial cells (or other cells) synthesize sufficient amounts of this inhibitor in vivo to compensate for any decreased production by liver cells.

Topics: Animals; Carcinoma, Hepatocellular; Cattle; Cells, Cultured; Chronic Disease; Disseminated Intravascular Coagulation; Factor VII; Factor VIIa; Humans; Infant, Newborn; Leukemia, Myeloid, Acute; Liver Diseases; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Pulmonary Artery; Rabbits; Thromboplastin; Umbilical Veins

Topics: Animals; Disseminated Intravascular Coagulation; Endotoxins; Female; Glycoproteins; Leukocytes; Rats; Thromboplastin; Trypsin Inhibitors

We examined the effect of a synthetic thrombin inhibitor, MCI-9038, on two experimental animal models of disseminated intravascular coagulation (DIC). In a model that DIC induced by the intravenous infusion of thrombin, MCI-9038 suppressed the decrease of platelet count by about 50% at a dose of 0.2 micrograms/kg/min and almost completely at 2 micrograms/kg/min. When MCI-9038 was administered orally, the suppressive effect was also observed. Heparin suppressed the platelet count decrease by about 50% at 1 unit/kg/min. In another model of DIC induced by lactic acid and tissue thromboplastin infusion, MCI-9038 prevented the decrease of platelet count and the consumption of coagulation factors. The suppression effect by about 50% on these changes was observed at a dose of 3.16 micrograms/kg/min. Thromboelastogram pattern indicating the consumption coagulopathy in control experiments was normalized by the MCI-9038 administration. Heparin suppressed the decrease of fibrinogen content as effectively as MCI-9038, but it was less effective on the platelet count decrease. From these results, it was concluded that MCI-9038 might be useful for the treatment of DIC.

Topics: Animals; Antithrombin III; Antithrombins; Arginine; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Fibrinogen; Heparin; Male; Partial Thromboplastin Time; Pipecolic Acids; Platelet Count; Rabbits; Sulfonamides; Thromboplastin

Rats were subjected to gram-negative septicemia induced by cecal perforation or were sham-operated. Thromboplastin values increased in blood monocytes (40-fold), peritoneal macrophages (115-fold) pleural macrophages (5-fold), splenic macrophages (3-fold), and lung alveolar macrophages (1.4-fold) in septic animals as compared to controls. In septic animals disseminated intravascular coagulation was evidenced by a significant (p less than 0.05) fall in fibrinogen, factor VII, X and platelets. A simultaneous and significant (p less than 0.05) decrease in thromboplastin content of tissue-specimens from lung and spleen was observed in rats with septicemia, whereas increased thromboplastin values were demonstrated in tissue-samples from cecum - the infectious focus. This might reflect mobilization of mononuclear phagocytes in favour of the site of infection.

Topics: Animals; Blood Coagulation Factors; Cell Movement; Disease Models, Animal; Disseminated Intravascular Coagulation; Gram-Negative Bacteria; Macrophages; Male; Monocytes; Peritoneal Cavity; Pleura; Pulmonary Alveoli; Rats; Rats, Inbred Strains; Sepsis; Spleen; Thromboplastin; Tissue Distribution

Tissue factor activity (TFA) of 10(8) leukemia cells was measured in 82 patients with acute nonlymphoid leukemia by the clotting method. The TFA bore a significant correlation to the development of disseminated intravascular coagulation (DIC) in these cases. Mean TFA value with standard deviation (SD) was 8.3 +/- 6.3 U in 48 cases with DIC, which was significantly higher than 0.3 +/- 4.2 U in 34 cases without DIC. Whereas Mean TFA in non-M3 was 0.9 +/- 6.3 U which was significantly lower than 37.2 +/- 2.3 U in M3, some non-M3 showed TFA as high as M3 and were complicated by DIC. In heparin treatment, dosage of heparin could not be controlled by either APTT or AcCT but was controlled by the extent of TFA of leukemia cells. Retrospective analysis of clinical features revealed that 97000X + 9000 units/day (X = logarithm value of TFA) of heparin is an adequate dosage for the successful treatment of DIC when TFA of leukemia cells is 0.8 U or more.

Topics: Adolescent; Adult; Aged; Antigens; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Leukemia; Male; Middle Aged; Retrospective Studies; Thromboplastin

Three cases of abnormal bleeding during suboccipital excision of large acoustic neuroma are reported. The possible role of limited operative intravascular coagulation is discussed.

Topics: Arteries; Cerebellum; Disseminated Intravascular Coagulation; Female; Humans; Intraoperative Complications; Male; Methods; Middle Aged; Neuroma, Acoustic; Thromboplastin

The apoprotein (AP) of tissue factor (TF) has been purified 72,000-fold to homogeneity from human placenta using acetone delipidation, sodium deoxycholate (DOC) extraction, Sephacryl S-300 column chromatography, preparative polyacrylamide-gel electrophoresis (PAGE) in DOC and tryptic digestion. The purified AP had an apparent molecular weight of 54,000 by sodium dodecyl sulfate/PAGE. A radioimmunoassay (RIA) for quantitation of the TF-AP using an antibody against this purified AP of TF was devised which was sensitive enough to measure as small a quantity as 100 pg/ml of TF-AP accurately with high reproducibility. In addition to TF clotting activity (TFA), the immunoreactive TF-AP (IR-TFR) in the homogenates of leukemic leukocytes from patients with acute non-lymphoid leukemia (ANLL) was determined using this RIA. In 30 patients with ANLL, the mean IR-TFR with standard deviation (SD) of 21 cases with DIC was 157.9 +/- 188.1 ng/10(8) cells, which was significantly higher than that (37.1 +/- 29.9 ng/10(8) cells) of 9 cases with no DIC during remission induction chemotherapy (p less than 0.01).

Topics: Apoproteins; Disseminated Intravascular Coagulation; Female; Humans; Leukemia; Molecular Weight; Placenta; Pregnancy; Radioimmunoassay; Thromboplastin

The possibility of prevention of intravascular blood coagulation in rats by DIP-alpha-thrombin devoid of proteolytic activity and capable of stimulating the reaction of anticoagulation system was studied. The injection of lethal thromboplastin dose was shown to produce a sharp increase in soluble fibrin blood content, total disappearance of fibrinolytic activity and intravascular blood coagulation. The animals died of thrombosis in 90% of cases. It was established that the injection of lethal thromboplastin dose 5 min after DIP-alpha-thrombin injection caused a 13% lethality from thrombosis. No reliable changes in fibrinolytic activity and soluble fibrin content were observed. A significant increase in thrombin and recalcification time was recorded. It is suggested that DIP-alpha-thrombin prevents intravascular blood coagulation induced by lethal thromboplastin dose due to mobilization of the reserve capacities of neuro-humoral anticoagulation system.

Topics: Animals; Disseminated Intravascular Coagulation; Male; Rats; Thrombin; Thromboplastin

Intravenous injection of homologous lung or brain tissue thromboplastin in dogs under general anesthesia induced changes of conventional hemostasis variables consistent with acute DIC (prolongation of prothrombin times, thrombin times, APTT, drop of fibrinogen and a transient reduction of the platelet count). The animals reacted with accelerated respiration and pulse rates. After recovery from anesthesia they resumed their normal activity as before. Fibrinogen reached a minimum within 40 min after the DIC trigger dose had been injected. Dependent on the size of the latter up to 80% of clottable fibrinogen was consumed. No consumption of antithrombin III and heparin cofactor II could be demonstrated by functional assays based on thrombin inhibition by diluted plasma in the presence of heparin or dermatan sulfate. Prothrombin measured amidolytically by an Echis Carinatus venom assay remained practically unchanged. These findings are consistent with free thrombin concentrations in the nanomolar range sufficient to clot fibrinogen rapidly without visibly affecting the up to 1,000 fold higher concentrations of inhibitors and prothrombin. Heparin administered before tissue thromboplastin virtually suppressed the evolution of DIC but its protective effect was overcome by higher trigger doses. Heparin injected after the induction of DIC had no protective effect. The reversible DIC model in dogs may be a promising tool to study activated coagulation in vivo at practically constant inhibitor concentrations. One dog can be used for several acute experiments with homologous tissue thromboplastin, thus the number of animals and their costs may remain within reasonable limits.

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Dogs; Fibrinogen; Heparin; Platelet Count; Thromboplastin; Time Factors

Disseminated intravascular coagulation (DIC) is a frequent occurrence in acute promyelocytic leukemia (APL), especially after onset of chemotherapy. We have used a human promyelocytic leukemic established cell line (HL-60) and various other human leukemic cells to investigate the effect of cytotoxic drugs on generation of procoagulant activity (PCA). The results indicate that, unlike normal human peripheral blood monocytes and certain other cell types where PCA induction requires active mRNA and protein synthesis, in HL-60 cells, compounds such as actinomycin D, puromycin, and cytosine arabinoside and a variety of other cytotoxic agents, induced generation of a potent PCA. Although different in its mechanism of induction, this HL-60 cell PCA was similar, and may be identical, to mononuclear cell tissue factor. The PCA induction was rapid and preceded the lytic effect of the drugs. It was first detected on the outer cell surface but, following prolonged exposure to the drugs, upon lysis of the cells, it was also found in the extracellular medium. This in vitro effect mimics the development of DIC in patients with APL. The system may, therefore, serve as a model for the study of the cellular and molecular events associated with PCA generation by malignant promyelocytes and DIC occurrence in patients with APL and other malignancies.

Topics: Antimetabolites; Antimetabolites, Antineoplastic; Cell Line; Dactinomycin; Disseminated Intravascular Coagulation; Granulocytes; Humans; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Puromycin; Thromboplastin

Tissue thromboplastin generation in monocytes was studied during various stages of Escherichia coli endotoxinaemia in pigs. The pigs were monitored in halothane anaesthesia and mechanically ventilated. Blood was sampled from the superior caval vein before and during endotoxin infusion and up to 6 hours after its start. Monnuclear leukocytes were harvested with Lymphoprep separation and monocyte counts were made, using TRITC-labelled sheep erythrocytes, acridine orange and a fluorescence microscope. Thromboplastin was quantified in a two-stage assay by incubating the test sample together with purified factor X, factor VII and Ca++. The generated factor Xa was thereafter assayed. There was statistically significant increase of tissue thromboplastin activity in monocytes after endotoxin infusion. Maximum level was reached at the end of the infusion and was maintained throughout the observation period. Decrease occurred in platelets, leukocytes, antithrombin III, fibrinogen and clotting factors V, VII and VIII, and clotting time was prolonged. These findings indicated significant disseminated intravascular coagulation. The endotoxin-stimulated monocytes with their elevated tissue thrombo-plastin activity thus may play an important part in development of the DIC which so often follows septicemia.

Topics: Animals; Antithrombin III; Blood Pressure; Disseminated Intravascular Coagulation; Endotoxins; Escherichia coli Infections; Factor V; Factor VII; Factor VIII; Female; Fibrinogen; Leukocyte Count; Male; Monocytes; Platelet Count; Prothrombin Time; Swine; Thromboplastin

The procoagulant cellular activity (PCA) of intact and lysed leukaemic cells was evaluated at diagnosis in 23 patients with acute non-lymphoid leukaemia (ANLL). The leukaemic cells of all 13 patients having DIC feature (excess of fibrin monomers, serum FDP and plasma fibrino-peptide A) showed a significant (P less than 0.0001) increase of PCA, while a pattern similar to that of normal granulocytes and lymphomonocytes was observed in the remaining 10 patients without evidence of DIC. When the patients were subdivided according to the FAB cytological classification, features of DIC and increased PCA were demonstrated in 3/3 M3 patients, 5/6 M5 patients and only in 5/14 remaining patients. These findings indicate that in ANLL patients: (1) the increased PCA of leukaemic cells is closely related to the occurrence of DIC; (2) the increased PCA seems related to the differentiation line and maturation level of the leukaemic cells.

Topics: Acute Disease; Adolescent; Adult; Aged; Blood Coagulation Tests; Bone Marrow; Disseminated Intravascular Coagulation; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Leukemia; Lymphocytes; Male; Middle Aged; Monocytes; Thromboplastin

Monozygotic twinning has been associated with a variety of vascular disruptive defects including congenital hydranencephaly/porencephaly. Data involving 24 cases of congenital hydranencephaly/porencephaly associated with twinning are reported. In these cases, the finding of a preponderance of monozygotic twins and the common association of a deceased co-twin support the hypothesis of a vascular disruptive etiology. These defects are presumed to be secondary to embolic phenomena or thromboplastin release from the deceased co-twin to the survivor via the vascular interconnections of a conjoined monochorionic placenta. In all cases of hydranencephaly/porencephaly, a careful examination of the placenta and membranes for evidence of a deceased co-twin is warranted prior to providing recurrence risk counseling.

Topics: Anencephaly; Brain; Diseases in Twins; Disseminated Intravascular Coagulation; Embolism; Female; Fetal Death; Humans; Hydranencephaly; Infant, Newborn; Male; Placenta; Pregnancy; Thromboplastin; Twins; Twins, Monozygotic

Topics: Antibodies; Aspirin; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Cell Adhesion; Cell Communication; Cyclooxygenase Inhibitors; Disseminated Intravascular Coagulation; Epoprostenol; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinopeptide A; Humans; Indomethacin; Monocytes; Neoplasm Transplantation; Neoplasms; Syndrome; Thrombocytopenia; Thrombocytosis; Thromboembolism; Thromboplastin

Topics: Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Kidney Glomerulus; Male; Nephritis; Rats; Rats, Inbred Strains; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Dogs; Heparin; Thromboplastin

Procoagulant activity of gastric cancer tissues and leukocytes obtained from various types of leukemia have been studied with special reference to TTP. The following results were obtained. Homogenates of APL leukocytes and gastric cancer tissues contained strong procoagulant activities, most of which have been identified as TTP since the activities were neutralized by a specific antibody against purified human placenta TTP, inactivated by the removal of phospholipid with heptane-butanol mixture, and inactivated by the addition of phospholipase C. The delipidated homogenates regained procoagulant activities by relipidation procedures. These results also confirmed that TTP from APL leukocytes and gastric cancer tissues have the same lipoprotein properties as those of TTP in normal tissues. Though slight proteolytic activity and fibrinolytic activity were demonstrated in the homogenate of gastric cancer tissues, it was noted that the TTP activity was different from these two activities by partial purification of TTP from gastric cancer tissues. The TTP activity of 9 homogenates of gastric cancer tissues was 301 +/- 289 (mean +/- SD) units per mg protein, being higher in homogenates of mucinous adenocarcinoma and signet-ring cell carcinoma than in those of tubular and poorly differentiated adenocarcinoma. The mean TTP activity of leukocyte homogenates from 14 patients with APL and one out of 4 patients with CML in blastic crisis was 81 +/- 76 units/10(7) cells. The TTP activity of the homogenates of leukocytes from 7 out of 18 patients with AML and another patient with CML in blastic crisis ranged from one to six units/10(7) cells with a mean of 3.3 +/- 1.2. The TTP activity of leukocyte homogenates from the other 11 cases of AML, two cases of CML in blastic crisis, 6 cases of CML, and one case each of ALL and CLL were less than one unit/10(7) cells. In leukemic patients, all cases with a value of more than 202 for the product of units of TTP activity per 10(7) cells and differential count (%) of leukemic cells in the bone marrow smear (MU value) were accompanied by DIC. The MU value of leukemic patients correlated well to the plasma fibrinogen and serum FDP levels. All patients with a MU value of more than 277 died of DIC when a sufficient amount of heparin was not administered. On the other hand, no DIC developed in any of the patients with a MU value of less than 90.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Gastric Mucosa; Humans; Leukemia; Leukocytes; Stomach Neoplasms; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Factor V; Factor VIII; Injections, Intravenous; Oxygen; Phospholipases; Platelet Aggregation; Platelet Count; Pulmonary Gas Exchange; Sheep; Thromboplastin; Type C Phospholipases

Relapsing fever caused by Borrelia spirochetes is characterized by episodes of spirochetemia, fever, and DIC. We examined the ability of Borrelia hermsii to induce production of leukocytic pyrogen and thromboplastin from human blood leukocytes in vitro. Organisms were found devoid of endotoxin by the Limulus assay. Human peripheral blood leukocytes were separated into MNC and PMN fractions and were incubated with two to five spirochetes per cell in 10% human serum. Supernatant fluids from MNC-spirochete mixtures produced mean increases in the temperature of rabbits of 0.80 degree to 1.35 degrees C, which were significantly higher than those caused by supernatant fluids of MNC or spirochetes alone (p less than 0.05). MNC-spirochete mixtures possessed seven to 15 times the thromboplastic activity of MNC suspensions alone, assayed with a modified one-stage prothrombin time. Supernatant fluids of PMNs and spirochetes, on the other hand, did not contain leukocytic pyrogen, and PMN suspensions did not produce thromboplastin. Cycloheximide (10 micrograms/ml), and inhibitor of protein synthesis, completely suppressed both pyrogen and thromboplastin production. Although intracellular spirochetes were observed within phagosomes of blood monocytes by electron microscopy, the production of leukocytic pyrogen and thromboplastin was not significantly altered by serum opsonins or by the inhibitors of phagocytosis cytochalasin B (5 micrograms/ml) or phenylbutazone (2 mg/ml). These results showed that Borrelia spirochetes stimulated human MNCs to produce increased amounts of leukocytic pyrogen and thromboplastin and that this stimulation required de novo synthesis of protein, was not mediated by endotoxin, and was not prevented by omitting opsonic proteins or by inhibiting phagocytosis.

Topics: Borrelia; Disseminated Intravascular Coagulation; Endotoxins; Humans; In Vitro Techniques; Leukocytes; Monocytes; Neutrophils; Phagocytosis; Pyrogens; Relapsing Fever; Thromboplastin

The impact of blood coagulation caused by endotoxins (ET) is reported in a survey. In this connection the activation of factor XII by ET and the activation of the intrinsic system of coagulation due to it are discussed, the mechanism of blood platelet damage with subsequent thrombocytopenia is dealt with, and the induction for liberating of a thromboplastin-like procoagulant from leukocytes as well as the factors influencing this liberation are described. Furthermore, the mechanisms leading to the damage of the endothelia cell are discussed and the correlations to the complement system are described. On the basis of facts known up till now special attention is devoted to the role of the thromboplastin-like procoagulant and the activation of the extrinsic system caused by it in developing a DIC syndrome.

Topics: Blood Coagulation; Blood Platelets; Blood Vessels; Complement Activation; Disseminated Intravascular Coagulation; Endothelium; Endotoxins; Factor VII; Factor XII; Humans; Leukocytes; Thromboplastin

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Endopeptidases; Factor X; Factor Xa; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hemorrhage; Humans; Male; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Thromboembolism; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Blood Vessels; Disseminated Intravascular Coagulation; Endotoxins; Factor VII; Hemolysis; Humans; Leukocytes; Thromboplastin

Topics: Aged; Disseminated Intravascular Coagulation; Female; Humans; Male; Middle Aged; Myocardial Infarction; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Humans; Leukocytes; Thromboplastin

A patient undergoing subtotal pancreatectomy and intraportal islet tissue autotransplantation for chronic pancreatitis developed severe portal hypertension (49 cm of H(2)O) and acute disseminated intravascular coagulation (DIC). In an attempt to identify the cause of these problems, portal pressure and the activities of the coagulation and fibrinolytic systems were studied in dogs undergoing intraportal autotransplantation of islet tissue. Following intraportal injection of the pancreatic tissue in five control dogs, the portal pressure rose to a maximum of 43.2 cm of H(2)O +/- 2.4 and major coagulation abnormalities occurred. The mean hematocrit value fell to 18% +/- 8.6, the mean platelet count to 218,000 +/- 31,000, the mean plasma fibrinogen to 40 mg/dl +/- 18, and the mean euglobulin clot lysis time (ECLT) to 25 min +/- 4. Partial thromboplastin time (PTT) became prolonged (233 secs +/- 30) and significant quantities of fibrinogen-fibrin degradation products (FDP-fdp) (1:128 +/- 32) appeared. These changes indicate the development of DIC probably secondary to significant amounts of tissue thromboplastin detected in the tissue homogenate infused at time of autotransplantation. In a group of seven dogs in whom heparin and Trasylol (aprotinin) were added to the pancreatic tissue at the time of transplantation, portal pressure rose only to a peak of 28.3 cm of H(2)O +/- 3.6 and no significant abnormalities occurred in mean hematocrit value, plasma fibrinogen, platelet count or ECLT. Minor prolongation of PTT occurred secondary to the activity of heparin. FDP-fdp (1:16) were present transiently during tissue injection. Four patients in whom heparin and Trasylol were added to the pancreatic tissue at the time of autotransplantation developed only minor elevations of portal pressure (mean 15.5 cm of H(2)O) without intravascular coagulopathy.

Topics: Animals; Blood Coagulation Tests; Blood Pressure; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Female; Humans; Hypertension, Portal; Islets of Langerhans Transplantation; Liver; Male; Pancreas; Pancreatectomy; Pancreatitis; Postoperative Complications; Thromboplastin; Transplantation, Autologous

A case is described of acute defibrination following blunt head injury in a patient with a Spitz-Holter drain. The cause of the disseminated intravascular coagulation is thought to be due to brain thromboplastins entering the systemic circulation through the Spitz-Holter drain, thus bypassing the blood-brain barrier.

Topics: Accidents, Traffic; Adolescent; Afibrinogenemia; Brain Injuries; Cerebrospinal Fluid Shunts; Disseminated Intravascular Coagulation; Female; Humans; Thromboplastin; Wounds, Nonpenetrating

The inhibitory effects of a newly synthesized protease inhibitor, Gabexate mesilate (FOY), on experimental disseminated intravascular coagulation were studied as compared with those of aprotinin or heparin. Thrombin, tissue thromboplastin, and endotoxin were used as DIC trigger substances. As parameters on DIC, platelet counts, white blood cell counts, neutrophilic leukocyte counts, fibrinogen, fibrin degradation products, platelet retention, platelet aggregation, prothrombin time, partial thromboplastin time were served. The drug efficacy in each parameter were expressed by the score system and analyzed statistically. The results were summarized as follows; (1) In thrombin-induced DIC, FOY was apparently superior to the other drugs (p less than 0.05). (2) In thromboplastin-induced DIC, heparin was slightly more effective than FOY or aprotinin. (3) In endotoxin infusion, there were no significant differences among them. In conclusion, the results of the present study suggest that FOY was more effective than heparin or aprotinin on experimental DIC.

Topics: Animals; Aprotinin; Blood Platelets; Disseminated Intravascular Coagulation; Endotoxins; Fibrinogen; Guanidines; Heparin; Male; Mesylates; Platelet Aggregation; Protease Inhibitors; Rabbits; Thrombin; Thromboplastin

Coagulation data were collected before and after peritoneovenous shunting for intractable ascites in 19 shunting procedures. After insertion of the shunts, changes consistent with disseminated intravascular coagulation developed in all cases in which good flow of ascitic fluid was obtained. In cases with temporary shunt function, the coagulation variables suggestive of disseminated intravascular coagulation returned toward normal when the flow of ascitic fluid ceased. A fall in the level of fibrinogen degradation products indicated that the shunt had clotted. Bleeding attributable to disseminated intravascular coagulation alone was uncommon. Clotting of the shunts was frequent. The use of heparin improved some of the coagulation variables but did not prevent shunt clotting or clinical bleeding. We conclude that the peritoneovenous shunt induces a moderate disseminated intravascular coagulation and that measurement of fibrinogen degradation products is useful in assessing shunt function.

Topics: Adult; Aged; Ascites; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Peritoneal Cavity; Postoperative Complications; Prothrombin Time; Thromboplastin; Vena Cava, Superior

The effects of slow temporary infusion of a tissue thromboplastin solution into the superior vena cava on pulmonary as well as circulating megakaryocytes were studied in 40 rabbits (2-48 hours after infusion) and related to 6 noninfused and 7 infused with normal saline. This is a simple and specific method of inducing a fall in blood platelet levels and thereby an activation of thrombocytopoiesis and megakaryocytopoiesis. The induced intravascular coagulation is probably counterbalanced by an activated fibrinolysis allowing the animals to survive the infusion and thereby offering the possibility of studying the long-term effects. An increase to about 300% of the normal values in circulating as well as pulmonary megakaryocytes was found 20 and 24 hours after the onset of the infusions respectively. The number of circulating and pulmonary megakaryocytes, showing great individual variations, however, dropped to normal levels within 28 hours after onset of the infusions, which means that megakaryocytes remain detectable for less than eight hours in the lungs. No increase was found in pulmonary megakaryocytes in the control (saline infused) group. In our opinion the entrance of megakaryocytes from the bone marrow into the blood circulation in an incidental event, the number in the circulation reflecting the activity of megakarycocytopoiesis. This experiment supports our suggestion that intravascular coagulation is one of the major pathophysiological mechanisms leading to an increase in pulmonary megakaryocytes.

Topics: Animals; Blood Cell Count; Blood Platelets; Disseminated Intravascular Coagulation; Fibrinogen; Infusions, Parenteral; Lung; Male; Megakaryocytes; Pulmonary Embolism; Rabbits; Sodium Chloride; Thromboplastin

Topics: Animals; Blood Coagulation; Cattle; Disseminated Intravascular Coagulation; Ellagic Acid; Factor IX; Factor X; Fibrin; Humans; Lung; Male; Rabbits; Thrombin; Thrombophlebitis; Thromboplastin

The hemostasis function was studied in 33 patients with epileptical seizures of a different etiology. The studies were conducted at the moment of the epileptical seizure or epileptical status and in the interattack period during hyperventilation. The concentration of products of blood fibrinogen degradation, the degree of platelet agregation, their number and prothrombine index were estimated. The data obtained were compared with those of normals. The results of the studies indicate the existence of the syndrome of intravascular coagulation during an epileptical seizure and epileptical status.

Topics: Blood Cell Count; Blood Platelets; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Epilepsy; Fibrin Fibrinogen Degradation Products; Humans; Intracranial Embolism and Thrombosis; Male; Platelet Aggregation; Status Epilepticus; Thromboplastin

The laboratory pattern of intravascular coagulation is the result of complex mechanisms. The accelerated disappearance of substrates may be partially or completely compensated by increased production, depending on the integrity of liver and bone marrow. Ischemic complications are to be expected almost exclusively in acute cases, because of efficient mechanisms for the elimination of fibrin and other products. The typical laboratory pattern may be produced by loss of plasma from the circulation and extravasal proteolysis of the coagulation substrates. Chronic intravascular coagulation may be compensated, with resultant hyper-coagulability and increased risk of thromboembolic complications.

Topics: Anticoagulants; Blood Coagulation Factors; Collagen; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Fibrin Fibrinogen Degradation Products; Humans; Plasminogen; Thromboplastin

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; Leukocytes; Plasminogen Activators; Platelet Aggregation; Thromboplastin

When 125I-labeled canine prothrombin was given to normal adult dogs intravenously, it was calculated that 240% of the plasma prothrombin crossed the capillary barrier per day, 410% of the interstitial prothrombin returned to the blood stream daily, and 79% of the plasmatic prothrombin was catabolized per day. These data are in close agreement with those observed for bovine prothrombin in calves by Takeda (1970). When derived from normal dog prothrombin, prethrombin-1 is a mixture of 2 polypeptides, one larger than the other, and both present in about equal amounts. The longer peptide, "prethrombin-1-long," was catabolized twice as fast as prothrombin, and the shorter, "prethrombin-1-short," 4 times faster. Prothrombin fragment-1 was catabolized by the normal dog still more rapidly. The catabolism of prothrombin was not accelerated in 3 dogs receiving continuous infusions of a thromboplastic emulsion of dog brain. Nor was the level of prothrombin in their plasma remarkably altered.

Topics: Afibrinogenemia; Animals; Chromatography, Gel; Disseminated Intravascular Coagulation; Dogs; Iodine Radioisotopes; Kinetics; Prothrombin; Thrombocytopenia; Thromboplastin; Trichloroacetic Acid

Topics: Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Endotoxins; Factor XII; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Leukocytes; Peptide Hydrolases; Prothrombin; Thrombin; Thromboplastin

Disseminated intravascular coagulation was induced in dogs by infusion of tissue thrombokinase. Its course was followed by coagulation tests, determination of the rate of microthrombosis, and measurement of organ functions and oxygen consumption. The therapeutic result of streptokinase administration at an early stage of pathological changes is demonstrated by improvement of the disturbed organ functions and oxygen supply as well as by the decrease in plasma-haemoglobin level. When streptokinase was administered at an advanced stage of organ damages, they remained irreversible, although repatency of the microvasculature had been reached.

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Dogs; Fibrin; Fibrinogen; Kinetics; Oxygen Consumption; Streptokinase; Thromboplastin

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Female; Humans; Hypoxia; Pregnancy; Pregnancy Complications; Puerperal Disorders; Thromboplastin; Toxins, Biological

Topics: Blood Platelets; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Female; Fibrin Fibrinogen Degradation Products; Humans; Pre-Eclampsia; Pregnancy; Protamines; Prothrombin; Thrombin; Thromboplastin

Lysates of leukocytes of healthy persons and of patients with acute and chronic leukemias possess a weak tissue factor activity. This procoagulant activity is increased greatly when leukocytes are stimulated by endotoxin. The tissue factor is derived almost exclusively from the monocytes and not from lymphocytes and granulocytes. Monocytes are stimulated to the same extent by adherence to plastic surfaces. The fibrinolytic activity of lysates of mixed leukocytes is due to a nonspecific protease and a plasminogen activator. Only granulocytes can cause fibrinolyses. Endotoxin stimulation enhances the plasminogen activator but not the protease. Normal leukocytes and leukocytes of patients with chronic leukemias also exert an antithrombin activity.

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxins; Fibrinolysis; Humans; Leukemia; Leukocytes; Monocytes; Thrombin; Thromboplastin

This is an investigation into thromboplastin time, partial thromboplastin time, plasma thrombin time, fibrinogen, and platelets in 30 patients with severe brain injury over 7--14 days. Platelets showed a very marked initial decrease and a slow return to normal around the seventh day. Fibrinogen was initially lowered in most of the cases, and raised from the second day onward. Changes in the other laboratory values were less definite. Latent signs of consumption coagulopathy were not accompanied by bleeding disorders, or by disseminated intravascular coagulation at autopsy. The severity of laboratory value changes clearly correlated with the extent of brain damage, and was significantly higher when the patient did not survive the first week after injury.

Topics: Blood Cell Count; Blood Coagulation; Blood Platelets; Brain Injuries; Disseminated Intravascular Coagulation; Female; Fibrinogen; Humans; Male; Protease Inhibitors; Skull; Thrombin; Thromboplastin

Topics: Aged; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Male; Prostatic Neoplasms; Shock, Cardiogenic; Thrombocytopenia; Thromboplastin

Topics: Blood Coagulation Tests; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Thrombin; Thromboplastin

Autoprothrombin II-A anticoagulant was isolated from bovine prothrombin. Purified prothrombin was applied to DEAE-cellulose chromatography after incubation with thrombin. Four protein peaks were obtained where the third peak corresponded to the anti-coagulant effect. The fractions under the third peak were pooled together and the anticoagulant effect was evaluated with different methods. From 25,470 +/- 2,800 U of prothrombin, 5,800 +/- 1,400 U of inhibitor were obtained. The inhibitor was found to be most effective at pH 7.2--7.8. In vitro, the inhibitor inhibited the thrombin time and the plasma clotting time highly significantly but had no effect on euglobulin lysis time and fibrin plates. In vivo, when injected into rabbits, the inhibitor effect was also significant on the same tests. The autoprothombin II-A anticoagulant had a protective effect on DIC formation with rabbit brain thromboplastin administration. This protective effect was found to be statistically significant.

Topics: Animals; Anticoagulants; Blood Coagulation; Cattle; Disseminated Intravascular Coagulation; Factor IX; Prothrombin; Prothrombin Time; Rabbits; Thromboplastin

When an emulsion of dog brain thromboplastin was infused continuously into dogs for 1--4 weeks only platelets and factor XI were consistently depressed. The remaining clotting factors fell in a dose-dependent fashion but there was a tendency toward recovery despite continued infusion of thromboplastin. Fibrinogen and factor V were unique in that with weaker emulsions of thromboplastin, they often rose without a preliminary fall.

Topics: Animals; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Factor VIII; Fibrinogen; Heparin; Platelet Factor 4; Prothrombin; Thromboplastin

Topics: Adenocarcinoma; Adult; Aged; Animals; Blood Coagulation; Carcinoma; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Male; Middle Aged; Prothrombin; Rabbits; Stomach Neoplasms; Thrombin; Thromboplastin

Topics: Adult; Animals; Blood Coagulation; Brain; Brain Injuries; Brain Mapping; Cerebral Ventricle Neoplasms; Disseminated Intravascular Coagulation; Dogs; Factor VIII; Female; Humans; Oligodendroglioma; Postoperative Complications; Thromboplastin

This discussion has outlined several simple and reliable test systems which have been found useful in assessing disorders of hemostasis in the hemorrhaging CPB patient. When these tests are utilized as described in the preceding article, they have been extremely helpful in studying hemostasis in the CPB patient to be reexplored; they are equally helpful to quickly render a differential diagnosis of altered hemostasis when hemorrhage occurs. In addition, several "special" procedures, the AT-III and heparin assays, have been reviewed; these have been found quite useful in special instances of CPB hemorrhage, and community cardiovascular teams may wish them to be available. This paper has not presumed to be "authoritative" with respect to the "best" tests for assessing CPB hemostasis, but rather has offered only an approach helpful to the authors. The intent has, however, been to provide guidelines for instituting simple, reliable, and workable procedures for the community hospital where CPB is now routinely performed.

Topics: Antithrombins; Blood Coagulation Factors; Blood Coagulation Tests; Cardiopulmonary Bypass; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Fibrinolysin; Fibrinolysis; Hemorrhage; Hemostasis; Heparin; Humans; Plasminogen; Protamines; Thrombin; Thromboplastin

The possible association between acute respiratory failure and disseminated intravascular coagulation was examined in eight patients with severe acute respiratory failure--a condition characterized by tachypnea, right to left intrapulmonary shunting of blood greater than 30 per cent of cardiac output, increased pulmonary artery pressure with low or normal pulmonary artery wedge pressure and roentgenologic interstitial pulmonary edema. Treatment consisted of mechanical ventilation with positive end expiratory pressure sufficient to minimize intrapulmonary shunting. There was no abnormality in platelet concentration fibrin split product concentration, fibrinogen concentration, prothrombin time or activated partial thromboplastin time during the period of most severe respiratory failure in any patient. However, mean platelet concentration fell to 90,000+/-9,000 per cubic millimeter, less than 0.001, and mean fibrin split product levels rose to 60+/-10 micrograms per milliliter, p less than 0.05, the fourth day after the onset of acute respiratory failure. No significant change occurred in other coagulation parameters. Disseminated intravascular coagulation developed in none of the patients nor was there any correlation between coagulation abnormalities and severity of acute respiratory failure that would suggest a cause and effect relationship.

Topics: Acute Disease; Adult; Blood Cell Count; Blood Platelets; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Oxygen; Positive-Pressure Respiration; Prothrombin Time; Respiratory Insufficiency; Thromboplastin

Our previous studies suggested that disseminated intravascular coagulation (DIC) may be a sequel to saline-induced abortion. A hypothetical mechanism for the DIC is that hypertonic saline produces cellular disruption in the products of conception with the release of thromboplastic substances into the amniotic fluid. These substances, in turn, diffuse through the damaged membranes into the maternal circulation. To examine this hypothesis we obtained samples of amniotic fluid (AF) from 5 patients just prior to and at 1 hour, 6 hours, and 24 hours after intraamniotic instillation of hypertonic saline. The procoagulant and thromboplastic properties of the various AF specimens were quantitated using the prothrombin time (PT), partial thromboplastin time (PTT), and activated clotting time (ACT) as in vitro test systems. The results indicate that a change in the procoagulant and/or thromboplastic activity of AF following saline instillation is not afactor in the pathophysiology of DIC associated with saline abortion.

Topics: Abortion, Induced; Amniotic Fluid; Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Female; Humans; Pregnancy; Prothrombin; Saline Solution, Hypertonic; Sodium; Sodium Chloride; Thromboplastin

A prospective study was performed on 32 consecutive patients undergoing elective operations on the abdominal aorta. Dacron prosthetic grafts were used to replace resected abdominal aortic aneurysms or to bypass aorta-iliac occlusive disease. Complete coagulation studies were performed preoperatively, immediately postoperatively and 24 hours postoperatively. Twenty to 30 per cent of the patients had significant postoperative alterations in prothrombin time, partial thromboplastin time and platelet count. Fibrin monomer, fibrin split products and plasminogen were abnormal in 40 to 80 per cent of the patients postoperatively. Results of preoperative studies showed no significant abnormalities. One of the 32 patients had mild clinical evidence of disseminated intravascular coagulation postoperatively, which was treated with 5 units of heparin per kilogram per hour. Results of the study indicate that aortic grafting procedures frequently produce intravascular coagulation, either local or disseminated. In most patients, this is offset by activation of the fibrinolytic system. However, clinically significant sequelae may result, requiring prompt recognition and treatment.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Blood Vessel Prosthesis; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Male; Middle Aged; Postoperative Complications; Prospective Studies; Prothrombin Time; Thromboplastin

Intravascular coagulation was induced by two appropriately spaced doses of endotoxin and by infusion of thromboplastin. The resulting fibrin deposition was measured by a previously described quantitative technique. Evidence of thrombin elaboration was obtained indirectly by measurement of fibrin monomer (FM) and by the detection and isolation of a thrombin-induced anticlotting activity. Venous segments were isolated at intervals and examined for thrombus formation following 40 minutes of stasis. Endotoxin triggered thrombin elaboration was not detectable in the circulation for at least one hour and was not accompanied by any thrombosis in isolated venous segments. No thrombin elaboration was found in leukopenic rabbits given endotoxin. In the thromboplastin infused animals, the quantity of fibrin deposited in the organs was comparable to that found after endotoxin. However, thrombin was found in the blood immediately and was associated with thrombosis in the isolatet venous segments. Less thrombin-induced anticoagulant activity was found after thromboplastin than after endotoxin. The findings suggest that endotoxin-induced intravascular coagulation is probably not caused by a mechanism of systemic hypercoagulability due to the release of thromboplastic material into the blood stream. A focal process of thrombin elaboration involving leukocytes is postulated. The study is believed relevant to patients with disseminated intravascular coagulation in whom venous thromboembolism is rarely found despite evidence of extensive microvascular fibrin deposition.

Topics: Animals; Blood Coagulation Disorders; Blood Vessels; Disseminated Intravascular Coagulation; Endotoxins; Fibrin; Fibrinogen; Leukocytes; Leukopenia; Mechlorethamine; Rabbits; Thrombin; Thromboplastin

Topics: Animals; Disseminated Intravascular Coagulation; Male; Phospholipases; Rats; Thromboplastin; Wounds and Injuries

Topics: Acute Disease; Animals; Aprotinin; Blood Coagulation; Chromatography, Gel; Disseminated Intravascular Coagulation; Fibrinolysis; Heparin; Humans; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Rabbits; Thrombin; Thromboplastin; Tranexamic Acid; Trypsin Inhibitors

Topics: Animals; Blood Coagulation; Cat Diseases; Cats; Disseminated Intravascular Coagulation; Diuresis; Dog Diseases; Dogs; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Heparin; Ischemia; Kidney; Platelet Aggregation; Shock; Thromboplastin; Urine

Topics: Adult; Aged; Animals; Blood Coagulation Disorders; Carcinoma, Bronchogenic; Carcinoma, Ehrlich Tumor; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Thromboembolism; Thromboplastin

Human adult and umbilical cord-derived leukocytes were shown to be capable of generating tissue factor activity on exposure to endotoxin and to reduced pH. Blood for leukocyte separation was collected from normal adults and from newly delivered sections of umbilical cord and mixed leukocyte preparations were obtained by separation over methyl cellulose Hypaque. The coagulant activity of the cell suspension was assayed using a one-stage or two-stage method. Cord-derived leukocytes were shown to develop greater coagulant activity than adult-derived leukocytes when stimulated by endotoxin in vitro at 2,000 cells/mm-3. This response to endotoxin was partially inhibited by prior exposure of the cells to prostaglandin (PG) E1 an to L-epinephrine. Acetylcholine stimulated the production of coagulant activity in the absence of endotoxin. Both cord and adult-derived leukocytes (20,000/mm-3) developed coagulant activity when exposed to pH reduction by lactic or hydrochloric acids and this activity was shown to be tissue factor.

Topics: Acetylcholine; Adult; Blood Coagulation; Diatrizoate; Disseminated Intravascular Coagulation; Endotoxins; Eosinophils; Epinephrine; Fetal Blood; Humans; Hydrochloric Acid; Hydrogen-Ion Concentration; Lactates; Leukocytes; Lymphocytes; Monocytes; Prostaglandins; Thromboplastin

Evidence of disseminated intravascular coagulation (DIC) was dought in normal baboons infused with autologous hemolyzed whole blood, preceded or followed by infusion of dextran (molecular weight, 70,000). Mean peak plasma hemoglobin following a rapid single injection was 370 mg/100 ml in 2 animals and 1,236 mg/100 ml in 1 animal, while levels during continuous 5 hour infusion in 2 animals averaged 326 and 474 mg/100 ml, respectively. Dextran infusion immediately preceded hemoglobin injection in 2 baboons and followed hemoglobin injection by 1 1/2 and 2 1/2 hours, respectively, in 2 baboons. Coagulation studies showed a moderate although significant fall in platelet count with prolongation of the partial thromboplastin time following hemoglobin infusion, and shortening of the thrombin time after dextran. Fibrin degradation products developed in four of five experiments after hemolysate injection. The induction of acute experimental hemoglobinemia results, therefore, in the development of coagulation changes consistent with milk DIC. Preliminary infusion of dextran (molecular weight, 70,000) may facilitate this response by either initiating the development or impeding the clearance of fibrin degradation products.

Topics: Acute Disease; Animals; Blood Cell Count; Blood Coagulation; Blood Platelets; Dextrans; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Haplorhini; Hemoglobins; Hemolysis; Molecular Weight; Papio; Prothrombin Time; Thrombin; Thromboplastin; Time Factors

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Humans; Leukemia, Myeloid, Acute; Leukocytes; Methods; Pregnancy; Prothrombin; Rabbits; Snake Venoms; Thrombin; Thromboplastin

Total hemolytic complement activity and the third component of complement were found to be significantly depressed in vivo in rabbits following the induction of disseminated intravascular coagulation by both thrombin and thromboplastin. Production of severe thrombocytopenia by the administration of platelet antiserum prior to the infusion of thrombin or thromboplastin partially prevented complement activation. The data show that, when clotting is triggered, complement activation takes place and that platelets are required to some extent for this reaction.

Topics: Animals; Antigen-Antibody Complex; Blood Platelets; Cattle; Complement System Proteins; Disseminated Intravascular Coagulation; Endotoxins; Escherichia coli; Female; Goats; Hemolysis; Immune Sera; Infusions, Parenteral; Male; Rabbits; Sodium Chloride; Thrombin; Thromboplastin

Four patients had clinical manifestations of the hemolytic-uremic syndrome. No evidence of active intravascular coagulation was found during the acute phase of the illness, using a sensitive assay to measure soluble circulating fibrin in the plasma of these patients, three of whom developed the clinical syndrome while hospitalized for gastro-enteritis. These findings, coupled with the findings of others, suggest that either the episode of intravascular coagulation precedes the development of the clinical manifestations, or that platelet thrombosis is occurring in the absence of activation of plasma clotting factors. In any case, heparin anticoagulant therapy does not seem indicated.

Topics: Anuria; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Blood Pressure; Blood Urea Nitrogen; Carbon Radioisotopes; Child; Child, Preschool; Creatinine; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Female; Fibrin; Fibrinogen; Hematuria; Hemoglobins; Hemolytic-Uremic Syndrome; Heparin; Humans; Infant; Male; Proteinuria; Prothrombin Time; Thromboplastin; Thrombosis

The role of disseminated intravascular clotting (DIC) in the pathogenesis of the bleeding diathesis kwashiorkor was investigated in 22 patients. According to the severity of the clinical and haematological findings, two grades of DIC were observed. A severe grade of DIC was shown in 6 cases (5 fatal) presenting with thrombocytopenia, hypofibinogenaemia, and multiple coagulation defects, and with abnormally prolonged partial thromboplastin,prothombin, and thrombin times]. A second goups of 16 patients (7 fatal) showed a less severe grade of DIC manifested by thrombocytopenia, low fibringoen level, and a clotting factor defect shown by rpolonged prothrombin and thrombin times.

Topics: Blood Cell Count; Blood Platelets; Child, Preschool; Dehydration; Disseminated Intravascular Coagulation; Female; Fibrinogen; Hemorrhagic Disorders; Humans; Infant; Kwashiorkor; Male; Prothrombin Time; Thrombin; Thromboplastin

Blood coagulation tests were performed on admission to the hospital and on consecutive days after severe and moderate head injury in 34 patients. Platelet counts and fibrinogen were normal at admission and raised thereafter. The partial thromboplastin time was shortened at admission and lengthened in the following days. Fibrinolytic activity was enhanced at admission. The ethanol gelation test was negative in all patients during the post-traumatic time course. It was concluded that, in the first 24 hours after injury, activated coagulation was present after head injury. In contrast with data of other authors, disseminated intravascular coagulation did not occur in these series.

Topics: Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Craniocerebral Trauma; Disseminated Intravascular Coagulation; Factor V; Fibrin; Fibrinogen; Fibrinolysis; Humans; Prothrombin Time; Thrombin; Thromboplastin

When intermediate-strength thromboplastin was continuously infused into dogs for 10 days or more, platelet counts decreased sharply and factor VIII concentrations decreased by more than 50%. There was little change in plasma fibrinogen, prothrombin, factor V, antithrombin III, plasminogen, prothrombin time, and thrombin time values. When heparin was infused (25-50 U/kg per h) along with the same thromboplastin, there was no change in onset or degree of thrombocytopenia. However, the decrease in factor VIII was abolished and there were significant increases in fibrinogen, prothrombin, and factor V. The absolute concentrations of the various clotting factors seemed to give no indication of their turnover rates. Unexplained is the remarkable heparin tolerance that developed in these dogs.

Topics: Animals; Antithrombins; Blood Cell Count; Blood Coagulation; Blood Platelets; Disseminated Intravascular Coagulation; Dogs; Factor V; Factor VIII; Fibrinogen; Fibrinolysis; Heparin; Male; Plasminogen; Prothrombin; Thromboplastin

Disseminated intravascular coagulation (DIC) developed in two patients following head trauma. Brain parenchyma and highly vascular connective tissue of the choroid plexus and meninges are important pools of systemic coagulation components. This is an important consideration in the treatment of head injury.

Topics: Accidents, Traffic; Adolescent; Autopsy; Brain; Brain Edema; Brain Injuries; Craniocerebral Trauma; Disseminated Intravascular Coagulation; Hematoma, Epidural, Cranial; Humans; Male; Prothrombin Time; Subarachnoid Hemorrhage; Thromboplastin

Topics: Disseminated Intravascular Coagulation; Fibrinogen; Hemorrhage; Humans; Thromboplastin; Thrombosis

Topics: Aged; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinolysin; Fibrinolysis; Hemoptysis; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Plasminogen; Prothrombin Time; Thrombin; Thrombophlebitis; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Proteins; Dextrans; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Fibrinolysin; Gelatin; Guinea Pigs; Heparin Antagonists; Immune Sera; Immunodiffusion; Male; Platelet Adhesiveness; Platelet Aggregation; Rabbits; Thrombin; Thromboplastin

In an experimental study in the rabbit, the modifications of some haemostasis parameters (platelet count, platelet retention and aggregation, platelet factors 3 and 4, platelet and plasma plasmin inhibiting activities, fibrinogen and other plasma factor levels, FDP), and histological findings are compared in both the normal animal and the animal with disseminated intravascular coagulation (DIC) induced by thrombin perfusion after administration of fibrinolytic inhibitors (plasminogen antiactivators and proteinase inhibitors). In the normal animal, the administration of fibrinolytic inhibitors is followed by haemostatic changes similar to those found in thrombophilic states. The modifications are more pronounced with plasminogen antiactivators than with proteinase inhibitors. In the animal with DIC, the administration of fibrinolytic inhibitors enhances the haemostatic and the biological disorders produced by thrombin perfusion. The effect of the plasminogen antiactivators is even more evident. The preventive administration of heparin reduces or abolishes the biological and histological disorders induced by thrombin; its beneficial effect is considerably reduced when thrombin is combined with fibrinolytic inhibitors. The administration of acetylsalicylic acid appears to be ineffective for the prevention of haemostatic and histological changes induced by thrombin perfusion.

Topics: Aminocaproates; Animals; Aprotinin; Aspirin; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Cyclohexanecarboxylic Acids; Disseminated Intravascular Coagulation; Enzyme Activation; Enzyme Inhibitors; Fibrin; Fibrinogen; Fibrinolysin; Heparin; Heparin Antagonists; Kidney; Lung; Methylamines; Plasminogen; Platelet Aggregation; Protease Inhibitors; Thrombin; Thromboplastin

Topics: Aged; Autopsy; Chronic Disease; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrosarcoma; Hematoma; Hematuria; Humans; Leiomyosarcoma; Pulmonary Artery; Sarcoma; Thromboplastin

Topics: Adult; Aged; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Prothrombin Time; Sex Factors; Surgical Procedures, Operative; Thrombin; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Tests; Clot Retraction; Disseminated Intravascular Coagulation; Half-Life; Hemorrhage; Hemostasis; Heparin; Humans; Infusions, Parenteral; Injections, Intravenous; Injections, Subcutaneous; Pulmonary Embolism; Thrombin; Thrombophlebitis; Thromboplastin; Time Factors

Topics: Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Blood Coagulation; Chronic Disease; Disseminated Intravascular Coagulation; Fibrinogen; Humans; Male; Prothrombin; Thrombelastography; Thrombophlebitis; Thromboplastin

Topics: Amidines; Animals; Anticoagulants; Antithrombins; Blood Coagulation; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Pyruvates; Rabbits; Thrombelastography; Thromboplastin

Plasminogen activator activity in blood vessels of various organs was determined in three untreated (control) male dogs and in two male dogs that received a continous infusion of canine brain thromboplastic emulsion for 2 weeks. Activator was measured by the speed and degree of lysis of fibrin films that were overlaid with slices of tissue. Depletion of vascular plasminogen activator occurred in the vena cava of treated dogs at the site of the tip of the catheter, which was surrounded by a clot. A decrease of activator was found in most organs and particularly in certain endocrine organs (thyroid, pituitary, and testis). Of organs that normally contained the most activator, the greatest depletion was found in the skin, lung, and penis. The wide variation of plasminogen activator activity in organs of normal dogs is described.

Topics: Adrenal Glands; Animals; Blood Cell Count; Blood Platelets; Blood Vessels; Disseminated Intravascular Coagulation; Dogs; Enzyme Activation; Fibrinogen; Fibrinolysis; Liver; Lung; Male; Plasminogen; Spleen; Thromboplastin

Topics: Abortion, Induced; Adolescent; Adult; Blood Coagulation; Blood Platelets; Disseminated Intravascular Coagulation; Ethanol; Factor V; Factor VIII; Female; Fibrin; Fibrinogen; Heparin; Humans; Hypertonic Solutions; Models, Biological; Peptides; Pregnancy; Radioimmunoassay; Serum Albumin; Sodium Chloride; Technetium; Thrombin; Thromboplastin

Topics: Acid-Base Equilibrium; Blood; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Buffers; Disseminated Intravascular Coagulation; Factor V; Factor VII; Humans; Hydrogen-Ion Concentration; Prothrombin; Shock; Thrombelastography; Thrombin; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Platelets; Depression, Chemical; Disseminated Intravascular Coagulation; Ethanol; Factor V; Female; Fibrinogen; Gastrointestinal Hemorrhage; Hematocrit; Infusions, Parenteral; Male; Rabbits; Thromboplastin; Time Factors; Warfarin

Topics: Animals; Aprotinin; Blood Coagulation; Cyclohexanecarboxylic Acids; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Iodine Radioisotopes; Lung; Rats; Thrombin; Thromboplastin

Topics: Adult; Antigens; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Graft Rejection; Humans; Kidney Transplantation; Male; Middle Aged; Thromboplastin; Transplantation, Homologous

Topics: Animals; Blood Coagulation; Blood Platelets; Chromatography, Gel; Chromatography, Ion Exchange; Depression, Chemical; Disseminated Intravascular Coagulation; Ethanol; Factor V; Female; Fibrin; Fibrinogen; Fluorescent Antibody Technique; Guinea Pigs; Hematocrit; Immune Sera; Infusions, Parenteral; Kidney; Male; Rabbits; Thromboplastin

Topics: Blood Coagulation Tests; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Daunorubicin; Disseminated Intravascular Coagulation; Fibrinogen; Hemorrhage; Hemorrhagic Disorders; Hemostasis; Heparin; History, 20th Century; Humans; Leukemia, Myeloid, Acute; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Embolism; Female; Humans; Leukemia; Male; Postoperative Complications; Pregnancy; Pregnancy Complications, Hematologic; Shock; Thromboplastin; Thrombosis; Wounds and Injuries

Evidence of disseminated intravascular coagulation (DIC) was sought in New Zealand white rabbits infused with autologous, hemolyzed whole blood. Hemoglobinemia was induced in 17 rabbits by rapid intravenous injection of frozenthawed whole blood. Three dose regimens yielded mean peak plasma hemoglobin concentrations of 325, 615 and 860 mg/100 ml respectively (range 260 to 1050 mg/100 ml). Eleven control animals were infused with autologous, nonhemolyzed whole blood in similar doses. Rabbits were killed at either 15, 60, 120 or 180 minutes following infusion and multiple organ biopsies obtained immediately post-mortem. Coagulation studies demonstrated no significant alterations in prothrombin time, partial thromboplastin time, thrombin time or fibrinogen. Fibrin degradation products were not found. Histologic examination of lung, heart, liver, spleen and kidney revealed no fibrin deposition, thrombus formation or other abnormalities. We conclude from our study that induction of brief, experimental hemoglobinemia in New Zealand white rabbits, utilizing moderately large doses of autologous, hemolyzed whole blood, does not result in the development of DIC.

Topics: Animals; Blood Coagulation; Blood Coagulation Tests; Blood Protein Disorders; Blood Transfusion, Autologous; Disseminated Intravascular Coagulation; Fibrinogen; Hemoglobins; Kidney; Liver; Lung; Myocardium; Prothrombin Time; Rabbits; Spleen; Thrombin; Thromboplastin; Urine

Topics: Blood Coagulation Tests; Brain; Brain Injuries; Craniocerebral Trauma; Disseminated Intravascular Coagulation; Hemostasis; Humans; Thromboplastin

Topics: Afibrinogenemia; Aneurysm; Bacteria; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Diagnosis, Differential; Disseminated Intravascular Coagulation; Enzyme Activation; Fibrin; Fibrinogen; Fibrinolysis; Hemostasis; Heparin; Models, Biological; Prothrombin; Sepsis; Shwartzman Phenomenon; Thrombin; Thromboplastin

Topics: Adenosine Diphosphate; Animals; Blood Cell Count; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Chromium Radioisotopes; Disseminated Intravascular Coagulation; Dogs; Infusions, Parenteral; Platelet Adhesiveness; Thromboplastin

Topics: Anti-Bacterial Agents; Blood Coagulation Tests; Diagnosis, Differential; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Fibrinogen; Heparin; Humans; Infant, Newborn; Infant, Premature, Diseases; Male; Parenteral Nutrition; Prothrombin Time; Thromboplastin; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

Topics: Animals; Cyclohexanecarboxylic Acids; Disseminated Intravascular Coagulation; Dogs; Fibrin; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Injections, Intravenous; Methylamines; Thromboplastin

Topics: Adenocarcinoma, Mucinous; Animals; Arginine; Blood Coagulation; Blood Coagulation Tests; Brain Chemistry; Bronchi; Chemical Precipitation; Disseminated Intravascular Coagulation; Esterases; Factor V Deficiency; Factor VII; Factor VII Deficiency; Factor X; Fibrinogen; Hemophilia B; Humans; Hypoprothrombinemias; Kaolin; Mucins; Mucus; Muramidase; Phospholipids; Prothrombin; Rabbits; Thromboplastin; Time Factors; Venoms

Topics: Animals; Animals, Newborn; Cell Membrane; Cesarean Section; Disseminated Intravascular Coagulation; Epithelial Cells; Female; Heparin; Humans; Infant, Newborn; Isotonic Solutions; Microcirculation; Microscopy, Electron; Pregnancy; Pulmonary Alveoli; Pulmonary Surfactants; Rabbits; Respiratory Distress Syndrome, Newborn; Sodium Chloride; Thrombin; Thromboplastin

Topics: Aged; Blood Coagulation Tests; Blood Platelet Disorders; Chronic Disease; Disseminated Intravascular Coagulation; Fibrin; Gastrointestinal Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms; Prothrombin Time; Thromboplastin

Topics: 5-Hydroxytryptophan; Abruptio Placentae; Animals; Blood Coagulation Factors; Desoxycorticosterone; Disease Models, Animal; Disseminated Intravascular Coagulation; Female; Fibrinogen; Fibrinolysis; Humans; Hypertension; Platelet Adhesiveness; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Hematologic; Pulmonary Circulation; Rabbits; Rats; Thrombocytopenia; Thromboplastin

Topics: Adult; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Fibrinogen; Humans; Malaria; Male; Plasmodium falciparum; Prothrombin Time; Thromboplastin

Topics: Blood Cell Count; Blood Platelets; Chronic Disease; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Fibrinolysis; Heparin; Humans; Liver Cirrhosis; Pregnancy; Pregnancy Complications, Hematologic; Prothrombin Time; Thrombin; Thromboplastin

Topics: Blood Coagulation Tests; Blood Platelets; Child; Child, Preschool; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Heparin; Humans; Infant; Meningococcal Infections; Prothrombin Time; Thromboplastin

Topics: Blood Cell Count; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Prothrombin Time; Renal Veins; Thromboplastin; Thrombosis

Topics: Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Factor V Deficiency; Factor VIII; Fibrinogen; Heparin; Humans; Liver Diseases; Prothrombin Time; Thromboplastin; Vitamin K; Vitamin K Deficiency

Topics: Blood Coagulation Tests; Blood Transfusion; Brain; Brain Injuries; Debridement; Disseminated Intravascular Coagulation; Heparin; Humans; Male; Middle Aged; Thromboplastin; Wounds, Gunshot

Topics: Aged; Blood Coagulation Tests; Diagnosis, Differential; Disseminated Intravascular Coagulation; Female; Fibrinolysis; Hemorrhagic Disorders; Heparin; Humans; Male; Methods; Protamines; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Humans; Oxygen Consumption; Prothrombin Time; Pulmonary Edema; Sepsis; Shock; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Depression, Chemical; Disseminated Intravascular Coagulation; Ethanol; Factor V; Female; Fibrinogen; Hemoglobins; Hemolysis; Indicators and Reagents; Male; Methods; Rabbits; Stimulation, Chemical; Thromboplastin; Time Factors

Topics: Adolescent; Adult; Afibrinogenemia; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Child; Child, Preschool; Disseminated Intravascular Coagulation; Factor V; Factor VIII; Female; Fibrinogen; Humans; Infant; Liver; Liver Diseases; Male; Middle Aged; Prothrombin; Prothrombin Time; Serum Globulins; Solubility; Thromboplastin

Topics: Animals; Blood Platelets; Depression, Chemical; Disease Models, Animal; Disseminated Intravascular Coagulation; Dogs; Factor V; Factor VII; Factor VIII; Factor XI; Factor XII; Factor XIII; Fibrinogen; Fibrinolysis; Prothrombin Time; Stimulation, Chemical; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Factor V; Female; Fibrinogen; Hematocrit; Hemoglobins; Hemolysis; Heparin; Infusions, Parenteral; Male; Prothrombin Time; Rabbits; Thromboplastin; Water

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Factor VIII; Female; Fibrin; Fibrinogen; Fibrinolysis; Hemagglutination Inhibition Tests; Humans; Liver Cirrhosis; Male; Plasminogen; Thromboplastin

Topics: Blood Coagulation Tests; Child; Child, Preschool; Disseminated Intravascular Coagulation; Female; Hemolytic-Uremic Syndrome; Heparin; Humans; Infant; Infant, Newborn; Male; Thromboplastin

Topics: Animals; Chickens; Disseminated Intravascular Coagulation; Endotoxins; Lung; Male; Microscopy, Electron; Platelet Adhesiveness; Polymers; Thromboplastin; Warfarin

Topics: Disseminated Intravascular Coagulation; Embolism; Female; Humans; Maternal-Fetal Exchange; Microcirculation; Placenta; Pregnancy; Pregnancy Complications, Hematologic; Thromboplastin

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrinogen; Humans; Placenta; Pre-Eclampsia; Pregnancy; Rabbits; Thromboplastin

Topics: Blood; Disseminated Intravascular Coagulation; Female; Hemagglutination Tests; Humans; Infant, Newborn; Infant, Newborn, Diseases; Labor, Obstetric; Pregnancy; Thromboplastin; Time Factors; Umbilical Veins; Vitamin K Deficiency Bleeding

Topics: Adult; Age Factors; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Factor V; Female; Fibrinogen; Fibrinolysin; Gestational Age; Humans; Hypertension; Parity; Plasminogen; Pre-Eclampsia; Pregnancy; Prothrombin Time; Thrombin; Thromboplastin

Topics: Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelet Disorders; Blood Platelets; Diagnosis, Differential; Disseminated Intravascular Coagulation; Female; Hemoglobinometry; Hemophilia A; Hemophilia B; Hemorrhage; Humans; Male; Prothrombin Time; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Rheumatic Diseases; Telangiectasia, Hereditary Hemorrhagic; Thromboplastin; von Willebrand Diseases

Topics: Animals; Blood Coagulation Disorders; Blood Platelets; Blood Pressure; Cardiac Output; Disseminated Intravascular Coagulation; Escherichia coli Infections; Fibrinolysis; Hematocrit; Hydrogen-Ion Concentration; Male; Oxygen; Papio; Prothrombin Time; Sepsis; Shock, Septic; Thromboplastin; Vascular Resistance

Topics: Blood Coagulation; Disseminated Intravascular Coagulation; Fibrinolysis; Humans; In Vitro Techniques; Leukemia; Leukemia, Myeloid, Acute; Leukocytes; Phosphatidylethanolamines; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Coagulation Tests; Blood Platelet Disorders; Blood Platelets; Disseminated Intravascular Coagulation; Factor V; Factor VII; Female; Fibrin; Fibrinogen; Hematocrit; Injections, Intravenous; Male; Rabbits; Thrombin; Thromboplastin

Topics: Adenosine Diphosphate; Animals; Aspirin; Blood Cell Count; Blood Platelets; Calcium; Carcinoma 256, Walker; Collagen; Disseminated Intravascular Coagulation; Female; Fibrinogen; Hypercalcemia; Hyperparathyroidism; Neoplasm Transplantation; Parathyroid Hormone; Platelet Adhesiveness; Radiation Effects; Rats; Sarcoma, Yoshida; Thromboplastin; Time Factors; Transplantation, Homologous

Topics: Animals; Disseminated Intravascular Coagulation; Dogs; Fibrinolysis; Heparin; Rabbits; Thrombin; Thromboplastin

To assess the effect of a hypertonic saline infusion abortion upon the coagulation mechanism, 39 women from Roosevelt and Harlem Hospitals in New York were studied prior to and at 3 and 24, or 24 and 48 hours after the abortion. The prothrombin and partial thromboplastin times were unaffected at 24 and 48 hours when compared with the pre-infusion data. The platelet counts were decreased at 24 hours by 22% of their pre-abortion levels (246,000 vs. 193,000). Profibrinolysin was lower than pre-infusion levels at 24 and 48 hours by 21 and 17% respectively. Fibrinolytic inhibitors were lower at 24 hours by 22% of their pre-infusion levels, while fibriogin levels were not significantly changed. The plasma protamine paracoagulation test showed a change in 40, 68, and 40% of the women at 3, 24, and 48 hours respectively, from a clear plasma to one with a fine or coarse precipitate. The addition of protamine sulfate to plasma showed evidence of fibrin monomer in 60% of the patients at 3 hours, 20% at 24 hours, and 35% at 48 hours. This suggests the incomplete early activation of the coagulation mechanism. The results from the 6 patients studied at 3 and 24 hours showed a small decrease in Factor VIII at 3 hours and a more pronounced decrease at 24 hours. Results suggest changes in the coagulation mechanism begin at 3 hours, become more intensive at 24 hours, and are returning to normal at 48 hours.

Topics: Abortion, Therapeutic; Adult; Amnion; Blood Platelets; Disseminated Intravascular Coagulation; Factor VIII; Female; Fibrinogen; Hematocrit; Humans; Hypertonic Solutions; Immunoelectrophoresis; Injections; Plasminogen; Pregnancy; Prothrombin Time; Thromboplastin

Topics: Animals; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Male; Rabbits; Thrombelastography; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Ethanol; Evaluation Studies as Topic; Factor V; Factor X; Female; Fibrinogen; Heparin; Male; Rabbits; Thromboplastin; Time Factors

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Child; Disseminated Intravascular Coagulation; Factor IX; Factor V Deficiency; Factor VII; Factor VIII; Factor X; Fibrinolysin; Humans; Middle Aged; Plasminogen; Prognosis; Prothrombin Time; Thromboplastin; Wounds and Injuries

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Infant, Newborn; Infant, Premature, Diseases; Maternal-Fetal Exchange; Placenta; Pregnancy; Thromboplastin; Viruses

Topics: Amniotic Fluid; Animals; Blood Pressure; Disseminated Intravascular Coagulation; Embolism, Amniotic Fluid; Female; Fetal Heart; Haplorhini; Heart Rate; Hydrogen-Ion Concentration; Oxygen; Pregnancy; Respiration; Thromboplastin

Topics: Autopsy; Blood Cell Count; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Blood Vessels; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Erythroblastosis, Fetal; Female; Fibrin; Fibrinogen; Hemoglobins; Hemorrhage; Humans; Infant, Newborn; Liver; Lung; Pregnancy; Retrospective Studies; Subarachnoid Hemorrhage; Thrombin; Thromboplastin

Topics: Aged; Aortic Valve; Disseminated Intravascular Coagulation; Endocarditis; Hernia, Inguinal; Humans; Hyaline Membrane Disease; Infant, Newborn; Intestine, Small; Kidney; Lung; Male; Postoperative Complications; Shwartzman Phenomenon; Thromboplastin

Topics: Aminocaproates; Blood Coagulation Tests; Clot Retraction; Disseminated Intravascular Coagulation; Fibrinogen; Heparin; Humans; Thromboplastin

Topics: Animals; Chronic Disease; Disseminated Intravascular Coagulation; Dogs; Thromboplastin

Topics: Afibrinogenemia; Amniotic Fluid; Animals; Antifibrinolytic Agents; Brain Chemistry; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Lethal Dose 50; Placenta; Placental Extracts; Pregnancy; Protease Inhibitors; Rats; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Platelets; Disseminated Intravascular Coagulation; Endotoxins; Factor XII; Fatty Acids; Humans; In Vitro Techniques; Rabbits; Thromboplastin; Thrombosis

Topics: Blood; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Disseminated Intravascular Coagulation; Fibrin; Fibrinogen; Humans; Infant, Newborn; Thrombin; Thromboplastin; Umbilical Cord

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Platelets; Blood Proteins; Blood Urea Nitrogen; Cryosurgery; Disseminated Intravascular Coagulation; Dogs; Fibrinogen; Hemostasis; Liver; Necrosis; Postoperative Complications; Shock, Hemorrhagic; Thromboplastin

Topics: Aged; Anticoagulants; Autopsy; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Disseminated Intravascular Coagulation; Female; Humans; Kidney Glomerulus; Melanoma; Methods; Myocardium; Neoplasm Metastasis; Proteus; Prothrombin Time; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Endotoxins; Factor IX; Factor X; Factor XII; Fibrinolysis; In Vitro Techniques; Male; Rabbits; Sodium; Stearic Acids; Thrombin; Thromboplastin

Topics: Adenine Nucleotides; Anaphylaxis; Antigen-Antibody Complex; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Disseminated Intravascular Coagulation; Endotoxins; Enzyme Activation; Factor XII; Fibrinogen; Fibrinolysis; Heparin; Humans; Iodine Isotopes; Lipids; Lipoproteins; Peptide Hydrolases; Shwartzman Phenomenon; Sulfonic Acids; Thromboplastin; Venoms

Topics: Adult; Aged; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxins; Female; Fibrinolysis; Humans; Infant; Male; Pregnancy; Thrombin; Thromboplastin

Topics: Afibrinogenemia; Ammonium Compounds; Animals; Anti-Infective Agents, Local; Blood Coagulation Disorders; Deoxyribonuclease I; Disseminated Intravascular Coagulation; Dogs; Fibrinolysis; Liver Circulation; Pathology; Pulmonary Circulation; Quaternary Ammonium Compounds; Research; Shock; Shock, Hemorrhagic; Streptodornase and Streptokinase; Streptokinase; Thrombin; Thromboplastin