thromboplastin and Blood-Coagulation-Disorders

The need for a more precise test that replicates the in vivo hemostatic conditions is increasingly being recognized. Up to now, the thrombin generation assay (TGA) has become the most reliable approach to evaluate the status of coagulation activation. The clinical potential for the TGA is most promising in the prediction of venous thromboembolism recurrence. However, there is currently an urgent need for a standardized global test that can reliably detect, predict and monitor coagulation disorders in both clinical and experimental studies. We have recently modified the TGA to analyze not only tissue factor-driven coagulation, but the intrinsic coagulation pathway as well. In the present review, we discuss different TG tests, emphasizing the requirement for a better understanding of the evaluation of distinct coagulation pathways using this technique, as well as the standardization and clinical validation.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Thrombin; Thromboplastin

Evidence of micro- and macro-thrombi in the arteries and veins of critically ill COVID-19 patients and in autopsies highlight the occurrence of COVID-19-associated coagulopathy (CAC). Clinical findings of critically ill COVID-19 patients point to various mechanisms for CAC; however, the definitive underlying cause is unclear. Multiple factors may contribute to the prothrombotic state in patients with COVID-19. Aberrant expression of tissue factor (TF), an initiator of the extrinsic coagulation pathway, leads to thrombotic complications during injury, inflammation, and infections. Clinical evidence suggests that TF-dependent coagulation activation likely plays a role in CAC. Multiple factors could trigger abnormal TF expression and coagulation activation in patients with severe COVID-19 infection. Proinflammatory cytokines that are highly elevated in COVID-19 (IL-1β, IL-6 and TNF-α) are known induce TF expression on leukocytes (e.g. monocytes, macrophages) and non-immune cells (e.g. endothelium, epithelium) in other conditions. Antiphospholipid antibodies, TF-positive extracellular vesicles, pattern recognition receptor (PRR) pathways and complement activation are all candidate factors that could trigger TF-dependent procoagulant activity. In addition, coagulation factors, such as thrombin, may further potentiate the induction of TF via protease-activated receptors on cells. In this systematic review, with other viral infections, we discuss potential mechanisms and cell-type-specific expressions of TF during SARS-CoV-2 infection and its role in the development of CAC.

Topics: Blood Coagulation Disorders; COVID-19; Critical Illness; Humans; SARS-CoV-2; Thromboplastin; Thrombosis

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

Activation of stromal response pathways in cancer is increasingly viewed as both a local and systemic extension of molecular alterations driving malignant transformation. Rather than reflecting passive and unspecific responses to anatomical abnormalities, the coagulation system is a target of oncogenic deregulation, impacting the role of clotting and fibrinolytic proteins, and integrating hemostasis, inflammation, angiogenesis and cellular growth effects in cancer. These processes signify, but do not depend on, the clinically manifest coagulopathy and thrombosis. In this regard, the role of driver mutations affecting oncoprotein coding genes such as RAS, EGFR or MET and tumour suppressors (PTEN, TP53) are well described as regulators of tissue factor (TF), protease activated receptors (PAR-1/2) and ectopic coagulation factors (FVII). Indeed, in both adult and pediatric brain tumours the expression patterns of coagulation and angiogenesis regulators (coagulome and angiome, respectively) reflect the molecular subtypes of the underlying diseases (glioblastoma or medulloblastoma) as defined by their oncogenic classifiers and clinical course. This emerging understanding is still poorly established in relation to the transforming effects of non-coding genes, including those responsible for the expression of microRNA (miR). Indeed, several miRs have been recently found to regulate TF and other effectors. We recently documented that in the context of the aggressive embryonal tumour with multilayered rosettes (ETMR) the oncogenic driver miR (miR-520g) suppresses the expression of TF and correlates with hypocoagulant tumour characteristics. Unlike in adult cancers, the growth of pediatric embryonal brain tumour cells as spheres (to maintain stem cell properties) results in upregulation of miR-520g and downregulation of TF expression and activity. We postulate that oncogenic protein and miR coding genes form alternative pathways of coagulation system regulation in different tumour settings, a property necessitating more personalised and biologically-based approaches to anticoagulation.

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Brain; Brain Neoplasms; Glioblastoma; Humans; Medulloblastoma; MicroRNAs; Oncogenes; Precision Medicine; Thromboplastin

Progressive hemorrhagic injury (PHI) can be divided into coagulopathy-related PHI and normal coagu- lation PHI. Coagulation disorders after traumatic brain injuries can be included in trauma-induced coagulopathy (TIC). Some studies showed that TIC is associated with PHI and increases the rates of disability and mortality. In this review, we discussed some mechanisms in TIC, which is of great importance in the development of PHI, including tissue factor (TF) hypothesis, protein C pathway and thrombocytopenia. The main mechanism in the relation of TIC to PHI is hypocoagulability. We also reviewed some coagulopathy parameters and proposed some possible risk factors, predictors and therapies.

Topics: Blood Coagulation Disorders; Brain Injuries, Traumatic; Cerebral Hemorrhage; Fibrin Fibrinogen Degradation Products; Humans; Incidence; Protein C; Risk Factors; Thromboplastin

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

Sickle cell disease is the most common inherited haematological disorder that leads to the irreversible damage of multiple organs. Although sickling of red blood cells and vaso-occlusion are central to the pathophysiology of sickle cell disease, the importance of haemolytic anaemia and vasculopathy has been recently recognized. A hypercoagulable state is another prominent feature of sickle cell disease and is mediated by activation of both intrinsic and extrinsic coagulation pathways. Growing evidence demonstrates that coagulation may not only contribute to the thrombotic complications, but also to vascular inflammation associated with this disease. This article summarizes the role of vascular inflammation and coagulation activation, discusses potential mechanisms responsible for activation of coagulation and reviews recent data demonstrating the crosstalk between coagulation and vascular inflammation in sickle cell disease.

Topics: Anemia, Sickle Cell; Blood Coagulation; Blood Coagulation Disorders; Enzyme Activation; Humans; Protein Multimerization; Thromboplastin; Thrombosis; Vasculitis; von Willebrand Factor

Polytraumatic injury results in tissue factor (TF) release from damaged cells. The acute coagulopathy of trauma (ACT) occurs early and results from significant tissue injury and tissue hypoperfusion. ACT is augmented by therapies resulting in acidemia, hypothermia, and hemodilution contributing to trauma-induced coagulopathy. Coagulopathy associated with traumatic brain injury (TBI) results from the interplay of numerous variables. Because of the high concentration of TF in brain tissue, TBI has been believed to be associated with a greater degree of coagulopathy compared with injury in other body systems. TBI has also recently been shown to cause platelet dysfunction. Platelet receptor inhibition prevents cellular initiation and amplification of the clotting cascade, limiting thrombin incorporation, and stabilization of clot to stop hemorrhage. Therefore, head injury in the presence of polytrauma does appear to augment ACT and warrants close monitoring and appropriate intervention.

Topics: Blood Coagulation Disorders; Brain; Brain Hemorrhage, Traumatic; Brain Injuries; Humans; Models, Biological; Multiple Trauma; Signal Transduction; Thromboplastin

The increasing understanding of trauma-induced coagulopathy has led to an expansion of treatment strategies in the acute management of trauma patients. The aim of this manuscript is to give a summary of current recommendations for the treatment of trauma-induced coagulopathy based on current literature and valid guidelines. Thetrauma-induced coagulopathyis an independentacutemultifactorial diseasewith significantimpact on the mortalityof severelyinjured patients. Largely responsible for the occurrence and severity of trauma-induced coagulopathy seems to be tissue trauma and shock-induced hypoperfusion. Coagulopathy is amplified by accompanying factors such as hypothermia or dilution. Diagnosis and therapy of deranged coagulation should start as soon as possible. Routinely tested coagulation parameters are of limited use to confirm diagnosis. Therapy follows the concept of "damage control resuscitation". Infusion of large volumes should be avoided and a mean arterial pressure of 65mmHg (in consideration of contraindications!) may be aimed.A specific protocol for massive transfusion should be introduced and continued.Acidaemia should be prevented and treated by appropriate shock therapy.Loss of body temperature should be prevented and treated. Hypocalcaemia <0.9 mmol/l should be avoided and may be treated. For actively bleeding patients, packed red blood cells (pRBC) may be given at haemoglobin<10g/dl(0,62mmol/l). If massive transfusion is performed using fresh frozen plasma (FFP), a ratio of FFP to pRBC of 1:2 to 1:1 should be achieved.For treatment of hyperfibrinolysis after severe trauma the use of tranexamic acid should be considered at an early stage. Fibrinogen should be substituted at levels <1,5g/l (4,41μmol/l). Prothrombin complex concentrates may be helpfull for treatment of diffuse bleeding or anticoagulativemedikation. In acute bleeding, platelets may be transfused at a platet count <100000/μl. For diffuse bleeding or thrombocytopathic patients desmopressin might be a therapeutic option.If a factor XIII (FXIII) measurement is not promptly available, a factor XIII blind-dose should be considered in severe ongoing bleeding. The use of recombinant activated coagulation factor VII (rFVIIa) be considered if major bleeding persists despite standard attempts to control bleeding and best practice use of blood components.

Topics: Acidosis; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Calcium; Evidence-Based Medicine; Hemodilution; Humans; Hypotension, Controlled; Hypothermia, Induced; Inflammation; Platelet Activation; Resuscitation; Thromboplastin; Wounds and Injuries

Traumatic injury is a common cause of coagulopathy, primarily due to blood loss and hemodilution secondary to fluid resuscitation. Traumatic injury-associated coagulopathy often follows a course of transition from hyper- to hypocoagulable state exemplified in disseminated intravascular coagulation. The incidence of coagulopathy is significantly higher in patients with traumatic brain injury (TBI), especially those with penetrating trauma compared to injury to the trunk and limbs. This occurs despite the fact that patients with isolated TBI bleed less and receive restricted volume load of fluids. TBI-associated coagulopathy is extensively documented to associate with poor clinical outcomes, but its pathophysiology remains poorly understood. Studies in the past have shown that brain tissue is highly enriched in key procoagulant molecules. This review focuses on the biochemical and cellular characteristics of these molecules and pathways that could make brain uniquely procoagulant and prone to coagulopathy. Understanding this unique procoagulant environment will help to identify new therapeutic targets that could reverse a state of coagulopathy with minimal impacts on hemostasis, a critical requirement for neurosurgical treatments of TBI.

Topics: Animals; Blood Coagulation Disorders; Brain Hemorrhage, Traumatic; Brain Injuries; Endothelium, Vascular; Humans; Phosphatidylserines; Phospholipids; Platelet Activating Factor; Platelet Count; Thromboplastin

In the guidelines for patients with acute coronary syndrome (ACS), reperfusion, antiplatelet treatment, completed with parenteral anticoagulant are the standard therapy. It is because ACS is the result of occlusion of related artery by thrombus compound mostly of platelets, with processes of aggregation and adhesion in its pathogenesis. However, many patients after ACS experience major adverse cardiovascular events (MACE) despite optimal long term antiplatelet therapy. The possible reasons seem to be not only the resistance to this drugs but also underestimated coagulation processes. This review describes the dysfunction of particular coagulation parameters in patients with coronary artery disease and their relationship with MACE after ACS.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Blood Coagulation Disorders; Fibrinogen; Fibrinopeptide A; Humans; Peptide Fragments; Platelet Aggregation Inhibitors; Protein Precursors; Prothrombin; Thromboplastin; von Willebrand Factor

The tissue factor (TF)/factor (F)VIIa complex is the primary initiator of coagulation in vivo. Tissue factor pathway inhibitor (TFPI) is the physiological inhibitor of the TF/FVIIa complex. Deficiencies of either TF or TFPI have not been reported in humans, and a complete absence of either of these two proteins in mice is embryonically lethal. To maintain normal hemostasis, levels of TF and TFPI need to be balanced. Increased levels of TF can overwhelm the inhibitory capacity of TFPI, resulting in thrombosis. Decreased levels of TF are associated with bleeding. Global assays of coagulation are defined as tests capable of evaluating all components of the clotting cascade that are present in plasma. In these tests the thrombogenic surface is either provided by platelets or exogenous phospholipids. Clotting assays currently used in clinical practice are not designed to measure endogenous levels of TF and TFPI. Therefore, there is a need to develop sensitive and specific assays for measuring levels of functional TF and TFPI in whole blood and plasma. These assays could be useful in patient management in many scenarios.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Hemostasis; Humans; Lipoproteins; Mice; Thromboplastin; Thrombosis; Venous Thromboembolism

Topics: Blood Coagulation Disorders; Cell-Derived Microparticles; Endothelium, Vascular; Hemostasis; Humans; Models, Biological; Neoplasm Proteins; Neoplasms; Thrombophilia; Thromboplastin

To review the veterinary and human literature on the role of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in health and disease states.. Original research articles and scientific reviews from both human and veterinary literature were searched for relevance to TF and TFPI.. Interest in both TF and TFPI has grown widely over the last several years. The impact TF plays in coagulation, inflammation, angiogenesis, tumor metastasis, and cellular signaling has become apparent. Treatment with TFPI for severe sepsis has been examined and is still currently under investigation. Inhibition of the TF pathway is being studied as an aid in the treatment of neoplasia. The important physiologic and pathophysiologic role these molecules play has only begun to be understood.. There is a paucity of publications that discuss the importance of TF and TFPI in veterinary medicine. An enhanced understanding of the TF pathway in human medicine, in experimental animal models treating sepsis with TFPI, and in animal models demonstrating the proangiogenic properties of TF provides relevance to veterinary medicine.. It is apparent that TF and TFPI are important in health and disease. An enhanced understanding of the physiologic and pathophysiologic roles of these factors provides better insight into coagulation, inflammation, angiogenesis, disseminated intravascular coagulation, and tumor metastasis. This greater understanding may provide for the development of therapeutics for sepsis, disseminated intravascular coagulation, and neoplasia.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Humans; Lipoproteins; Thromboplastin

Oncogenic upregulation of tissue factor (TF) and release of TF-containing microvesicles play an important role in cancer-related coagulopathy (Trousseau's syndrome), angiogenesis, and disease progression. In addition, certain types of host cells (stromal cells, inflammatory cells, activated endothelium) may also express TF. Although the relative contribution of host-related versus tumor-related TF to tumor progression is not known, our recent studies indicate that the role of both sources of TF in tumor formation is complex and context-dependent. Disruption of TF expression/activity in cancer cells leads to tumor growth inhibition in immunodeficient mice, even in cases where TF overexpression is driven by potent oncogenes ( K-RAS or EGFR). Interestingly, TF expression in vivo appears to be influenced by many factors, including the level of oncogenic transformation, tumor microenvironment, and differentiation from cancer stem-like cells. We postulate that activation of TF signaling and coagulation may deliver growth-promoting stimuli (e.g., fibrin, thrombin, platelets) to dormant cancer stem cells (CSCs). Functionally, these influences may be tantamount to formation of a provisional (TF-dependent) cancer stem cell niche. As such, these changes may contribute to the involvement of CSCs in tumor growth, angiogenesis, and metastasis.

Topics: Blood Coagulation Disorders; Disease Progression; Neoplasms; Neovascularization, Pathologic; Oncogenes; Thromboplastin; Up-Regulation

Superwarfarins are anticoagulant rodenticides similar to warfarin, but which have various substituted phenyl groups replacing the terminal methyl group, resulting in a fat-soluble, long-acting anticoagulant that is nearly 100 times more potent than the parent compound. Since their development, many accidental and intentional cases of consumption have been reported. We describe two cases of consumption, one related to unknown etiology, and the other related to utilization of the superwarfarin to potentiate a drug of abuse. The clinical manifestations including bleeding symptoms and abnormal coagulation assays are discussed. The differential diagnosis is quite broad, and includes all causes of vitamin K deficiency, factor deficiency or inhibitor, disseminated intravascular coagulation (DIC), and liver disease. Differentiating superwarfarin ingestion from the other causes can be quite difficult, but extremely important, as management requires prolonged administration of vitamin K. Other treatment options are discussed as well including, fresh frozen plasma (FFP), and recombinant factor VIIa. Finally, the significance of "lacing" drugs of abuse with superwarfarin to potentiate their effect is discussed, as well as the complications that could develop from such a habit.

Topics: 4-Hydroxycoumarins; Adult; Blood Coagulation Disorders; Diagnosis, Differential; Humans; Male; Middle Aged; Pain; Platelet Count; Prothrombin Time; Thromboplastin; Time Factors; Vitamin K Deficiency

Patients with sickle cell disease (SCD) exhibit high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis steady state. In addition, platelets and other cellular elements are chronically activated in the non-crisis state. Despite an abundance of evidence for coagulation and platelet activation, it remains uncertain whether these changes contribute to the pathophysiology of SCD or are, rather, simple epiphenomena. With the occurrence of macrovascular thrombotic complications in SCD, as well as the recognition that soluble CD40 ligand is biologically active in SCD, coagulation and platelet activation may indeed play a role in SCD pathophysiology. Defining a role for hypercoagulability in SCD requires further understanding of its pathogenesis. Furthermore, the conduct of well-controlled clinical trials using anticoagulants and antiplatelet agents and using a variety of clinical endpoints is warranted.

Topics: Anemia, Sickle Cell; Blood Coagulation Disorders; Blood Platelets; Endothelium, Vascular; Humans; Thromboplastin

Progression of human malignancies is accompanied by vascular events, such as formation and remodeling of blood vessels and systemic coagulopathy. Though long appreciated as comorbidity of cancer (Trousseau syndrome), vascular involvement is increasingly recognized as a central pathogenetic mechanism of tumor growth, invasion and metastasis. The major outstanding question in relation to this role has been, whether vascular perturbations are simply a reaction to the conditions of the tumor microenvironment, or are linked to the known genetic lesions causal for the onset and progression of malignancy. In this regard, we have previously hypothesized, and recently demonstrated experimentally that deregulation of certain hemostatic mechanisms, namely upregulation of tissue factor (TF) and possibly other changes (e.g. expression of thrombin receptor - PAR-1) are controlled by cancer-associated oncogenic events, such as activation of K-ras, epidermal growth factor receptor (EGFR), or inactivation of the p53 tumor suppressor gene in various human cancer cells. It appears that these respective transforming alterations exert their impact on both, cell-associated and soluble/circulating (microvesicle- associated) TF, i.e. may cause a systemic hypercoagulable state. Other genes, which more recently emerged as regulators of cancer coagulopathy include: PML-RARalpha, PTEN, and MET. While the spectrum of procoagulant targets of these genes may vary somewhat it includes: TF, PAI-1, COX-2 and possibly other hemostatic proteins. It is noteworthy that these prothrombotic changes may impact the malignant process directly (e.g. stimulate angiogenesis, tumor growth or metastasis) as a consequence of both coagulation-dependent and -independent effects. The latter are mostly related to cellular signaling events and changes in gene expression which are now known to be induced by the TF/FVIIa/Xa complex, thrombin and PARs, expressed on the surface of cancer cells, as well as tumor-associated endothelium. Interestingly, certain anticoagulants possess antimetastatic and anticancer properties (e.g. LMWH), an observation that further suggests that hypercoagulability may act as an effector mechanism of genetically driven tumor progression. Conversely, we suggest that oncogene-directed (targeted) anticancer agents could, at least in some cases, ameliorate not only cellular transformation itself, but also some of the chronic components of the cancer-related coagulopathy, something that ma

Topics: Animals; Blood Coagulation Disorders; Disease Progression; Genes, Tumor Suppressor; Hemostasis; Humans; Neoplasms; Neovascularization, Pathologic; Paraneoplastic Syndromes; Thromboplastin

The adhesion receptor P-selectin has long been known to support leukocyte rolling and emigration at sites of inflammation. Recently, P-selectin was also revealed to be a key molecule in hemostasis and thrombosis, mediating platelet rolling, generating procoagulant microparticles containing active tissue factor and enhancing fibrin deposition. Elevated levels of plasma P-selectin are indicative of thrombotic disorders and predictive of future cardiovascular events. Because the interaction between P-selectin and its receptor P-selectin glycoprotein ligand-1 (PSGL-1) represents an important mechanism by which P-selectin induces the formation of procoagulant microparticles and recruits the microparticles to thrombi, anti-thrombotic strategies are currently aimed at inhibiting this interaction. Recent developments also suggest that the procoagulant potential of P-selectin could be used to treat coagulation disorders such as hemophilia A.

Topics: Animals; Blood Coagulation Disorders; Cardiovascular Diseases; Cell Adhesion; Fibrin; Humans; Inflammation; Leukocytes; Membrane Glycoproteins; Mice; Models, Biological; P-Selectin; Phenotype; Protein Binding; Protein Structure, Tertiary; Thromboplastin; Thrombosis

The biochemical mechanisms by which activated platelets participate in exposing receptors for the assembly of enzyme-cofactor-substrate complexes at all stages of the blood coagulation cascade are reviewed. Information derived from studies conducted during the last 30 years supports the concept that the initiation of blood coagulation is triggered by exposure of tissue factor at injury sites, leading to the generation of minute quantities of thrombin (limited by tissue factor pathway inhibitor), sufficient to activate platelets, factors XI, VIII, and V, and trigger the consolidation pathway (i.e., the sequential activation of factors XI, IX, X, and prothrombin on the activated platelet surface), leading to the generation of sufficient thrombin to convert fibrinogen to fibrin and effect hemostasis. Platelets localize coagulation to the hemostatic thrombus and protect coagulation enzymes from inhibition by both plasma and platelet inhibitors (e.g., protease nexin 2), thus preventing disseminated intravascular coagulation.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Hemostasis; Humans; 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

The aim of this paper is to review the thrombogram and its use for phenotyping the haemostatic system. The thrombogram can be readily obtained through Calibrated Automated Thrombography (CAT), using a commercially available fluorometer, dedicated software (Thrombinoscope) and a calibrator. Here we explore the possibility to use platelet-rich plasma (PRP) triggered with a low amount of recombinant human tissue factor (approximately 0.5 pM) and also explore the function of the protein C system by adding activated protein C (APC) or soluble recombinant thrombomodulin (TM). Examples are shown: inherited antithrombin (AT) and protein C deficiencies, and antiphospholipid antibodies.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Platelets; Calibration; Fluorometry; Hemostasis; Humans; Phenotype; Plasma; Protein C; Recombinant Proteins; Risk; Software; Specimen Handling; Thrombomodulin; Thromboplastin; Thrombosis; Time Factors

To present and discuss the rationale and the results of clinical trials using supplementation with physiologic anticoagulants (Tissue Factor Pathway Inhibitor (TFPI), AntiThrombin (AT), and Protein C (PC) in patients with severe sepsis.. An early activation of the coagulation cascade occurs in severe sepsis. TFPI, AT, and PC are major inhibitors of the coagulation cascade, and additionally modulate inflammatory and vascular reactions. They are consumed or inhibited in the sepsis pathologic process. Therapeutic supplementation with these inhibitors could improve the sepsis-induced organ failures and mortality.. Randomized controlled studies were recently completed. No effect on the mortality rate could be documented after treatment with recombinant TFPI. AT concentrates neither improve mortality, but a biological interaction with heparin therapy could have biased the study results. Treatment with recombinant activated PC (alpha-drotrecogin) was associated with a significant reduction in the mortality rate of severely ill patients and received recently the approval from FDA and EC authorities in this indication. An increase in the rate of hemorrhagic adverse effects has been observed with these compounds, justifying a strict observance of contraindications and of patients selection. PROSPECTIVE: Additional studies are needed to give confirmation of the positive effects of activated PC supplementation in less severely ill patients, children and specific clinical situations. The effects of new anticoagulant compounds are currently evaluated in preclinical studies.

Topics: Anticoagulants; Antithrombins; Blood Coagulation Disorders; Drug Evaluation, Preclinical; Drug Interactions; Drug Monitoring; Heparin; Humans; Inflammation; Multiple Organ Failure; Patient Selection; Protein C; Randomized Controlled Trials as Topic; Recombinant Proteins; Sepsis; Severity of Illness Index; Thromboplastin; Treatment Outcome

Tissue factor (TF) is the primary cellular initiator of blood coagulation. At sites of vascular injury, formation of a TF:FVIIa complex leads to the generation of FXa, thrombin and the deposition of fibrin to limit hemorrhage. In contrast to its beneficial role in hemostasis, TF initiates life-threatening intravascular thrombosis in sepsis, atherosclerosis and cancer. More recently, TF has been proposed to play a role in other biological processes, including tumor-associated angiogenesis, metastasis and inflammation. Indeed, gene targeting of TF resulted in embryonic lethality, which appeared to be due to a defect in the yolk sac vasculature.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Gene Silencing; Gene Targeting; Hemostasis; Humans; Mice; Neoplasm Metastasis; Neovascularization, Physiologic; Signal Transduction; Thrombin; Thromboplastin; Yolk Sac

To review the preclinical and clinical evidence that provides the therapeutic rationale for recombinant human tissue factor pathway inhibitor (rTFPI) as a novel treatment for human sepsis.. A summary of published English-language literature regarding preclinical studies and limited information published about three phase II clinical studies for the evaluation of rTFPI safety in sepsis patients.. Tissue factor pathway inhibitor, the physiologic inhibitor of the tissue factor pathway, interrupts activation of coagulation at multiple steps, including tissue factor VIIa activity, Xa activity, prothrombinase complex, and thrombin generation. Recombinant human TFPI exhibits anticoagulant and anti-inflammatory activities in animal models and humans with sepsis. These activities appear to have an important therapeutic role in protecting the microvasculature from injury and preventing multiple organ failure in sepsis.. Tissue factor pathway inhibitor is a potent inhibitor of clotting in the microvasculature, which is thought to protect organs from injury. Recombinant TFPI improved survival of septic animals in multiple models. Recent phase II results suggest that rTFPI is well tolerated, and they show a trend toward reduction in 28-day all-cause mortality in rTFPI-treated patients; in addition, rTFPI demonstrated significant reduction in thrombin generation. These results suggest that a powered study is indicated to further evaluate rTFPI utility for the adjunctive management of severe sepsis.

Topics: Animals; Anticoagulants; Blood Coagulation Disorders; Disease Models, Animal; Drug Evaluation, Preclinical; Fibrinolytic Agents; Humans; Inflammation; Lipoproteins; Sepsis; Survival Analysis; Thromboplastin; Treatment Outcome

Topics: Biochemistry; Blood Coagulation; Blood Coagulation Disorders; Factor Xa; History, 19th Century; History, 20th Century; Humans; Molecular Biology; Prothrombin Time; Terminology as Topic; Thromboplastin

Cytokines are low molecular weight polypeptides that act as pleiotropic mediators of inflammation and may contribute significantly to regulation of hemostatic balance in both physiologic and pathologic conditions. The purpose of this review is to underline the most significant progresses recently achieved in this rapidly growing area.. The authors have been involved both at home and abroad in experimental and clinical research in this field for years and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles published in journals covered by the Science Citation Index and Medline.. Tissue factor, a transmembrane glycoprotein that serves as a surface receptor for coagulation factor VIIa, plays a key role in the initiation of coagulation processes. Very little, if any, tissue factor activity is detectable in normal conditions on the cell surface of monocytes and endothelial cells. However, upon proper stimulation by a number of agents such activity may be expressed in these cells, which can then contribute significantly to clotting activation. Pro-inflammatory cytokines (IL-1, IL-6 and TNF) are effective inducers of tissue factor upregulation and may trigger endothelial cells to change their antithrombotic properties into a procoagulant, clot-promoting state. Indeed, much experimental and clinical evidence has been accumulated to suggest that cytokines play a key role in the pathophysiology of hemostatic abnormalities in different disease states. These include, inter alia, the coagulopathy observed during septicemia, the veno-occlusive disease of the liver after bone marrow transplantation, the prothrombotic state associated with atherosclerotic vessels, the occurrence of deep venous thrombosis after major abdominal surgery and the thrombotic tendency of patients with cancer. Several new antithrombotic strategies based on these new concepts have been attempted in experimental models of thrombosis and also in man. Examples of new possible antithrombotic agents are the tissue factor pathway inhibitor, Fab fragments of monoclonal antibodies directed against factor VII or factor VIIa, mutant forms of biologically inactive tissue factor and inhibition of cytokines involved in the regulation of tissue factor expression. Many of these studies have produced positive or interesting results, although more must be learned before the appropriate drug and the adequate dose are defined in the different clinical situations.. Pro-inflammatory cytokines (IL-1, IL-6 and TNF) play a key role in tissue factor expression on monocytes and on endothelial cells and contribute significantly to regulation of hemostatic balance in physiologic and pathologic conditions. This effect is of great interest from both speculative and practical viewpoints.

Topics: Animals; Blood Coagulation Disorders; Cytokines; Fibrinolytic Agents; Hemostasis; Hemostatics; Humans; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Platelets; Cytokines; Fibrinolysis; Humans; Lung Neoplasms; Macrophages; Thromboplastin

Hemostasis is a result of interactions between fibrillar structures in the damaged vessel wall, soluble components in plasma, and cellular elements in blood represented mainly by platelets and platelet-derived material. During formation of a platelet plug at the damaged vessel wall, factors IXa and VIIIa form the "tenase" complex, leading to activation of factor X on the surface of activated platelets. Subsequently, factors Xa and Va form the "prothrombinase" complex, which catalyzes the formation of thrombin from prothrombin, leading to fibrin formation. An enhanced expression of negatively charged phosphatidylserine in the outer membrane leaflet resulting from a breakdown of the phospholipid asymmetry is essential for the formation of the procoagulant surface. An ATP-driven and inward-acting aminophospholipid "translocase" and a "floppase" counterbalancing this have been postulated to maintain the dynamic state of phospholipid asymmetry. A phospholipid-nonspecific "scramblase," believed to be responsible for the fast breakdown of the asymmetry during cell activation, has recently been isolated from erythrocytes, cloned, and characterized. An intracellular calcium-binding segment and one or more thioesterified fatty acids are probably of importance for calcium-induced activation of this transporter protein. Cytosolic calcium ions also activate the calcium-dependent protease calpain associated with shedding of microvesicles from the transformed platelet membrane. These are shed with a procoagulant surface and with surface-exposed P-selectin from the alpha-granules. Theoretically, therefore, microvesicles can be involved in both coagulation and inflammation. Scott syndrome is probably caused by a defect in the activation of an otherwise normal scramblase, resulting in a relatively severe bleeding tendency. In Stormorken syndrome, the patients demonstrate a spontaneous surface expression of aminophospholipids. Activated platelets and the presence of procoagulant microvesicles have been demonstrated in several clinical conditions, such as thrombotic and idiopathic thrombocytopenia, disseminated intravascular coagulation, and HIV-1 infection, and have been found to be associated with fibrin in thrombosis. Procoagulant microvesicles may also be formed from other cells as a result of apoptosis.

Topics: Blood Coagulation Disorders; Blood Platelets; Hemostasis; Humans; Microcirculation; Thromboplastin

TF (tissue factor) is a physiological inhibitor of blood coagulation in normal hemostasis and is a major initiator of clotting in thrombotic disease. TF functions as a protein cofactor for FVIIa. Coagulation at a site of injury is initiated by exposure of blood to cell-surface formation of TF/VIIa complex. The TF/VIIa complex then activates both factors IX and X leading to thrombin generation and fibrin formation. TFPI (tissue factor pathway inhibitor) appears to play a primary role in regulating TF-induced coagulation. Abnormal coagulation may contribute to the pathogenesis of many serious illnesses. In particular, induced expression of TF and TF-mediated coagulation occurs in atherosclerotic plaques, sepsis, malignancy, ARDS and glomerulonephritis. Several observations support the need for exogenous TFPI administration to effectively turn off the TF/VIIa complex in several clinical conditions with TF-induced coagulopathy. There are some reports about successful administration of rTFPI for antithrombotic therapy in humans.

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Drug Interactions; Factor Xa Inhibitors; Hemostasis; Heparin; Humans; Lipoproteins; Reference Values; Thromboplastin

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: Amino Acid Sequence; Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Enzyme Activation; Enzyme Precursors; Factor VIIa; Female; Humans; Lipoproteins; Male; Molecular Sequence Data; Protein Conformation; Thromboplastin

Certain epidemiological studies have implicated elevated factor VII coagulant activity as a risk factor for ischaemia heart disease. However, progress in understanding the clinical significance of elevated plasma factor VII levels has been hampered by: (1) differences between laboratories in the methodology for measuring factor VII; (2) the existence of multiple forms of factor VII in plasma (i.e. factor VIIa, zymogen factor VII, and a possible phospholipase-sensitive form of factor VII); (3) the resulting uncertainty regarding what is actually being measured in factor VII coagulant assays. Recent mutagenesis studies of tissue factor (the obligate protein cofactor for factor VIIa) have led to new assay technologies capable of quantifying trace levels of plasma factor VIIa without interference from zymogen factor VII. This review article focuses on the current status of measurement of plasma factor VII/VIIa levels and the relationship between various plasma forms of factor VII and risk of thrombotic disease.

Topics: Blood Coagulation Disorders; Factor VII; Factor VIIa; Humans; Thromboplastin

Topics: Blood Coagulation Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Thromboplastin

Tissue factor (TF) exists in a cryptic form [i.e. without procoagulant activity (PCA)] in peripheral blood monocytes and quiescent tissue macrophages but is expressed constitutively in most human tumor cells. Induction and cell surface expression of TF in these cells in vivo is associated with activation of intravascular and extravascular coagulation in patients with a variety of inflammatory or malignant diseases. The regulation of TF synthesis in cells is complex and new information from transfection studies suggests that changes in cellular glycosylation pathways impair cell surface expression of functional TF. Such dysregulation may also characterize the lineage-unfaithful expression of TF in leukemic cells and perhaps explain some of the thrombohemorrhagic complications in patients with acute progranulocytic leukemia. The importance of carbohydrate modification of TF is reviewed.

Topics: Acute Disease; Animals; Blood Coagulation Disorders; Carbohydrate Sequence; Cell Differentiation; CHO Cells; Cricetinae; Cricetulus; Cysteine Endopeptidases; Glycosylation; HL-60 Cells; Humans; Leukemia; Leukocytes; Molecular Sequence Data; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Thromboplastin

Monocytes/macrophages and endothelial cells express tissue factor (TF), an initiator for blood clotting pathway, following their activation accompanied by immune response and/or inflammation. This TF expression results in thrombin generation and fibrin formation around these cells and possibly participates in host-defense mechanism. TF expression by these cells is also a risk-factor to vascular diseases including arteriosclerosis and thrombosis. In cancer and leukemia patients elevation of their plasma TF level associated with DIC and related coagulation disorders.

Topics: Animals; Blood Coagulation Disorders; Humans; Immunity, Cellular; Thrombin; Thromboplastin; Vascular Diseases

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

Some effects of bacterial endotoxin on leukocytes and platelets are reviewed. The release of two mediators, Leukocyte Inhibiting Factor (LIF) and Tissue Factor (TF) from human mononuclear cells are described. These factors may play either beneficial effects (LIF) or noxious activities (TF liberation in certain pathological conditions). Regarding the activities of LPS on platelets the AA. report some personal data about the electrokinetic modification of platelets due to endotoxin. This LPS effect can be performed directly or via a lymphokine release, Platelet Slowing Factor (PSF). In the light of all the mentioned considerations, a scheme of interaction LPS/platelets is suggested.

Topics: Animals; Blood Coagulation Disorders; Blood Platelets; Humans; Infant, Newborn; Leukocytes; Lipopolysaccharides; Lymphokines; Mice; Rabbits; Rats; T-Lymphocytes; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Transfusion; Calcium; Factor V Deficiency; Factor VIII; Factor X Deficiency; Factor XI Deficiency; Factor XII Deficiency; Factor XIII Deficiency; Female; Hemophilia A; Hemophilia B; Humans; Hypoprothrombinemias; Male; Pedigree; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Capillary Permeability; Factor VII; Factor XII; Factor XII Deficiency; Hemostasis; Humans; Kininogens; Molecular Weight; Plasminogen; Prekallikrein; Syndrome; Thromboplastin

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Child; Factor X; Factor XII; Female; Fibrinolysin; Fibrinolysis; Hemostasis; Humans; Lipoproteins; Male; Prothrombin Time; Purpura, Thrombocytopenic; Thrombin; Thromboplastin; Thrombosis; von Willebrand Diseases

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 Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Calcium; Factor IX; Factor V; Factor VIII; Factor X; Factor XII; Fibrin; Fibrinogen; Humans; Liver Diseases; Phospholipids; Prothrombin; Prothrombin Time; Thromboplastin; Vitamin K Deficiency

Topics: Aminocaproates; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Proteins; Hemophilia A; Hemorrhagic Disorders; Humans; Plasminogen; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Butter; Chromatography, Thin Layer; Contraceptives, Oral, Synthetic; Dietary Fats; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Male; Oils; Phosphatidylethanolamines; Phosphatidylinositols; Phosphatidylserines; Pregnancy; Rabbits; Rats; Thromboplastin; Thrombosis; Time Factors; Wounds and Injuries; Zea mays

Topics: Adult; Antibodies; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Transfusion; Factor VIII; Female; Hemophilia A; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Prothrombin Time; Thrombin; Thromboplastin

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: Aminocaproates; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Transfusion; Factor V Deficiency; Factor VII Deficiency; Factor VIII; Fibrinogen; Freezing; Hemophilia A; Hemophilia B; Hemorrhage; Hemostasis; Humans; Hypoprothrombinemias; Plasma; Plasma Volume; Prothrombin; Prothrombin Time; Thromboplastin; Vitamin K

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Factor VIII; Fibrinolytic Agents; Hematuria; Hemostasis; Heparin; Humans; Kidney; Kidney Cortex Necrosis; Kidney Transplantation; Methods; Renal Dialysis; Thromboembolism; Thromboplastin; Uremia

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Animals; Antigen-Antibody Reactions; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Catecholamines; Dibenzylchlorethamine; Endotoxins; Female; Fibrinolysis; Haplorhini; Hemolysis; Hemorrhage; Humans; Kidney; Microscopy, Electron; Mononuclear Phagocyte System; Necrosis; Phagocytosis; Phenoxybenzamine; Pregnancy; Pregnancy, Animal; Shock, Septic; Shwartzman Phenomenon; Thromboplastin

Topics: Abruptio Placentae; Adrenal Glands; Aminocaproates; Animals; Basement Membrane; Biopsy; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Brain; Female; Fibrin; Fibrinogen; Fibrinolysis; Fluorescent Antibody Technique; Hemorrhage; Hemorrhagic Disorders; Heparin; Humans; Hypertension, Malignant; Kidney Cortex Necrosis; Kidney Failure, Chronic; Kidney Glomerulus; Liver; Maternal Mortality; Microscopy, Electron; Myocardium; Placental Extracts; Pre-Eclampsia; Pregnancy; Rabbits; Shwartzman Phenomenon; Thromboplastin; Thrombosis

Topics: Aminocaproates; Animals; Anticoagulants; Antifibrinolytic Agents; Antigens; Aprotinin; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Chromatography; Chromatography, Gel; Dogs; Epidermolysis Bullosa; Fibrinogen; Fibrinolysis; Hematocrit; Immunoelectrophoresis; Injections, Intravenous; Iodine Isotopes; Liver Cirrhosis; Peptides; Polycythemia Vera; Potassium Iodide; Thrombin; Thromboplastin; Thrombosis

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Flow Velocity; Child; Child, Preschool; Clinical Laboratory Techniques; Dextrans; Female; Fibrinolytic Agents; Glomerulonephritis; Hemangioma, Cavernous; Heparin; Humans; Infections; Liver Cirrhosis; Male; Mycoses; Parasitic Diseases; Pregnancy; Pregnancy Complications; Purpura; Shock; Thrombocytopenia; Thromboplastin; Uremia

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Cell Membrane Permeability; Fibrinogen; Fibrinolysis; Hemorrhagic Disorders; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Thrombocythemia, Essential; Thrombocytopenia; Thromboplastin

Topics: Abortion, Induced; Abruptio Placentae; Afibrinogenemia; Amniotic Fluid; Anticoagulants; Blood Coagulation Disorders; Embolism; Embolism, Amniotic Fluid; Female; Fetal Death; Fibrinolysis; History; Humans; Obstetrics; Postpartum Hemorrhage; Postpartum Period; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Thromboplastin

Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver of disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown.. ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days.. rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8.. URL: https://www.. gov; Unique identifier: NCT04655586.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; COVID-19; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Heparin; Humans; Inflammation; Male; Middle Aged; Thromboplastin; Venous Thromboembolism

The hypercoagulable state caused by the use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been cited in anecdotal reports. Since tissue factor (TF) is the main initiator of the coagulation cascade, we examined if rhG-CSF had an inductive effect on the TF-dependent pathway in 18 healthy donors receiving rhG-CSF (10 microg/kg/day x 5 days) for peripheral blood progenitor cell mobilization. After rhG-CSF, there were increases both in TF antigen (TF:Ag) (P=0.01) and TF procoagulant activity (TF:PCA) (P=0.06) plasma levels and in TF:Ag cytofluorimetric expression on CD33 (+) cells (P=0.04). Mean activities of FVIII and vWF also increased significantly. Thrombin time was slightly prolonged (P=0.06) due to significant increases in plasma D-dimer levels. In addition, while FIX activity remained stable, there were marked reductions in mean plasma FX and FII activities and a slight decrease in FVII activity that resulted in a significant prolongation of prothrombin time within normal ranges. In conclusion, the administration of rhG-CSF led to a "prothrombotic state" via stimulation of TF and increased endothelial markers, such as F VIII and vWF. In the light of these findings, the use of rhG-CSF for stem cell mobilization should be undertaken cautiously in healthy donors with underlying thrombotic risk factors.

Topics: Adult; Blood Coagulation; Blood Coagulation Disorders; Factor IX; Factor VII; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Prothrombin; Recombinant Proteins; Thrombin Time; Thromboplastin; Tissue Donors

Clinical trials show that interleukin (IL)-6 represents a predictive marker in human sepsis. Furthermore, IL-6 has been proposed as a candidate mediator for endotoxin (lipopolysaccharide)-induced coagulation activation: In a primate model, an (alphaIL-6 antibody (alphaIL-6 Ab) almost abolished lipopolysaccharide-induced coagulation activation. Therefore, we wished to determine if an alphaIL-6 Ab (B-E8) may also attenuate lipopolysaccharide-induced activation of coagulation in humans.. The study was a randomized, double blind, placebo-controlled parallel group trial (n = 12 per group).. University medical center.. Healthy volunteers.. Healthy volunteers were randomized to receive either 80 mg of a monoclonal anti-IL-6 Ab (B-E8) or placebo intravenously before bolus infusion of 2 ng/kg lipopolysaccharide.. B-E8 effectively decreased IL-6 bioactivity as measured by a Bg-bioassay in vitro and concentrations of C reactive protein. However, B-E8 did not decrease lipopolysaccharide-induced tissue factor-messenger RNA transcription or plasma concentrations of downstream coagulation variables (prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, and D-dimer concentrations). Similarly, tumor necrosis factor-alpha concentrations, fibrinolytic activity (plasmin-antiplasmin complexes), endothelial activation (soluble E-selectin), and IL-10 were unaffected.. IL-6 does not appear to mediate early-phase lipopolysaccharide-induced coagulation activation in humans.

Topics: Adult; Antibodies, Monoclonal; Blood Coagulation Disorders; C-Reactive Protein; Dose-Response Relationship, Immunologic; Double-Blind Method; E-Selectin; Endotoxemia; Escherichia coli; Escherichia coli Infections; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Humans; Infusions, Intravenous; Interleukin-10; Interleukin-6; Lipopolysaccharides; Male; Polymerase Chain Reaction; Thromboplastin; Transcription, Genetic; Treatment Outcome; Tumor Necrosis Factor-alpha

Complex coagulopathies follow cardiopulmonary bypass (CPB) in children. However, objective laboratory data that can be acquired rapidly to guide their management are lacking. Because thromboelastography has proven useful in this regard, we evaluated the use of celite or tissue factor (TF) activation and heparinase modification of blood samples to allow rapid determination of thromboelastogram data in children younger than 2 yr undergoing CPB. Celite or TF activation shortened the initiation of clotting and, thus, the time required for the important thromboelastogram alpha and maximum amplitude values to begin evolving. Although thromboelastogram alpha and maximum amplitude values were increased with these activators, correlations persisted between platelet count or fibrinogen level and each of these values. The additional use of heparinase allowed thromboelastograms to be obtained during CPB with values not different from those obtained without heparinase after protamine administration. Therefore, celite- or TF-activated, heparinase-modified thromboelastograms begun during CPB allow objective data to be available by the conclusion of protamine administration to help restore hemostasis after CPB in children. Thromboelastography identified transient fibrinolysis during CPB in some children that resolved by the conclusion of protamine administration. Future investigations of the effectiveness of modified thromboelastography-guided coagulopathy management after CPB in children are needed.. Thromboelastography is useful in assessing the coagulopathies that follow cardiopulmonary bypass in children. Modifying blood samples with celite or tissue factor and heparinase allows thromboelastography begun before the termination of cardiopulmonary bypass to become a rapid point-of-care monitor to provide objective data for guiding blood component therapy to manage these coagulopathies.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Cardiopulmonary Bypass; Diatomaceous Earth; Female; Hemostatics; Heparin; Heparin Antagonists; Heparin Lyase; Humans; Infant; Infant, Newborn; Male; Postoperative Complications; Protamines; Thrombelastography; Thromboplastin

The area under the thrombin generation curve (the endogenous thrombin potential; ETP) has been proposed as a parameter for plasma-based hypercoagulability and to monitor anticoagulant treatment. We present an ETP assay for the routine laboratory using a centrifugal analyser. Throughput is 30 samples/h, within and between run imprecision is 4-5.6%. Suitable substrates were developed for the ranges of 10-500% and 2-100% of normal. Independent of tissue factor concentration (if > 4 pM), the normal value of the extrinsic ETP is 384.8 +/- 51.7 nM.min. The intrinsic ETP, triggered by ellagic acid, is 414 +/- 41 nM.min. The ETP is decreased to 15 and 35% of normal by oral anticoagulation (INR 2.5-4.0) and by heparin administration (APTT 1.5-2.5 x control). The ETP is increased in untreated subjects with congenital antithrombin deficiency and in women using oral contraceptives. In deep vein thrombosis (phlebographically confirmed), it is increased by 29.4% (extrinsic) and 53% (intrinsic). In (angiographically assessed) coronary artery disease the increase is by 10% and 17% respectively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Area Under Curve; Blood Coagulation Disorders; Diagnostic Tests, Routine; Disease Susceptibility; Female; Humans; Male; Middle Aged; Reference Values; Reproducibility of Results; Thrombin; Thromboplastin; Thrombosis

Three members of a Virginia family with a bleeding disorder were found to have a serum defect in thromboplastin generation similar to the previously reported "Car. factor" deficiency. Sera from three members of the original Car. family did not correct the defect of affected members of the Virginia family. Partial thromboplastin times of Car. deficient individuals and affected members of the Virginia family were normal. Although correction with normal serum is attained in vitro, the serum defect persisted after infusion of fresh frozen plasma. Platelet function studies of the Virginia family revealed less than 30% aggregation after the addition of exogenous ADP and disaggregation within 2 min. Evaluation of children with Noonan's syndrome, albinism, and "Portsmouth" syndrome showed coexistent platelet aggregation defects and nonspecific serum defects.

Topics: Adenosine Diphosphate; Adolescent; Adult; Aspirin; Black People; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Blood Protein Electrophoresis; Child; Child, Preschool; Clinical Trials as Topic; Collagen; Female; Humans; Male; Norepinephrine; Platelet Adhesiveness; Platelet Aggregation; Thrombin; Thromboplastin; White People

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with excessive coagulation, thrombosis, and mortality.. To provide insight into mechanisms that contribute to excessive coagulation in coronavirus 2019 (COVID-19) disease.. Blood from COVID-19 patients was investigated for coagulation-related gene expression and functional activities.. Beyond local lung injury, SARS-CoV-2 infection increases systemic TF (F3) transcript levels and elevates circulating extracellular vesicles that likely contribute to disease-associated coagulation, thrombosis, and related mortality.

Topics: Blood Coagulation Disorders; COVID-19; Extracellular Vesicles; Humans; Leukocytes, Mononuclear; SARS-CoV-2; Thromboplastin; Thrombosis

Viscoelastic coagulation monitor (VCM-Vet) is a point-of-care device that has been used to characterize hemostatic abnormalities in sick pets but has not been validated in veterinary patients.. We aimed to compare VCM-Vet and thromboelastography (TEG) in sick dogs with suspected disorders of hemostasis.. Duplicate VCM-Vet tests using untreated native blood performed concurrently on two VCM-Vet machines, and simultaneous TEG tests were performed (one citrated native (CN), and one activated with tissue factor (TF) at a 1:3600 dilution). Each VCM-Vet result was compared with both TF-activated and CN TEG.. Fifty-three dogs were enrolled. Eleven cases displayed apparent hyperfibrinolysis. Spearman correlation coefficients for individual VCM-Vet devices and CN and TF TEG were obtained between R and CT values and ranged from 0.21 to 0.27, CFT and K (r = 0.60-0.67), angles (r = 0.51-0.62), and MCF and MA (r = 0.85-0.87). Comparison of the two VCM-Vet devices displayed positive correlations for all clot formation parameters with Lin's concordance correlation coefficients of 0.75-0.95. Variable lysis parameter agreement existed between the VCM-Vet devices and VCM-Vet and TEG. When samples were classified as hypercoagulable or coagulopathic, VCM-Vet had a low positive predictive value (17-33%) for the detection of hypercoagulable states and a moderate negative predictive value (64-74%) for the detection of coagulopathy as defined by TEG.. VCM-Vet and TEG had variable correlations in clot formation values and a strong correlation for final clot strength. More information is needed to make conclusions about the lysis parameters. Artifact in the fibrinolysis portion of the test can confound the interpretation of VCM-Vet results.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Citrates; Citric Acid; Dog Diseases; Dogs; Hemostasis; Hemostatics; Point-of-Care Systems; Thrombelastography; Thromboplastin

Although cancer-associated thrombosis (CAT) is a frequent complication in patients with malignancies, its treatment remains a challenge in daily practice. Here, we report the clinical course of a 51-year-old woman presenting with a highly thrombogenic paraneoplastic coagulopathy. Despite therapeutic anticoagulation with various agents, including rivaroxaban, fondaparinux, and low-molecular-weight heparin, the patient suffered from recurrent venous and arterial thromboembolism. Locally advanced endometrial cancer was identified. Tumor cells showed strong expression of tissue factor (TF), and significant concentrations of TF-bearing microvesicles were detected in patient plasma. Coagulopathy was controlled only by continuous intravenous anticoagulation with the direct thrombin inhibitor, argatroban. Multimodal antineoplastic treatment, including neoadjuvant chemotherapy followed by surgery and postoperative radiotherapy, resulted in clinical cancer remission, which was paralleled by normalization of tumor markers, CA125 and CA19-9, D-dimer levels, and TF-bearing microvesicles. In summary, continuous anticoagulation with argatroban and multimodal anticancer treatment may be necessary to control TF-driven coagulation activation with recurrent CAT in endometrial cancer.. Obwohl die tumorassoziierte Thrombose (CAT) eine häufige Komplikation bei Patienten mit malignen Erkrankungen darstellt, bleibt ihre Behandlung in der täglichen Praxis eine Herausforderung. Wir berichten über den klinischen Fall einer 51-jährigen Patientin, die sich mit einer hochgradig thrombogenen paraneoplastischen Gerinnungsstörung vorstellte. Trotz therapeutischer Antikoagulation mit verschiedenen Präparaten, unter anderem Rivaroxaban, Fondaparinux und niedermolekulares Heparin, entwickelte die Patientin rezidivierende venöse und arterielle Thromboembolien. Es konnte ein lokal fortgeschrittenes Endometriumkarzinom nachgewiesen werden mit starker Expression von Gewebefaktor (Tissue-Faktor, TF) auf den Tumorzellen. Es fanden sich zudem signifikant erhöhte Konzentrationen von TF-tragenden Mikrovesikeln im Plasma der Patientin. Die Koagulopathie konnte nur durch eine kontinuierliche intravenöse Antikoagulation mit dem direkten Thrombininhibitor Argatroban kontrolliert werden. Eine multimodale antineoplastische Behandlung, einschließlich einer neoadjuvanten Chemotherapie mit anschließender Operation und postoperativer Strahlentherapie, führte zu einer klinischen Remission des Tumors, welche mit einer Normalisierung der Tumormarker CA125 und CA19–9, der D-Dimere und der TF-exprimierenden Mikrovesikel einherging. Somit könnte die Kombination aus kontinuierlicher Antikoagulation mit Argatroban und multimodaler Krebstherapie erforderlich sein, um eine TF-vermittelte paraneoplastische Koagulopathie mit rezidivierender CAT bei Patientinnen mit Endometriumkarzinom zu kontrollieren.

Topics: Anticoagulants; Blood Coagulation Disorders; Endometrial Neoplasms; Female; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Neoplasm Recurrence, Local; Thromboembolism; Thrombophlebitis; Thromboplastin; Venous Thromboembolism

Rotational thromboelastometry (ROTEM) is used to rapidly identify trauma-induced coagulopathy (TIC) and direct targeted interventions in hemorrhaging trauma patients. A novel technology, Quantra System (HemoSonics), utilizes sonic estimation of elasticity via resonance sonorheometry, avoids mechanical clot interference, and may increase diagnostic accuracy, but there are limited data on bleeding in major trauma patients.. To compare the performance of Quantra with that of ROTEM for rapid diagnosis of TIC and prediction of transfusion requirements and mortality.. Samples were collected from adult trauma patients enrolled in a perpetual cohort study upon admission to a single level 1 trauma center between 2020 and 2021. Samples were analyzed using Quantra, ROTEM, multiple electrode aggregometry, and conventional coagulation assays.. Quantra and ROTEM have similar diagnostic performances in evaluating TIC and predicting clinically relevant outcomes. Larger studies are required to determine the utility of Quantra for goal-directed treatment of TIC.

Topics: Adult; Blood Coagulation Disorders; Cohort Studies; Fibrinogen; Hemorrhage; Humans; Prognosis; Thrombelastography; Thromboplastin

Conventional clotting tests are not expeditious enough to allow timely targeted interventions in trauma, and current point-of-care analyzers, such as rotational thromboelastometry (ROTEM), have limited sensitivity for hyperfibrinolysis and hypofibrinogenemia.. To evaluate the performance of a recently developed global fibrinolysis capacity (GFC) assay in identifying fibrinolysis and hypofibrinogenemia in trauma patients.. Exploratory analysis of a prospective cohort of adult trauma patients admitted to a single UK major trauma center and of commercially available healthy donor samples was performed. Lysis time (LT) was measured in plasma according to the GFC manufacturer's protocol, and a novel fibrinogen-related parameter (percentage reduction in GFC optical density from baseline at 1 minute) was derived from the GFC curve. Hyperfibrinolysis was defined as a tissue factor-activated ROTEM maximum lysis of >15% or LT of ≤30 minutes.. Compared to healthy donors (n = 19), non-tranexamic acid-treated trauma patients (n = 82) showed shortened LT, indicative of hyperfibrinolysis (29 minutes [16-35] vs 43 minutes [40-47]; p < .001). Of the 63 patients without overt ROTEM-hyperfibrinolysis, 31 (49%) had LT of ≤30 minutes, with 26% (8 of 31) of them requiring major transfusions. LT showed increased accuracy compared to maximum lysis in predicting 28-day mortality (area under the receiver operating characteristic curve, 0.96 [0.92-1.00] vs 0.65 [0.49-0.81]; p = .001). Percentage reduction in GFC optical density from baseline at 1 minute showed comparable specificity (76% vs 79%) to ROTEM clot amplitude at 5 minutes from tissue factor-activated ROTEM with cytochalasin D in detecting hypofibrinogenemia but correctly reclassified >50% of the patients with false negative results, leading to higher sensitivity (90% vs 77%).. Severe trauma patients are characterized by a hyperfibrinolytic profile upon admission to the emergency department. The GFC assay is more sensitive than ROTEM in capturing hyperfibrinolysis and hypofibrinogenemia but requires further development and automation.

Topics: Adult; Afibrinogenemia; Blood Coagulation Disorders; Fibrinolysis; Humans; Prospective Studies; Thrombelastography; Thromboplastin; Wounds and Injuries

The coagulopathy of traumatic brain injury (TBI) remains poorly understood. Contradictory descriptions highlight the distinction between systemic and local coagulation, with descriptions of systemic hypercoagulability despite intracranial hypocoagulopathy. This perplexing coagulation profile has been hypothesized to be due to tissue factor release. The objective of this study was to assess the coagulation profile of TBI patients undergoing neurosurgical procedures. We hypothesize that dura violation is associated with higher tissue factor and conversion to a hypercoagulable profile and unique metabolomic and proteomic phenotype.. This is a prospective, observational cohort study of all adult TBI patients at an urban, Level I trauma center who underwent a neurosurgical procedure from 2019 to 2021. Whole blood samples were collected before and then 1 hour following dura violation. Citrated rapid and tissue plasminogen activator (tPA) thrombelastography (TEG) were performed, in addition to measurement of tissue factory activity, metabolomics, and proteomics.. Overall, 57 patients were included. The majority (61%) were male, the median age was 52 years, 70% presented after blunt trauma, and the median Glasgow Coma Score was 7. Compared with pre-dura violation, post-dura violation blood demonstrated systemic hypercoagulability, with a significant increase in clot strength (maximum amplitude of 74.4 mm vs. 63.5 mm; p < 0.0001) and a significant decrease in fibrinolysis (LY30 on tPAchallenged TEG of 1.4% vs. 2.6%; p = 0.04). There were no statistically significant differences in tissue factor. Metabolomics revealed notable increases in metabolites involved in late glycolysis, cysteine, and one-carbon metabolites, and metabolites involved in endothelial dysfunction/arginine metabolism/responses to hypoxia. Proteomics revealed notable increase in proteins related to platelet activation and fibrinolysis inhibition.. A systemic hypercoagulability is observed in TBI patients, characterized by increased clot strength and decreased fibrinolysis and a unique metabolomic and proteomics phenotype independent of tissue factor levels.

Topics: Adult; Blood Coagulation Disorders; Brain Injuries, Traumatic; Cohort Studies; Female; Humans; Male; Middle Aged; Proteomics; Thrombelastography; Thrombophilia; Thromboplastin; Tissue Plasminogen Activator

Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and thrombocytopenia. APL cells express tissue factor (TF), a receptor and cofactor for factor VII/VIIa. This study had 2 goals. Firstly, we measured biomarkers of coagulation and fibrinolysis activation as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Secondly, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, and plasmin-antiplasmin complexes, reduced platelet counts, and increased tail bleeding in both mouse models of APL. Fibrinogen levels decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced the level of TAT, increased platelet count, and normalized tail bleeding in a xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased the levels of TAT but did not affect the platelet count. Our study demonstrates that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models of APL. These APL mouse models can be used to investigate the mechanisms of coagulopathy and thrombocytopenia in APL.

Topics: Animals; Antibodies, Monoclonal; Blood Coagulation; Blood Coagulation Disorders; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Rats; Thrombocytopenia; Thromboplastin

Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats.. Tissue factor expression of rat bone marrow-derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma.. Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow-derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe.. Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock.

Topics: Administration, Intravenous; Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Disease Models, Animal; Mesenchymal Stem Cell Transplantation; Multiple Trauma; Platelet Count; Rats; Shock, Hemorrhagic; Thromboplastin

COVID-19 causes hypercoagulability, but the association between coagulopathy and hypoxemia in critically ill patients has not been thoroughly explored. This study hypothesized that severity of coagulopathy would be associated with acute respiratory distress syndrome severity, major thrombotic events, and mortality in patients requiring intensive care unit-level care.. Viscoelastic testing by rotational thromboelastometry and coagulation factor biomarker analyses were performed in this prospective observational cohort study of critically ill COVID-19 patients from April 2020 to October 2020. Statistical analyses were performed to identify significant coagulopathic biomarkers such as fibrinolysis-inhibiting plasminogen activator inhibitor 1 and their associations with clinical outcomes such as mortality, extracorporeal membrane oxygenation requirement, occurrence of major thrombotic events, and severity of hypoxemia (arterial partial pressure of oxygen/fraction of inspired oxygen categorized into mild, moderate, and severe per the Berlin criteria).. In total, 53 of 55 (96%) of the cohort required mechanical ventilation and 9 of 55 (16%) required extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation-naïve patients demonstrated lysis indices at 30 min indicative of fibrinolytic suppression on rotational thromboelastometry. Survivors demonstrated fewer procoagulate acute phase reactants, such as microparticle-bound tissue factor levels (odds ratio, 0.14 [0.02, 0.99]; P = 0.049). Those who did not experience significant bleeding events had smaller changes in ADAMTS13 levels compared to those who did (odds ratio, 0.05 [0, 0.7]; P = 0.026). Elevations in plasminogen activator inhibitor 1 (odds ratio, 1.95 [1.21, 3.14]; P = 0.006), d-dimer (odds ratio, 3.52 [0.99, 12.48]; P = 0.05), and factor VIII (no clot, 1.15 ± 0.28 vs. clot, 1.42 ± 0.31; P = 0.003) were also demonstrated in extracorporeal membrane oxygenation-naïve patients who experienced major thrombotic events. Plasminogen activator inhibitor 1 levels were significantly elevated during periods of severe compared to mild and moderate acute respiratory distress syndrome (severe, 44.2 ± 14.9 ng/ml vs. mild, 31.8 ± 14.7 ng/ml and moderate, 33.1 ± 15.9 ng/ml; P = 0.029 and 0.039, respectively).. Increased inflammatory and procoagulant markers such as plasminogen activator inhibitor 1, microparticle-bound tissue factor, and von Willebrand factor levels are associated with severe hypoxemia and major thrombotic events, implicating fibrinolytic suppression in the microcirculatory system and subsequent micro- and macrovascular thrombosis in severe COVID-19.

Topics: Blood Coagulation Disorders; COVID-19; Critical Illness; Fibrinolysis; Humans; Hypoxia; Microcirculation; Oxygen; Plasminogen Activator Inhibitor 1; Prospective Studies; Respiratory Distress Syndrome; Retrospective Studies; Thrombophilia; Thromboplastin; Thrombosis

Captive reptiles often present with clinical signs suggestive of a clotting disorder or severe illness that can induce or exacerbate a coagulopathy. However, coagulopathies in reptiles are difficult to characterize due to lack of species-appropriate reagents to perform coagulation tests. The objective of this study was to develop screening tests to evaluate the extrinsic and common pathways of coagulation in green iguanas (Iguana iguana).. Reptile and avian thromboplastin, extracted from reptile and avian brains, respectively, were used to initiate coagulation in prothrombin time (PT) assays and commercially available reagents were used to determine Russell's viper venom time, thrombin time, and fibrinogen using the Clauss method. Coagulation assays were performed on citrate-anticoagulated plasma from 18 healthy green iguanas. Results were summarized as median (minimum-maximum): PT (reptile thromboplastin), 34.8 seconds (27.1-42.1 s), PT (avian thromboplastin), 78.5 seconds (51.6-114.23 s), Russell's viper venom time, 56.15 seconds (18.4-79.7 s), thrombin time, 10 seconds (7.0-36.5 s), and fibrinogen, 258 mg/dl (89-563.0) (2.58 [0.89-5.63 g/L]).. Commercial reagents can be used to evaluate the common pathway and fibrinogen; however, avian- or reptile-sourced thromboplastin is preferred for a reliable coagulation trigger to perform the PT assay and evaluate the extrinsic pathway.

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Citrates; Fibrinogen; Iguanas; Prothrombin Time; Thromboplastin

Trauma patients with abnormal fibrinolysis have increased morbidity and mortality. Knowledge of mechanisms differentiating fibrinolytic phenotypes is important to optimize treatment. We hypothesized that subjects with abnormal fibrinolysis identified by whole blood viscoelastometry can also be distinguished by plasma thrombin generation, clot structure, fibrin formation, and plasmin generation measurements.. Platelet-poor plasma (PPP) from an observational cross-sectional trauma cohort with fibrinolysis shutdown (% lysis at 30 minutes [LY30] < 0.9, n = 11) or hyperfibrinolysis (LY30 > 3%, n = 9) defined by whole blood thromboelastography were studied. Noninjured control subjects provided comparative samples. Thrombin generation, fibrin structure and formation, and plasmin generation were measured by fluorescence, confocal microscopy, turbidity, and a fluorescence-calibrated plasmin assay, respectively, in the absence/presence of tissue factor or tissue plasminogen activator (tPA).. Whereas spontaneous thrombin generation was not detected in PPP from control subjects, PPP from hyperfibrinolysis or shutdown patients demonstrated spontaneous thrombin generation, and the lag time was shorter in hyperfibrinolysis versus shutdown. Addition of tissue factor masked this difference but revealed increased thrombin generation in hyperfibrinolysis samples. Compared with shutdown, hyperfibrinolysis PPP formed denser fibrin networks. In the absence of tPA, the fibrin formation rate was faster in shutdown than hyperfibrinolysis, but hyperfibrinolysis clots lysed spontaneously; these differences were masked by addition of tPA. Tissue plasminogen activator-stimulated plasmin generation was similar in hyperfibrinolysis and shutdown samples. Differences in LY30, fibrin structure, and lysis correlated with pH.. This exploratory study using PPP-based assays identified differences in thrombin generation, fibrin formation and structure, and lysis in hyperfibrinolysis and shutdown subgroups. These groups did not differ in their ability to promote tPA-triggered plasmin generation. The ability to characterize these activities in PPP facilitates studies to identify mechanisms that promote adverse outcomes in trauma.. Prognostic/Epidemiological; Level III.

Topics: Blood Coagulation Disorders; Cross-Sectional Studies; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Thrombin; Thromboplastin; Tissue Plasminogen Activator

In SARS-CoV-2-infected humans, disease progression is often associated with acute respiratory distress syndrome involving severe lung injury, coagulopathy, and thrombosis of the alveolar capillaries. The pathogenesis of these pulmonary complications in COVID-19 patients has not been elucidated. Autopsy study of these patients showed SARS-CoV-2 virions in pulmonary vessels and sequestrated leukocytes infiltrates associated with endotheliopathy and microvascular thrombosis. Since SARS-CoV-2 enters and infects target cells by binding its spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2), and there is evidence that vascular endothelial cells and neutrophils express ACE2, we investigated the effect of S-proteins and cell-cell communication on primary human lung microvascular endothelial cells (HLMEC) and neutrophils expression of thrombogenic factors and the potential mechanisms. Using S-proteins of two different SARS-CoV-2 variants (Wuhan and Delta), we demonstrate that exposure of HLMEC or neutrophils to S-proteins, co-culture of HLMEC exposed to S-proteins with non-exposed neutrophils, or co-culture of neutrophils exposed to S-proteins with non-exposed HLMEC induced transcriptional upregulation of tissue factor (TF), significantly increased the expression and secretion of factor (F)-V, thrombin, and fibrinogen and inhibited tissue factor pathway inhibitor (TFPI), the primary regulator of the extrinsic pathway of blood coagulation, in both cell types. Recombinant (r)TFPI and a thiol blocker (5,5'-dithio-bis-(2-nitrobenzoic acid)) prevented S-protein-induced expression and secretion of Factor-V, thrombin, and fibrinogen. Thrombomodulin blocked S-protein-induced expression and secretion of fibrinogen but had no effect on S-protein-induced expression of Factor-V or thrombin. These results suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial-neutrophil interactions, viral S-proteins induce coagulopathy via the TF pathway and mechanisms involving functional thiol groups. These findings suggest that using rTFPI and/or thiol-based drugs could be a viable therapeutic strategy against SARS-CoV-2-induced coagulopathy and thrombosis.

Topics: Angiotensin-Converting Enzyme 2; Blood Coagulation Disorders; Cell Communication; COVID-19; Endothelial Cells; Endothelium; Fibrinogen; Humans; Lipoproteins; Lung; Neutrophils; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Sulfhydryl Compounds; Thrombin; Thrombomodulin; Thromboplastin; Thrombosis

Trauma induced coagulopathy (TIC) is common after severe trauma, increasing transfusion requirements and mortality among patients. TIC has several phenotypes, with primary hyperfibrinolysis being among the most lethal. We aimed to investigate the contribution of hypercoagulation, hemodilution, and fibrinolytic activation to the hyperfibrinolytic phenotype of TIC, by examining fibrin formation in a plasma-based model of TIC. We hypothesized that instabilities arising from TIC will be due primarily to increased fibrinolytic activation rather than hemodilution or tissue factor (TF) induced hypercoagulation.. The influence of TF, hemodilution, fibrinogen consumption, tissue plasminogen activator (tPA), and the antifibrinolytic tranexamic acid (TXA) on plasma clot formation and structure were examined using rheometry, optical properties, and confocal microscopy. These were then compared to plasma samples from trauma patients at risk of developing TIC.. Combining TF-induced clot formation, 15 % hemodilution, fibrinogen consumption, and tPA-induced fibrinolysis, the clot characteristics and hyperfibrinolysis were consistent with primary hyperfibrinolysis. TF primarily increased fibrin polymerization rates and reduced fiber length. Hemodilution decreased clot optical density but had no significant effect on mechanical clot stiffness. TPA addition induced primary clot lysis as observed mechanically and optically. TXA restored mechanical clot formation but did not restore clot structure to control levels. Patients at risk of TIC showed increased clot formation, and lysis like that of our simulated model.. This simulated TIC plasma model demonstrated that fibrinolytic activation is a primary driver of instability during TIC and that clot mechanics can be restored, but clot structure remains altered with TXA treatment.

Topics: Blood Coagulation Disorders; Fibrin; Fibrinogen; Hemodilution; Hemostatics; Humans; Thrombophilia; Thromboplastin; Tissue Plasminogen Activator; Tranexamic Acid

Topics: Blood Coagulation Disorders; Hemorrhagic Disorders; Hemostasis; Humans; Mutation; Thromboplastin

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent pathogen responsible for the coronavirus disease 2019 (COVID-19). Since its emergence, the novel coronavirus has rapidly achieved pandemic proportions causing remarkably increased morbidity and mortality around the world. A hypercoagulability state has been reported as a major pathologic event in COVID-19, and thromboembolic complications listed among life-threatening complications of the disease. Platelets are chief effector cells of hemostasis and pathological thrombosis. However, the participation of platelets in the pathogenesis of COVID-19 remains elusive. This report demonstrates that increased platelet activation and platelet-monocyte aggregate formation are observed in severe COVID-19 patients, but not in patients presenting mild COVID-19 syndrome. In addition, exposure to plasma from severe COVID-19 patients increased the activation of control platelets ex vivo. In our cohort of COVID-19 patients admitted to the intensive care unit, platelet-monocyte interaction was strongly associated with tissue factor (TF) expression by the monocytes. Platelet activation and monocyte TF expression were associated with markers of coagulation exacerbation as fibrinogen and D-dimers, and were increased in patients requiring invasive mechanical ventilation or patients who evolved with in-hospital mortality. Finally, platelets from severe COVID-19 patients were able to induce TF expression ex vivo in monocytes from healthy volunteers, a phenomenon that was inhibited by platelet P-selectin neutralization or integrin αIIb/β3 blocking with the aggregation inhibitor abciximab. Altogether, these data shed light on new pathological mechanisms involving platelet activation and platelet-dependent monocyte TF expression, which were associated with COVID-19 severity and mortality.

Topics: Adult; Betacoronavirus; Biomarkers; Blood Coagulation Disorders; Blood Platelets; Case-Control Studies; Coronavirus Infections; COVID-19; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monocytes; P-Selectin; Pandemics; Platelet Activation; Pneumonia, Viral; Prognosis; Prospective Studies; SARS-CoV-2; Survival Rate; Thromboplastin

Topics: Adenocarcinoma; Blood Coagulation Disorders; Humans; Pancreatic Neoplasms; Poland; Thromboplastin

To evaluate the role of microparticle (MP) derived from acute promyelocytic leukemia (APL) cells and tissue factor (TF) carried by the MP in hypercoagulable state, and the effect of treatment with cytotoxic chemotherapy/differentiating agents on procoagulant activity (PCA) of these MP.. Bone marrow mononuclear cells (BMMNC) were extracted from 5 APL patients and 5 sex- and age- matched patients with iron deficiency anemia as controls. The cells were cultured in vitro for 48 h, then MP-rich culture medium and MP-free culture medium were harvested and MP was further obtained from certain volume of MP-rich culture medium. Subsequently, TF expression on MP was measured by ELISA. PCA of MP-rich culture medium or MP-free culture medium was assessed with thrombin generation assay. The role of TF on MP-related PCA was evaluated using anti-human TF antibody. In addition, APL cells were treated with all-trans retinoic acid (ATRA), arsenic trioxide (ATO) or daunorubicin (DNR) for 48 h, then MP-rich culture medium were harvested and the PCA was determined.. No TF expression was found in the MP released from bone marrow MNC in control group, whereas the obvious TF expression was found in the MP originated from BMMNC of APL. MP from both APL and control BM-MNC had obvious PCA. However, compared with the MP derived from control MNC, the MP from APL BM-MNC induced significantly higher PCA. TF played a crucial role in the PCA of APL BM-MNC derived MP, while played no role in that of MP from control MNCs. DNR-treating APL BM-MNC resulted in an increase in the PCA of MP, whereas ATO or ATRA exposure lead to exactly the opposite results.. MP derived from APL BM-MNC posseses obvious PCA. TF plays a crucial role in the MP-related PCA. The PCA of MP increases after treating APL BM-MNC with chemotherapy agent DNR and decreases following exposure of APL BM-MNC to differentiating agents ATRA or ATO.

Topics: Arsenicals; Blood Coagulation Disorders; Cell-Derived Microparticles; Humans; Leukemia, Promyelocytic, Acute; Oxides; Thromboplastin; Tretinoin

In HIV infection, persistent inflammation despite effective antiretroviral therapy is linked to increased risk of noninfectious chronic complications such as cardiovascular and thromboembolic disease. A better understanding of inflammatory and coagulation pathways in HIV infection is needed to optimize clinical care. Markers of monocyte activation and coagulation independently predict morbidity and mortality associated with non-AIDS events. We identified a specific subset of monocytes that express tissue factor (TF), persist after virological suppression, and trigger the coagulation cascade by activating factor X. This subset of monocytes expressing TF had a distinct gene signature with up-regulated innate immune markers and evidence of robust production of multiple proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, ex vivo and in vitro upon lipopolysaccharide stimulation. We validated our findings in a nonhuman primate model, showing that TF-expressing inflammatory monocytes were associated with simian immunodeficiency virus (SIV)-related coagulopathy in the progressive [pigtail macaques (PTMs)] but not in the nonpathogenic (African green monkeys) SIV infection model. Last, Ixolaris, an anticoagulant that inhibits the TF pathway, was tested and potently blocked functional TF activity in vitro in HIV and SIV infection without affecting monocyte responses to Toll-like receptor stimulation. Strikingly, in vivo treatment of SIV-infected PTMs with Ixolaris was associated with significant decreases in D-dimer and immune activation. These data suggest that TF-expressing monocytes are at the epicenter of inflammation and coagulation in chronic HIV and SIV infection and may represent a potential therapeutic target.

Topics: Animals; Anti-Retroviral Agents; Antibodies, Viral; Blood Coagulation; Blood Coagulation Disorders; Chlorocebus aethiops; Chronic Disease; Cytokines; HIV Infections; Humans; Inflammation; Inflammation Mediators; Lipopolysaccharide Receptors; Lipopolysaccharides; Monocytes; Receptor, PAR-1; Signal Transduction; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Thromboplastin

We present a methodology for personalizing the clinical treatment of severely injured patients with acute traumatic coagulopathy (ATC), an endogenous biological response of impaired coagulation that occurs early after trauma and shock and that is associated with increased bleeding, morbidity, and mortality. Despite biological characterization of ATC, it is not easily or rapidly diagnosed, not always captured by slow laboratory testing, and not accurately represented by coagulation models. This lack of knowledge, combined with the inherent time pressures of trauma treatment, forces surgeons to treat ATC patients according to empirical resuscitation protocols. These entail transfusing large volumes of poorly characterized, nontargeted blood products that are not tailored to an individual, the injury, or coagulation dynamics. Massive transfusion mortality remains at 40 to 70% in the best of trauma centers. As an alternative to blunt treatments, time-consuming tests, and mechanistic models, we used dynamical systems theory to create a simple, biologically meaningful, and highly accurate model that (i) quickly forecasts a driver of downstream coagulation, thrombin concentration after tissue factor stimulation, using rapidly measurable concentrations of blood protein factors and (ii) determines the amounts of additional coagulation factors needed to rectify the predicted thrombin dynamics and potentially remedy ATC. We successfully demonstrate in vitro thrombin control consistent with the model. Compared to another model, we decreased the mean errors in two key trauma patient parameters: peak thrombin concentration after tissue factor stimulation and the time until this peak occurs. Our methodology helps to advance individualized resuscitation of trauma-induced coagulation deficits.

Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Disorders; Blood Transfusion; Calibration; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Thrombin; Thromboplastin; Thrombosis; Treatment Outcome; Wounds and Injuries

Rotational thromboelastometry (ROTEM) and thromboelastography (TEG) have been increasingly used to diagnose acute coagulopathy and guide blood transfusion. The tests are routinely performed using different triggering activators such as tissue factor and kaolin, which activate different pathways yielding different results. To optimize the global blood coagulation assays using ROTEM and TEG, we conducted a comparative study on the activation methods employing tissue factor and kaolin at different concentrations as well as standard reagents as recommended by the manufacturer of each device. Key parameter values were obtained at various assay conditions to evaluate and compare coagulation and fibrinolysis profiles of citrated whole blood collected from healthy volunteers. It was found that tissue factor reduced ROTEM clotting time and TEG R, and increased ROTEM clot formation time and TEG K in a concentration-dependent manner. In addition, tissue factor affected ROTEM alpha angle, and maximum clot firmness, especially in the absence of kaolin activation, whereas both ROTEM and TEG clot lysis (LI30, CL30, and LY30) remained unaffected. Moreover, kaolin reduced ROTEM clotting time and TEG R and K, but to a lesser extent than tissue factor, in-tem and ex-tem. Correlations in all corresponding parameters between ROTEM and TEG were observed, when the same activators were used in the assays compared with lesser correlations between standard kaolin TEG and ROTEM (INTEM/EXTEM). The two types of viscoelastic point-of-care devices provide different results, depending on the triggering reagent used to perform the assay. Optimal assay condition was obtained to reduce assay time and improve assay accuracy.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Kaolin; Male; Thrombelastography; Thromboplastin

Platelet- and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood.. Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factor-triggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet-fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B.. Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Flow Velocity; Blood Platelets; Case-Control Studies; Collagen; Elasticity; Fibrin; Hemophilia B; Humans; Regional Blood Flow; Thrombocytopenia; Thromboplastin; Thrombosis; Time Factors

Hyperfibrinolysis is one of the main causes of non-surgical bleeding during liver transplantation (LT). Viscoelastic haemostatic assays, including thromboelastometry (ROTEM(®)) and thrombelastography (TEG(®)), can detect hyperfibrinolysis at the bedside. No study has yet demonstrated which device or assay is more suitable for detecting hyperfibrinolysis.. This prospective observational study compared ROTEM(®) and TEG(®) in isolated adult LT. ROTEM(®) (EXTEM(®) [tissue factor activation], FIBTEM(®) [tissue factor activation with platelet inhibition], and APTEM(®) [tissue factor activation with tranexamic acid/aprotinin]) and TEG(®) (kaolin-TEG(®)) were simultaneously performed using arterial blood samples at eight time-points during LT: induction of general anaesthesia, 60 min after skin incision, 10 and 45 min after portal vein clamp, 15 min before graft reperfusion, and five, 30, and 90 min after graft reperfusion. Hyperfibrinolysis was identified per the manufacturers' definitions (maximum lysis >15% in ROTEM(®) or Lysis30>8% in TEG(®)) and confirmed with APTEM(®); incidence was compared between assays McNemar's test.. Among 296 possible measurement points from 376 consecutive LT recipients, 250 underwent final analysis: 46 measurement points were excluded because of missing assays or flat line. Hyperfibrinolysis was confirmed at 89 (36%) of 250 measurement points: FIBTEM(®), EXTEM(®), and kaolin-TEG(®) detected 84 (94%), 41 (46%), and 21 (24%) hyperfibrinolysis, respectively. These hyperfibrinolysis detection rates significantly differed from each other (P<0.001).. Tissue factor-triggered ROTEM(®) tests were more sensitive than contact-activated k-TEG(®) in identifying hyperfibrinolysis in LT patients. Inhibition of platelet-fibrin interaction in FIBTEM(®) enhanced sensitivity to hyperfibrinolysis detection compared with EXTEM(®).

Topics: Anesthesia, General; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinolysis; Humans; Intraoperative Complications; Liver Transplantation; Male; Middle Aged; Prospective Studies; Thrombelastography; Thromboplastin; Tranexamic Acid

The aim of this study was to compare the efficacy, safety, and cost-effectiveness of 3-factor prothrombin complex concentrate (3F-PCC) vs 4-factor prothrombin complex concentrate PCC (4F-PCC) in trauma patients requiring reversal of oral anticoagulants.. All consecutive trauma patients with coagulopathy (international normalized ratio [INR] ≥1.5) secondary to oral anticoagulants who received either 3F-PCC or 4F-PCC from 2010 to 2014 at 2 trauma centers were reviewed. Efficacy was determined by assessing the first INR post-PCC administration, and successful reversal was defined as INR less than 1.5. Safety was assessed by reviewing thromboembolic events, and cost-effectiveness was calculated using total treatment costs (drug acquisition plus transfusion costs) per successful reversal.. Forty-six patients received 3F-PCC, and 18 received 4F-PCC. Baseline INR was similar for 3F-PCC and 4F-PCC patients (3.1 ± 2.3 vs 3.4 ± 3.7, P = .520). The initial PCC dose was 29 ± 9 U/kg for 3F-PCC and 26 ± 6 U/kg for 4F-PCC (P = .102). The follow-up INR was 1.6 ± 0.6 for 3F-PCC and 1.3 ± 0.2 for 4F-PCC (P = .001). Successful reversal rates in patients were 83% for 4F-PCC and 50% for 3F-PCC (P = .022). Thromboembolic events were observed in 15% of patients with 3F-PCC vs 0% with 4F-PCC (P = .177). Cost-effectiveness favored 4F-PCC ($5382 vs $3797).. Three-factor PCC and 4F-PCC were both safe in correcting INR, but 4F-PCC was more effective, leading to better cost-effectiveness. Replacing 3F-PCC with 4F-PCC for urgent coagulopathy reversal may benefit patients and institutions.

Topics: Aged; Anticoagulants; Blood Coagulation Disorders; Calcium; Cost-Benefit Analysis; Critical Care; Female; Hemostatics; Humans; International Normalized Ratio; Male; Retrospective Studies; Safety; Thromboplastin; Trauma Centers; Warfarin; Wounds and Injuries

Essentials Acidosis, an outcome of traumatic injury, has been linked to impaired procoagulant efficiency. In vitro model systems were used to assess coagulation dynamics at pH 7.4 and 7.0. Clot formation dynamics are slightly enhanced at pH 7.0 in blood ex vivo. Acidosis induced decreases in antithrombin efficacy offset impairments in procoagulant activity.. Background Disruption of hydrogen ion homeostasis is a consequence of traumatic injury often associated with clinical coagulopathy. Mechanisms by which acidification of the blood leads to aberrant coagulation require further elucidation. Objective To examine the effects of acidified conditions on coagulation dynamics using in vitro models of increasing complexity. Methods Coagulation dynamics were assessed at pH 7.4 and 7.0 as follows: (i) tissue factor (TF)-initiated coagulation proteome mixtures (±factor [F]XI, ±fibrinogen/FXIII), with reaction progress monitored as thrombin generation or fibrin formation; (ii) enzyme/inhibitor reactions; and (iii) TF-dependent or independent clot dynamics in contact pathway-inhibited blood via viscoelastometry. Results Rate constants for antithrombin inhibition of FXa and thrombin were reduced by ~ 25-30% at pH 7.0. At pH 7.0 (+FXI), TF-initiated thrombin generation showed a 20% increase in maximum thrombin levels and diminished thrombin clearance rates. Viscoelastic analyses showed a 25% increase in clot time and a 25% reduction in maximum clot firmness (MCF). A similar MCF reduction was observed at pH 7.0 when fibrinogen/FXIII were reacted with thrombin. In contrast, in contact pathway-inhibited blood (n = 6) at pH 7.0, MCF values were elevated 6% (95% confidence interval [CI]: 1%-11%) in TF-initiated blood and 15% (95% CI: 1%- 29%) in the absence of TF. Clot times at pH 7.0 decreased 32% (95% CI: 15%-49%) in TF-initiated blood and 51% (95% CI: 35%-68%) in the absence of TF. Conclusions Despite reported decreased procoagulant catalysis at pH 7.0, clot formation dynamics are slightly enhanced in blood ex vivo and suppression of thrombin generation is not observed. A decrease in antithrombin reactivity is one potential mechanism contributing to these outcomes.

Topics: Acidosis; Antithrombin III; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Elasticity; Fibrin; Fibrinogen; Healthy Volunteers; Humans; Hydrogen-Ion Concentration; Ions; Proteome; Thrombin; Thromboplastin; Time Factors; Viscosity

Valproic acid (VPA) is an antiepileptic drug that has been associated with impaired hemostasis and increased risk for postsurgical bleeding. However, the published reports provide controversial results. We measured parameters of primary hemostasis in VPA-treated patients with epilepsy, focusing on adenosine nucleotide-dependent platelet responses, which play a central role in primary hemostasis. We enrolled 20 cases (epileptic patients receiving treatment with VPA) and 20 controls (12 epileptic patients receiving treatment with drugs different from VPA and 8 healthy subjects). Measurements included prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, platelet function analyzer (PFA)-100 closure times, plasma von Willebrand factor levels, platelet content of ADP, ATP, and serotonin (all stored in platelet dense granules), and platelet shape change and aggregation induced by ADP and other platelet agonists, including the ATP analog α,β-methylene-ATP. The plasma concentration of VPA was in the therapeutic range in 17 patients and slightly above the upper limit in 3 patients. There were no statistically significant differences in any of the studied parameters in cases versus controls. Our thorough controlled study failed to show that chronic treatment with VPA induces significant abnormalities of coagulation and primary hemostasis. Therefore, VPA, when present in the circulation in the therapeutic range, does not impair hemostasis.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adolescent; Adult; Anticonvulsants; Blood Coagulation Disorders; Case-Control Studies; Child; Drug Administration Schedule; Epilepsy; Female; Hemostasis; Humans; Male; Platelet Function Tests; Prothrombin; Serotonin; Thromboplastin; Time Factors; Valproic Acid; Young Adult

The initiation of coagulation in trauma is thought to originate from exposed tissue factor (TF); recent data have led to the alternative hypothesis that damage-associated molecular patterns may contribute to postinjury coagulation. In acute traumatic coagulopathy, aberrant coagulation is mediated via the activated protein C (aPC) pathway; the upstream regulators of this process and its relation to TF remain uncharacterized. To examine the role of the TF pathway in mediating acute traumatic coagulopathy, we used specific antibody blockades in an established murine model of traumatic hemorrhagic shock, hypothesizing that both coagulation activation after injury and aPC-mediated coagulopathy are driven by TF via thrombin.. Mice underwent an established model of trauma and hemorrhage and were subjected to either sham (vascular cannulation) or trauma-hemorrhage (cannulation, laparotomy, shock to mean arterial pressure of 35 mm Hg); they were monitored for 60 minutes before sacrifice. Mice in each group were pretreated with either targeted anti-TF antibody to block the TF pathway or hirudin for specific blockade of thrombin. Plasma was assayed for thrombin-antithrombin (TAT) and aPC by enzyme-linked immunosorbent assay.. Compared with controls, trauma-hemorrhage mice treated with anti-TF antibody had significantly reduced levels of TAT (2.3 ng/mL vs. 5.7 ng/mL, p = 0.016) and corresponding decreases in aPC (16.3 ng/mL vs. 31.6 ng/mL, p = 0.034), with reductions to levels seen in sham mice. Direct inhibition of thrombin yielded similar results, with reduction in aPC to levels below those seen in sham mice.. In this study, blockade of the TF pathway led to the attenuation of both thrombin production and aPC activation observed in traumatic shock. Specific thrombin inhibition achieved similar results, indicating that aPC-related coagulopathy is mediated via thrombin activated by the TF pathway. The near-complete blockade of TAT and aPC observed in this model argues for a dominant role of the TF-thrombin pathway in both coagulation activation after injury and traumatic coagulopathy.

Topics: Animals; Blood Coagulation Disorders; Enzyme-Linked Immunosorbent Assay; Hirudins; Male; Mice; Mice, Inbred C57BL; Protein C; Shock, Hemorrhagic; Shock, Traumatic; Thrombin; Thromboplastin; Wounds and Injuries

Bleeding tendency, coagulopathy and platelet disorders are recurrent manifestations in snakebites occurring worldwide. We reasoned that by damaging tissues and/or activating cells at the site of the bite and systemically, snake venom toxins might release or decrypt tissue factor (TF), resulting in activation of blood coagulation and aggravation of the bleeding tendency. Thus, we addressed (a) whether TF and protein disulfide isomerase (PDI), an oxireductase involved in TF encryption/decryption, were altered in experimental snake envenomation; (b) the involvement and significance of snake venom metalloproteinases (SVMP) and serine proteinases (SVSP) to hemostatic disturbances.. Crude Bothrops jararaca venom (BjV) was preincubated with Na2-EDTA or AEBSF, which are inhibitors of SVMP and SVSP, respectively, and injected subcutaneously or intravenously into rats to analyze the contribution of local lesion to the development of hemostatic disturbances. Samples of blood, lung and skin were collected and analyzed at 3 and 6 h. Platelet counts were markedly diminished in rats, and neither Na2-EDTA nor AEBSF could effectively abrogate this fall. However, Na2-EDTA markedly reduced plasma fibrinogen consumption and hemorrhage at the site of BjV inoculation. Na2-EDTA also abolished the marked elevation in TF levels in plasma at 3 and 6 h, by both administration routes. Moreover, increased TF activity was also noticed in lung and skin tissue samples at 6 h. However, factor VII levels did not decrease over time. PDI expression in skin was normal at 3 h, and downregulated at 6 h in all groups treated with BjV.. SVMP induce coagulopathy, hemorrhage and increased TF levels in plasma, but neither SVMP nor SVSP are directly involved in thrombocytopenia. High levels of TF in plasma and TF decryption occur during snake envenomation, like true disseminated intravascular coagulation syndrome, and might be implicated in engendering bleeding manifestations in severely-envenomed patients.

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Bothrops; Crotalid Venoms; Edetic Acid; Fibrinogen; Hemorrhage; Lung; Male; Metalloproteases; Prothrombin; Rats; Rats, Wistar; Serine Proteases; Serine Proteinase Inhibitors; Skin; Sulfones; Thrombocytopenia; Thromboplastin

Six new spirostane glycosides (1-6), named polygodosides A-F, one new furostanol glycoside, polygodoside G (7), one new cholestane glycoside, polygodoside H (8), and one new steroidal sapogenin, polygodosin A (9), together with thirteen known compounds (10-22) were isolated from a 90% MeOH extract of the fibrous roots of Polygonatum odoratum (Mill.) Druce. The structures of new compounds were elucidated by extensive 1D and 2D NMR spectroscopic analyses and mass spectrometry. The effects on TF procoagulant activity in THP-1 cells were tested for most of the compounds.

Topics: Blood Coagulation Disorders; Cholestanes; Drugs, Chinese Herbal; Glycosides; Humans; Molecular Structure; Plant Roots; Polygonatum; Sapogenins; Steroids; Sterols; Thromboplastin

Trauma-induced coagulopathy following severe injury is associated with increased bleeding and mortality. Injury may result in alteration of cellular phenotypes and release of cell-derived microparticles (MP). Circulating MPs are procoagulant and support thrombin generation (TG) and clotting. We evaluated MP and TG phenotypes in severely injured patients at admission, in relation to coagulopathy and bleeding.. As part of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, research blood samples were obtained from 180 trauma patients requiring transfusions at 5 participating centers. Twenty five healthy controls and 40 minimally injured patients were analyzed for comparisons. Laboratory criteria for coagulopathy was activated partial thromboplastin time (APTT) ≥ 35 sec. Samples were analyzed by Calibrated Automated Thrombogram to assess TG, and by flow cytometry for MP phenotypes [platelet (PMP), erythrocyte (RMP), leukocyte (LMP), endothelial (EMP), tissue factor (TFMP), and Annexin V positive (AVMP)].. 21.7% of patients were coagulopathic with the median (IQR) APTT of 44 sec (37, 53), and an Injury Severity Score of 26 (17, 35). Compared to controls, patients had elevated EMP, RMP, LMP, and TFMP (all p<0.001), and enhanced TG (p<0.0001). However, coagulopathic PROMMTT patients had significantly lower PMP, TFMP, and TG, higher substantial bleeding, and higher mortality compared to non-coagulopathic patients (all p<0.001).. Cellular activation and enhanced TG are predominant after trauma and independent of injury severity. Coagulopathy was associated with lower thrombin peak and rate compared to non-coagulopathic patients, while lower levels of TF-bearing PMPs were associated with substantial bleeding.

Topics: Adult; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Blood Transfusion; Cell-Derived Microparticles; Female; Hemorrhage; Humans; Injury Severity Score; Male; Middle Aged; Partial Thromboplastin Time; Phenotype; Predictive Value of Tests; Prospective Studies; Risk Factors; Thrombelastography; Thrombin; Thromboplastin; United States; Wounds and Injuries; Young Adult

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

Among circulating cell-derived microparticles, those derived from red cells (RMP) have been least well investigated. To exploit potential haemostatic benefit of RMP, we developed a method of producing them in quantity, and here report on their haemostatic properties. High-pressure extrusion of washed RBC was employed to generate RMP. RMP were identified and enumerated by flow cytometry. Their size distribution was assessed by Doppler electrophoretic light scattering analysis (DELSA). Interaction with platelets was studied by platelet aggregometry, and shear-dependent adhesion by Diamed IMPACT-R. Thrombin generation and tissue factor (TF) expression was also measured. The effect of RMP on blood samples of patients with bleeding disorders was investigated ex vivo by thromboelastography (TEG). Haemostatic efficacy in vivo was assessed by measuring reduction of blood loss and bleeding time in rats and rabbits. RMP have mean diameter of 0.45 µm and 50% of them exhibit annexin V binding, a proxy for procoagulant phospholipids (PL). No TF could be detected by flow cytometry. At saturating concentrations of MPs, RMP generated thrombin robustly but after longer delay compared to PMP and EMP. RMP enhanced platelet adhesion and aggregation induced by low-dose ADP or AA. In TEG study, RMP corrected or improved haemostatic defects in blood of patients with platelet and coagulation disorders. RMP reduced bleeding time and blood loss in thrombocytopenic rabbits (busulfan-treated) and in Plavix-treated rats. In conclusion, RMP has broad haemostatic activity, enhancing both primary (platelet) and secondary (coagulation) haemostasis, suggesting potential use as haemostatic agent for treatment of bleeding.

Topics: Adenosine Diphosphate; Animals; Bleeding Time; Blood Coagulation Disorders; Busulfan; Cell Separation; Cell-Derived Microparticles; Clopidogrel; Disease Models, Animal; Erythrocytes; Flow Cytometry; Hemostasis; Humans; Male; Platelet Aggregation; Rabbits; Rats; Rats, Sprague-Dawley; Thrombelastography; Thrombin; Thrombocytopenia; Thromboplastin; Ticlopidine

Blood dilution is a frequent complication of massive transfusion during trauma and surgery. This article investigates the quantitative effects of blood plasma dilution on thrombin generation in the context of intersubject variability.. A thoroughly validated computational model was used to simulate thrombin generation curves for 472 healthy subjects in the Leiden Thrombophilia Study. Individual thrombin curves were calculated for undiluted blood and for different dilution scenarios. For every such curve, five standard quantitative parameters of thrombin generation were calculated and analyzed.. Thrombin generation parameters in diluted blood plasma displayed significant intersubject variability (with a coefficient of variation up to approx. 28%). Nevertheless, dilutional effects in the majority (or all) of the subjects in the study group were characterized by persistent patterns. In particular, the largest dilution-induced change typically occurred in the maximum slope (MS) of the thrombin curve, followed by a change in thrombin peak height (PH), whereas the smallest change often occurred in the area under the curve. The identified patterns demonstrated considerable robustness to variations in dilution scenario and tissue factor concentration.. Dilutional effects on thrombin generation in a human population can be predicted from trends identified for the "average" subject and then refined by performing an analysis of actual subjects in the study group. The MS and PH are dilution indicators that are both sensitive and reliable across a large subject group and could potentially be used as disease markers in the diagnosis of coagulopathic conditions.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Computer Simulation; Hemodilution; Humans; Models, Biological; Predictive Value of Tests; Resuscitation; Thrombin; Thromboplastin; Transfusion Reaction

There are concerns that some anticoagulants can paradoxically increase thrombogenesis under certain circumstances. We have shown that low-dose administration of a direct thrombin inhibitor, melagatran, significantly worsens the coagulation status induced by tissue factor injection in rats. We compared the effect of inhibition of thrombin and factor Xa for their potential to aggravate tissue factor-induced coagulation in rats. Hypercoagulation was induced by the injection of 2.8 U/kg tissue factor after administration of melagatran, heparin and edoxaban in rats. Blood samples were collected 10min after tissue factor injection. Platelet numbers, thrombin-antithrombin complex concentrations and plasma compound concentrations were measured. Though a high dose of melagatran (1mg/kg, i.v.) suppressed platelet consumption and thrombin-antithrombin complex generation induced by tissue factor, lower doses of melagatran (0.01, 0.03 and 0.1mg/kg, i.v.) significantly enhanced platelet consumption and thrombin-antithrombin complex generation. In addition, although melagatran (3mg/kg, i.v.) improved coagulation status when tissue factor was given 5min after the drug administration, and 2, 4 and 8h after melagatran dosing, it deteriorated coagulation status. These results were well explained by the plasma melagatran concentration. Low concentrations (15-234ng/ml) of melagatran aggravated coagulation status whereas it was mended by high concentrations (1190ng/ml or more) of the compound. In contrast, edoxaban and heparin did not show any exacerbation under these examination conditions. These results show that subtherapeutic concentrations of melagatran are associated with coagulation pathway activation, whereas factor Xa inhibition with edoxaban has a low risk of paradoxical hypercoagulation.

Topics: Animals; Antithrombins; Azetidines; Benzylamines; Blood Coagulation Disorders; Factor Xa Inhibitors; Heparin; Male; Pyridines; Rats; Rats, Wistar; Thiazoles; Thromboplastin

Objective of this study was to detect the level of tissue factor-positive microparticles (TF(+)MP) by flow cytometry (FCM) and to analyze its clinical significance in the haemostatic disorder. TF(+) MP was detected by FCM using antibody CD142-PE in 25 cases of acute promyelocytic leukemia (APL), 20 cases of hemostatic diseases and 20 healthy adults as controls. The differences of TF(+) MP between various groups were determined. The results showed that the level of TF(+) MP in the patients with thrombotic complications was significantly higher than that in the healthy adults (P < 0.05). The TF(+) MP level was higher in the patient with APL than that in the healthy adults, especially in course before therapy (P < 0.01), but the difference was not statistically significant in the patient with APL after therapy and the healthy adults. Among these patient with APL, the level of TF(+) MP in the 18 patients who complicated with disseminated intravascular coagulation (DIC) was also higher than that in the healthy adults (P < 0.05), but the level of TF(+) MP in the other 7 patients who did not complicate with DIC was similar before and after treatment. It is concluded that the method of TF(+) MP detection by FCM is feasible and simple, it is useful for the diagnosis of thrombotic disorder, and helps evaluation for the prognosis of APL patient.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation Disorders; Case-Control Studies; Female; Flow Cytometry; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Thromboplastin; Young Adult

Long-term parenteral nutrition (PN) is a standardized treatment in many patients who are unable to use their gastrointestinal tract to absorb nutrients and water. Catheter-related thrombosis (CRT) is one of the most common complications of PN. Several factors predispose patients to CRT. The main objective of this study was to assess the platelet membrane glycoprotein (GP) activation and coagulopathy induced by PN.. Fifteen patients with intestinal failure were given PN for 47.9 days (range, 30-92 days) and 15 oral-fed healthy volunteers served as controls. Complete blood counts and coagulation and biochemical parameters were determined. The platelet surface GPs, P-selectin and GPIIb/IIIa were measured by flow cytometry.. There was no significant difference between the control group and PN group in coagulation and biochemical parameters. Platelet P-selectin expression of the PN group was significantly higher than that of the control group (3.43% ± 1.22% and 1.99% ± 0.58%, respectively; P < .01). There was no significant difference in GPIIb/IIIa expression between the 2 groups.. Long-term PN (>30 days) induced the activation of platelet membrane GPs, which may be a significant risk factor for the development of CRT in patients with intestinal failure who require PN.

Topics: Adolescent; Adult; Blood Coagulation Disorders; Case-Control Studies; Catheters; Female; Fibrinogen; Flow Cytometry; Humans; Male; Middle Aged; P-Selectin; Parenteral Nutrition; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Prothrombin; Risk Factors; Thromboplastin; Young Adult

The study was undertaken to assess commercial thromboplastins for compliance to the WHO guidelines and to substantiate the validity of the results of a prothrombin test carried out using these thromboplastins. The test thromboplastins were shown to meet the WHO guidelines for assessment of thromboplastins. Over 5-8 years of the authors'participation in two external quality control programs (Federal External Quality Control System, Russia; 72 trials; NEQAS, United Kingdom; 60 trials), the international normalized ratio derived through the use of assessed thromboplastins did not differ from that established due to the interlaboratory consensus value of both external quality control systems. It is concluded that correct thromboplastin assessment provide accurate results of determination of prothrombin time.

Topics: Blood Coagulation Disorders; Guideline Adherence; Humans; International Normalized Ratio; Practice Guidelines as Topic; Prothrombin Time; Quality Assurance, Health Care; Quality Control; Reproducibility of Results; Russia; Thromboplastin; World Health Organization

Malignancy often results in clotting abnormalities. The aetiology of haemostasis problems in cancer is complex, and is still not completely understood. We describe a case of a patient with malignant mesothelioma, who was found to have elevated activated partial thromboplastin time, due to lupus anticoagulant. We suggest that patients with malignancy should have their coagulation checked prior to any invasive procedures.

Topics: Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Male; Mesothelioma; Radiography; Thromboplastin

Bovine topical thrombin is commonly used for local hemostasis in pediatric surgery. Acquired inhibitors to coagulation factors, particularly to factor V and bovine thrombin, have been infrequently reported in the pediatric population. We report a 3-year-old male who developed a coagulopathy and clinical bleeding after cardiothoracic surgery, during which bovine topical thrombin was used for local hemostasis. Laboratory tests revealed elevated prothrombin, partial thromboplastin, and thrombin times, and a low factor V activity level. He was found to have both human-thrombin and factor V inhibitors, among the first reported cases of these combined inhibitors secondary to bovine topical thrombin. He was treated with intravenous immunoglobulin and steroids with a rapid and durable response.

Topics: Administration, Topical; Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Cattle; Child, Preschool; Factor V; Hemorrhage; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Male; Prognosis; Prothrombin Time; Thrombin; Thrombin Time; Thromboplastin

It is argued that the practice of omitting outliers when calibrating thromboplastin time, as recommended by the World Health Organization, should not continue unless it can be justified statistically and that possible harmful effects of omitting such data should be investigated.

Topics: Bioethical Issues; Blood Coagulation Disorders; Calibration; Ethics, Medical; Humans; Prothrombin Time; Thromboplastin; World Health Organization

The coagulation "cascade" model accurately represents the mechanisms of the prothrombin time and activated partial thromboplastin time tests. However, these tests and the "cascade" model do not accurately reflect the risk of hemorrhage or thrombosis in vivo. In hepatic insufficiency, a balanced reduction in the levels of most of pro- and anticoagulant proteins produced in the liver does not impair thrombin generation until levels are quite low. However, the ability of the coagulation system to tolerate or recover from an insult is markedly impaired in liver disease. This allows the coagulation system to be more easily tipped into a state favoring either hemorrhage or thrombosis.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Hemorrhage; Hemostasis; Humans; Liver Cirrhosis; Liver Failure; Models, Biological; Prothrombin Time; Thrombin; Thromboplastin; Thrombosis

Early recognition of coagulopathy may improve the care of patients with multiple injuries. Rapid thrombelastography (RapidTEG) is a new variant of thrombelastography (TEG), in which coagulation is initiated by the addition of protein tissue factor. The kinetics of coagulation and the times of measurement were compared for two variants of TEG--RapidTEG and conventional TEG, in which coagulation was initiated with kaolin. The measurements were performed on blood samples from 20 patients with multiple injuries. The RapidTEG results were also compared with conventional measurements of blood coagulation. The mean time for the RapidTEG test was 19.2 +/- 3.1 minutes (mean +/- SD), in comparison with 29.9 +/- 4.3 minutes for kaolin TEG and 34.1 +/- 14.5 minutes for conventional coagulation tests. The mean time for the RapidTEG test was 30.8 +/- 5.72 minutes, in comparison with 41.5 +/- 5.66 minutes for kaolin TEG and 64.9 +/- 18.8 for conventional coagulation tests---measured from admission of the patients to the resuscitation bay until the results were available. There were significant correlations between the RapidTEG results and those from kaolin TEG and conventional coagulation tests. RapidTEG is the most rapid available test for providing reliable information on coagulopathy in patients with multiple injuries. This has implications for improving patient care.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Coagulation; Blood Coagulation Disorders; Emergency Service, Hospital; Female; Humans; Kaolin; Male; Middle Aged; Multiple Trauma; Point-of-Care Systems; Thrombelastography; Thromboplastin; Young Adult

Development of coagulopathy is a serious complication arising from isolated traumatic brain injury, and it predicts poor outcome. The underlying mechanism has not yet been established, although coagulopathy arising from brain tissue injury and the release of tissue factor may represent the pathophysiology. The authors investigated dynamic whole-blood clot formation (ROTEM) in a recently developed porcine model of induced severe intracranial hypertension.. In this prospective, randomized experimental study, 17 pigs were designated for severe intracranial hypertension or sham operation. Intracranial hypertension was induced by inflation of an intracranial balloon. Whole-blood clot formation was assessed by clot initiation, and clot propagation and clot strength through thrombelastometry. The authors also assessed thrombin generation and prothrombin time, which were obtained at baseline, immediately after intervention, and 5 h after intervention.. A dramatic shortening in time to clot initiation and an increase in clot propagation were observed after induction of intracranial hypertension as compared to the control group. These results were further substantiated by a pronounced increase in thrombin generation and a significantly shortened prothrombin time in the intervention group. No difference in clot strength was detected between the groups.. In a porcine model, induction of increased intracranial pressure causing severe intracranial hypertension was associated with a pronounced activation of the coagulation system. Taken together, the various results indicate that tissue factor probably represents the main trigger of hypercoagulopathy found in these pigs.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Brain; Catheterization; Female; Hemostasis; Intracranial Hypertension; Prothrombin Time; Swine; Thrombelastography; Thrombin; Thromboplastin; Thrombosis

To gain insight into the contribution of platelet-dependent thrombin formation in haemostasis and thrombosis, we investigated under flow conditions the haemostatic functions of platelets from a patient with Scott syndrome. Scott platelets are characterised by a diminished platelet-dependent thrombin generation. Thrombin generation was determined by calibrated automated thrombography and flow-based experiments were performed to reveal collagen-mediated platelet activation and fibrin deposition. Our studies indicate that adherent Scott platelets do not differ from control platelets in the formation of stable platelet aggregates under static and flow conditions. While for adherent control platelets a shape change, e.g. balloon formation, and externalisation of phosphatidylserine (PS) is associated with an increase in intracellular calcium concentration, this is not the case for Scott platelets. The calcium-induced morphological changes in control platelets are accompanied with a diminished recruitment of free flowing platelets. Scott platelets, not showing a calcium-induced shape change, also lost the ability to recruit free flowing platelets. These findings rebut the hypothesis that the mild bleeding tendency of Scott syndrome patients is due to a preserved adhesive activity of patient's platelets. Perfusion of tissue factor (TF)-activated control blood over immobilised collagen results in the formation of fibrin fibers that radiate from platelet aggregates. Although platelet aggregates were also observed after perfusion with TF-activated Scott blood, fibrin deposition was not observed. In conclusion, our findings indicate that platelet adhesion and spreading on a collagen matrix in the absence of fibrin formation is sufficient to sustain haemostasis under non-traumatic conditions.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Calcium; Female; Fibrin; Hemorrhage; Humans; Middle Aged; Platelet Aggregation; Regional Blood Flow; Syndrome; Thrombin; Thromboplastin

Progressive postinjury coagulopathy has become the fundamental rationale for damage control surgery, and the decision to abort operative intervention must occur prior to overt laboratory confirmation of coagulopathy. Current coagulation testing is most commonly performed for monitoring anticoagulation therapy, the results are delayed, and the applicability of these tests in the trauma setting is questionable. Point-of-care (POC) rapid thrombelastography (r-TEG) provides real time analysis of thrombostatic function, which may allow for accurate, goal directed therapy. The test differs from standard thrombelastography (TEG) because the clotting process and subsequent analysis is accelerated by the addition of tissue factor to the whole blood sample, but is limited by the requirement that the analysis be performed within 4 min of blood draw to prevent clot formation. Consequently, citrated specimens have been proposed to obviate this time limitation. We hypothesized that the speed of r-TEG analysis following tissue factor addition to citrated blood might compromise accurate determinations compared with noncitrated whole blood. Additionally, we sought to compare the use of r-TEG with conventional coagulation tests in analysis of postinjury coagulopathy.. We conducted a retrospective study of severely injured patients entered into our trauma database between January and June 2008 who were at risk for postinjury coagulopathy. Patients needed simultaneous conventional coagulation (INR, fibrinogen, platelet count) and r-TEG specimens with either fresh or citrated whole blood for inclusion in the study. kappa-Statistics were used to determine the agreement between the tests in predicting hypocoagulability. McNemar's chi(2) tests were used to compare theoretical blood product administration between r-TEG and conventional coagulation tests for noncitrated specimens. Therapeutic transfusion triggers were: INR (>1.5) and r-TEG ACT (>125 s) for FFP administration; fibrinogen (<133 mg/dL) and alpha-angle (<63 degrees ) for cryoprecipitate; and platelet count (<100K) and maximum amplitude (MA) (<52 mm) for aphaeresis platelets. Statistical significance was established as P<0.05 using two-sided tests.. Forty-four patients met the inclusion criteria. kappa-Values (correlation) were higher in noncitrated versus citrated specimens for all comparisons between conventional and r-TEG tests, indicating better performance of r-TEG with the noncitrated specimens. FFP would have been administered to significantly more patients based on conventional transfusion triggers (61.5% by INR transfusion triggers versus 26.9% by r-TEG-ACT triggers, P=0.003). There was no statistically significant difference in potential cryoprecipitate or aphaeresis platelet administration.. POC r-TEG is superior when performed with uncitrated versus citrated whole blood for evaluation of postinjury coagulation status. As a real time measure of total thrombostatic function, our preliminary data suggest that r-TEG may effectively guide transfusion therapy and result in reduced FFP administration compared with conventional coagulation tests.

Topics: Adult; Blood Coagulation Disorders; Citric Acid; Female; Humans; Male; Middle Aged; Pilot Projects; Point-of-Care Systems; Retrospective Studies; Thrombelastography; Thromboplastin; Wounds and Injuries; Young Adult

Topics: Animals; Antithrombin III; Blood Coagulation; Blood Coagulation Disorders; Factor VIIa; Humans; Mice; Peptide Hydrolases; Prognosis; Systemic Inflammatory Response Syndrome; Thromboplastin

Chronometric hypocoagulation was observed in children, suffering an acute hematogenic ostheomyelitis, witnessed by processes of thrombin formation according to internal (the prolonged time of the blood plasm recalcification and activated partial thromboplastin time) and external (the thrombin time enhancement) ways of the blood coagulation process, as well as changes in fibrinogenesis mechanisms (the thrombin time prolongation). The lowering of anticoagulant capacity of the blood (the antithrombin III activity inhibition by 18.5%) was combined with significant increase of the thrombocytes functional activity (the rising of their adhesive and aggregational properties) in more than two times, which have occurred on the background of constant content of fibrinogen in the blood. Changes in the system of the plasm fibrinolysis in an acute hematogenic ostheomyelitis was characterized by inhibition of cofermental and, mainly, fermental fibrinolytic activity of the blood plasm, in conjunction with Hageman-dependent fibrinolysis intensification and was accompanied by accumulation of soluble complexes of fibrin-monomer in the blood. So far, chronometric hypocoagulation is secondary process, caused by the influence of soluble complexes of fibrin-monomer, which blocks fibrinogenesis. That's why the general potential of the blood coagulation system in children with an acute hematogenic ostheomyelitis must be regarded as a structural hypercoagulation.

Topics: Acute Disease; Adolescent; Blood Coagulation Disorders; Child; Child, Preschool; Female; Fibrinolytic Agents; Hemostatics; Humans; Male; Osteomyelitis; Thromboplastin

Topics: Apoptosis; Blood Coagulation Disorders; Blood Platelets; Cell Membrane; Endothelium, Vascular; Hemostasis; Humans; Inflammation; Ischemia; Microspheres; Neovascularization, Physiologic; Platelet Activation; Thrombin; Thromboplastin

Hemodilution (HD) has been associated with hypercoagulability. It was hypothesized that HD with lactated Ringer's solution (LR) would result in hypercoagulability in rabbits. Sedated rabbits (n = 12) underwent HD with LR (40% estimated blood volume replaced with five volumes of LR) via ear vessels. Key procoagulants and anticoagulant activities were assessed prior to and 3 h after HD. Hemostatic function was assessed with the activated coagulation time and platelet-inhibited thrombelastography. Circulating tissue factor activity was much more diluted (-67.2% from baseline) than tissue factor pathway inhibitor (-45.2%) or antithrombin (-9.5%) activities after HD. HD significantly decreased factor VIII complex activity (-31.5%) more than protein C activity (-5.9%), and factor X activity (-29.2%) was more diluted than antithrombin activity. The activated coagulation time and thrombelastography demonstrated a significant decrease in hemostatic function after HD. Hemodilution with LR caused hypocoagulability in the rabbit. A greater decrease in circulating procoagulant activity than anticoagulant activity appears to be the mechanism underlying HD-mediated decreases in hemostasis.

Topics: Animals; Antithrombins; Blood Coagulation; Blood Coagulation Disorders; Factor VIII; Factor X; Hemodilution; Isotonic Solutions; Lipoproteins; Rabbits; Ringer's Lactate; Thrombelastography; Thromboplastin

Hyperacute rejection of vascularized discordant xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the xenograft and the induction of AVR, coagulopathy, or both.. In vitro, heat-inactivated, naive or sensitized baboon sera containing xenoreactive natural or elicited antibodies were used to activate porcine aortic endothelial cells (PAEC) in vitro. Tissue factor expression on PAEC was determined as an index of heightened procoagulant activity. In vivo, porcine renal xenografts were transplanted into immunosuppressed baboons, and at the time of rejection or the development of a consumptive coagulopathy, biopsy specimens were obtained for studies of xenoreactive antibody binding and tissue factor expression.. In vitro, incubation of PAEC with naive baboon sera containing natural anti-Galalpha1,3Gal (Gal) antibodies resulted in minimal tissue factor induction; the addition of complement boosted procoagulant responses. Elicited xenoreactive antibodies, and to non-Gal epitopes alone, induced high amounts of procoagulant activity on PAEC; the addition of complement resulted in overt cytotoxicity. In vivo, AVR was associated with xenoreactive antibody deposition in the graft. When vascular endothelial binding of xenoreactive antibody was combined with the expression of tissue factor, consumptive coagulopathy developed irrespective of histopathologic features of AVR.. Our in vitro results indicate that elicited antibodies, potentially to non-Gal epitopes, induce endothelial cell activation and tissue factor expression; in vivo, a consumptive coagulopathy occurred when there was xenoreactive antibody deposition and increase of tissue factor.

Topics: Acute Disease; Animals; Antibodies, Heterophile; Aorta; Blood; Blood Coagulation Disorders; Cells, Cultured; Endothelium, Vascular; Graft Rejection; Immunization; Kidney Transplantation; Papio; Plant Lectins; Swine; Thromboplastin; Transplantation, Heterologous

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

The endogenous thrombin potential (ETP) represents the balance between pro- and anti-coagulant forces operating in plasma and can be used to investigate hyper- and hypo-coagulability. As a preliminary step to larger clinical studies we investigated the effect on ETP of phospholipids, tissue factor (TF) and residual platelets in frozen plasma.. We investigated platelet-poor and platelet-rich plasmas from healthy subjects, patients on oral anticoagulants (OA), or with hemophilia and women on oral contraceptives (OC), chosen as examples of the normal, hypo- and hyper-coagulable states in which ETP has been reported to be impaired.. Phospholipids had only a slight effect on ETP in all conditions except in women on OC, in whom the best diagnostic efficacy was observed at 0.5 microM. TF had only a slight effect in all conditions except hemophilia, in which an ETP impairment was observed only at low (1 pM) concentration. Residual platelets had considerable effects on ETP in frozen plasmas, but this was abrogated by filtration before freezing. ETP in platelet-rich plasma at 150x103/mm3 was similar to that obtained in filtered-plasma with 1.5 microM phospholipids in healthy subjects, patients on OA and patients with severe hemophilia, but not in those with mild- or moderate-hemophilia, where the ETP was higher in platelet-rich plasma.. The results suggest that the method can be used for investigations on the clinical value of ETP. Platelet-rich and platelet-poor plasma are suitable testing materials. The latter should be filtered before freezing to minimize the effect of residual platelets.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Contraceptives, Oral; Dose-Response Relationship, Drug; Female; Freezing; Hemophilia A; Humans; Phospholipids; Reproducibility of Results; Thrombin; Thrombophilia; Thromboplastin

Calibrated automated thrombography displays the concentration of thrombin in clotting plasma with or without platelets (platelet-rich plasma/platelet-poor plasma, PRP/PPP) in up to 48 samples by monitoring the splitting of a fluorogenic substrate and comparing it to a constant known thrombin activity in a parallel, non-clotting sample. Thus, the non-linearity of the reaction rate with thrombin concentration is compensated for, and adding an excess of substrate can be avoided. Standard conditions were established at which acceptable experimental variation accompanies sensitivity to pathological changes. The coefficients of variation of the surface under the curve (endogenous thrombin potential) are: within experiment approximately 3%; intra-individual: <5% in PPP, <8% in PRP; interindividual 15% in PPP and 19% in PRP. In PPP, calibrated automated thrombography shows all clotting factor deficiencies (except factor XIII) and the effect of all anticoagulants [AVK, heparin(-likes), direct inhibitors]. In PRP, it is diminished in von Willebrand's disease, but it also shows the effect of platelet inhibitors (e.g. aspirin and abciximab). Addition of activated protein C (APC) or thrombomodulin inhibits thrombin generation and reflects disorders of the APC system (congenital and acquired resistance, deficiencies and lupus antibodies) independent of concomitant inhibition of the procoagulant pathway as for example by anticoagulants.

Topics: Anticoagulants; Area Under Curve; Automation; Blood Coagulation Disorders; Blood Coagulation Tests; Calibration; Coumarins; Fibrinogen; Fluorescent Dyes; Fluorometry; Humans; Oligopeptides; Plasma; Protein C; Recombinant Proteins; Reference Values; Software; Thrombin; Thrombomodulin; Thromboplastin

Recombinant coagulation factor VIIa (rFVIIa) is generally accepted for treatment of patients with inhibitor-complicated hemophilia. Recently, rFVIIa variants with a specific enhancement of the tissue factor (TF)-independent proteolytic activity have been described.. The procoagulant and [thrombin-activatable fibrinolysis inhibitor (TAFI)-dependent] antifibrinolytic potentials of two superactive rFVIIa variants were compared with those of wild-type rFVIIa in a hemophilic setting.. Clot lysis assays were performed in plasma from six patients with inhibitor-complicated hemophilia A or in antibody-induced factor VIII-deficient platelet-rich plasma in the presence of different concentrations of the rFVIIa variants.. In the plasma model, M298Q-rFVIIa had a moderately increased procoagulant and antifibrinolytic potential, whereas V158D/E296V/M298Q/K337A-rFVIIa had a strongly increased procoagulant and antifibrinolytic activity compared with wild-type rFVIIa. The increased antifibrinolytic potential of the rFVIIa variants was completely dependent on enhancement of TAFI activation. In the platelet-rich plasma model similar results were obtained. The presence of TF was mandatory for clot formation in the absence of exogenous rFVIIa. At lower concentrations of rFVIIa (wild-type or variants), clot formation did occur but was significantly slower when TF activity was blocked. At increasing concentrations of rFVIIa, clotting times were no longer dependent on TF. In conclusion, should a TF-independent mechanism be involved in the efficacy of rFVIIa in patients with hemophilia, the superactive rFVIIa variants studied here might be clinically advantageous, as both procoagulant and antifibrinolytic potencies are significantly enhanced compared with those of wild-type rFVIIa. This ought to result in more efficient cessation of bleeding episodes and reduced risk of rebleeding.

Topics: Antifibrinolytic Agents; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Carboxypeptidase B2; Coagulants; Dose-Response Relationship, Drug; Factor VII; Factor VIIa; Hemophilia A; Hemorrhage; Humans; In Vitro Techniques; Plasma; Recombinant Proteins; Thromboplastin

In a patient who presented with a severe coagulation deficiency in plasma contrasting with a very mild hemorrhagic diathesis a homozygous Arg67His mutation was identified in the prothrombin gene. Wild-type (factor IIa [FIIa]-WT) and mutant Arg67His thrombin (FIIa-MT67) had similar amidolytic activity. By contrast, the k(cat)/K(m) value of fibrinopeptide A hydrolysis by FIIa-WT and FIIa-MT67 was equal to 2.1 x 10(7) M(-1)s(-1) and 9 x 10(5) M(-1)s(-1). Decreased activation of protein C (PC) correlated with the 33-fold decreased binding affinity for thrombomodulin (TM; K(d) = 65.3 nM vs 2.1 nM, in FIIa-MT67 and in FIIa-WT, respectively). In contrast, hydrolysis of PC in the absence of TM was normal. The Arg67His mutation had a dramatic effect on the cleavage of protease-activated G protein-coupled receptor 1 (PAR-1) 38-60 peptide (k(cat/)K(m) = 4 x 10(7) M(-1)s(-1) to 1.2 x 10(6) M(-1)s(-1)). FIIa-MT67 showed a weaker platelet activating capacity, attributed to a defective PAR-1 interaction, whereas the interaction with glycoprotein Ib was normal. A drastic decrease (up to 500-fold) of the second-order rate constant pertaining to heparin cofactor II (HCII) interaction, especially in the presence of dermatan sulfate, was found for the FIIa-MT67 compared with FIIa-WT, suggesting a severe impairment of thrombin inhibition by HCII in vivo. Finally, the Arg67His mutation was associated with a 5-fold decrease of prothrombin activation by the factor Xa-factor Va complex, perhaps through impairment of the prothrombin-factor Va interaction. These experiments show that the Arg67His substitution affects drastically both the procoagulant and the anticoagulant functions of thrombin as well as its inhibition by HCII. The mild hemorrhagic phenotype might be explained by abnormalities that ultimately counterbalance each other.

Topics: Arginine; Blood Coagulation Disorders; Cell Line; Consanguinity; Factor Va; Factor Xa; Female; Fibrinopeptide A; Hemorrhagic Disorders; Heparin Cofactor II; Histidine; Homozygote; Humans; Hydrolysis; Infant; Mutagenesis, Site-Directed; Mutation; Protein C; Prothrombin; Receptor, PAR-1; Receptors, Thrombin; Thrombin; Thrombomodulin; Thromboplastin; Transfection

Topics: Anticoagulants; Apoenzymes; Blood Coagulation Disorders; Heparin; Humans; Multiple Trauma; Thromboplastin

To study the effect of arsenic trioxide (As2O3) or all-trans retinoic acid (ATRA) on coagulopathy in patients with acute promyelocytic leukemia (APL), and the mechanism of hemorrhage in these patients.. Thrombomodulin (TM) or tissue factor (TF) transcription of mRNA of freshly isolated bone marrow blast from APL patients was detected by semi-quantitative RT-PCR. The parameters of coagulation and cell procoagulation activity (PCA) were assessed in plasmic levels. Bleeding symptom was observed during As2O3 or ATRA treatment.. TM expression in the APL cell surface was significantly upregulated from (14.31 +/- 1.60) ng/10(7) to (21.61 +/- 6.82) ng/10(7) cells. The levels of P-selectin, soluble fibrin monomer complex (SFMC) and D-dimer (D-D) decreased after ATRA or As2O3 treatment. Abnormal high expression of TF in APL cell was downregulated in patients treated with ATRA or As2O3. The expression level was (14.81 +/- 6.23) ng/L before treatment, but undetected after 20 days of treatment. In addition, the membrane PCA of fresh APL cells was predominantly FVII-dependent after ATRA or As2O3 treatment. Bleeding symptom was ameliorated during As2O3 or ATRA treatment.. Bleeding symptom was controlled in patients with APL after As2O3 or ATRA treatment.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Down-Regulation; Female; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; RNA, Messenger; Thrombomodulin; Thromboplastin; Tretinoin

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

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease. These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability state seen in cardiac transplant recipients.. Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay.. Monocyte TF activity was found to be significantly increased in cardiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation.. Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.

Topics: Adult; Aged; Blood Coagulation Disorders; Coronary Disease; Female; Heart Transplantation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Monocytes; RNA, Messenger; Simvastatin; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Cell Communication; Cytokines; Humans; Inflammation; Sepsis; Thromboplastin

Automated human plasma, continuous monitoring of the formation and inactivation of thrombin during the coagulation process provides an adequate way to detect hypo- and hypercoagulant conditions. Here, we describe an analogous procedure to determine the endogenous thrombin potential (ETP), i. e. the free thrombin concentration-time integral, of coagulating rat plasma. When activated with tissue factor, the ETP of plasma from Wistar rats was comparable to the ETP of human plasma, in spite of a relatively short half-life time of free thrombin in rat plasma. The ETP was highly sensitive to heparin as well as to administration of vitamin K antagonist or feeding of the animals with a vitamin K-deficient diet. In plasma that was activated under sub-optimal conditions (reduced levels of tissue factor or vitamin K-dependent coagulation factors), the ETP increased with the rate of thrombin formation in the first minutes of the coagulation process. Since both parameters are dependent of the prothrombin concentration, it appears that this level plays an important role in determining both the initial and total activity of the coagulation system. Thus, automated measurement of free thrombin during the coagulation process of rat plasma allows a detailed analysis of hypocoagulability in this animal model.

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Disease Models, Animal; Electronic Data Processing; Humans; Kinetics; Male; Rats; Rats, Wistar; Sensitivity and Specificity; Thrombin; Thromboplastin; Warfarin

Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Kupffer cells and minimal TFPI and thrombomodulin in endothelial cells. The destruction of sinusoidal endothelial cells as well as hepatocytes may occur as a result of microcirculatory disturbance caused by such sinusoidal fibrin deposition.

Topics: Alanine Transaminase; Animals; Blood Coagulation Disorders; Endotoxins; Hepatectomy; Humans; Injections, Intravenous; Kupffer Cells; Lipoproteins; Liver; Male; Necrosis; Purine-Nucleoside Phosphorylase; Rats; Rats, Inbred F344; Recombinant Proteins; Thrombomodulin; Thromboplastin; Tissue Distribution

To assess coagulation activation and endothelial cell injury in normotensive and pre-eclamptic pregnant women, a comparison was made of plasma levels of tissue factor, fibronectin, fibrinopeptide A and D-dimer. Samples were taken from 50 nonpregnant women, 40 normotensive pregnant women in the third trimester and 27 women with pre-eclampsia after diagnosis and before treatment. High levels of fibrinopeptide A and D-dimer were found in pre-eclamptic women. Moreover, the ratio fibrinopeptide A:D-dimer was much greater in the pre-eclampsia group than in normotensive pregnant women. The levels of fibronectin and tissue factor were also higher in the pre-eclampsia group. The increase of tissue factor levels suggests an alteration of the extrinsic coagulation pathway in pre-eclampsia. The increase of fibrinopeptide A:D-dimer ratio shows that the activation of coagulation is associated with a relative hypofibrinolysis in pre-eclampsia.

Topics: Adult; Antifibrinolytic Agents; Blood Coagulation Disorders; Female; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Thromboplastin

Scott syndrome is an hereditary bleeding disorder characterized by a deficiency in platelet procoagulant activity. Unlike normal blood cells, Scott platelets, as well as erythrocytes and lymphocytes, are strongly impaired in their ability to scramble their membrane phospholipids when challenged with Ca2+. In normal cells this collapse of membrane asymmetry leads to surface exposure of phosphatidylserine. Here we report that Scott erythrocytes show an apparent defect in tyrosine phosphorylation on treatment with Ca2+-ionophore. Diminished tyrosine phosphorylation was also apparent in activated Scott platelets, but much less pronounced than observed in red blood cells. On the other hand, tyrosine phosphorylation profiles observed in Scott red blood cell ghosts after sealing in the presence of adenosine triphosphate (ATP) were indistinguishable from those obtained from normal ghosts. Several observations argue in favor of a mechanism in which tyrosine phosphorylation in red blood cells is facilitated by, rather than required for scrambling of membrane lipids. Staurosporin blocks tyrosine phosphorylation in normal red blood cells, but does not inhibit the lipid scrambling process. White ghosts from normal erythrocytes, resealed in the absence of ATP, exhibit Ca2+-induced lipid scrambling without tyrosine phosphorylation. A selective inhibitor of Ca2+-induced lipid scrambling also showed an apparent inhibition of tyrosine phosphorylation in ionophore-treated normal red blood cells, similar to that observed in Scott erythrocytes. While this inhibitor also suppressed Ca2+-induced lipid scrambling in ghosts that were sealed in the presence of ATP, it did not inhibit tyrosine kinase activity. We conclude that the apparent deficiency in tyrosine phosphorylation in Scott cells is an epiphenomenon, possibly associated with a defect in phospholipid scrambling, but not causal to this defect.

Topics: Adenosine Triphosphate; Blood Coagulation Disorders; Blood Platelets; Calcium; Carrier Proteins; Cell Membrane; Enzyme Inhibitors; Erythrocyte Membrane; Humans; Ionophores; Membrane Lipids; Membrane Proteins; Methomyl; Phosphatidylserines; Phospholipid Transfer Proteins; Phospholipids; Phosphorylation; Protein Processing, Post-Translational; Protein-Tyrosine Kinases; Staurosporine; Syndrome; Thromboplastin

To obtain systematic information on the extrinsic coagulation pathway, as well as to investigate the time course of the coagulation abnormalities in sepsis.. Prospective observational study.. General intensive care unit.. Nineteen patients with the diagnosis of severe sepsis or septic shock and nine control patients.. None.. Tissue factor antigen concentration (tissue factor antigen), prothrombin fragment F1+2, thrombin antithrombin III complex, fibrinopeptide A, D-dimer, and antithrombin III concentrations were measured on the day of diagnosis of severe sepsis and septic shock, and on days 1, 2, 3, and 4 after diagnosis. The concentrations of tissue factor antigen, prothrombin fragment F1+2, fibrinopeptide A, and D-dimer were significantly increased in patients with severe sepsis and septic shock compared with control subjects. However, the concentrations of thrombin antithrombin III complex showed no statistical differences between the septic patients and the control subjects. Significantly, low antithrombin III concentrations were observed in the septic patient groups compared with control subjects. With the exception of D-dimer, the concentrations of the hemostatic markers were similar between severe sepsis and septic shock patients. Significant correlations were noted between tissue factor antigen and the disseminated intravascular coagulation score (r2=.236, p< .0001) and the number of dysfunctioning organs (r2=.229, p=.035).. We systematically elucidated coagulation disorders in newly defined sepsis. The extrinsic coagulation pathway is activated in patients with severe sepsis and septic shock. In these patients, enhanced thrombin generation and activation, and fibrin formation were demonstrated when compared with the control subjects. Furthermore, the thrombin generated appears not to be fully neutralized by antithrombin III.

Topics: Adult; Aged; Antithrombin III; Biomarkers; Blood Coagulation; Blood Coagulation Disorders; Case-Control Studies; Female; Fibrin Fibrinogen Degradation Products; Fibrinopeptide A; Humans; Male; Middle Aged; Peptide Fragments; Peptide Hydrolases; Prospective Studies; Protein Precursors; Prothrombin; Sepsis; Shock, Septic; Thromboplastin

In order to develop decentralized anticoagulant care by off-site blood sampling and transport of samples to a centralized laboratory for International Normalized Ratio (INR) determination we have performed a direct comparative study of INR stability. Analysis was performed daily for 5 d using nine thromboplastins. The overall mean difference of INR after 3d was only 0.05 INR units for samples with a therapeutic INR. After 5 d there was a mean difference of 0.11 INR units with 'non-Manchester' reagents and 0.44 INR units with 'Manchester' reagents. With over-anticoagulated samples mean differences of 0.55-0.72 INR units were observed after 3 d and 1.16-2.46 INR units after 5 d. Although there was some variation in stability of results with different thromboplastins, the difference over time with each thromboplastin was much less than the difference between thromboplastins. In conclusion, there is no clinically significant change in INR when analysis is delayed for up to 3 d. Off-site blood sampling can accommodate a large increase in patient workload without a major revenue increase in primary care and with continued total quality management and central expert advice.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Prothrombin Time; Reproducibility of Results; Specimen Handling; Thromboplastin; Time Factors

Topics: Adult; Aged; Aged, 80 and over; Blood Coagulation Disorders; Blood Platelets; Female; Humans; Male; Middle Aged; Syndrome; Thromboplastin

A functional clotting assay was recently reported to detect the factor V-Leiden mutation (R506Q) in patients receiving oral anticoagulants and in patients with Lupus Anticoagulant inhibitor. The original assay (Dahlback) to detect resistance to activated protein C (aPC-resistance) frequently gave unreliable findings in these patients. The change in the method is the use of bovine thromboplastin in a PT-derived assay, with a 1:10 sample dilution. In these conditions a reference normal plasma gives a prolongation of more than 35 seconds, while samples with a heterozygous or homozygous mutation give a prolongation respectively of 10-18 seconds or less 2 seconds. The test is easily automated and quickly performed on ACL/3000, and the reproducibility is good.

Topics: Animals; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Cattle; Drug Resistance; Evaluation Studies as Topic; Factor V; Factor VIII; Heparin; Heterozygote; Homozygote; Humans; In Vitro Techniques; Lupus Coagulation Inhibitor; Point Mutation; Protein C; Rabbits; Reproducibility of Results; Thromboplastin

Topics: Blood Coagulation Disorders; Humans; Leukemia, Promyelocytic, Acute; Thromboplastin; Tretinoin

In a multicentre study of four thromboplastin reference materials (three from rabbit brain and one from bovine brain combined with adsorbed bovine plasma), three types of lyophilized plasmas were included. One was a pooled normal plasma, another was made by pooling plasmas of coumarin-treated patients, and the third was prepared by adsorption of vitamin K dependent clotting factors (artificially depleted). The purpose of this study was to investigate whether these lyophilized plasmas could be used for reliable calibration of the four thromboplastins. Calibration line slopes were calculated for the lyophilized plasmas and compared to the slopes based on fresh plasmas. When a rabbit thromboplastin was calibrated against a similar but not identical reagent (like-to-like comparison), the slopes for lyophilized plasmas and for fresh plasmas were the same. However, significant differences between lyophilized and fresh plasmas were observed in the calibration of unlike thromboplastins. The deviation of the slope with artificially depleted plasma was greater than that with lyophilized coumarin plasma. Indiscriminate use of these lyophilized plasmas for thromboplastin calibration should be avoided.

Topics: Administration, Oral; Blood; Blood Coagulation Disorders; Freeze Drying; Humans; Reference Standards; Thromboplastin

Tissue factor (TF) is the cellular receptor for coagulation factor VI/VIIa and is the membrane-bound glycoprotein that is generally viewed as the primary physiological initiator of blood coagulation. To define in greater detail the physiological role of TF in development and hemostasis, the TF gene was disrupted in mice. Mice heterozygous for the inactivated TF allele expressed approximately half the TF activity of wild-type mice but were phenotypically normal. However, homozygous TF-/- pups were never born in crosses between heterozygous mice. Analysis of mid-gestation embryos showed that TF-/- embryos die in utero between days 8.5 and 10.5. TF-/- embryos were morphologically distinct from their TF+/+ and TF+/- littermates after day 9.5 in that they were pale, edematous, and growth retarded. Histological studies showed that early organogenesis was normal. The initial failure in TF-/- embryos appeared to be hemorrhaging, leading to the leakage of embryonic red cells from both extraembryonic and embryonic vessels. These studies indicate that TF plays an indispensable role in establishing and/or maintaining vascular integrity in the developing embryo at a time when embryonic and extraembryonic vasculatures are fusing and blood circulation begins.

Topics: Animals; Base Sequence; Blood Coagulation Disorders; DNA Primers; Fetal Death; Genes, Lethal; Hemorrhage; Heterozygote; Homozygote; Mice; Molecular Sequence Data; Phenotype; Thromboplastin

Prothrombin-time (PT) sensitivity and specificity to mild clotting factor II, V, VII and X deficiencies have rarely been studied. We therefore carried out a prospective study, in 350 patients, of eight commercial thromboplastins (CTs) in their ability to detect mild clotting factor deficiencies, notably in factor VII. In each patient the factor II, V, VII and X clotting activities and PT performed with each CT were determined. For each CT, PT sensitivity and specificity in detecting factor deficiencies below 0.5 U/ml or below 0.4 U/ml were determined at various PTs, and then Receiver Operator Characteristic curves constructed. At optimum PT threshold level (sensitivity = specificity), exactitude varied from 0.64 to 0.74 (p < 0.01) and from 0.67 to 0.81 (p < 0.0001) in detecting deficiencies below 0.5 and 0.4 U/ml respectively. In conclusion, this study shows the limits of the PT test as performed with 8 CTs in patients with mild clotting factor deficiencies. The impact of such differences in sensitivity and specificity on monitoring certain patients subjects to decrease in coagulation factor, and, in particular, of those under low dose oral anticoagulant, remains to be determined.

Topics: Blood Coagulation Disorders; Calibration; Case-Control Studies; Evaluation Studies as Topic; Factor VII Deficiency; Female; Humans; Linear Models; Male; Predictive Value of Tests; Prospective Studies; Prothrombin Time; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Thromboplastin

Topics: Blood Coagulation Disorders; Heparin; Hexadimethrine Bromide; Humans; Partial Thromboplastin Time; Sensitivity and Specificity; Thromboplastin

Factor VII is a vitamin K-dependent zymogen of a serine protease that participates in the initial phase of blood coagulation. A factor VII molecular variant (factor VII Central) was identified in a 24-year-old male with severe factor VII deficiency and whose plasma factor VII antigen was 38% of normal, but expressed <1% factor VII procoagulant activity. DNA sequence analysis of the patient's factor VII gene revealed a thymidine to cytidine transition at nucleotide 10907 in exon VIII that results in a novel amino acid substitution of Phe328 to Ser. The patient was homozygous for this mutation, whereas each parent of the patient was heterozygous for this mutation. To investigate the molecular properties of this variant, a recombinant F328S factor VII mutant was prepared and analyzed in relation to wild-type factor VII. F328S factor VII exhibited <1% factor VII procoagulant activity and a 2-fold decreased affinity for tissue factor and failed to activate factor X or IX in the presence of tissue factor following activation by factor Xa. In addition, F328S factor VIIa exhibited no detectable amidolytic activity in the presence of tissue factor. The rate of F328S factor VII activation by factor Xa was markedly decreased relative to the rate of wild-type factor VII activation as revealed by densitometry scanning of SDS gels. Temporal analysis of this reaction by SDS-polyacrylamide gel electrophoresis also revealed the formation of two novel F328S factor VII degradation products (40 and 9 kDa) resulting from factor Xa proteolysis of the Arg315-Lys316 peptide bond in intact F328S factor VII. Computer modeling and molecular dynamics simulations of the serine protease domain of factor VIIa suggested that the inability of F328S factor VIIa to cleave substrates may result from the apparent formation of a hydrogen bond between Tyr377 and Asp338, a residue at the bottom of the substrate-binding pocket important for the interaction of substrate arginine side chains with the enzyme. These findings suggest that Phe328, which is conserved in prothrombin, factor IX, factor X, factor VII, and trypsin, is important for factor VIIa catalysis.

Topics: Adult; Aspartic Acid; Blood Coagulation Disorders; Factor VII; Factor Xa; Humans; Hydrogen Bonding; Male; Models, Molecular; Point Mutation; Recombinant Proteins; Structure-Activity Relationship; Thromboplastin; Tyrosine

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 purpose of the present study was to compare the results obtained with a human recombinant thromboplastin (Innovin, Baxter) (IN) and a high-sensitivity rabbit brain reagent (Thromboplastin IS, Baxter) (IS), on the performance of prothrombin time (PT) test and the functional assay of factors included in the extrinsic coagulation system, in order to establish possible differences on imprecision, diagnostic accuracy and sensitivity to the oral anticoagulant defect, between the two products.. Six Spanish hospital took part in the study. Plasma samples from 221 healthy subjects, 100 patients with severe liver disease, 27 with dysfibrinogenaemia, 10 with lupus anticoagulant and from 13 individuals propositus and their relatives with congenital deficiencies of the extrinsic coagulation pathway, and their relatives were studied; 188 patients stabilized on oral anticoagulant therapy and 82 on heparin therapy were also included. The in vitro effect of heparin was tested by addition of increasing amounts of heparin (0.3 to 10.0 IU/mL) to aliquots of normal plasma.. Both in the intra-assay and in the inter-assay imprecision study, a better coefficient of variation was obtained with IN when the PT was performed on abnormal samples. Prothrombin time ratio from patients with liver disease had significantly higher values with IS. On the contrary, IN had a higher sensitivity in samples from patients with dysfibrinogenaemia or from those stabilized on oral anticoagulant therapy. In showed a very low sensitivity to heparin at concentrations corresponding to the therapeutic range.. The results of this field study indicate that IN, compared with a high-sensitivity rabbit brain thromboplastin, is a suitable reagent for PT determination in normal subjects, patients with liver disease or with congenital deficiencies of clotting factors. It shows a higher sensitivity in cases of dysfibrinogenaemia and in patients on oral anticoagulant therapy. In addition, the recombinant reagent had better reproducibility when the PT was performed on abnormal samples, and it was hardly affected by heparin within the therapeutic range.

Topics: Afibrinogenemia; Animals; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Heparin; Humans; Indicators and Reagents; Liver Diseases; Lupus Coagulation Inhibitor; Phospholipids; Prothrombin Time; Rabbits; Recombinant Fusion Proteins; Reproducibility of Results; Sensitivity and Specificity; Thromboplastin

To check out the reproducibility and costs of prothrombin time (PT) determination as a control of oral anticoagulant therapy (OAT) in plasma and capillary blood.. The study was carried out in two phases: along two years, 1,700 patients with OAT were controlled, 700 of them in the hospital outpatient clinic. In 149 patients INR was simultaneously determined in both capillary and venous blood. The 700 patients receiving acenocoumarin who had been controlled in 1991 according to the conventional plasma-sample fashion, were controlled in the second year (i.e., 1992) by means of capillary blood testing, a comparison of the costs of each method and the need for anticoagulant drugs being undertaken. Venous blood PT was assessed with reagent thromboplastin (Tromborel S) in an Electra-1000 (MLA) system. An automated Trombotrack system was used for the capillary blood tests using Thrombotest as current procedure. The results were expressed as INR in both methods. The statistical evaluation of the results was carried out by means of Student's t, variance analysis, and correlation study.. No significant differences were found in the anticoagulation intervals attained from venous or capillary blood samples. No significant differences were seen in 87 patients on whom the test was repeated in two samples drawn from a single capillary puncture. The weekly OAT doses of 30 patients along six months were analysed. The need for anticoagulant drugs was similar (17.4 vs 17.2 mg/patient/week). The mean INR in 1991 was 2.82 and the mean drug-need was 15.24 mg/week, whereas in 1992 the mean INR was 2.86 and the need for anticoagulant was 15.49 mg/week. The costs of the conventional method were 103.6 Pta, this being 70 Pta for capillary blood, which means a 32% savings.. OAT control by means of PT performed on capillary blood must be considered a substitutive method for the venous blood assay due to its efficacy, simplicity and lower costs.

Topics: Acenocoumarol; Administration, Oral; Blood Coagulation; Blood Coagulation Disorders; Blood Specimen Collection; Capillaries; Costs and Cost Analysis; Humans; Prothrombin Time; Reference Standards; Reproducibility of Results; Thromboplastin; Veins

Topics: Animals; Blood Coagulation Disorders; Chronic Disease; Graft Rejection; Kidney Glomerulus; Kidney Transplantation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Thromboplastin; Tissue Plasminogen Activator; Transplantation, Homologous

After liver surgery, two patients developed unexplainable prolonged prothrombin times (PT) that were not associated with bleeding tendency. The substitution of rabbit thromboplastin for either human or monkey thromboplastin in performing PT tests resulted in a normal clotting time. Tissue factor (TF) procoagulant activity assays and an immunoblotting analysis showed that these patients had developed IgG lambda-type immediate anticoagulants directed against both rabbit and bovine TF that did not crossreact with human or monkey TF. In a chromogenic assay, the patient IgG caused a decrease in both the Km and the Vmax of the factor X activation by rabbit TF-factor VIIa complex. The lack of reactivity of the patient IgG with human TF presumably explained why there was no clinical bleeding. Both patients had been treated earlier with a topical hemostatic agent prepared from bovine corium, microfibrillar collagen hemostat, while undergoing previous surgery. In an immunoblotting analysis, the patient IgG stained a 42-Kd band in the Triton extract of the collagen preparation under either reducing or nonreducing conditions. The Triton extract of the collagen preparation blocked the binding of the patient IgG to bovine TF. Thus, it is suggested that the iatrogenic immunization by intraoperative exposure of bovine TF retained in the collagen preparation may be responsible for the development of anti-TF antibodies in these patients. The anti-TF antibodies resulted in a clinical error in the evaluation of coagulation status after the use of rabbit thromboplastin.

Topics: Animals; Autoantibodies; Blood Coagulation Disorders; Cattle; Female; Humans; Liver; Male; Middle Aged; Prothrombin Time; Rabbits; Species Specificity; Thromboplastin

We measured factor VII activity and antigen levels in plasma of pregnant women and patients with elevated serum FDP including patients with DIC who were supposed to be in hypercoagulable state, and compared the values with normal subjects. Both FVII activities measured by human placenta thromboplastin (hTF/FVIIc) and bovine brain thromboplastin (bTF/FVIIc) in normal plasma were correlated well with the FVII antigen levels (FVIIag). Measured hTF/FVIIc, bTF/FVIIc and FVIIag in pregnant women were 163 +/- 44%, 205 +/- 49% and 175 +/- 44% respectively, and each value had correlation. Thrombin-antithrombin III complex in these subjects was increased (7.85 +/- 2.25 mg/ml). However, antithrombin III, plasmin-plasmin inhibitor complex and FDP D-dimer were within normal range. These observations indicated that pregnant women were in hypercoagulable state but not in hyperfibrinolytic state. hTF/FVIIc, bTF/FVIIc and FVIIag in plasma from patients with elevated serum FDP were 59.6 +/- 29%, 94 +/- 65% and 61.6 +/- 26% respectively. We divided these patients into 2 groups: Group A (both prolonged PT and APTT) and Group B (shortened APTT). hTF/FVIIc, bTF/FVIIc and FVIIag in plasma of Group A were 47 +/- 21%, 48 +/- 24% and 48 +/- 21% respectively. The corresponding values of Group B were 80 +/- 24%, 155 +/- 54% and 74 +/- 23% which were correlated each other. Low levels of FVII observed in Group A seemed to be due to increased consumption of coagulation factors. In Group B, the pattern of FVII activities and FVII antigen was similar to that of pregnant women, though FVII levels were lower.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomarkers; Blood Coagulation Disorders; Factor VII; Female; Humans; Pregnancy; Thromboplastin

Although patients with thromboembolic disease frequently have family histories of thrombosis, well-defined defects such as inherited deficiencies of anticoagulant proteins are found only in a minority of cases. Based on the hypothesis that a poor anticoagulant response to activated protein C (APC) would predispose to thrombosis, a set of new coagulation assays was developed that measure the anticoagulant response in plasma to APC. A middle-aged man with a history of multiple thrombotic events was identified. The addition of APC to his plasma did not result in a normal anticoagulant response as measured by prolongation of clotting time in an activated partial thromboplastin time (APTT) assay. Four of the proband's relatives had medical histories of multiple thrombotic events, and they and several other family members responded poorly to APC in the APTT-based assay. Subnormal anticoagulant responses to APC were also found in factor IXa- and Xa-based assays. Several possible mechanisms for the observed phenomenon were ruled out, such as functional protein S deficiency, a protein C-inhibitory antibody, or a fast-acting protease inhibitor against APC. Moreover, restriction fragment-length polymorphism analysis excluded possible linkage of the underlying molecular defect to factor VIII and von Willebrand factor genes. We now describe a previously unrecognized mechanism for familial thromboembolic disease that is characterized by poor anticoagulant response to APC. This would appear to be explained best by a hypothesized inherited deficiency of a previously unrecognized cofactor to APC. As we have identified two additional, unrelated cases with thrombosis and inherited poor anticoagulant response to APC, this may constitute an important cause for familial thrombophilia.

Topics: Adult; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Factor IXa; Female; Humans; Male; Pedigree; Protein C; Thromboplastin; Thrombosis

Microvascular perfusion defects occur after occlusion and reperfusion of the middle cerebral artery in examples of focal cerebral ischemia. In addition to cellular (eg, polymorphonuclear leukocyte) contributors to the focal "no-reflow" phenomenon, activation of coagulation may also play a role. We have tested a potential role of tissue factor-mediated coagulation in the microvascular perfusion defects seen after focal cerebral ischemia-reperfusion in a baboon model of reversible middle cerebral artery occlusion with the murine anti-tissue factor monoclonal antibody TF9-6B4. Tissue factor is the principal resident procoagulant substance in cerebral tissues and has a distinct perivascular distribution.. Microvascular patency in the basal ganglia after 3-hour middle cerebral artery occlusion and 1-hour reperfusion was quantified by computerized video imaging of carbon-tracer perfused tissues. Animals were randomized to receive intravenous TF9-6B4 (10 mg/kg) 10 minutes before middle cerebral artery occlusion (n = 6) or no treatment (n = 6) in an open study.. In the control animals, a significant decrease in patency was confirmed in microvessels less than 30 microns in diameter. Infusion of TF9-6B4 before middle cerebral artery occlusion produced a stable maximal level of circulating antibody within 10 minutes, which lasted the duration of ischemia and reperfusion. An increase in reflow in microvessels of all size classes occurred after TF9-6B4 infusion, which was significant in those 7.5 to 30 microns (P = .038) and 30 to 50 microns (P = .013) in diameter.. These results indicate that tissue factor-mediated events may also contribute to no-reflow in noncapillary microvessels after focal cerebral ischemia.

Topics: Animals; Antibodies, Monoclonal; Blood Coagulation Disorders; Brain Ischemia; Cerebral Arteries; Disease Models, Animal; Male; Microcirculation; Papio; Reperfusion Injury; Thromboplastin

We report two cases of renal vein thrombosis, unusual because of acute expression, right renal vein localization, absence of the usual renal or perirenal causes, surgical management and a never before reported etiology. In one case the thrombosis was secondary to primary antiphospholipid syndrome, in the other it was secondary to heparin associated thrombocythemia. In this case surgical management was performed during prostacyclin infusion.

Topics: Acute Disease; Autoantibodies; Blood Coagulation Disorders; Combined Modality Therapy; Epoprostenol; Female; Heparin; Humans; Male; Middle Aged; Phospholipids; Renal Veins; Syndrome; Thrombocytopenia; Thromboplastin; Thrombosis

Topics: Animals; Blood Coagulation Disorders; Brain Chemistry; Cattle; DNA Mutational Analysis; Factor VII; Factor VII Deficiency; Humans; Thromboplastin; von Willebrand Diseases

Immunohistochemical techniques were applied to rheumatoid synovium in order to detect components of coagulation and fibrinolysis pathways within these tissues. These techniques revealed an intact coagulation pathway and plasminogen activator inhibitor-2 associated with macrophage-like cells that were present throughout these tissues, especially in subsurface areas. Cell-associated thrombin generation appeared to account for conversion of abundant fibrinogen to fibrin. Occasional macrophage-like cells also stained for urokinase but tissue-type plasminogen activator and plasminogen activator inhibitor-1 were restricted to vascular endothelium. Intense synovial fibrin deposition (with the limited evidence for associated fibrinolysis) may contribute to local inflammation and explain certain clinical features of rheumatoid arthritis. These findings suggest novel treatment hypotheses for this disease.

Topics: Arthritis, Rheumatoid; Blood Coagulation Disorders; Factor V; Factor VII; Factor X; Factor XIII; Fibrin; Fibrinogen; Humans; Immunohistochemistry; Macrophages; Plasminogen Inactivators; Synovial Membrane; Thromboplastin

Relipidated recombinant tissue factor (r-TF) has been assessed in comparison with conventional rabbit brain thromboplastin (Manchester Reagent) for its suitability for measurement of prothrombin time (PT). The International Sensitivity Index (ISI) of r-TF calibrated against the International Reference Preparation BCT/253 (human plain) was found to be 0.96 and 1.12 with instrumental and manual techniques. Our study of plasmas from patients with congenital deficiencies of clotting factors covering a wide range of severity demonstrates that r-TF is able to detect even minor deficiencies of factors involved in the extrinsic and common coagulation pathways. Patients with liver diseases were correctly diagnosed with a prevalence of abnormal results comparable for both reagents. Between-assay reproducibility expressed as coefficient of variation was 2.3% and 3.9% at normal and abnormal PT levels. In conclusion, our evaluation shows that relipidated r-TF possesses the necessary requisites of sensitivity, diagnostic accuracy and reproducibility which make it a suitable candidate for PT determination both for monitoring oral anticoagulant therapy and diagnosing congenital and acquired clotting factor deficiencies. Moreover, being a highly defined reagent it may constitute a step forward in the standardization of PT testing.

Topics: Anticoagulants; Blood Coagulation Disorders; Evaluation Studies as Topic; Humans; Indicators and Reagents; Liver Diseases; Prothrombin Time; Recombinant Proteins; Reference Standards; Reproducibility of Results; Thromboplastin

The erythrocytes from a patient with Scott syndrome, a bleeding disorder characterized by an isolated defect in expression of platelet procoagulant activity, have been studied. When incubated with the calcium ionophore A23187, Scott syndrome red blood cells (RBCs) expressed less than 10% of the prothrombinase (enzyme complex of coagulation factors Va and Xa) activity of A23187-treated RBCs obtained from normal controls. Consistent with the results from enzyme assay, the ionophore-treated Scott syndrome erythrocytes exhibited diminished membrane vesiculation and decreased exposure of membrane binding sites for factor Va compared with identically treated controls. When examined by scanning electron microscopy, untreated Scott syndrome RBCs were indistinguishable from normal cells. After incubation with A23187, however, the morphology of Scott syndrome RBCs contrasted markedly from normal erythrocytes. Whereas the Ca2+ ionophore induced marked echinocytosis and spiculation of normal RBCs, Scott syndrome RBCs remained mostly discoid under these conditions, with only an occasional echinocyte-like cell observed. These aberrant responses to intracellular Ca2+ were also observed for resealed ghosts prepared from Scott syndrome erythrocytes, indicating that they are related to a defect in the membrane or membrane-associated cytoskeleton. The finding that the erythrocytes of this patient share many of the membrane abnormalities reported previously for Scott syndrome platelets suggests that this defect is common to both cell lines and involves a membrane component required for vesicle formation and for expression of prothrombinase sites.

Topics: Adult; Blood Coagulation Disorders; Blood Platelets; Calcimycin; Calcium; Erythrocyte Membrane; Erythrocytes; Factor Va; Flow Cytometry; Fluorescent Antibody Technique; Humans; Kinetics; Magnesium; Membrane Proteins; Microscopy, Electron, Scanning; Syndrome; Thromboplastin

For the laboratory control of oral anticoagulant treatment, the prothrombin time (PT) is used universally as the primary measurement. Important variability of the PT ratio (patient PT: mean health persons' PT) caused by different brands and batches of thromboplastin and instruments exists not only in North America, but throughout the world. To achieve uniformity of reporting, it is recommended that the PT ratio be transformed to the International Normalized Ratio (INR). This is possible if the thromboplastin manufacturer provides calibration data for each batch of thromboplastin. The INR scale facilitates the achievement of consensus on optimal therapeutic ranges for various clinical conditions. The INR will further improve the stability of anticoagulant treatment of travelling patients.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Calibration; Clinical Trials as Topic; Humans; International Normalized Ratio; Prothrombin Time; Quality Control; Reference Standards; Reproducibility of Results; Thromboplastin; Travel

The influence of heparin and thromboplastin on the halflife of 125I-protein C in rat blood was under investigation. It was found that t1/2 of protein C was of 2.3 h. The intravenous administration of heparin resulted in the prolongation of t1/2 to 6.5 h, that could be explained by inhibition of thrombin generation. Upon the 40-min infusion of thromboplastin the rate of 125I-protein C decay in blood enhanced. That could be explained by the generation of the endogenous thrombin and participation of thrombomodulin in the protein C activation as well as in the removal of the endogenous thrombin from blood.

Topics: Animals; Blood Coagulation Disorders; Half-Life; Heparin; Iodine Radioisotopes; Protein C; Rats; Thromboplastin; Time Factors

Topics: Blood Coagulation Disorders; Endothelium, Vascular; Epoprostenol; Factor VII; Fibrinolysis; Fibrinolytic Agents; Humans; Lipoproteins; Nitric Oxide; Thromboplastin

Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs, possibly due to the accumulation of 125I fibrin in the lungs, followed by a rapid decline of radioactivity, suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight), but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight, rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Factor VII; Fibrinogen; Humans; Lipoproteins; Partial Thromboplastin Time; Protease Inhibitors; Prothrombin Time; Rabbits; Recombinant Proteins; Thromboplastin

Coagulopathy results from many diverse events, including several neurogenic causes. Using a rabbit model, we produced coagulopathy by injecting autologous spinal cord and extracted thromboplastin intravenously. Serial coagulation panels were performed to evaluate the activation of the thrombotic and fibrinolytic pathways. Group 1 animals (n = 4) received intravenous injections of homogenized spinal cord tissue. Coagulopathy was not produced with 36 mg of homogenized spinal cord tissue, but 50 mg or more resulted in death. Group 2 animals (n = 12) received intravenous injections of extracted rabbit cord thromboplastin, which contained approximately 60% activity of a commercially purified rabbit brain thromboplastin. Five animals receiving 2.5 to 5.5 mg of thromboplastin per kilogram of body weight survived with evidence of coagulopathy. Seven animals receiving 2.5 to 100 mg of thromboplastin per kilogram of body weight died. Group 3 (4 control animals) received normal saline injections without changes in clinical or laboratory status. The thrombotic pathway was activated in all animals as evidenced by decreased platelet counts and fibrinogen levels. Activation of the fibrinolytic system was demonstrated by increased concentrations of protamine sulfate and abnormal euglobulin clot lysis times. The most sensitive parameters were the platelet count, protamine sulfate concentration, and white cell count (margination), which became abnormal within 15 minutes after the injections and returned to normal within 1 hour.

Topics: Animals; Blood Coagulation Disorders; Disease Models, Animal; Injections, Spinal; Platelet Count; Rabbits; Sodium Chloride; Spinal Cord; Thromboplastin

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

Topics: Animals; Blood Coagulation Disorders; Dogs; Immunoglobulin G; Liver Transplantation; Partial Thromboplastin Time; Thromboplastin; Transplantation, Homologous

Tissue factor (TF), the primary cellular initiator of the coagulation protease cascade, is implicated in having important roles in hemostasis, thrombogenesis, inflammation, and the cellular immune response, although the cytologic distribution of TF in tissues has yet to be described. This study used epitope-defined monoclonal antibodies to human tissue factor for immunohistochemical localization of TF in normal human tissues. TF was selectively expressed in tissues and was associated with cells rather than extracellular matrix. It was anatomically sequestered from blood, being undetectable in endothelium and peripheral blood cells. TF was present in vascular adventitia, organ capsules, epidermis, and mucosal epithelium. Most dermal and submucosal fibroblasts were negative. Except for alveolar macrophages and possibly dendritic cells of some lymphoid follicles, tissue macrophages did not express TF; (expression was demonstrable in LPS stimulated monocytes). Cerebral cortex, renal glomeruli, and cardiac myocytes were additional sites of prominent TF expression. Based on the cellular distribution of TF, it is hypothesized that intravascular initiation of coagulation requires induced expression by intravascular cells, and that the normal distribution of TF represents a hemostatic "envelope" ready to activate coagulation when vascular integrity is disrupted.

Topics: Blood Cells; Blood Coagulation Disorders; Blood Vessels; Humans; Immunohistochemistry; Muscles; Myocardium; Thromboplastin; Thrombosis; Tissue Distribution

Coagulation disorders have been noted during orthotopic liver transplantation (OLT) especially just after reperfusion of the grafted liver. This study was undertaken to clarify the coagulation disorders following reperfusion of the liver graft. OLT was carried out in adult mongrel dogs using a cuff technique. Fresh and 24-hour preserved livers were grafted. Platelet count (P1), activated partial thromboplastin time (A-PTT), prothrombin time (PT) and plasma fibrinogen levels (Fng) were measured before and after OLT. Next perfusate obtained from fresh livers or preserved livers for 24-hours or 48-hours was determined for their ability of inducing coagulation disorders when infused in untreated dogs, and was also tested for their activity of platelet aggregation, tissue thromboplastin (F-III), and plasminogen activator (PA). All dogs which received preserved livers showed a marked coagulation disorders including a decrease in P1 and Fng, and prolongation of A-PTT and PT, but the dogs with fresh liver grafts did not. Infusion of the perfusate collected from a perfusion of the preserved liver induced similar coagulation disorders in untreated dogs. The perfusate obtained from the preserved liver showed significant increased F-III activity as compared with that from fresh liver. On the other hand, neither direct platelet aggregation activity nor PA activity was seen or very low if any. These results indicate that F-III liberated from a damaged liver is responsible for the coagulation disorders after reperfusion of the graft in liver transplantation.

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Dogs; Liver; Liver Transplantation; Organ Preservation; Perfusion; Plasminogen Activators; Platelet Aggregation; Reperfusion; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Drug Evaluation; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Intraoperative Complications; Male; Postoperative Care; Postoperative Complications; Premedication; Prostatectomy; Prostatic Hyperplasia; Rats; Thromboplastin; Vitamins

Mechanisms for initiation of glomerular fibrin deposition were studied using renal tissue obtained from two patients with rapidly progressive, crescentic glomerulonephritis. Histological examination showed extensive glomerular monocyte infiltration and fibrin deposition in both patients. Sonicated cell suspensions of isolated glomeruli from these patients contained markedly augmented levels of procoagulant activity (PCA) compared with the levels found in normal glomeruli. This PCA was characterized as tissue factor by its functional dependence on Factors VII and V, independence of Factors VIII and XII, inhibition by concanavalin A and phospholipase C, and association with cell membranes. Its coagulant activity was also inhibited by a specific monoclonal anti-human tissue factor antibody. Tissue factor could be identified in glomeruli from these two patients by indirect immunofluorescence using this antibody. These studies implicate extrinsic pathway activation via tissue factor in intraglomerular deposition of fibrin in these patients. Activated monocytes, known to be a potent source of procoagulant activity and seen in large numbers within glomeruli from these patients, are a likely source of this tissue factor.

Topics: Adolescent; Aged; Blood Coagulation Disorders; Blood Coagulation Factors; Concanavalin A; Female; Glomerulonephritis; Humans; Kidney Cortex; Kidney Glomerulus; Male; Thromboplastin; Type C Phospholipases

The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.

Topics: Biomechanical Phenomena; Bleeding Time; Blood Coagulation; Blood Coagulation Disorders; Blood Specimen Collection; Fibrinopeptide A; Humans; Platelet Factor 4; Reference Values; Thromboplastin; Thromboxane B2

The sensitivity and responsiveness of seven activated partial thromboplastin time reagents to the presence of lupus anticoagulants (LAs) was evaluated with a panel of 50 well-characterized LA plasmas. The results document that some reagents are clearly less responsive and sensitive to LAs; however, there is considerable variability between individual LA samples in these features. In addition, with 16% of these samples, immediate mixing studies showed correction of the activated partial thromboplastin time to the normal range with a 1:1 mixture of normal and LA plasma and 8% to 10% showed either a normal platelet neutralization procedure or a normal tissue thromboplastin inhibition procedure. Together, these findings provide further evidence of the laboratory heterogeneity of these inhibitors. The effect of this variability on the diagnosis of these inhibitors is discussed.

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Evaluation Studies as Topic; Humans; Indicators and Reagents; Lupus Coagulation Inhibitor; Partial Thromboplastin Time; Platelet Function Tests; Thromboplastin

An acutely ill 4-year-old girl with Rocky Mountain spotted fever (RMSF) was found to have a coagulation inhibitor. This child had no serious bleeding manifestations and minimal hemorrhagic skin manifestations despite severe RMSF, concurrent thrombocytopenia, as well as the coagulation inhibitor. Hemostatic abnormalities that occur with RMSF as well as other infectious illnesses associated with coagulation inhibitors are reviewed.

Topics: Autoantibodies; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Child, Preschool; Female; Humans; Lupus Erythematosus, Systemic; Partial Thromboplastin Time; Rocky Mountain Spotted Fever; Thromboplastin

Hyperthromboplastinemia in rats and dogs was induced by the infusion of xenogenic or allogenic brain suspension or extract. The suspension caused fatal blood coagulation due to fibrin-platelet isolation of cytolemma fractions. The infusion of extracts produced hypotension, caused by hyperkininemia, and primary hypocoagulation due to simultaneous fibrin-formation and fibrinolysis. Severe hepatic, renal and myocardial lesions were discovered 3-4 min after the allogenic brain extract infusion. Xenogenic brain infusion caused inverse changes. The mechanism of this phenomenon is unknown. The organs were affected by lysosomal enzymes activated not by hypoxia but by thrombin- and plasmin-induced glycocalix destruction.

Topics: Animals; Blood Coagulation Disorders; Dogs; Female; Hypoxia; Kinins; Male; Multiple Organ Failure; Nerve Tissue; Rats; Thromboplastin; Time Factors; Transplantation, Heterologous; Transplantation, Homologous

Topics: Animals; Blood Coagulation Disorders; Brain Chemistry; Humans; Indicators and Reagents; Prothrombin Time; Quality Control; Rabbits; Thromboplastin

The physiopathological role of antithromboplastin-type circulating anticoagulants in habitual abortion may be envisaged since the presence of antithromboplastin has been reported in most studies on women at high risk of abortion. To avoid a possible statistical bias, we conducted a prospective study in a sufficiently large group of women with habitual abortion (n = 99) compared with a control group of women with normal fecundity (n = 50). In addition, all women were investigated for lupus symptoms. The circulating antibody was detected by the diluted thromboplastin time and activated cephalin time methods. The results were considered positive when the patient/control diluted thromboplastin time ratio was 1.2 and/or when the increase in activated cephalin time was not corrected by a control plasma. In the patients' group, 10 women (10%) had an anti-thromboplastin type circulating anticoagulant, whereas no circulating anticoagulant could be detected in the control group. Three women with circulating anticoagulant had signs of systemic lupus erythematosus. None of the patients presented with Soulier-Boffa syndrome. These data have established a significant correlation between habitual abortion and circulating anticoagulant whilst avoiding statistical bias. Our results suggest that women with idiopathic habitual abortion should be subjected to systematic immunological exploration and that a small number of them should be followed attentively.

Topics: Abortion, Habitual; Antibodies, Antinuclear; Autoantibodies; Blood Coagulation Disorders; Female; Hemostasis; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Partial Thromboplastin Time; Pregnancy; Prospective Studies; Thromboplastin

The apparent amount of factor VII as determined in a one-stage test depends on the type of thromboplastin used: bovine thromboplastin only reacts with human factor VIIa whereas human thromboplastin interacts with unactivated human factor VII as well. Therefore the ratio factor VII activity as measured with bovine thromboplastin divided by the factor VII activity as assessed with human thromboplastin reflects the state of activation of factor VII in plasma. This approach was used to study the process of cold promoted factor VII activation and the involvement of different clotting factors therein. It could be shown that cold promoted activation does not occur in the absence of factors II and XII and is reduced for about 50% in factor IX deficient plasma. The other coagulation factors have a minor influence on the process. The results indicate that the cold promoted factor VII activation is the result of activation by both activated contact products and thrombin.

Topics: Adult; Animals; Blood Coagulation Disorders; Cattle; Cold Temperature; Factor VII; Factor VIIa; Female; Hirudins; Humans; Kallikreins; Male; Specimen Handling; Thrombin; Thromboplastin; Time Factors

We have studied factor VII activation by measuring the ratio of factor VII clotting to coupled amidolytic activity (VIIc/VIIam) and cleavage of 125I-factor VII. In purified systems, a low concentration of Xa or a higher concentration of IXa rapidly activated 125I-factor VII, yielding a VIIc/VIIam ratio of 25 and similar gel profiles of heavy and light chain peaks of VIIa. On further incubation, VIIa activity diminished and a third 125I-peak appeared. When normal blood containing added 125I-factor VII was clotted in a glass tube, the VIIc/VIIam ratio rose fivefold, and 20% of the 125I-factor VII was cleaved. Clotting normal plasma in an activated partial thromboplastin time (APTT) system yielded a VIIc/VIIam ratio of 25 and over 90% cleavage of 125I-factor VII. Clotting factor XII-deficient plasma preincubated with antibodies to factor X in an APTT system with added XIa yielded a VIIc/VIIam ratio of 19 and about 60% cleavage, which indicates that IXa, at a concentration achievable in plasma, can effectively activate factor VII. Clotting normal plasma with undiluted tissue factor yielded a VIIc/VIIam ratio of 15 to 20 and 60% cleavage of 125I-factor VII, whereas clotting plasma with diluted tissue factor activated factor VII only minimally. We conclude that both Xa and IXa can function as significant activators of factor VII in in vitro clotting mixtures but believe that only small amounts of factor VII may be activated in vivo during hemostasis.

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Factor IX; Factor IXa; Factor VII; Factor VIIa; Factor X; Factor X Deficiency; Factor Xa; Humans; In Vitro Techniques; Kinetics; Partial Thromboplastin Time; Rabbits; Thromboplastin

Topics: Binding Sites; Blood Coagulation; Blood Coagulation Disorders; Factor VII; Factor XII; Factor XIIa; Humans; Kininogens; Molecular Weight; Peptide Fragments; Prekallikrein; Prothrombin Time; Thromboplastin

Using a canine model, leukocyte populations enriched for monocytes and lymphocytes were isolated from blood during three week periods after kidney allotransplantation corresponding to episodes of acute rejection. Relative to controls, these cells incubated in vitro for five hours were found to generate increased amounts of PCA (procoagulant activity) characterized as tissue factor, the extrinsic clotting pathway activator. Controls included comparable blood leukocyte populations isolated from kidney autograft recipients and healthy animals. Differences in results for these two control groups were insignificant. These contrasts observed between allografted animals and controls demonstrate that leukocyte PCA generation is stimulated by the allogeneicity of histoincompatible kidneys rather than by direct effects of organ transplantation or non-specific postoperative effects. Results of in vitro transfer experiments provide evidence that cellular stimulation or induction in vivo accounted for the PCA increases observed. Stimulation of leukocyte tissue factor generation as a consequence of allogeneic kidney transplantation may in part account for coagulopathies and fibrin deposition during kidney rejection.

Topics: Animals; Blood Coagulation Disorders; Dogs; Female; Graft Rejection; In Vitro Techniques; Kidney Transplantation; Leukocytes; Thromboplastin; Transplantation, Autologous; Transplantation, Homologous

Platelets from a platelet factor 3-deficient patient, which was first described by Weiss et al (Am J Med 67:206, 1979), were found to be equally impaired in their ability to promote factor X and prothrombin activation. Compared to normal platelets, the patient's platelets showed upon stimulation with thrombin plus collagen a much slower generation and a considerably lower level of platelet prothrombin- and factor X-converting activities. Treatment of stimulated platelets with phospholipases revealed a decreased exposure of negatively charged phospholipid at the outer surface of the patient's platelets, relative to control's. We suggest that the combined impairment of prothrombin- and factor X-converting activities in this patient is due to a defect in the mechanism by which phosphatidylserine becomes exposed at the outer surface of stimulated platelets.

Topics: Blood Coagulation Disorders; Blood Platelets; Collagen; Enzyme Activation; Factor V; Factor Va; Factor X; Female; Humans; Phospholipids; Prothrombin; Thrombin; Thromboplastin

One of the reasons why oral anticoagulants fell into disrepute is the absence of internationally accepted standardised procedures for controlling the level of anticoagulation. This deplorable situation resulted in over- and under-coagulation and uncertainty in the therapeutic range. International conformity can now be obtained by using an International Normalised Ratio (INR) which is derived from the individual result obtained in a given plasma sample and the International Sensitivity Index (ISI) of the tissue thromboplastin reagent used. Any thromboplastin reagent can be calibrated against an international primary or secondary W. H. O. reference preparation, so as to obtain its International Sensitivity Index. The new system of reporting the level of anticoagulation was designed and can only safely be applied in patients taking oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation Disorders; Calibration; Humans; Prothrombin Time; Reference Standards; Reference Values; Thromboplastin; United Kingdom; World Health Organization

Kidney allografting was performed in a group of ten beagles, and viable leukocytes infiltrating the transplanted organs were isolated during episodes of acute rejection 5 or 6 days postoperatively. These infiltrate populations, consisting predominantly of lymphocytes and monocytes/macrophages, were found to have significantly increased amounts of procoagulant activity relative to control leukocytes isolated from circulating blood and lymph. Using nonspecific esterase staining in an agar microclot assay, procoagulant activity in the infiltrate leukocytes was found to reside in monocytes/macrophages rather than other coisolated cell types. By contrast, control monocytes from blood had no activity in this microclot assay. Procoagulant activity in the infiltrate cells was characterized as tissue factor. Increased amounts of this activator of the extrinsic pathway, as found in infiltrate monocytes/macrophages, may initiate clotting reactions and fibrin deposition within allografts.

Topics: Animals; Blood Coagulation Disorders; Cell Movement; Cell Separation; Dogs; Female; Graft Rejection; Histocytochemistry; Kidney; Kidney Transplantation; Macrophages; Monocytes; Thromboplastin

Fibrin deposition and platelet thrombus dimensions on subendothelium were studied in four groups of patients with coagulation factor deficiencies. Five patients with factor VIII deficiency (APTT 120 +/- 8 sec) and three patients with factor IX deficiency (APTT 125 +/- 11 sec) were severe bleeders, whereas four patients with factor XII deficiency and seven with factor XI deficiency were either asymptomatic or only mild bleeders despite APTT values of 439 +/- 49 and 153 +/- 13 sec, respectively. Everted segments of deendothelialized rabbit aorta were exposed at a shear rate of 650 sec(-1) for 5 and 10 min to directly sampled venous blood in an annular chamber. Blood coagulation was evaluated by measuring fibrin deposition (percent surface coverage) on the subendothelium and post-chamber fibrinopeptide A levels; platelet thrombus dimensions on the subendothelium were evaluated by determining the total thrombus volume per surface area (using an optical scanning technique) and the average height of the three tallest thrombi. Consistent differences were observed among the patient groups for both the 5-min and 10-min exposure times. The larger of the 5- and 10-min exposure-time values was used to calculate group averages. Fibrin deposition in normal subjects was 81% +/- 5% surface coverage, and post-chamber fibrinopeptide A values were 712 +/- 64 ng/ml. Markedly decreased fibrin deposition and fibrinopeptide A levels were observed in factor VIII deficiency (2% +/- 1% and 102 +/- 19 ng/ml) and factor IX deficiency (11% +/- 7% and 69 +/- 11 ng/ml). In contrast, significantly higher values were obtained in patients deficient in factor XI (33% +/- 5% and 201 +/- 57 ng/ml) and factor XII (66% +/- 12% and 306 +/- 72 ng/ml). Differences in thrombus dimensions were also observed. In normal subjects, the value for thrombus volume and average height of the tallest thrombi were 8.3 +/- 1.3 cu micron/sq micron and 145 +/- 11 micron, respectively, and in patients were as follows: FVIII, 2.7 +/- 0.6 and 71 +/- 7; FIX, 4.5 +/- 1.8 and 88 +/- 14; FXI, 11.8 +/- 1.9 and 125 +/- 10; and FXII, 7.9 +/- 3.1 and 130 +/- 25. Platelet thrombus dimensions were normal in a patient with fibrinogen deficiency, indicating that the smaller thrombi in factor VIII and factor IX deficiencies were probably due to impaired evolution of thrombin rather than diminished fibrin formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Blood Platelets; Endothelium; Factor XI Deficiency; Factor XII Deficiency; Female; Fibrin; Fibrinogen; Fibrinopeptide A; Hemophilia A; Hemophilia B; Humans; In Vitro Techniques; Male; Middle Aged; Partial Thromboplastin Time; Platelet Adhesiveness; Prothrombin Time; Thromboplastin

The clinical usefulness of a chromogenic method for prothrombin time (PT) determination has been assessed in a wide range of clinical conditions, and it is compared with the conventional clotting method for PT. The new method appears to be as sensitive as the clotting PT to deficiencies of clotting factors of the extrinsic and common pathway, except for fibrinogen. Patients with proven liver disease were correctly diagnosed with a prevalence of abnormal results comparable to that by the clotting PT. Results by the two methods correlated highly (r = 0.96) for normal and congenitally deficient plasmas as well as for plasmas from patients on oral anticoagulant treatment (r = 0.95). High reproducibility (between-assay CV less than 3%) and easy adaptation to centrifugal analyzers make it a suitable candidate to replace the conventional method.

Topics: Adolescent; Adult; Anticoagulants; Autoanalysis; Blood Coagulation Disorders; Chromogenic Compounds; Evaluation Studies as Topic; Female; Humans; Male; Middle Aged; Oligopeptides; Prothrombin Time; Reference Values; Spectrophotometry; Thromboplastin

A new patient with factor VII Padua abnormality is presented. The propositus is a 70 old man who showed a mild bleeding tendency characterized by occasional epistaxis and a laboratory pattern of prolonged prothrombin time corrected by normal serum, normal partial thromboplastin time and normal Thrombotest. Factor VII activity was 7% using rabbit brain thromboplastin and 105% of normal using ox-brain thromboplastin. Intermediate levels were found by using thromboplastin of human origin. Factor VII cross-reacting material was normal. Parents were not consanguineous but both came from the same area. Two children of the propositus were found, as expected, to be homozygous for the abnormality. No relationship could be traced between the propositus and the other homozygous patients already reported. However, the patient came from the same geographic area, namely the Piave river valley in northeastern Italy. The discovery of the present patient, the fifth in four years, indicates that the defect might be more frequent than originally assumed.

Topics: Aged; Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Brain Chemistry; Cattle; Factor VII; Homozygote; Humans; Lung; Male; Pedigree; Rabbits; Thromboplastin

Bernard-Soulier syndrome (BSS) was described in 1948 as a constitutional platelet disorder characterized by giant sized platelets, a prolonged bleeding time, and a defect in prothrombin consumption. The accurate mechanisms of these abnormalities remain unexplained, especially the defect in prothrombin consumption on which we focus in this paper. Several hypotheses are proposed: firstly, a defective reaction between the platelet membrane, where the phospholipid composition is abnormal, and the proteins which initiate thromboplastin generation such as collagen, factor XI; secondly, an abnormal reaction between thrombin, whose synthesis is increased, and its receptor, possibly glycoprotein V, which is defective; lastly, as factor VIII/vW binding is diminished, an abnormal dissociation of the complex VIII/vW-VIIIc at the site of the platelet membrane, which leads to an inactivation of factor VIIIc.

Topics: Binding Sites; Blood Coagulation Disorders; Blood Platelets; Cell Membrane; Collagen; Factor V; Factor VIII; Factor XI; Glycoproteins; Humans; Membrane Proteins; Platelet Factor 3; Platelet Membrane Glycoproteins; Thrombin; Thrombocythemia, Essential; Thrombocytopenia; Thromboplastin

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

The relationship of triglyceride levels to coagulation abnormalities was studied in 43 patients, who were divided into two groups. Group 1 consisted of patients with triglyceride levels less than 200 mg% (range, 75 to 190 mg%), and Group 2 consisted of patients with triglyceride levels greater than 250 mg% (range, 255 to 890 mg%). Analysis of the data revealed that patients with high triglyceride levels also have a high incidence of low antithrombin III activity and increased platelet aggregation. It is likely that hyperlipidemic patients are more prone to thrombosis of diseased coronary arteries or saphenous vein bypass grafts, and should definitely be placed on appropriate anticoagulants.

Topics: Adult; Aged; Anticoagulants; Antithrombin III; Blood Coagulation Disorders; Coronary Disease; Female; Fibrinogen; Humans; Hyperlipidemias; Male; Middle Aged; Platelet Aggregation; Prospective Studies; Thromboplastin; Thrombosis; Triglycerides

Thromboplastins vary in their sensitivity to the haemostatic defect induced by oral anticoagulants. To provide a means of standardising prothrombin time tests, the World Health Organization adopted in 1977 a scheme for calibrating thromboplastins in terms of an International Reference Preparation. Unfortunately, the model on which this scheme was based does not always hold. A revised calibration model has therefore been developed and this has been tested in a recent collaborative study. The revised model, which retains fundamentally the same principle for standardising prothrombin time tests, has proved suitable for calibrating thromboplastins of different species and types and, moreover, has certain statistical advantages over its predecessor. In September 1982, the WHO Expert Committee on Biological Standardization adopted the revised model. This paper explains the nature and rationale of this change and considers its practical implications.

Topics: Blood Coagulation Disorders; Blood Preservation; Calibration; Drug Stability; Freeze Drying; Humans; International Cooperation; Prothrombin Time; Reference Values; Thromboplastin; World Health Organization

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: Aflatoxins; Animals; Blood Coagulation Disorders; Chickens; Factor V; Factor VII; Factor X; Male; Ochratoxins; Thromboplastin

Congenital factor VII deficiency is a well known clotting disorder first identified in 1951. Several congenital abnormalities of factor VII have been described during the past decade. These abnormalities were all characterized by the presence of a discrepancy between factor VII clotting activity and factor VII cross reacting material or antigen. Recently other factor VII abnormalities have been described which showed peculiar sensitivities to ox-brain thromboplastins as compared to thromboplastins of other origin. These discoveries have complicated the differential diagnosis of prothrombin complex factors deficiences and abnormalities. A correct diagnosis may be reached only by means of a battery of tests which employ tissue thromboplastins of different origin.

Topics: Animals; Antigens; Blood Coagulation Disorders; Cattle; Cross Reactions; Factor VII; Humans; Thromboplastin

The effect of various plasma expanders on blood coagulation was studied using the thromboelastography (TEG). Solutions of 5, 10, 20, and 50% concentration of each expander (6% low molecular weight hydroxyethyl-starch (6% Hespander), 3% dextran-40, 6% high molecular weight hydroxyethyl-starch (6 HES), and 6% dextran-70) or solvent (lactated Ringer solution and normal saline) in blood were prepared and their coagulability was examined by TEG. In the low molecular weight plasma expanders (6% Hespander and 3% dextran-40), in general, the coagulability decreased when the concentration was increased. In the high molecular weight plasma expanders (6 HES and 6% dextran-70), the coagulability increased slightly at low and high concentrations and the coagulability was reduced. As a conclusion, at clinically used concentrations of less than 20% in blood, changes in the TEG of the plasma expanders are minimum and have no clinical significance.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Dextrans; Elasticity; Fibrinolysis; Humans; Hydroxyethyl Starch Derivatives; Plasma Substitutes; Sodium Chloride; Starch; Thrombin; Thromboplastin; Time Factors

Topics: Afibrinogenemia; Blood Coagulation Disorders; Blood Coagulation Tests; Factor V Deficiency; Factor VII Deficiency; Factor X Deficiency; Factor XI Deficiency; Factor XII Deficiency; Factor XIII Deficiency; Hemophilia A; Hemophilia B; Humans; Hypoprothrombinemias; Kaolin; Phosphatidylethanolamines; Prekallikrein; Prothrombin Time; Thrombin; Thromboplastin; von Willebrand Diseases

Five commercially available activated partial thromboplastin time (APTT) test systems were compared with the kaolin partial thromboplastin time (KPTT) method to determine sensitivity in detecting minor coagulation defects. All reagent systems detected severe factor VIII-, IX-, and XI-deficient hemophilia. Homozygous states of factor XII deficiency, Fletcher factor deficiency, and high-molecular-weight kininogen deficiency (Fitzgerald trait) also showed abnormally long APTTs by all systems. Of 19 samples from patients with deficiencies of factors XII, VIII, IX, XI, and II ranging from 2.5 to 52%, eight had deficiencies that were not detected by reagent A (ellagic acid); two, by reagent B (ellagic acid); two, by reagent C (kaolin); one, by reagent D (silica); one, by the KPTT method. All deficiencies were detected by reagent E (celite). Heparin effect on plasma was less well detected by reagent A (ellagic acid) than with the other test systems. APTT test systems can vary greatly in their abilities to detect minor coagulation abnormalities.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Male; Methods; Reference Values; Thromboplastin

Under study were coagulation and fibrinolytic properties of cancerous tumor, their role in the ethiopathogenesis of thromb-formation is defined. It was found that the cervical tissue involved contains a large quantity of thromboplastic substances and shows an intense antiheparin, antithrombin and antifibrinolytic activity.

Topics: Blood Coagulation; Blood Coagulation Disorders; Cervix Uteri; Female; Fibrinolysis; Genital Neoplasms, Female; Humans; Thromboplastin; Thrombosis

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Costs and Cost Analysis; Hospitals; Humans; Preoperative Care; Thromboplastin

Topics: Aged; Blood Coagulation Disorders; Child; Child, Preschool; Female; Humans; Male; Mass Screening; Thromboplastin

Topics: Administration, Oral; Animals; Anticoagulants; Biomarkers; Blood Coagulation Disorders; Blood Proteins; Cattle; Cold Temperature; Factor VII; Factor VII Deficiency; Factor X; Factor X Deficiency; Humans; Hypoprothrombinemias; Kaolin; Protein Precursors; Prothrombin; Prothrombin Time; Rabbits; Thromboplastin; Vitamin K

Topics: Adolescent; Adult; Antigens; Blood Coagulation Disorders; Cross Reactions; Factor VII; Female; Heterozygote; Humans; Pedigree; Prothrombin Time; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Dog Diseases; Dogs; Thromboplastin

Thrombotest clotting times of mixtures of coumarin plasmas and normal plasma yielded a patterm similar to that observed in mixtures of plasma with congenital coagulation disorders and normal plasma. The presence of 10 or 20% of test plasma in the mixture failed to affect the clotting times which resulted in normal limits. The only exception to this rule was the hemophilia BM plasma. In this case even the presence of 10-20% of patient plasma in the mixture caused a prolongation of the clotting time. This indicates that no inhibitor is present in coumarin plasmas and in the plasma of congenital coagulation disorders of the prothrombin complex save for hemophilia BM plasma which does contain an inhibitor.

Topics: Acenocoumarol; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hemophilia B; Humans; Male; Prothrombin; Thromboplastin; Warfarin

A few neonates born to mothers receiving anticonvulsant drugs during pregnancy have shown defects in vitamin K dependent clotting factors with or without clinical bleeding. Experimentally, phenytoin (diphenyl hydantoin, DPH) has induced clotting defects in cats and inhibited production of clotting factors in rat liver slices. Phenobarbital has produced similar but milder defects. Anticonvulsants have been observed to produce clotting defects in 9 children, 2 weeks to 8 years in age. Elevated levels of phenytoin or other anticonvulsants, or a combination of anticonvulsants were measured in the children. Six patients were on drug combination including two or more of the following: phenytoin, phenobarbital, primidone, carbamazepine, diazepam, ethosuximide. Clotting defects included: elevated prothrombin time, elevated partial thromboplastin time, diminished factors V, VII or X. All children had neurologic symptoms of anticonvulsant toxicity, but the only hematologic problems were oozing from venipuncture sites and increased bruising in 3. All patients were on normal diets and had normal liver function tests. By lowering the level of anticonvulsants, clotting factors returned toward normal. Elevated levels of anticonvulsants can potentially produce clotting defects in neonates and young children.

Topics: Anticonvulsants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Child; Child, Preschool; Factor V Deficiency; Factor VII Deficiency; Factor X Deficiency; Female; Hemophilia A; Humans; Infant; Infant, Newborn; Male; Maternal-Fetal Exchange; Pregnancy; Prothrombin Time; Thromboplastin

Blood clotting tests in 55 polytraumatized patients showed that a lapse in the hemostatic potential may already occur at a very early stage of the traumatic-hemorrhagic shock. The extent of these changes which are complex in their pathogenesis, is closely related to the degree of injury. Coagulation-analysis control of the development shows clearly that shock treatment and maintenance of adequate circulation, starting at the earliest possible moment at the scene of the accident, are important for spontaneous recompensation of the hemostatic defect.

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinogen; Hematocrit; Humans; Male; Prothrombin Time; Serum Globulins; Shock, Hemorrhagic; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Quality Control; Thromboplastin

The activation and function of surface-bound Hageman factor in human plasma are dependent upon both high molecular weight (HMW) kininogen and prekallikrein. HMW kininogen does not affect the binding of Hageman factor to surfaces, but it enhances the function of surface-bound Hageman factor as assessed by its ability to activate prekallikrein and Factor XI. The initial conversion of prekallikrein to kallikrein by the surface-bound Hageman factor in the presence of HMW kininogen is followed by a rapid enzymatic activation of Hageman factor by kallikrein. The latter interaction is also facilitated by HMW kininogen. Kallikrein therefore functions as an activator of Hageman factor by a positive feedback mechanism and generates most of the activated Hageman factor during brief exposure of plasma to activating surfaces. HMW kininogen is a cofactor in the enzymatic activation of Hageman factor by kallikrein and it also augments the function of the activated Hageman factor generated. The stoichiometry of the Hagman factor interaction with HMW kininogen suggests that it enhances the activity of the active site of Hageman factor. Since HMW kininogen and prekallikrein circulate as a complex, HMW kininogen may also place the prekallikrein in an optimal position for its reciprocal interaction with Hageman factor to proceed. The surface appears to play a passive role upon which bound Hageman factor and the prekallikrein-HMW kininogen complex can interact.

Topics: Binding Sites; Blood Coagulation Disorders; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Factor XI; Factor XI Deficiency; Factor XII; Humans; Kallikreins; Kininogens; Molecular Weight; Prekallikrein; Protein Binding; Thromboplastin

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Humans; Thromboplastin

We found distinct alterations of the clotting and fibrinolytic mechanisms in a 27-year-old man who suffered from typical bilateral vasculitis, clinically and fluoroangiographically manifest as obstruction of the central retinal veins. The partial thromboplastin time was slightly increased, a partial clot lysis occurred after one hour, the plasminogen level was markedly low, and alpha2-macroglobulin was decreased, as were factor XII and IgG. Kallikrein was absent. Similar changes, though not so pronounced, were also found in the patient's son and in his brother.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Child, Preschool; Clot Retraction; Edema; Factor XII; Fluorescein Angiography; Humans; Immunoglobulin G; Macroglobulins; Male; Papilledema; Plasminogen; Retinal Diseases; Retinal Hemorrhage; Thromboplastin; Vasculitis

Consumptive coagulopathy and disseminated intravascular coagulation can be observed in rats exposed to 4 ata of oxygen. These events clearly precede the death of the animal and appear to be initiated by an activation of coagulation factor XII (Hageman). The onset and the extent of consumptive coagulapathy are greatly enhanced by a single and low intravenous dose of lead acetate. Mechanisms of activation of the intrinsic coagulation system and its role in oxygen toxicity are being discussed.

Topics: Animals; Blood Coagulation Disorders; Fibrin; Lead; Lead Poisoning; Lung; Male; Microscopy, Electron; Oxygen; Prothrombin Time; Rats; Species Specificity; Thromboplastin

A series of collaborative exercises on the partial thromboplastin-time (P.T.T.) test, involving over three hundred hospital centres in Britain and overseas, were performed in 1975. Lyophilised test plasmas were issued from the World Health Organisation Collaborating Centre for Anticoagulant Control Reagents to participants, together with a standardised reference P.T.T. reagent and a standard technique. Hospitals were asked to test the plasma samples with the standardised reagent and technique in parallel with their customary local P.T.T. reagent and method. The overall success-rate in detecting the intrinsic clotting abnormality in the eight abnormal test samples was higher with the standardised reagent and technique than with all other reagents. Furthermore, fewer hospitals obtained false positive results when the normal plasma sample was tested with the standardised method rather than with their usual routine reagents. An index was used to measure the success-rate of the P.T.T. reagents in correctly identifying the test plasmas as normal or abnormal. The eight test plasmas showed a varying degree of abnormality. A system of "weighting" was therefore introduced as the failure of a P.T.T. method to detect more severe defects was regarded as more serious. Although hospitals were unfamiliar with the standardised method, the results established its superiority over all other P.T.T. reagents included in the trials in sufficient numbers for analysis. Failures with commercial reagents may have been caused by insensitivity of the cephalin extracts or the unreliability of the manufacturers recommended techniques. Since the same laboratories obtained good results with the standardised method technical failure can be excluded.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Evaluation Studies as Topic; False Negative Reactions; False Positive Reactions; Humans; Indicators and Reagents; International Cooperation; Thromboplastin

Topics: Acute Disease; Adaptation, Physiological; Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Cardiovascular Diseases; Chronic Disease; Convalescence; Coronary Disease; Fibrinolysin; Fibrinolysis; Humans; Myocardial Infarction; Rheumatic Diseases; Thrombelastography; Thromboplastin; Time Factors

Platelet aggregation to common inductors and to Ristocetin, Thrombofax and Ionophore is normal in congenital factor X deficiency and in factor X Friuli coagulation disorders. Washed normal platelets resuspended in the patient's plasma and in adsorbed normal plasma showed a normal aggregation. On the contrary, normal platelets resuspended in normal serum failed to aggregate. These studies indicate that factor X plays no role in normal platelet aggregation.

Topics: Adenosine Diphosphate; Blood Coagulation Disorders; Calcimycin; Collagen; Epinephrine; Factor X Deficiency; Humans; Hypoprothrombinemias; Platelet Adhesiveness; Platelet Aggregation; Ristocetin; Thromboplastin

The case of a patient who, while being treated for an acute myocardial infarction, was found to have Fletcher factor deficiency with a Fletcher factor concentration of less than 1% of normal is described. Fletcher factor deficiency is associated with defects in several interrelated systems, including clotting, fibrinolysis and kinin generation, all of which play a role in the pathogenesis and evolution of infarction. The development of myocardial infarction in a patient who had severe Fletcher factor deficiency emphasizes the importance of alternate pathways for activation of these systems.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Electrocardiography; Humans; Kallikreins; Male; Myocardial Infarction; Prekallikrein; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Cattle; Factor XII; Fibrinolysis; Histidine; Humans; Kininogens; Molecular Weight; Peptide Fragments; Prekallikrein; Thromboplastin; Time Factors

With the kaolin-cephalin activated partial thromboplastin time technic, the plasmas of persons who have Fletcher factor deficiency have shown considerable shortening of clotting times when contact activation has been lengthened from 3 (PTT-3) to 10 minutes (PTT-10). The authors demonstrate that in plasma of most normal individuals, and in coagulopathies of other sorts, only slight shortening usually occurs. Abnormal shortening occurs in plasmas of a few otherwise normal people, the "slow activators," and patients receiving coumarin drugs, who have greatly prolonged prothrombin times. Longer activation may produce greatly prolonged PTT's in plasmas containing heparin in relatively high concentrations. The authors discuss the significance of these findings.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Heparin; Humans; Prekallikrein; Thromboplastin; Time Factors; Warfarin

Prothrombin times, partial thromboplastin times and platelet counts were performed to determine normal values and to screen for coagulation defects of precolostral calves. The precolostral calves were in two groups: one group of a few calves was tested two years before the second larger group. The results for both groups were similar. The tests were performed on postcolostral calves and on mature cows to compare their values with those of precolostral calves. The mean values of prothrombin times and partial thromboplastin times of precolostral calves in the first group were 18.8 seconds and 54.8 seconds respectively. The mean values of prothrombin times and partial thromboplastin times of precolostral calves in the second group were 18.8 seconds and 50.8 seconds respectively. The mean platelet count was 422,400/cmm for the first group and 482,800/cmm for the second group.

Topics: Animals; Animals, Newborn; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Cattle; Cattle Diseases; Colostrum; Horses; Prothrombin Time; Sheep; Swine; 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

A rapid, simple, semimicro method for neutralization of heparin effect by titration with protamine sulfate is described. Protamine sulfate can be effectively employed to eliminate the effect of heparin on the APTT. Determination of true abnormalities of coagulation has important prognostic and therapeutic implications for the sick newborn infant.

Topics: Batroxobin; Blood Coagulation Disorders; Blood Coagulation Tests; Catheterization; Chemical Phenomena; Chemistry; Heparin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Protamines; Thromboplastin; Umbilical Arteries

Partial-Thromboplastin-Time (PTT) has been used as a bedside-method to control the dosage of heparin in haemodialysis patients at a high bleeding risk. The practical procedures and the advantages of the method as compared to current coagulation controls are outlined. As a result a technique of "minimal intermittent heparinization" has been developed which effectively prevents bleeding in the heparinized patient on haemodialysis.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Heparin; Humans; Renal Dialysis; Thromboplastin

This study evaluated the existence of abnormally increased coagulation and fibrinolysis in 33 severely toxemic and eclamptic women by means of a combined hemotologic profile with clinical and morphologic correlations. The dominant findings were: different degrees of thrombocytopenia, abnormal levels of blood fibrinogen, prolonged thrombin time, and positive protamine sulfate test. Altered activated partial thromboplastin time and positive ethanol gelation test were slightly less frequent, and only few cases showed prolonged prothrombin time or early lysis of euglobulins. These abnormalities seemed to be more numerous and more pronounced in the worst cases of the series and their severity seemed to be associated with the age of the patient and the presence of previous underlying disease. These variously handicapped pregnant women exhibited worse hematologic hematologic abnormalities, and provided most of the fatal cases in the series. Finally, the main findings were discussed and commented upon.

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Eclampsia; Ethanol; Female; Fibrinogen; Fibrinolysis; Humans; Pre-Eclampsia; Pregnancy; Protamines; Prothrombin Time; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Thromboplastin

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

A case report of a patient with primary fibrinolysis resulting in hemorrhage after an oral surgical procedure has been presented. A comparison was made between DIC and primary fibrinolysis in patients with carcinoma of the prostate gland; etiology, clinical findings, diagnosis, and treatment were discussed.

Topics: Aged; Alveoloplasty; Aminocaproates; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Blood Transfusion; Chlorothiazide; Diethylstilbestrol; Estrogens, Conjugated (USP); Fibrin; Fibrinolysis; Hematocrit; Hemoglobins; Humans; Male; Methyldopa; Oral Hemorrhage; Postoperative Complications; Prothrombin Time; Thromboplastin; Tooth Extraction

The case of a patient with Hageman trait and his family study are reported. Commercial plasma thromboplastin time (PTT) reagents showed a good sensitivity for detecting the plasma defect. By prolonging the incubation time of the mixture containing PTT reagent and factor XII-deficient plasma the abnormal coagulation times were not corrected. Thus, a concomitant Fletcher factor deficiency could be excluded.

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Child; Factor XII; Humans; Italy; Male; Pedigree; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Fibrin; Fibrinolysis; Hemostasis; Humans; Thrombin; Thromboplastin

Reagents may be prepared from normal plasma and used with the prothrombin time and partial thromboplastin time tests to distinguish isolated defects of factors I, II, VII, VIII, IX, X, XI, or XII.

Topics: Adolescent; Adult; Aluminum Hydroxide; Blood Coagulation Disorders; Blood Coagulation Tests; Child; Child, Preschool; Factor XI Deficiency; Female; Hemophilia A; Hemophilia B; Humans; In Vitro Techniques; Kaolin; Male; Middle Aged; Phospholipids; Plasma; Prothrombin Time; Thromboplastin; Tromethamine; von Willebrand Diseases

Topics: Blood Coagulation Disorders; Humans; Methods; Thromboplastin

A report is presented of a young, otherwise apparently healthy, woman who had three pregnancies which for some unknown reason terminated in intrauterine death (macerated foetuses). During the third pregnancy a coagulation defect was diagnosed, which was characterized by prolonged coagulation times and prolonged one-stage prothrombin time. This defect disappeared after the end of the pregnancy, but returned during the fourth pregnancy. This time a circulating anticoagulant was found, which inhibited the action of thromboplastin. The values found for the various coagulation factors were normal. The anticoagulant titre rose during the pregnancy from 1/2 to 1/10. Leucocyte agglutinating as well as lymphocytotoxic antibodies directed against the husband's cells were demonstrated in the patient during the pregnancy. In this case, by passage of cell fragments and thromboplastic substances to the mother, the foetus had probably induced the development of antibodies against the foetal tissues. The foetus may be regarded as an incompatible transplant. The fourth pregnancy was terminated by caesarean section in the 34th week. The child weighed 1440 g and, after three exchanges of blood, did very well. The placenta was severely infarcted. It is postulated that the development of antithromboplastin during pregnancy may be a contributory cause of intrauterine death.

Topics: Adult; Antibodies; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Female; Fetal Death; Fibrinolytic Agents; Humans; Male; Pregnancy; Pregnancy Complications; Thromboplastin; Time Factors

The maximal rate of change in optical density (Vmax-deltaOD)of plasma clots forming in the activated partial thromboplastin time test (APTT) may be significantly influenced by reductions in factor VIII activity insufficient to also cause a distinctly abnormal timed clotting endpoint. Analysis of relationships between Vmax-deltaOD of clotting plasma in the APTT, prothrombin time, and thrombin time tests provides a basis for increasing the screening value of the APTT in suggesting intrinsic system abnormalities. Three illustrative case reports support the added benefit of thrombokinetics in the detection of mild factor VIII deficiency in hemophilia A and in von Willebrand's disease.

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Factor VIII; Fibrin; Hemophilia A; Humans; Kinetics; Male; Middle Aged; Prothrombin; Prothrombin Time; Thrombin; Thromboplastin

A study of 300 patients is presented to demonstrate the effectiveness of the activated plasma recalcification time (APRT) as a measure of the intrinsic pathway and platelet function in the detection of bleeders. The activated partial thromboplastin time (APTT) and platelet count were determined in all patients having both normal and abnormal APRT's and the results correlated with overt bleeding tendencies. Abnormality of the APTT is closely paralleled by abnormality of the APRT, independent of the platelet count. When the APTT is normal, an abnormal APRT will characterize clinical bleeders with greater frequency than will the platelet count. The value of the APRT is greatest when done in concert with other standard coagulation measurements, as it both reinforces and expands their diagnostic capability.

Topics: Adolescent; Adult; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Female; Hemorrhage; Humans; Male; Risk; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Humans; Liver Diseases; Prothrombin; Thromboplastin

The case of an 18-year-old girl with a moderately severe Hageman factor deficiency (Factor XII 2.5%) is described. In this girl, an osteotomy of the pelvis after Chiari was carried out. Both the operation itself and the postoperative healing process were without complications and no signs of any abnormal tendency to haemorrhage were observed. Blood transfusions were not necessary. On the basis of this observation and a review of the literature for the attempt is made to establish general guide lines the procedure to be adopted for surgery in cases of Hageman factor deficiency.

Topics: Blood Coagulation Disorders; Factor XII; Female; Hip Dislocation, Congenital; Humans; Pelvic Bones; Thromboplastin; Time Factors

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Brain Injuries; Ethanol; Factor V; Fibrinogen; Fibrinolysis; Gels; Humans; Platelet Aggregation; Syndrome; Thromboplastin

Topics: Adolescent; Adult; Aged; Animals; Blood Coagulation Disorders; Blood Protein Electrophoresis; Brain; Child; Factor X; Female; Heterozygote; Humans; Immune Sera; Italy; Lung; Male; Middle Aged; Pedigree; Placenta; Prothrombin Time; Rabbits; Thromboplastin; Tissue Extracts

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: Blood; Blood Coagulation Disorders; Blood Coagulation Tests; Buffers; Colloids; Evaluation Studies as Topic; Heparin; Humans; Hydrogen-Ion Concentration; Indicators and Reagents; Photometry; Silicon Dioxide; Thromboplastin; Time Factors

Topics: Animals; Atmospheric Pressure; Blood Coagulation Disorders; Decompression Sickness; Diving; Environment, Controlled; Fever; Fibrinogen; Hemostasis; Male; Platelet Adhesiveness; Prothrombin Time; Rats; Thrombocytopenia; Thromboplastin; Time Factors

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Factor VII Deficiency; Hemophilia A; Humans; Prothrombin Time; Thrombocytopenia; Thromboplastin; Vitamin K Deficiency

Topics: Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Dog Diseases; Dogs; Female; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Coumarins; Evaluation Studies as Topic; Factor V; Factor VII; Factor X; Humans; Liver Diseases; Prothrombin; Thromboplastin; Time Factors

Topics: Automation; Blood Coagulation Disorders; Blood Coagulation Tests; Evaluation Studies as Topic; Hemophilia A; Humans; Indicators and Reagents; Male; Thromboplastin; Time Factors

Topics: Biopsy, Needle; Blood Coagulation Disorders; Hemorrhagic Disorders; Hepatitis; Humans; Hypoprothrombinemias; Infant; Infusions, Parenteral; Iron; Liver Function Tests; Malabsorption Syndromes; Male; Prothrombin Time; Thromboplastin; Vitamin K; Vitamin K Deficiency

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Proteins; Coumarins; Factor IX; Humans; Thromboplastin; Vitamin K Deficiency

Topics: Blood; Blood Coagulation Disorders; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Trimester, Third; Thromboplastin; Umbilical Cord

Topics: Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Cardiovascular Diseases; Humans; Kaolin; Male; Platelet Adhesiveness; Prothrombin Time; Purpura; Radiation Injuries; Risk; Thromboplastin; Thrombosis; Thyroid Diseases

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: Adolescent; Adult; Blood Coagulation Disorders; Child, Preschool; Culture Techniques; Factor VII; Factor X; Factor XI; Factor XI Deficiency; Factor XII; Female; Fibroblasts; Hemophilia A; Hemophilia B; Humans; Male; Middle Aged; Skin; Thromboplastin; von Willebrand Diseases

An 85 year old woman was studied because of severe bleeding. Acquired inhibitors to factor VIII and to phospholipid procoagulants were demonstrated. Platelet factor 3 (Pf3) assay was prolonged with both kaolin and Russell's Viper Venom (Stypven-R). It was normal with patient's washed platelets and normal plasma, but abnormal when normal platelets were incubated with patient's plasma. The inhibitor also blocked the coagulant action of Bell and Alton thromboplastin, inosithin, phosphatidyl ethanolamine and phosphatidyl choline, but not that of tissue thromboplastin or cardiolipin. All other platelet functions were normal. The inhibitors were purified by Al (OH3) absorption, heating at 56degrees, precipitation by 50% ammonium sulfate, followed by dialysis and DEAE-cellulose chromatography. A partial separation of the two inhibitors was achieved. Cyclophosphamide treatment resulted in cessation of bleeding and dissappearance of the inhibitors. This seems to be the first instance of an acquired circulating inhibitor specifically directed against phospholipid procoagulants in a patient who also had an inhibitor to Factor VIII.

Topics: Aged; Antibodies, Anti-Idiotypic; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Chromatography, DEAE-Cellulose; Cyclophosphamide; Factor VIII; Female; Humans; Immune Sera; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Inositol; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Platelet Adhesiveness; Platelet Aggregation; 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: Blood Coagulation Disorders; Blood Coagulation Tests; Drug Hypersensitivity; Heparin; Humans; Injections, Intravenous; Methods; Monitoring, Physiologic; Thrombin; Thromboplastin; Time Factors

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

Topics: Adolescent; Adult; Antithrombins; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Contraceptives, Oral; Factor VIII; Female; Fibrinogen; Humans; Male; Physical Exertion; Platelet Adhesiveness; Prothrombin Time; Sports; Sports Medicine; Thromboplastin; Time Factors

Topics: Abortion, Induced; Amniotic Fluid; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Factor VIII; Female; Fibrin; Fibrinogen; Humans; Hypertonic Solutions; Plasminogen; Pregnancy; Serum Globulins; Sodium Chloride; Solubility; Thromboplastin; Time Factors; Uterine Hemorrhage

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Female; Humans; Indicators and Reagents; Male; Middle Aged; Thromboplastin

Topics: Antithrombins; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Heparin; Hip; Humans; Injections, Subcutaneous; Leg; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Thromboplastin; Thrombosis

Topics: Biological Assay; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Buffers; Capillary Permeability; Citrates; Esterases; Factor IX; Factor VIII; Factor XI; Factor XII; Fibrinolysis; Humans; In Vitro Techniques; Kaolin; Kinins; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Calcium; Drug Stability; Fibrinogen; Heparin; Humans; Injections, Intravenous; Male; Methods; Protamines; Temperature; Thrombin; Thromboplastin

Topics: Abortion, Induced; Adenocarcinoma; Blood Coagulation Disorders; Carcinoma in Situ; Carcinoma, Squamous Cell; Curettage; Dilatation; Embryo, Mammalian; Female; Fetus; Gestational Age; Humans; Hypernatremia; Hypertonic Solutions; Lymphatic Metastasis; Oxytocin; Pregnancy; Prognosis; Thromboplastin; United States; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Smears

Topics: Alanine Transaminase; Anemia; Aspartate Aminotransferases; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Transfusion; Cerebral Hemorrhage; Ecchymosis; Female; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Male; Prognosis; Prothrombin; Prothrombin Time; Seizures; Spinal Puncture; Subarachnoid Hemorrhage; Thrombin; Thromboplastin; Vitamin K

Utilizing a disposable unit, intraoperative autotranfusion was employed during surgery in 53 patients admitted to the Bexar County Teaching Hospital at the University of Texas Health Science Center at San Antonio. During the two-year period of study, 26 patients underwent surgery for major traumatic injuries, 8 for ruptured ectopic pregnancy and 19 for miscellaneous emergency or elective conditions. The indication for intraoperative autotransfusion was an anticipated blood loss of 1,000 ml or more. Contraindications for its use were colon injury or localized infection. Over 325 units of blood were salvaged and returned directly to these patients during surgery. One death related to the use of the autotransfusor unit was due to massive air embolism. Twenty other deaths were associated with severe injuries and irreversible shock requiring greater than 3,600 ml of both autologous and homologous blood. Eight of these patients demonstrated severe pancoagulopathies. In the remaining patients, clotting factors and plasma or urine hemoglobin levels were transiently abnormal. However, there were no clinically apparent bleeding defects or renal problems detected. Postoperative blood cultures were consistently negative. It is concluded that intraoperative autotransfusion, when properly employed, is a safe, practical and technically feasible procedure.

Topics: Abdominal Injuries; Adult; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Blood Transfusion, Autologous; Blood Volume; Disposable Equipment; Emergencies; Female; Humans; Male; Pregnancy; Pregnancy, Ectopic; Prothrombin Time; Rupture, Spontaneous; Surgical Procedures, Operative; Thoracic Injuries; Thromboplastin; Time Factors; Wounds and Injuries; Wounds, Gunshot

Topics: Animals; Blood Coagulation Disorders; Cattle; Factor VII Deficiency; Factor X; Humans; Hypoprothrombinemias; Prothrombin; Rabbits; Swine; Thromboplastin; Warfarin

Topics: Antithrombins; Blood Coagulation Disorders; Blood Coagulation Tests; Fibrinogen; Hemorrhage; Heparin; Humans; Methods; Phospholipids; Prothrombin Time; Temperature; Thrombelastography; Thrombin; Thromboplastin; Time Factors

Topics: Blood Coagulation Disorders; Heparin; Humans; Inhalation; Postoperative Complications; Therapeutic Irrigation; Thromboplastin

Topics: Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Factor XI; Factor XI Deficiency; Factor XII; Hemophilia B; Humans; Phosphatidylethanolamines; Prothrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Factor VIII; Hemophilia A; Hemophilia B; Humans; Hypoprothrombinemias; Methods; Thromboplastin; Time Factors

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

Topics: Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Blood Platelets; Humans; Mass Screening; Methods; Prothrombin Time; Thrombin; Thromboplastin

Blood plasma obtained from an individual with abnormal thromboplastin formation, due to deficiency of Fletcher factor, was fully corrected by 2% of normal, Hageman factor- or PTA-deficient plasma. It was also reconstituted by addition of highly purified human or rabbit prekallikrein. The plasma failed to generate kinin upon exposure to kaolin, a defect which was also corrected by addition of prekallikrein. Prekallikrein antigen was not detectable in this plasma. Fletcher factor-deficient plasma did not support the normal generation of PF/dil when dilute plasma was incubated in glass vessels and injected intracutaneously. Small quantities of Fletcher factor-deficient or Hageman factor-deficient plasma corrected the ability of the other to generate PF/dil. The formation of plasmin in dilute, acidified plasma incubated with kaolin was also abnormal in Fletcher factor-deficient plasma. Plasmin generation was normalized by addition of prekallikrein or small quantities of Hageman factor-deficient plasma. The data support the identity of Fletcher factor and prekallikrein.

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Enzyme Precursors; Humans; Kallikreins; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Fibrinogen; Humans; Thromboplastin; Tuberculosis, Pulmonary

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 Disorders; Clot Retraction; Humans; Indicators and Reagents; Methods; Thromboplastin; Time Factors

Topics: Animals; Blood Cell Count; Blood Chemical Analysis; Blood Coagulation Disorders; Blood Platelets; Dogs; Hypoxia; Male; Thrombin; Thromboplastin; Time Factors

Topics: Adenosine Diphosphate; Adolescent; Adult; Animals; Blood Coagulation Disorders; Blood Platelets; Cholesterol; Contraceptives, Oral; Ethynodiol Diacetate; Female; Humans; Norethindrone; Norgestrel; Platelet Adhesiveness; Pregnancy; Prothrombin Time; Rats; Thrombin; Thromboplastin

Topics: Adult; Animals; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Contraceptives, Oral; Ethinyl Estradiol; Ethynodiol Diacetate; Female; Humans; Mestranol; Methods; Middle Aged; Norethindrone; Norgestrel; Phosphatidylethanolamines; Platelet Adhesiveness; Pregnancy; Prothrombin Time; Rats; Thromboplastin

Topics: Agglutination; Agglutinins; Animals; Blood Coagulation; Blood Coagulation Disorders; Coagulase; Fibrinogen; Fibrinolysis; Hot Temperature; Humans; Models, Biological; Prothrombin; Rabbits; Species Specificity; Staphylococcus; Thrombin; Thromboplastin; Time Factors

Topics: Adolescent; Blood Coagulation Disorders; Blood Coagulation Tests; Child; Child, Preschool; Humans; Infant; Kaolin; Male; Surgical Procedures, Operative; Thromboplastin

Topics: Acute Disease; Blood Coagulation Disorders; Blood Urea Nitrogen; Factor VIII; Fibrin; Fibrinolysin; Fibrinolysis; Glomerulonephritis; Humans; Thromboplastin; Time Factors

Topics: Animals; Arthritis; Blood Coagulation Disorders; Chlorambucil; Chromatography, Gel; Electrophoresis, Starch Gel; Factor VIII; gamma-Globulins; Humans; Immune Sera; Immune System Diseases; Immunoglobulin M; Male; Middle Aged; Prothrombin Time; Rabbits; Raynaud Disease; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Physiological Phenomena; Blood Proteins; Chemoreceptor Cells; Enzymes; Fibrinogen; Fibrinolysin; Fibrinolysis; Heparin; Humans; Neurotransmitter Agents; Reflex; Stress, Psychological; Thrombin; Thromboplastin; Thrombosis

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Calcium; Coumarins; Fibrinolysis; Ions; Lethal Dose 50; Mice; Mice, Inbred Strains; Prothrombin; Prothrombin Time; Rabbits; Rats; Snakes; Species Specificity; Thromboplastin; Venoms

Topics: Adenosine Diphosphate; Animals; Blood Coagulation; Blood Coagulation Disorders; Calcium; Kaolin; Snakes; Swine; Swine Diseases; Thromboplastin; Time Factors; Venoms

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: Adult; Aprotinin; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hemostasis; Humans; In Vitro Techniques; Placental Extracts; Postpartum Hemorrhage; Pregnancy; Thromboplastin

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: Animals; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Erythrocyte Count; Factor V; Factor VII; Factor X; Female; Fibrinogen; Hematocrit; Hemoglobins; Leukocyte Count; Prothrombin Time; Rats; Thromboplastin; Time Factors; Vitamin A; Vitamin E

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hemophilia A; Hemophilia B; Humans; Kaolin; Thromboplastin

Topics: Age Factors; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Fibrinogen; Humans; Infant, Newborn; Infant, Newborn, Diseases; Methods; Prothrombin Time; Thromboplastin

Topics: Aerospace Medicine; Blood Coagulation Disorders; Fibrinolysis; Hemostasis; Humans; Hypoxia; Oxygen; Platelet Adhesiveness; Thrombelastography; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Coumarins; Factor X; Humans; Italy; Thromboplastin; Vitamin K

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Cats; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Liver; Liver Function Tests; Maternal-Fetal Exchange; Phenytoin; Pregnancy; Prothrombin Time; Thromboplastin; Vitamin K; Warfarin

Topics: Blood Coagulation Disorders; Diagnosis, Differential; Factor VIII; Fibrinogen; Hemophilia A; Humans; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Proteins; Blood Sedimentation; Factor IX; Factor V; Factor VIII; Factor X; Factor XIII; Female; Fibrinogen; Hemorrhagic Disorders; Heterozygote; Humans; Infant; Infant, Newborn; Male; Prothrombin; Thrombelastography; Thrombin; Thromboplastin

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Chemical Phenomena; Chemistry; Chromatography, DEAE-Cellulose; Factor V Deficiency; Factor VII Deficiency; Factor XII; Hemophilia A; Humans; Hypoprothrombinemias; Phospholipids; Prothrombin; Prothrombin Time; Thrombin; Thromboplastin

Topics: Acenocoumarol; Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Evaluation Studies as Topic; Humans; Prothrombin Time; Rabbits; Thromboplastin

Topics: Acute Disease; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Deafness; Dextrans; Ear, Inner; Evaluation Studies as Topic; Female; Hearing Disorders; Humans; Ischemia; Labyrinth Diseases; Male; Nicotinic Acids; Prothrombin Time; Theophylline; Thrombelastography; Thromboplastin; Time Factors

Topics: Adolescent; Adult; Blood Coagulation Disorders; Female; Fibrinolysis; Hemorrhagic Disorders; Humans; Kidney Failure, Chronic; Male; Middle Aged; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Factor V; Factor VIII; Factor XIII; Fibrinogen; Humans; Microcirculation; Prothrombin; Thromboplastin; Thrombosis; Toxins, Biological; Transfusion Reaction

Topics: Animals; Behavior, Animal; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Brain; Cattle; Dog Diseases; Dogs; Factor VII Deficiency; Fish Diseases; Fresh Water; Humans; Immunization, Passive; Marine Biology; Plasma; Prothrombin Time; Reproduction; Salmon; Seawater; Species Specificity; Temperature; Thrombin; Thromboplastin; Tissue Extracts

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Blood Coagulation Disorders; Endotoxins; Histamine Release; Humans; Hypotension; Hypoxia; Intestinal Absorption; Ischemia; Mononuclear Phagocyte System; Pulmonary Atelectasis; Shock; Shock, Septic; Thromboplastin

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: Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Fibrinogen; Fibrinolysin; Fibrinolysis; Injections, Intravenous; Lichens; Platelet Adhesiveness; Prothrombin Time; Pulmonary Artery; Pulmonary Embolism; Pulmonary Veins; Rabbits; Spores; Thromboplastin

Topics: Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Gas Analysis; Blood Platelets; Dogs; Hypoxia; Oxygen; Thrombelastography; Thrombin; Thromboplastin

Topics: Aged; Anticoagulants; Antithrombins; Blood Coagulation Disorders; Factor VIII; Female; Hemophilia A; Hemorrhage; Hemorrhagic Disorders; Humans; Male; Middle Aged; Pregnancy; Pregnancy Complications, Hematologic; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Factor V; Fibrinogen; Graft Rejection; Kidney Transplantation; Methods; Rabbits; Thrombin; Thromboplastin; Thrombosis; Transplantation Immunology; Transplantation, Homologous

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: Adult; Antibodies; Antigens; Appendectomy; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Transfusion; Factor VII; Factor X; Female; Hematuria; Hemorrhage; Heterozygote; Humans; Hypoprothrombinemias; Immunodiffusion; Italy; Neutralization Tests; Pedigree; Phosphatidylethanolamines; Pregnancy; Pregnancy Complications, Hematologic; Puerperal Disorders; Thromboplastin; Tooth Extraction

Topics: Adult; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Transfusion; Fibrinogen; Fibrinolysis; Humans; Male; Military Medicine; Plasma; Prothrombin Time; Thrombin; Thromboplastin; Time Factors; United States; Vietnam; Wound Infection; Wounds and Injuries

Topics: Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Fibrinogen; Hemorrhagic Disorders; Hemostasis; Humans; Liver Diseases; Prothrombin Time; Thrombin; Thrombocytopenia; Thromboplastin

Topics: Abdomen; Adult; Aged; Antithrombins; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Cholelithiasis; Female; Fibrinolysis; Humans; Male; Middle Aged; Preoperative Care; Shock, Surgical; Stomach Ulcer; Surgical Procedures, Operative; Thoracic Surgery; Thorax; Thromboplastin; Time Factors

A severe, pure deficiency of factor VII has been defined in haematological and biochemical terms in the Alderley Park colony of beagle dogs. By modification of the conventional factor VII assay to improve its specificity an apparent low activity of between 1 and 2.5% of the normal beagle has been found. When this plasma is used as a substrate for factor VII assays it compares well with human factor VII-deficient plasma in the measurement of both raised and depressed factor VII activity. It also appears to be a valuable reagent in the quality control of tissue thromboplastin extracts.

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Chromatography, Gel; Dog Diseases; Dogs; Factor IX; Factor V; Factor VII; Factor VII Deficiency; Factor VIII; Factor X; Fibrinogen; Humans; Phosphatidylethanolamines; Prothrombin Time; Thrombelastography; Thrombin; Thromboplastin; Tissue Extracts

Topics: Animals; Blood Coagulation Disorders; Cricetinae; Embolism; Female; Fibrinogen; Humans; Infant, Newborn; Placenta; Pregnancy; Respiratory Distress Syndrome, Newborn; Thromboplastin

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

Topics: Absorption; Adult; Aluminum; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Contraceptives, Oral; Factor VIII; Female; Fibrinogen; Humans; Iodine Isotopes; Middle Aged; Thromboembolism; 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: Adolescent; Adult; Aged; Anticoagulants; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Child; Child, Preschool; Factor V; Factor VII; Factor VIII; Factor X; Female; Fibrinogen; Glucocorticoids; Humans; Infant; Male; Middle Aged; Nephrotic Syndrome; Prothrombin; Renal Veins; Thromboembolism; Thrombophlebitis; Thromboplastin

Topics: Blood Coagulation Disorders; Humans; Lung Neoplasms; Methods; Pneumonectomy; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Consanguinity; Enzyme Precursors; Factor IX; Factor VIII; Hemophilia A; Humans; Pedigree; Thromboplastin; von Willebrand Diseases

Topics: Adult; Aged; Arthritis; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Carcinoma; Factor VIII; Female; Fibrinolysin; Hepatitis; Humans; Liver Diseases; Male; Middle Aged; Necrosis; Rectal Neoplasms; Thrombin; Thromboplastin; Vaginal Neoplasms

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Heparin; Humans; Indicators and Reagents; Methods; Postoperative Care; Postoperative Complications; Preoperative Care; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Hemostasis; Humans; Methods; Thrombelastography; Thrombocytopenia; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Brain Neoplasms; Factor V; Factor VIII; Fibrinogen; Glioblastoma; Guinea Pigs; Humans; Neoplasm Transplantation; Neoplasms, Experimental; Prothrombin; Prothrombin Time; Thromboplastin; Transplantation, Heterologous

Topics: Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Blood Protein Disorders; Blood Protein Electrophoresis; Hemorrhagic Disorders; Hemostasis; Humans; Immunodiffusion; Immunoglobulin G; Immunoglobulin M; Leukemia, Lymphoid; Multiple Myeloma; Platelet Adhesiveness; Thromboplastin; Waldenstrom Macroglobulinemia

Topics: Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Diagnosis, Differential; Factor VII Deficiency; Factor X; Female; Genes, Recessive; Heterozygote; Humans; Hypoprothrombinemias; Immunodiffusion; Male; Middle Aged; Neutralization Tests; Prothrombin; Prothrombin Time; Thromboplastin

Topics: Anti-Bacterial Agents; Blood Cell Count; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Child; Cystic Fibrosis; Fibrinolysis; Gastrointestinal Hemorrhage; Hemoptysis; Hepatomegaly; Humans; Liver; Liver Function Tests; Lung; Prospective Studies; Prothrombin Time; Splenomegaly; Thrombocytopenia; Thromboplastin; Vitamin K

Topics: Analysis of Variance; Animals; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Brain; Cattle; Coumarins; Factor VII; Factor VII Deficiency; Factor X; Humans; Hypoprothrombinemias; Indicators and Reagents; Methods; Prothrombin Time; Rabbits; Thromboplastin; Warfarin

Topics: Animals; Blood Coagulation Disorders; Dextrans; Hemorrhage; Humans; Rabbits; Thrombin; Thromboplastin

Topics: Binding Sites; Blood Coagulation; Blood Coagulation Disorders; Calcium; Factor VIII; Humans; In Vitro Techniques; Protein Binding; Prothrombin; Thrombin; Thromboplastin; Vitamin K

Topics: Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Factors; Female; Humans; Male; Middle Aged; Prothrombin Time; Thrombin; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Epinephrine; Factor V; Factor VII; Factor VIII; Hypersplenism; Kaolin; Rats; Splenectomy; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Child; Female; Hematuria; Humans; Hypoprothrombinemias; Lupus Erythematosus, Systemic; Prednisone; Prothrombin; Prothrombin Time; Thromboplastin; Vitamin K

Topics: Adipose Tissue; Aminocaproates; Animals; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Brain; Embolism, Fat; Female; Fibrinolysis; Hemorrhage; Heparin; Injections, Intravenous; Intracranial Embolism and Thrombosis; Liver; Lung; Pulmonary Artery; Pulmonary Embolism; Pulmonary Veins; Radioactivity; Radioisotopes; Rats; Thromboplastin

Topics: Adult; Aged; Blood Coagulation Disorders; Blood Gas Analysis; Blood Platelets; Blood Transfusion; Cell Aggregation; Embolism, Fat; Factor V; Factor VIII; Female; Femoral Fractures; Fibrinogen; Humans; Hydrogen-Ion Concentration; Hypoxia; Intracranial Embolism and Thrombosis; Male; Middle Aged; Pelvic Bones; Prothrombin Time; Pulmonary Embolism; Shock, Traumatic; Thromboplastin; Tibial Fractures

Topics: Blood Coagulation Disorders; Blood Flow Velocity; Blood Transfusion; Fibrinogen; Humans; Prothrombin Time; Shock, Traumatic; Thromboembolism; Thromboplastin

Topics: Amniotic Fluid; Blood Coagulation Disorders; Female; Humans; Pregnancy; Pregnancy Complications, Hematologic; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hematocrit; Hemophilia A; Humans; Methods; Thromboplastin

Topics: Adolescent; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Factor IX; Furosemide; Glucocorticoids; Hemophilia B; Humans; Immune Sera; Immunization; Immunoelectrophoresis; Male; Nephrotic Syndrome; Prednisone; Proteinuria; Prothrombin Time; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Humans; Indicators and Reagents; Plasma; Prothrombin Time; Thromboplastin

Heparin therapy in 114 patients was controlled by daily blood tests-the whole blood coagulation time, kaolin-activated partial thromboplastin time of plasma, and plasma heparin assay. Bleeding episodes occurred in 7 out of 92 patients (7.6%) who had normal haemostatic mechanisms before therapy and in 11 out of 22 patients (50%) with defective haemostasis, mostly due to intravascular coagulation or renal failure. The dose of heparin ranged from 20,000 to 60,000 units in each 24-hour period. In some patients bleeding was related to overdosage, but in others the laboratory tests indicated satisfactory or suboptimal dosage at the time of bleeding. Though there were positive correlations between the results of the three tests, these were not close, and no one test was preferable. Hence laboratory control of heparin therapy is unsatisfactory and patients may bleed despite careful control of the dose by all three methods.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Hemorrhage; Heparin; Humans; Kaolin; Male; Middle Aged; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Enzyme Activation; Female; Fibrin; Fibrinogen; Fibrinolysis; Injections, Intravenous; Plasminogen; Rabbits; Thrombin; 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: Blood Coagulation Disorders; Blood Coagulation Tests; Humans; 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: Animals; Anticoagulants; Blood Coagulation Disorders; Blood Vessels; Dogs; Fibrinolysis; Hematologic Diseases; Hemorrhage; Hemostasis; Humans; Postoperative Complications; Rabbits; Rats; Stress, Physiological; Stress, Psychological; Surgical Procedures, Operative; Thromboplastin; Transfusion Reaction

Topics: Adult; Aged; Blood Coagulation Disorders; Female; gamma-Globulins; Humans; Immunoelectrophoresis; Lupus Erythematosus, Systemic; Prothrombin; Prothrombin Time; Thrombelastography; Thromboplastin

Topics: Alpha-Globulins; Antifibrinolytic Agents; Antithrombins; Blood Coagulation Disorders; Blood Coagulation Tests; Fibrinolysis; Humans; Macroglobulins; Thrombin; Thromboplastin

Topics: Acidosis; Adrenocorticotropic Hormone; Animals; Antibodies; Anticoagulants; Antigens; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Volume; Colloids; Cortisone; Endotoxins; Female; Fibrinolysis; Fluorescent Antibody Technique; Hemolysis; Humans; Hyperlipidemias; Kidney Cortex Necrosis; Leukocytes; Mononuclear Phagocyte System; Norepinephrine; Peptide Hydrolases; Phagocytosis; Phenoxybenzamine; Pregnancy; Rabbits; Shwartzman Phenomenon; Sympatholytics; Thromboplastin

Topics: Acute Kidney Injury; Anemia, Hemolytic; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Coronary Disease; Female; Heart Arrest; Hemorrhagic Disorders; Humans; Hyaline Membrane Disease; Infant, Newborn; Ischemia; Kidney Transplantation; Male; Obstetric Labor Complications; Pregnancy; Shock, Septic; Shwartzman Phenomenon; Thrombocytopenia; Thromboembolism; Thromboplastin; Toxemia; Wounds and Injuries

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Calcium; Citrates; Enzyme Activation; Factor VIII; Fibrin; Fibrinolysis; History of Medicine; Humans; Lipids; Prothrombin; Sodium; Thrombin; Thromboplastin

Topics: Adult; Alanine Transaminase; Aminocaproates; Angioedema; Animals; Aspartate Aminotransferases; Bilirubin; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Creatine Kinase; Creatinine; Dogs; Factor V; Factor VIII; Fibrinogen; Haplorhini; Hemolysis; Humans; Hyperbilirubinemia, Hereditary; Male; Methyltestosterone; Muscular Diseases; Myoglobinuria; Necrosis; Norepinephrine; Plasminogen; Rats; Spectrophotometry; Thromboembolism; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Platelets; Hemostasis; Humans; Oral Hemorrhage; Thrombin; Thromboplastin

Topics: Abruptio Placentae; Afibrinogenemia; Blood Coagulation Disorders; Embolism, Amniotic Fluid; Female; Humans; Obstetric Labor Complications; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications; Shock; Thromboplastin; Tissue Extracts

Topics: Blood Coagulation Disorders; Child; Erythrocyte Aggregation; Female; Humans; Infant; Infant, Newborn; Kidney Cortex Necrosis; Male; Meningitis, Meningococcal; Renal Veins; Thrombocytopenia; Thrombophlebitis; Thromboplastin

Topics: Abortion, Septic; Blood Coagulation Disorders; Embolism, Amniotic Fluid; Female; Fetal Death; Fibrinolysis; Gelatin; Hemorrhagic Disorders; Humans; Hydrogen-Ion Concentration; Placenta; Placenta Diseases; Plasma Substitutes; Pregnancy; Pregnancy Complications; Pulmonary Embolism; Shock, Hemorrhagic; Shock, Septic; Streptokinase; Thrombophlebitis; Thromboplastin; Thrombosis

Topics: Acidosis; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Flow Velocity; Blood Transfusion; Blood Volume; Capillaries; Fibrinogen; Fibrinolysis; Humans; Prothrombin Time; Shock, Hemorrhagic; Thrombelastography; Thrombocytopenia; Thromboplastin

Topics: Aged; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Chromatography; Factor V; Factor VII; Factor X; Female; Femoral Neck Fractures; Hemorrhage; Humans; Prothrombin; Prothrombin Time; Thromboplastin; Time Factors

Topics: Adult; Anticoagulants; Blister; Blood Coagulation Disorders; Blood Coagulation Tests; Dermatitis; Dermatitis Herpetiformis; Fibrinolysis; Humans; Male; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Capillary Resistance; Humans; Thromboplastin; Uremia

Coagulation studies were carried out on 30 patients with chronic liver disease. The clotting defect was complex and involved factors V, VII, IX (Christmas factor), and prothrombin. Some patients showed a significant depression of factor IX in the presence of a normal one-stage prothrombin time. Thrombotest was found to be a good indicator of factor IX deficiency in this group of patients and may be of use as an additional liver function test. The screening of patients with liver disease for surgery or liver biopsy should assess the coagulation factors involved in both intrinsic and extrinsic thromboplastin generation.

Topics: Adult; Aged; Blood Coagulation Disorders; Chronic Disease; Factor IX; Factor V; Factor VII; Female; Humans; Liver Diseases; Liver Function Tests; Male; Middle Aged; Prothrombin; Prothrombin Time; Thromboplastin

Topics: Anticoagulants; Antithrombin III; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Factor IX; Factor VII; Factor X; Fibrinogen; Hemostasis; Heparin; Humans; Prothrombin; Thrombelastography; Thrombin; Thromboplastin; Thrombosis; Vitamin K

Topics: Animals; Blood Coagulation Disorders; Endotoxins; Humans; Kidney Cortex Necrosis; Lung Diseases; Shwartzman Phenomenon; Thromboplastin

Topics: Blood Coagulation Disorders; Endotoxins; Humans; Kidney Cortex Necrosis; Thromboplastin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Child; Clinical Laboratory Techniques; Consanguinity; Exercise Test; Factor V Deficiency; Factor VIII; Female; Hemophilia A; Homozygote; Humans; Hypoprothrombinemias; Male; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Centrifugation; Hemophilia A; Humans; Methods; Thromboplastin; Uremia

Topics: Anemia; Anticoagulants; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Blood Transfusion; Fibrinogen; Fibrinolysis; Hematologic Diseases; Hemorrhage; Humans; Infant, Newborn; Postoperative Complications; Preoperative Care; Prothrombin; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Female; Fibrin; Fibrinogen; Fibrinolysis; Heparin; Humans; Middle Aged; Purpura, Thrombocytopenic; Thrombophlebitis; Thromboplastin

Topics: Adolescent; Adult; Blood Cell Count; Blood Coagulation Disorders; Blood Platelets; Capillary Fragility; Humans; Infant; Male; Medical Records; Physical Examination; Preoperative Care; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation Disorders; Hemolysis; Humans; Mononuclear Phagocyte System; Thromboplastin; Uremia

Topics: Animals; Arteries; Blood Coagulation Disorders; Blood Coagulation Tests; Calcium; Dogs; Fibrinolysin; Fibrinolysis; Hypoxia; Jugular Veins; Platelet Adhesiveness; Prothrombin Time; Thrombin; Thromboplastin; Time Factors; Veins

Topics: Adrenocorticotropic Hormone; Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Chorionic Gonadotropin; Contraceptives, Oral; Endotoxins; Factor V; Factor VII; Female; Fibrin; Kidney Glomerulus; Lipopolysaccharides; Liver; Lung; Mestranol; Myocardium; Norethynodrel; Pregnancy; Prothrombin; Rabbits; Shwartzman Phenomenon; Spleen; Thromboplastin; Thrombosis

Purified acid-soluble and insoluble human collagen accelerated the clotting of plateletpoor plasma in silicone-treated tubes. The clot-promoting effect did not appear to be due to thromboplastic activity since the collagen preparations did not activate factor X in the presence of factor VII and calcium. Instead, collagen appeared to accelerate clotting by activating Hageman factor (factor XII) on the basis of the following findings: collagen increased the clot-promoting activity of partially purified Hageman factor but exerted no further effect in the presence of kaolin, a known activator of Hageman factor; clot-promoting eluates were obtained from collagen exposed to normal, hemophilic, or PTC-deficient plasma but not from collagen exposed to Hageman or PTA-deficient plasma. The collagen molecule itself appeared to be required for the clot-promoting activity since digestion with collagenase or thermal denaturation at pH 2.5 (about 35 degrees C) resulted in very marked reduction in clot-promoting activity. Since thermal denaturation is associated with transformation of collagen structure from triple helical to random coil form, it is suggested that the native form of collagen is essential for the ability to activate Hageman factor. Blockage of the free amino groups by treatment with nitrous acid or dinitrofluorobenzene only slightly reduced the clot-promoting activity of collagen. In contrast, since addition of cationic proteins to collagen markedly reduced pro-coagulant activity it is suggested that negatively charged sites on the collagen molecule are critical for Hageman factor activation. This suggestion is supported by the finding that pepsin treatment of collagen, which removes the predominantly negatively charged telopeptides, results in significant decrease in coagulant activity. Esterification of collagen, which neutralizes 80-90% of the free carboxyl groups, reduced coagulant activity by over 90% and it is suggested that the free carboxyl groups of glutamic and aspartic acids provide the negatively charged sites critical for Hageman factor activation.

Topics: Adult; Aspartic Acid; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Viscosity; Calcium; Child; Collagen; Factor XII; Glutamates; Hot Temperature; Humans; Kaolin; Microbial Collagenase; Nitrobenzenes; Pepsin A; Skin; Sodium Chloride; Thromboplastin

Topics: Adult; Blood Circulation Time; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Breast Neoplasms; Carcinoma; Factor XI; Factor XI Deficiency; Female; Hemorrhage; Hemorrhagic Disorders; Humans; Mastectomy; Methods; Microscopy, Phase-Contrast; Plasma Substitutes; Prothrombin Time; Thromboplastin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Child; Female; Glycogen Storage Disease; Glycogen Storage Disease Type I; Humans; Infant; Male; Thromboplastin

Topics: Abruptio Placentae; Adult; Animals; Anuria; Bilirubin; Blood Coagulation Disorders; Dogs; Erythrocytes; Female; Fibrin; Fibrinolysis; Hematologic Diseases; Hemolysis; Humans; Mice; Pregnancy; Rabbits; Rats; Shock, Hemorrhagic; Thrombin; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Hematocrit; Heparin; Rabbits; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Factor VIII; Hemophilia B; Humans; Hypoprothrombinemias; Kaolin; Methods; Prothrombin Time; Thromboplastin; Time Factors

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Factor VIII; Humans; Methods; Phosphatidylethanolamines; Thromboplastin

Topics: Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelets; Blood Pressure; Child; Child, Preschool; Factor V; Fibrinogen; Heparin; Humans; Hypotension; Infant; Infant, Newborn; Prothrombin Time; Rocky Mountain Spotted Fever; Sepsis; Shock, Septic; Thrombocytopenia; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Child; Foot Diseases; Gangrene; Heparin; Humans; Male; Purpura; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hemophilia A; Humans; Methods; Thromboplastin; Time Factors

Topics: Aminocaproates; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinolysis; Humans; Intracranial Aneurysm; Liver Function Tests; Male; Potassium; Rupture, Spontaneous; Sodium; Subarachnoid Hemorrhage; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hemophilia A; Humans; Phosphatidylethanolamines; Prothrombin Time; Thromboplastin

Topics: Adult; Blood Coagulation Disorders; Child; Diagnosis, Differential; Factor VIII; Factor XIII; Hemorrhagic Disorders; Humans; Male; Thromboplastin

Topics: Adult; Aged; Arteriosclerosis; Blood Coagulation Disorders; Blood Coagulation Tests; Coronary Disease; Female; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Thromboplastin; Thrombosis

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Factor XII; Humans; Prothrombin Time; Thromboplastin

Topics: Adult; Antimetabolites; Blood Coagulation Disorders; Factor V; Factor X; Female; Humans; Prothrombin; Scotland; Thromboplastin; United States

Topics: Biological Assay; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Platelet Disorders; Female; Fibrin; Humans; Immunoelectrophoresis; Male; Neoplasms; Thrombin; Thrombocytopenia; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Specimen Collection; Blood Transfusion; Factor VIII; Female; Hematoma; Humans; Immunoglobulin G; Middle Aged; Thromboplastin

Topics: Animals; Biological Assay; Blood Coagulation Disorders; Brain; Cattle; Coumarins; Factor VII Deficiency; Humans; Hypoprothrombinemias; In Vitro Techniques; Methods; Prothrombin Time; Rabbits; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Humans; Methods; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Hemostasis; Humans; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Diagnosis, Differential; Hemophilia A; Hemophilia B; Humans; Prothrombin Time; Thromboplastin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Factors; Child; Child, Preschool; Factor VII; Factor VIII; Factor XIII; Female; Humans; Infant; Kaolin; Lymphoma, Non-Hodgkin; Male; Prothrombin Time; Pulmonary Embolism; Thrombocytopenia; Thrombophlebitis; Thromboplastin; Wiskott-Aldrich Syndrome

Topics: Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Electroconvulsive Therapy; Factor VIII; Fibrinolysis; Hemorrhagic Disorders; Humans; Male; Thromboplastin

Topics: Aged; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Blood Protein Disorders; Calcium; Collagen; Connective Tissue; Fibrin; Fibrinogen; gamma-Globulins; Hemorrhagic Disorders; Humans; Male; Multiple Myeloma; Nitrogen Mustard Compounds; Plasmapheresis; Prothrombin Time; Thromboplastin; Tryptophan

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Coronary Vessels; Factor VIII; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Prednisone; Shock; Spondylitis, Ankylosing; Thromboplastin

Topics: Animals; Anticoagulants; Blood Coagulation Disorders; Dogs; Endotoxins; Escherichia coli; Fibrinolysin; Prothrombin Time; Shock, Hemorrhagic; Shock, Septic; Thromboplastin

Topics: Adolescent; Adult; Aged; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Child; Child, Preschool; Female; Fibrinogen; Histocytochemistry; Humans; Infant; Male; Meningitis; Meningococcal Infections; Middle Aged; Neisseria meningitidis; Prothrombin Time; Sepsis; Shock, Septic; Skin Manifestations; Thrombocytopenia; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Dogs; Endotoxins; Escherichia coli; Fibrinogen; Heparin; Prothrombin Time; Sepsis; Thromboplastin

Topics: Abortion, Spontaneous; Adult; Antifibrinolytic Agents; Blood Coagulation Disorders; Decidua; Extraembryonic Membranes; Female; Fibrinolytic Agents; Humans; Muscle, Smooth; Phosphotransferases; Pregnancy; Thromboplastin; Uterus

Topics: Adolescent; Adult; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Chromosome Aberrations; Chromosome Disorders; Factor IX; Factor X; Female; Hemostasis; Humans; Male; Middle Aged; Thromboplastin

The conventional plasma recalcification test is improved by incubation of test plasma with Celite suspended in distilled water. This effectively activates factor XII and releases platelet factor 3, thereby markedly shortening the clotting time. The modified plasma recalcification test has several advantages that contribute to its usefulness as a general screening test for coagulation abnormalities. It is more precise and reproducible than any comparable test that assays a similar spectrum of coagulation factors.

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Calcium; Factor XII; Humans; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Platelet Disorders; Humans; Thromboembolism; Thrombophlebitis; Thromboplastin; Thrombosis

Topics: Adolescent; Adult; Blood Coagulation Disorders; Hemorrhagic Fevers, Viral; Humans; Kidney Diseases; Middle Aged; Thromboplastin

Topics: Blood Coagulation Disorders; Female; Fibrinogen; Fibrinolysis; Humans; Placenta; Pregnancy; Pregnancy Complications; Thrombelastography; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Menstruation Disturbances; Thromboplastin; Uterine Hemorrhage

Topics: Afibrinogenemia; Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Caseins; Fibrinolysis; Humans; Peptide Hydrolases; Streptokinase; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Child, Preschool; Factor XII; Female; Humans; Japan; Thromboplastin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Child; Child, Preschool; Hemorrhage; Humans; Mass Screening; Middle Aged; Preoperative Care; Surgical Procedures, Operative; Thromboplastin

Topics: Adult; Blood Coagulation Disorders; Blood Coagulation Tests; Calcium; Female; Heparin; Humans; Male; Middle Aged; Peptic Ulcer Hemorrhage; Prothrombin; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Vessels; Culture Techniques; Factor XII; Fibrin; Fibrinolysin; Humans; Plasminogen; Rats; Serum Albumin; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; In Vitro Techniques; Male; Pregnancy; Thromboplastin

Topics: Adenine Nucleotides; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Citrates; Densitometry; Factor XII; Freezing; Hemorrhagic Disorders; Humans; Silicones; Thrombin; Thromboplastin; von Willebrand Diseases

Topics: Blood Coagulation Disorders; Child; Chromatography; Factor V; Female; Humans; Thrombophlebitis; Thromboplastin

Topics: Aged; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Female; Fibrinolysis; Hemophilia B; Humans; Liver; Liver Cirrhosis; Male; Prothrombin Time; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Female; Humans; Male; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Enzyme Repression; Female; Fibrinogen; Fibrinolysis; Hematocrit; Humans; In Vitro Techniques; Male; Middle Aged; Peptones; Plasminogen; Prothrombin Time; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Glutathione; Humans; Thalassemia; Thromboplastin

Topics: Blood Coagulation Disorders; Endotoxins; Humans; Shwartzman Phenomenon; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Child; Child, Preschool; Hemophilia A; Humans; Thromboplastin

Topics: Arteriosclerosis; Blood Coagulation Disorders; Humans; Thromboplastin

Topics: Anticoagulants; Antithrombin III; Blood Coagulation; Blood Coagulation Disorders; Blood Platelets; Calcium; Chemical Phenomena; Chemistry; Drug Therapy; Enzyme Inhibitors; Factor VII Deficiency; Glucose; Glycine; Hemophilia A; Heparin; Humans; Hypoprothrombinemias; Mannitol; Phospholipids; Sucrose; Thiourea; Thrombin; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Drug Therapy; Hemorrhage; Humans; Prothrombin Time; Thromboplastin

Topics: Anemia, Sickle Cell; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Humans; Thromboplastin

Topics: Blood Coagulation Disorders; Fractures, Bone; Humans; Thromboplastin

Topics: Animals; Antithrombin III; Aprotinin; Blood Coagulation Disorders; Dogs; Fibrinogen; In Vitro Techniques; Injections, Intravenous; Thromboplastin; Thrombosis

Topics: Blood Coagulation Disorders; Female; Fibrinogen; Humans; Obstetric Labor Complications; Pregnancy; Thromboplastin; Thrombosis

Topics: Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Blood Transfusion; Child; Factor XI; Factor XII; Female; Humans; Thromboplastin

Topics: Adult; Aged; Blood Coagulation Disorders; Female; Humans; Male; Middle Aged; Thromboplastin; Vascular Diseases

Topics: Aged; Amputation, Surgical; Arteriosclerosis Obliterans; Blood Coagulation Disorders; Chronic Disease; Coumarins; Diabetes Mellitus; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Middle Aged; Myocardial Infarction; Thromboplastin

Topics: Adolescent; Adult; Blood Coagulation Disorders; Child; Hemoglobins, Abnormal; Humans; In Vitro Techniques; Thalassemia; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Burns; Heparin; Infusions, Parenteral; Injections; Injections, Intravenous; Mice; Prothrombin Time; Research; Shock; Skin; Thromboplastin; Tissue Extracts

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

Topics: Bile Acids and Salts; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Cholesterol; Diet, Atherogenic; Dietary Fats; Fibrinolysis; Pharmacology; Rats; Research; Salts; Thiouracil; Thromboplastin; Thrombosis

Topics: Amniotic Fluid; Blood; Blood Coagulation Disorders; Embolism; Embolism, Amniotic Fluid; Female; Fibrinolysis; Humans; Infant, Newborn; Meconium; Obstetric Labor Complications; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Prothrombin Time; Thrombelastography; Thromboplastin

Topics: Adrenochrome; Adrenocorticotropic Hormone; Aminocaproates; Aminocaproic Acid; Blood Coagulation Disorders; Blood Coagulation Tests; Classification; Cortisone; Diagnosis; Humans; Japan; Pathology; Prednisolone; Purpura; Statistics as Topic; Thrombelastography; Thromboplastin; Vitamins

Topics: Barium Sulfate; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Coumarins; Factor IX; Factor V; Factor VIII; Factor X; Female; Humans; Infant; Infant, Newborn; Lanthanoid Series Elements; Liver Cirrhosis; Pharmacology; Pregnancy; Thorium; Thromboplastin

Topics: Antithrombins; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Lipoproteins; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Pathology; Thrombin; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Classification; Fibrin; Genetics, Medical; Hemophilia A; Humans; Purpura; Surgery, Oral; Thrombin; Thromboplastin

Topics: Adenine Nucleotides; Adenosine Triphosphate; Adolescent; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelet Disorders; Blood Platelets; Child; Factor IX; Factor VIII; Humans; Kaolin; Serotonin; Thrombasthenia; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Tests; Hemorrhage; Humans; Prothrombin Time; Syndrome; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Dogs; Fibrinogen; Fibrinolysin; Hemolysis; Heparin; Prothrombin Time; Research; Shock; Shock, Hemorrhagic; Silicones; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Electrophoresis; Factor IX; Factor V; Factor VIII; Macroglobulins; Research; Thromboplastin

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Blood Platelets; Calcium; Cardiac Surgical Procedures; Dextrans; Extracorporeal Circulation; Factor IX; Factor VIII; Fibrinogen; Fibrinolysis; Heart, Artificial; Heparin; Humans; Prothrombin Time; Thoracic Surgery; Thrombin; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Diagnosis, Differential; Ecchymosis; Female; Humans; Menorrhagia; Minnesota; Thromboplastin; Toxicology; Warfarin

Topics: Antitoxins; Blood Coagulation Disorders; Coagulants; Dogs; Escherichia coli; Fibrinogen; Hemostatics; Pharmacology; Rabbits; Research; Thromboplastin; Toxins, Biological

Topics: Blood Coagulation Disorders; Blood Platelet Disorders; Blood Platelets; Diagnosis, Differential; Humans; Thromboplastin

Topics: Beta-Globulins; Blood Coagulation Disorders; Blood Protein Disorders; Genetics, Medical; Humans; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Disorders; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Thromboplastin

Topics: Arachnodactyly; Blood Coagulation Disorders; Ehlers-Danlos Syndrome; Humans; Marfan Syndrome; Osteogenesis Imperfecta; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Burns; Hematocrit; Heparin; Mice; Research; Skin; Thrombophilia; Thromboplastin; Tissue Extracts

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Factors; Dogs; Esophageal Fistula; Factor IX; Factor V; Factor VIII; Factor X; Fibrinogen; Hematocrit; Lymph; Prothrombin Time; Research; Thoracic Duct; Thromboplastin; Vitamin K

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Prothrombin Time; Thromboplastin

Topics: Afibrinogenemia; Amniotic Fluid; Blood Coagulation Disorders; Embolism; Embolism, Amniotic Fluid; Female; Humans; Hyaluronoglucosaminidase; Pregnancy; Thrombocytopenia; Thromboplastin

Topics: Amniotic Fluid; Blood Coagulation; Blood Coagulation Disorders; Female; Humans; Placenta; Placental Extracts; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Thromboplastin

Topics: Animals; Bees; Bites and Stings; Blood Coagulation Disorders; Humans; Lipoproteins; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Coagulation Tests; Humans; Thromboplastin

Topics: Afibrinogenemia; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Calcium; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Female; Fibrinogen; Fibrinolysis; Hemophilia B; Humans; Hypoprothrombinemias; Physiology; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Prothrombin; Thromboplastin

Topics: Acquired Immunodeficiency Syndrome; Blood Coagulation Disorders; Humans; Hypersensitivity; Lupus Erythematosus, Systemic; Neutrophils; Prothrombin Time; Thromboplastin

Topics: Adolescent; Anticoagulants; Autoantibodies; Blood Coagulation Disorders; Female; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Metrorrhagia; Thromboplastin

Topics: Animals; Blood Coagulation Disorders; Blood Coagulation Tests; Factor IX; Factor V; Factor VII; Factor VIII; Factor X; Factor XI; Factor XII; Fibrinogen; Hibernation; In Vitro Techniques; Prothrombin Time; Rodentia; Thromboplastin

Topics: Blood Coagulation Disorders; Factor XI Deficiency; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Thromboplastin

Topics: Blood Coagulation Disorders; Humans; Kaolin; Partial Thromboplastin Time; Plasma; Thromboplastin

Topics: Blood Coagulation Disorders; Hemophilia A; Humans; Thrombocytopenia; Thromboplastin; Thrombosis; von Willebrand Diseases

Topics: Blood Coagulation Disorders; Fibrinolysis; Humans; Spine; Thrombin; Thromboplastin; Trypsin

Topics: Acquired Immunodeficiency Syndrome; Blood Coagulation; Blood Coagulation Disorders; Humans; Thromboplastin

Topics: Aged; Blood Coagulation Disorders; Factor XI Deficiency; Hemophilia A; Hemorrhagic Disorders; Humans; Medical Records; Medicine; Thromboplastin

Topics: Blood Coagulation Disorders; Hemorrhage; Hemorrhagic Disorders; Plasma; Thromboplastin

Topics: Blood Coagulation Disorders; Hemorrhagic Disorders; Thromboplastin

Topics: Blood Coagulation Disorders; Hemophilia A; Hemophilia B; Hemorrhage; Hemorrhagic Disorders; Medicine; Thromboplastin

Topics: Anticoagulants; Autoimmune Diseases; Blood Coagulation Disorders; Collagen Diseases; Humans; Immunoglobulins; Lupus Erythematosus, Systemic; Thromboplastin

Topics: Blood Coagulation Disorders; Blood Platelets; Hemophilia A; Humans; Plasma; Thromboplastin; von Willebrand Diseases