thromboplastin and Thromboembolism

Venous and arterial thromboses, called as cancer-associated thromboembolism (CAT), are common complications in cancer patients that are associated with high mortality. The cell-surface glycoprotein tissue factor (TF) initiates the extrinsic blood coagulation cascade. TF is overexpressed in cancer cells and is a component of extracellular vesicles (EVs). Shedding of TF

Topics: Extracellular Vesicles; Humans; Neoplasms; Thromboembolism; Thromboplastin

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

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

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

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

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly become a worldwide threat to health, mainly causing severe acute respiratory syndrome. In addition to the widely described respiratory syndrome, COVID-19 may cause life-treating complications directly or indirectly related to this infection. Among these, thrombotic complications have emerged as an important issue in patients with COVID-19 infection, particularly in patients in intensive care units. Thrombotic complications due to COVID-19 are likely to occur due to a pro-coagulant pattern encountered in some of these patients or to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease. In the present authors' experience, from five different hospitals in Italy and the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance. The aim of this review is to illustrate thromboembolic complications directly or indirectly related to COVID-19 disease. Specifically, this review will show complications related to thromboembolism due to a pro-coagulant pattern from those likely related to an endothelial thrombo-inflammatory syndrome.

Topics: Adult; Aged; Anticoagulants; Brain Ischemia; Cause of Death; Communicable Diseases, Emerging; Coronavirus Infections; COVID-19; Female; Humans; Italy; Male; Middle Aged; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Radiography, Thoracic; Severe Acute Respiratory Syndrome; Survival Analysis; Thromboembolism; Thromboplastin; Tomography, X-Ray Computed

Behçet disease (BD) is a rare multisystem, inflammatory disease of unknown etiology with vascular involvement and associated thrombogenicity. This review aims to describe the involvement of various mediators in endothelial cell damage and in the hypercoagulable state of BD. The scenario of the chronic inflammation present in BD shows an increased oxidative condition that contributes to endothelial cell damage and induces platelet, leukocyte, and endothelial cell activation through the release of proinflammatory cytokines and chemokines. These factors, together with the increased levels of homocysteine observed in BD patients, induce the endothelial cell expression of adhesion molecules (VCAM-1 and ICAM-1) and tissue factor; the release of cytokines, soluble CD40L (sCD40L), matrix metalloproteinase-9, and blood coagulation factor V; the inhibition of fibrinolysis; the disruption of nitric oxide metabolism; and the increase in platelet reactivity and lipid peroxidation. Endothelial cell dysfunction leads to a prothrombotic and antifibrinolytic phenotype in BD patients. Increased levels of homocysteine, fibrinogen, and plasminogen activator inhibitor type 1 seem to be involved in the procoagulant condition of this pathology that has been verified by end-point tests as well as by global coagulation tests.

Topics: Autoantibodies; Behcet Syndrome; Blood Coagulation Tests; CD40 Antigens; CD40 Ligand; Cell Adhesion Molecules; Cytokines; Endothelium, Vascular; Fibrinolysis; Humans; Hyperhomocysteinemia; Inflammation; Leukocytes; Lipid Peroxidation; Matrix Metalloproteinase 9; Models, Biological; Nitric Oxide; Platelet Activation; Reactive Oxygen Species; Thromboembolism; Thrombophilia; Thromboplastin

Topics: Animals; Atrial Appendage; Atrial Fibrillation; Blood Flow Velocity; Drug Delivery Systems; Endothelium, Vascular; Factor Xa; Fibrinolytic Agents; Gene Expression Regulation; Humans; Intracranial Embolism; Mice; Mice, Inbred C57BL; Thrombin; Thromboembolism; Thromboplastin; Thrombosis

Topics: Animals; Blood Coagulation Factors; Cell Line, Tumor; Enzyme Activation; Humans; Mice; Neoplasm Proteins; Neoplasms; Thromboembolism; Thrombophilia; Thromboplastin

Topics: Angiogenesis Inhibitors; Blood Coagulation; Blood Coagulation Factors; Blood Platelets; Clinical Trials, Phase II as Topic; Humans; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Thromboembolism; Thrombophilia; Thromboplastin

Topics: Anticoagulants; Antineoplastic Agents; Blood Coagulation Factors; Clinical Trials as Topic; Disease Progression; Glucuronidase; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Selectins; Thrombin; Thromboembolism; Thrombophilia; Thromboplastin

Chemotherapy is an independent risk factor of thromboembolic events in cancer patients. Various pathogenetic mechanisms have been hypothesized in the past, but until now their individual contribution to the risk of thrombosis has been hardly investigated in clinical trials. In recent years, studies increasingly suggested an association between the prothrombotic state in cancer patients and circulating tissue factor-exposing microparticles. In this review, we discuss the roles of tissue factor and microparticles with regard to chemotherapy-induced hypercoagulability.

Topics: Antineoplastic Agents; Body Mass Index; Breast Neoplasms; Cell Membrane Structures; Hemostasis; Humans; Leukocyte Count; Pancreatic Neoplasms; Platelet Count; Risk Factors; Thromboembolism; Thromboplastin

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which confers a high risk of mortality and morbidity from stroke and thromboembolism. The precise mechanisms by which AF causes thromboembolism and subsequent cerebrovascular events have attracted much research interest, and are yet to be fully elucidated. Nonetheless, it is well recognised that AF fulfils Virchow's triad for thrombogenesis, with abnormal flow conditions with loss of atrial contractility and an irregularly irregular cardiac output, (i. e. flow abnormalities), as well as structural heart disease with endocardial damage (i. e. abnormal vessel wall) and abnormalities in platelet and haemostatic variables (i. e. abnormal blood constituents). This review is to summarise the evidence so far for the role of coagulation and fibrinolytic components, platelets and inflammation (that is blood constituents) in the generation of the prothrombotic state in AF, with particular focus on the endothelium and AF.

Topics: Atrial Fibrillation; Cyclic GMP; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Nitric Oxide; Stroke; Thromboembolism; Thromboplastin; von Willebrand Factor

Topics: Blood Coagulation Factors; Cardiovascular Diseases; Disease Susceptibility; Fibrinogen; Fibrinolysis; Humans; Polymorphism, Single Nucleotide; Prothrombin; Risk Factors; Thromboembolism; Thrombophilia; Thromboplastin; Thrombosis

Thromboembolism is well recognized as a major complication of cancer. Many tumor cells overexpress tissue factor (TF), which activates blood coagulation in cancer patients. Inflammatory cells expressing TF are also contributors to this activation. In prostate cancer, we believe that prostasomes may also be involved in the initiation of blood coagulation. Prostasomes are submicron secretory granules derived from the prostate gland. They are surrounded by membrane and their extracellular appearance and membrane architecture are complex. Seminal prostasomes are believed to be necessary for successful fertilization and act as protectors of the spermatozoa in the lower and upper female genital tract. Cells from prostate cancer and its metastases are able to produce and export prostasomes to the extracellular environment. These prostasomes may differ quantitatively rather than qualitatively from their normal counterparts with regard to protein composition and function. A majority of human prostate cancers have been found to overexpress TF, and we have demonstrated by various methods that prostasomes derived from prostate cancer cells express considerably higher levels of TF compared with prostasomes of nonmalignant cell origin. The mechanism related to thromboembolic disease generated by prostasomes in prostatic cancer patients may be the early release of prostasomes from prostate cancer cells into the blood circulation, where they will evoke their blood-clotting effects.

Topics: Female; Gene Expression Regulation, Neoplastic; Humans; Male; Prostate; Prostatic Neoplasms; Secretory Vesicles; Semen; Sperm Capacitation; Sperm Motility; Spermatozoa; Thromboembolism; Thromboplastin

The classic intrinsic pathway of coagulation is triggered by contact activation of the plasma protease factor (F)XII, followed by sequential proteolytic activation of FX1 and FIX. While a key mechanism for initiating coagulation in some clinically useful in vitro assays, the absence of abnormal bleeding associated with congenital FXII deficiency indicates that the intrinsic pathway is not important for normal blood coagulation in vivo. However, recent work with mice lacking FXII or FXI suggest that these proteases make important contributions to formation of pathologic intravascular thrombi. In models of arterial injury, FXII or FXI null mice are protected from formation of platelet rich occlusive thrombi to a degree similar to that seen in FIX deficient mice (a model for the severe bleeding disorder hemophilia B) or to wild type mice treated with high dose heparin. FXII or FXI deficiency does not appear to prevent the initiation of thrombus formation in these models, but instead causes significant thrombus instability that prevents occlusion of the vessel. These findings raise the possibility that a pathway similar or identical to the intrinsic pathway may operate in vivo under some circumstances. Furthermore, the disproportionate importance of FXII and FXI to occlusive thrombus formation compared to normal hemostasis makes these proteases attractive candidates for therapeutic inhibitors to treat or prevent thromboembolic disorders.

Topics: Animals; Anticoagulants; Blood Coagulation; Disease Models, Animal; Factor XI; Factor XII; Humans; Mice; Models, Cardiovascular; Thromboembolism; Thromboplastin

The relationship between increased clotting and malignancy is well recognized, though the bidirectional development of this association is often overlooked. In the challenging cancer biology, transforming genes often act in concert with numerous epigenetic factors, including hypoxia, inflammation, contact between blood and cancer cells, and emission of procoagulant vesicles from tumors, to determine a net imbalance of the hemostatic potential which is detectable by a variety of laboratory tests. Procoagulant factors, in particular, are intimately involved in all aspects of hemostatic, cell proliferation and cellular signalling systems. However, the biggest as yet unresolved question is why cancer patients develop thrombosis? Since the thrombus itself does not apparently contributes directly to the tumor biology, enhanced hemostasis activation in cancer patients may be interpreted according to the most recent biological evidences. Coagulation and cancer biology interact bidirectionally in a "vicious cycle", in which greater tumor burden supplies greater procoagulants (tissue factor, cancer procoagulant) and thrombin, which would in turn act as strong promoters of cancer growth and spread. In this perspective, thrombosis may be interpreted as a epiphenomenon of an intricate an effective biological feedback to maintain or promote cancer progression. In this review article, we briefly analyze the pathogenesis, laboratory, clinical and therapeutic features of cancer and thrombosis.

Topics: Blood Coagulation; Blood Flow Velocity; Blood Vessels; Humans; Neoplasms; Neovascularization, Pathologic; Thromboembolism; Thromboplastin; Thrombosis

Anticoagulant therapy is effective at preventing the development of venous thromboembolism in high-risk patients, and reduces morbidity and mortality in individuals with established thromboembolic disease. Vitamin K antagonists and heparins are currently the most commonly used anticoagulant drugs, but they have practical limitations. Therefore, new antithrombotic agents with predictable dose-responses (thereby decreasing the need for monitoring without compromising efficacy or safety), ideally available in an oral formulation and with a rapidly reversible anticoagulant effect, are needed. New drugs fulfilling some of the above criteria have been developed and have proven to be effective agents for the treatment and prevention of venous thromboembolism.

Topics: Animals; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Factor VII; Factor Xa Inhibitors; Fondaparinux; Helminth Proteins; Humans; Oligosaccharides; Polysaccharides; Recombinant Proteins; Thrombin; Thromboembolism; Thrombomodulin; Thromboplastin; Treatment Outcome; Venous Thrombosis

Venous and arterial thromboembolism are a major cause for morbidity and mortality. The list of established drugs for the prevention of thrombus formation and embolisation includes heparins, hirudin and derivatives, aspirin, ADP and glycoprotein IIb/IIIa receptor antagonists, as well as vitamin K antagonists. Several limitations exist for these drugs that have stimulated the search for new and better anticoagulants. A series of selective clotting factor Xa inhibitors and direct factor IIa (thrombin) inhibitors are on the horizon, two of which are getting close to broad clinical application. Additional therapeutics that are still under preclinical and clinical investigation include inhibitors of the tissue factor pathway/factor VII complex, clotting factor VIII and XIII inhibitors and modulators of the protein C pathway or of endogenous fibrinolysis, as well as novel antiplatelet drugs. This review is focused on the current status of development of novel antithrombotics and their clinical potential. Even though only a few of a broad array of antithrombotic agents have reached clinical testing, some hold the potential for significant improvement in efficacy and safety of anticoagulant therapy.

Topics: Factor VII; Factor Xa Inhibitors; Fibrinolytic Agents; Hemostatics; Humans; Plasminogen Activator Inhibitor 1; Platelet Aggregation Inhibitors; Thrombin; Thromboembolism; Thromboplastin

The possible role of tissue factor (TF) in colorectal cancer (CRC) is reviewed. A correlation between TF expression and advanced stages of malignancy, and a correlation between TF expression and overall survival have been suggested in CRC. This is supported by experimental studies indicating that TF plays a key role in growth, invasion and dissemination of tumour cells, and in tumour related angiogenesis as well. In addition, the activation of TF in CRC patients in relation to the surgical trauma, perioperative blood transfusion and development of postoperative bacterial infectious complications are discussed. Finally, future directions for the development of anticancer modalities directed against regulation of TF are considered.

Topics: Animals; Biomarkers, Tumor; Colorectal Neoplasms; Endothelial Growth Factors; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Prognosis; Thromboembolism; Thromboplastin

The limitations of heparin and warfarin have prompted the search for new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Although many such agents are in development, only a few have reached phase II or higher levels of clinical testing. This article reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants currently under development, describes the agents in more advanced stages of clinical testing, and provides clinical perspective on the opportunities for new anticoagulant drugs.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Heparin; Humans; Lipoproteins; Protein C; Thromboembolism; Thromboplastin; Thrombosis; Warfarin

To describe the characteristics of thrombus formation on atherosclerotic plaques, the clinical expression of atherothrombosis in vascular disease, and some of the most recent therapeutic approaches in cardiovascular disease.. MEDLINE search for English-language articles on thrombosis and atherosclerosis published up to January 2000. Abstracts of recent international meetings on new aspects of thrombus formation and new therapeutic options were reviewed, and references from identified articles were selected and reviewed.. Experimental, basic, clinical, and epidemiologic studies related to the pathophysiology of thrombosis on atherosclerotic lesions. Therapeutic approaches were obtained from experimental studies and large clinical investigations.. Arterial vessel wall substrate, rheologic conditions, and blood thrombogenicity influence the process of thrombus formation in arteries. Thrombus formation on disrupted atherosclerotic plaques or arterial erosions frequently causes acute coronary syndromes. Severe atherosclerosis of the aorta has been identified as an important morphologic indicator of an increased risk for thromboembolism. Current antithrombotic therapies available as long-term treatment for patients with cardiovascular disease are often not effective enough to prevent acute thrombotic events and deterioration of atherosclerosis.. Improved understanding of the pathophysiology of thrombus formation on atherosclerotic plaques has led to the development of new therapeutic approaches. Glycoprotein IIb/IIIa, tissue factor, factor Xa, and thrombin inhibitors as well as combined antithrombotic therapy, such as aspirin plus a thienopyridine plus warfarin, are being evaluated as new possible options for the treatment of arterial thrombosis.. Long-term treatment with potent antithrombotic drugs, such as tissue factor or factor Xa inhibitors, that effectively block thrombosis without causing bleeding complications could help reduce death from cardiovascular disease.

Topics: Arteriosclerosis; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorheology; Humans; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Risk Factors; Thromboembolism; Thromboplastin

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Home Care Services, Hospital-Based; Humans; Randomized Controlled Trials as Topic; Risk Factors; Thromboembolism; Thromboplastin; Venous Thrombosis

The paper reviews the current studies on mechanism of thrombo-embolic complications in patients with malignancy. The neoplastic cells can express procoagulants like tissue factor (TF), cancer procoagulant (CP) and others, which induce thrombin formation in blood plasma and cause thrombo-embolic events, disseminated intravascular coagulation and other complications. Both procoagulants are acting via extrinsic pathway--TF makes complexes with factor VII and calcium ions, while CP acts directly on factor X transforming it into active form (Xa). Gynecological tumor-related complications occur in 20-30% patients with ovarian or uterine cancer.

Topics: Antineoplastic Agents; Female; Humans; Neoplasms; Ovarian Neoplasms; Thromboembolism; Thromboplastin; Uterine Neoplasms

Post-surgical deep vein thrombosis (DVT) is often underdiagnosed by clinical assessment alone. Subclinical DVT is a major source of pulmonary embolism, which is an important cause of death, particularly following total hip replacement surgery. Results from pathophysiological studies and recently conducted, prospective double-blind venographic studies in Europe and North America suggest that, in patients undergoing total hip replacement surgery, thromboprophylaxis with a low-molecular-weight heparin should be continued for at least 5 weeks post-operatively to minimize this serious complication.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Double-Blind Method; Europe; Heparin, Low-Molecular-Weight; Humans; Leg; Multicenter Studies as Topic; North America; Outpatients; Phlebography; Postoperative Complications; Postoperative Period; Prevalence; Prospective Studies; Pulmonary Embolism; Randomized Controlled Trials as Topic; Regional Blood Flow; Risk Factors; Thromboembolism; Thromboplastin; Venous Thrombosis; Warfarin

The basic mechanisms of atherosclerotic progression leading to the acute coronary syndromes (ACS) have been elucidated during the last few years. In this brief presentation, we outline 1) Definition of Atherosclerotic Lesions: eight morphologically different lesions are defined (Type I to VI) in various phases of disease. 2) Vulnerable Lipid-Rich Plaques and the ACS: The type IV and Va lesions tend to be relatively small in size, but soft or vulnerable to a "passive" phenomenon of plaque disruption; in addition, an "active" macrophage-dependent enzymatic (genesis of metalloproteinase) phenomenon of plaque disruption is evolving. 3) Thrombosis: we have shown that monocytes/macrophages in lipid-rich plaques may play a detrimental role after plaque disruption, promoting thrombin generation and thrombosis through the tissue factor pathway that can be prevented by tissue factor pathway inhibition; such pathway of thrombosis appears to be critical in the development of the ACS. 4) Effect of Lipid-Modifying Strategies and other Risk Factors on the Vulnerable Lipid-Rich Plaques: when high LDL-cholesterol is reduced therapeutically, efflux from the plaques of the liquid or sterified cholesterol, and also its hydrolysis into cholesterol crystals depositing in the vessel wall, predominate over the influx of LDL-cholesterol; consequently, there is a decrease in the softness of the plaque and so, presumably in the "passive" phenomenon of plaque disruption; modification of other risk factors presumably also favorably affect LDL-cholesterol influx and efflux. 5) Antithrombotic Strategies: the evolving antithrombotic approaches under investigation are briefly outlined.

Topics: Anticoagulants; Arteriosclerosis; Aspirin; Clinical Trials as Topic; Coronary Thrombosis; Disease Progression; Drug Therapy, Combination; Endothelium, Vascular; Fibrinolytic Agents; Humans; Lipids; Models, Biological; Platelet Aggregation Inhibitors; Rupture, Spontaneous; Thromboembolism; Thromboplastin; Warfarin

Antiphospholipid antibodies are autoantibodies that can be detected in plasma or serum with phospholipid-dependent coagulation tests or solid-phase immunoassays. The presence of these autoantibodies is strongly associated with an increased risk for arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. This paradoxical association of the in vitro prolongation of clotting assays and in vivo thrombosis has stimulated the search for the real antigen to which the autoantibodies are directed. A large number of potential pathological mechanisms have been proposed, and although disturbance of a certain metabolic pathway by the antibodies can explain a thrombotic tendency in one patient, no general pathological mechanism explaining thrombosis in the whole patient population has been found. This suggests that the antiphospholipid antibodies are a heterogeneous group of autoantibodies and is supported by the recent observations that antiphospholipid antibodies are not directed against phospholipids alone but against a combination of phospholipids and phospholipid-binding proteins. Both the phospholipid and the protein are part of the antigen. For the detection of antiphospholipids in an ELISA set-up, beta 2-glycoprotein I is the protein cofactor. In the coagulation tests, beta 2-glycoprotein, as well as prothrombin, can act as cofactor. However, the presence of these two proteins as a part of the epitope of the antiphospholipid antibodies does not explain the thrombotic tendency in the patient group. We have found that more physiologically relevant cofactors such as protein C and protein S, for which it is known that a partial deficiency is correlated with a thrombotic tendency, can also act as cofactors for the binding of antiphospholipid antibodies. It is concluded that antiphospholipid antibodies are a heterogeneous group of autoantibodies with varying affinity for different protein-phospholipid complexes and that inhibition of the biological activity of the protein part of the complex determines the pathological capacity of the antibodies.

Topics: Abortion, Habitual; Antibodies, Antiphospholipid; Antibody Specificity; Antiphospholipid Syndrome; beta 2-Glycoprotein I; Endothelium, Vascular; Epoprostenol; Female; Glycoproteins; Humans; Lupus Coagulation Inhibitor; Monocytes; Phospholipids; Platelet Aggregation; Pregnancy; Protein C; Thrombocytopenia; Thromboembolism; Thrombomodulin; Thromboplastin; von Willebrand Factor

Topics: Administration, Oral; Animals; Anticoagulants; Cattle; Clinical Trials as Topic; Humans; Prothrombin Time; Rabbits; Random Allocation; Thromboembolism; Thrombophlebitis; Thromboplastin; Warfarin

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin

Topics: Blood Coagulation; Fibrinogen; Humans; Neoplasms; Phlebitis; Platelet Aggregation; Thromboembolism; Thromboplastin

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

Topics: Arthritis; Blood Coagulation Factors; Collagen Diseases; Diabetes Complications; Endocrine Glands; Glucocorticoids; Humans; Myeloproliferative Disorders; Obesity; Sex Factors; Thromboembolism; Thrombophlebitis; Thromboplastin; Thyroid Diseases

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: Anticoagulants; Blood Coagulation Tests; Cerebral Hemorrhage; Cerebrovascular Disorders; Coumarins; Heparin; Humans; Middle Aged; Myocardial Infarction; Phenindione; Postoperative Care; Prothrombin Time; Rheumatic Heart Disease; Thromboembolism; Thrombophlebitis; Thromboplastin

Angiotensin receptor blockers (ARBs) are widely used for the treatment of hypertension. It has been reported that the ARB losartan has antiplatelet, anticoagulant and profibrinolytic effects experimentally. These properties could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk. To examine the antithrombotic effects of losartan in hypertension, 20 consecutive patients with hypertension complicated by atrial fibrillation (AF) were enrolled in this study. The patients were treated with losartan 50 mg for 8 weeks followed by 100 mg for 4 weeks. Blood samples were obtained from each patient at 0 (pretreatment), 8 and 12 weeks after initiating treatment. Platelet aggregability, plasma levels of tissue factor (TF) and type 1 plasminogen activator inhibitor (PAI-1) activity levels were measured. The area under the curve for small platelet aggregability decreased from 100 to 42.8% at 12 weeks (P<0.0001). TF levels (ng ml(-1)) and PAI-1 activity (IU ml(-1); mean±s.d.) also changed from 14.2±3.6 to 10.9±4.5 at 12 weeks (P=0.0299) and from 11.7±3.6 to 8.5±3.1 at 12 weeks (P=0.0122), respectively. Losartan inhibited platelet activity and coagulation factors in a dose- and time-dependent manner in patients with hypertension complicated by AF, whereas the fibrinolytic capacity was increased. The use of losartan could be advantageous in the treatment of hypertensive patients with high atherothrombotic risk.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Atrial Fibrillation; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Hypertension; Losartan; Male; Middle Aged; Pilot Projects; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Risk Factors; Thromboembolism; Thromboplastin; Time Factors; Treatment Outcome

Elevated levels of circulating tissue factor-bearing microparticles (TFMP) have been associated with an increased risk of developing venous thromboembolism (VTE) in cancer patients. We performed a randomized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP randomized to enoxaparin or observation. The cumulative incidence of VTE at 2 months in the higher TFMP group randomized to enoxaparin (N = 23) was 5·6% while the higher TFMP group observation arm (N = 11) was 27·3% (Gray test P = 0·06). The cumulative incidence of VTE in the low TFMP was 7·2% (N = 32). No major haemorrhages were observed in the enoxaparin arm. The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin (P = 0·58). In a prospective randomized trial, increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE. Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP, with an overall rate of VTE similar in magnitude to the lower TFMP group.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cell-Derived Microparticles; Enoxaparin; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Neoplasms; Survival Analysis; Thromboembolism; Thromboplastin

There is compelling evidence that blood-borne tissue factor that is predominantly found on circulating microparticles (MPs) plays an important role in both, cancer biology and organ and stem-cell transplantation (SCT). Therefore, we hypothesized that numbers of tissue factor bearing MPs might be associated with complications and outcome in allogeneic SCT (allo-SCT).. In a prospective study, we enumerated total, platelet, endothelial, and tissue factor bearing MPs in plasma samples obtained from up to 60 patients with hematologic diseases at different time-points during the course of allo-SCT by flow cytometry. Patient- and transplant-related risk factors were included in statistical analysis.. Mean follow-up time was 968 days (0-1981 days). Thirty-four (56.7%) patients died, 17 due to transplant-related mortality (28.3%). High numbers of tissue factor positive MPs more than 500/μL before conditioning were predictive for shorter overall survival (P=0.017, hazard ratio=4.5) in multivariate analysis. This was mainly caused by an increase in transplant-related mortality (P=0.010, hazard ratio=11.0) with cumulative incidences at 1 year of 68.8% compared with patients with lower values (20.1%; P=0.002).. Tissue factor bearing MPs might be useful biomarkers for risk stratification in allo-SCT patients and further studies should investigate their origin, functional properties, and optimal cut-off values.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Platelets; Cell-Derived Microparticles; Endothelium, Vascular; Female; Flow Cytometry; Graft vs Host Disease; Hematologic Diseases; Humans; Incidence; Male; Middle Aged; Mucositis; Predictive Value of Tests; Prospective Studies; Recurrence; Risk Factors; Stem Cell Transplantation; Thromboembolism; Thromboplastin; Transplantation, Homologous; Young Adult

A number of instruments have been developed for determination of prothrombin time (PT) and International Normalised Ratio (INR) at locations not limited to central laboratories.. To evaluate one such portable instrument, the Thrombolytic Assessment System (TAS), which can be used in a near-patient setting.. Samples from 20 normal subjects and 48 patients treated with warfarin for venous thromboembolic disease were studied. The warfarin group was divided into: initiation phase (n = 10), combined warfarin and heparin (n = 10), stabilised therapy (n = 20), and over anticoagulated patients (n = 8). PTs and INRs were determined in each group using three conventional thromboplastins (Diagen Activated, Manchester Reagent, and Instrumentation Laboratory) and two TAS techniques (whole blood or plasma). An independent International Sensitivity Index (ISI) calibration of the TAS system was performed.. Calculated ISIs for the TAS were 1.028 and 0.984 for plasma and whole blood analysis, respectively, compared with manufacturer's values of 0.98 and 0.97. INR results with TAS (whole blood) were 11% less than those obtained with Diagen Activated (p < 0.01) and 16% less than those obtained with Instrumentation Laboratory (p < 0.001) when manufacturers' mean normal PT and ISI were used for TAS INRs. TAS (whole blood) results were similar to TAS plasma or Manchester Reagent results. The use of a locally determined mean normal prothrombin time (MNPT) improved agreement between TAS and the other reagents, abolishing the significant difference between INRs determined with TAS (whole blood) and Diagen Activated techniques.. The TAS system can be used with whole blood or plasma and produces similar INRs to those obtained with Diagen Activated or Manchester Reagent using manufacturer's ISI and a locally determined MNPT. Results were lower with TAS or Manchester Reagent compared with those obtained with Instrumentation Laboratory thromboplastin.

Topics: Anticoagulants; Drug Monitoring; Drug Therapy, Combination; Heparin; Humans; International Normalized Ratio; Point-of-Care Systems; Prothrombin Time; Reproducibility of Results; Thromboembolism; Thromboplastin; Warfarin

A prospective open study was performed in a series of 547 patients undergoing gynecologic surgery. A dose of 20 mg of enoxaparin was administered to all patients 2 hours before surgery. Then patients at high risk of thrombosis (mostly oncologic surgery) received 40 mg of enoxaparin daily whereas those at moderate risk received 20 mg of enoxaparin daily. The principal aim of this prospective open study was to monitor amidolytic anti Xa activity and to study the inhibition of intrinsic prothrombinase using prothrombin consumption measurement as a simple and global test. A second aim was to investigate efficacy and tolerance of these regimens. Treatment tolerance was satisfactory with both regimens since the total incidence of bleeding was 1.8%. A single patient developed a clinically significant thrombosis during hospital stay. The results confirm and extend previous reports regarding a dose effect relationship between the dose of Enoxaparin and plasma Anti Xa activity 3 hours after s.c. injection. A significant relationship was found between Anti Xa activity and patients body weight. Interestingly a dose dependent inhibition of intrinsic prothrombinase was observed when using a one stage prothrombin consumption assay in whole blood. This test in whole blood can be considered as closer to physiological conditions than assays performed in citrated platelet rich or platelet poor plasma samples. The mechanism of intrinsic prothrombinase inhibition during prophylactic treatment with enoxaparin requires further investigation.

Topics: Adult; Body Weight; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Genital Diseases, Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Prospective Studies; Prothrombin; Risk Factors; Thromboembolism; Thromboplastin

Topics: Administration, Oral; Animals; Anticoagulants; Cattle; Clinical Trials as Topic; Humans; Prothrombin Time; Rabbits; Random Allocation; Thromboembolism; Thrombophlebitis; Thromboplastin; Warfarin

Among 100 consecutive patients receiving heparin in therapeutic dosage, major bleeding occurred in 21, and minor bleeding in 16. Two patients died from bleeding, and two had recurrent pulmonary embolism. Major bleeding occurred in 21% when therapy was regulated with whole-blood clotting time and in 20% when heparin was given without clotting tests. In a subsequent prospective trial patients received heparin by intermittent intravenous injection with or without laboratory control according to the partial thromboplastin time or continuously by intravenous infusion. Recurrent thromboembolism occurred once in each group. Major bleeding was seven times more frequent with intermittent injection than with continuous infusion. Control with the partial thromboplastin time did not prevent major bleeding in patients receiving intermittent injections. With continuous infusion, one-fourth less heparin was required than with intermittent injections. Administration of heparin by continuous infusion appears safer than intermittent injection with or without laboratory control and is no less effective for prevention of thromboembolism.

Topics: Administration, Oral; Adolescent; Adult; Aged; Arterial Occlusive Diseases; Blood Coagulation Tests; Cerebrovascular Disorders; Clinical Trials as Topic; Hemorrhage; Heparin; Humans; Infusions, Parenteral; Injections, Intravenous; Middle Aged; Myocardial Infarction; Prospective Studies; Prothrombin Time; Pulmonary Embolism; Recurrence; Thromboembolism; Thromboplastin; Thrombosis; Time Factors

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

Many cell types, including cancer cells, release tissue factor (TF)-exposing extracellular vesicles (EVs). It is unknown whether MSC-EVs pose a thromboembolism risk due to TF expression. Knowing that MSCs express TF and are procoagulant, we hypothesize that MSC-EVs also might. Here, we examined the expression of TF and the procoagulant activity of MSC-EVs and the impact of EV isolation methods and cell culture expansion on EV yield, characterization, and potential risk using a design of experiments methodology. MSC-EVs were found to express TF and have procoagulant activity. Thus, when MSC-derived EVs are employed as a therapeutic agent, one might consider TF, procoagulant activity, and thromboembolism risk and take steps to prevent them.

Topics: Extracellular Vesicles; Humans; Mesenchymal Stem Cells; Thromboembolism; Thromboplastin; Umbilical Cord

The Quantikine

Topics: Extracellular Vesicles; Humans; Pancreatic Neoplasms; Thromboembolism; Thromboplastin

Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation.. In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95-119).. Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0-70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26-7.17, p < 0.001 and HR 6.21, 95% CI 3.40-11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately.. To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents.

Topics: Aged; Blood Coagulation Tests; Coronary Artery Disease; Factor IX; Factor XIa; Female; Humans; Male; Middle Aged; Myocardial Infarction; Risk Factors; Stroke; Thromboembolism; Thromboplastin

Tissue factor-procoagulant activity (TF-PCA) on cells is modified by multiple molecular mechanisms of encryption and decryption. The risk of thrombosis is higher for patients with a high tissue factor antigen level at registration as this enables patient's blood more PCA-high status before the onset of cancer-associated thromboembolism (CAT). ELISA, including the Quantikine assay with validation as performed in our study, can contribute to more precise prediction of CAT.

Topics: Humans; Pancreatic Neoplasms; Thromboembolism; Thromboplastin

Pancreatic cancer frequently involves cancer-associated thromboembolism, which is strongly associated with poor prognosis. Tissue factor, a blood coagulation factor largely produced in cancer patients as a component of extracellular vesicles, plays a key role in the incidence of cancer-associated thromboembolism in patients with pancreatic cancer. However, no prospective studies have been published on the relationship between tissue factor and cancer-associated thromboembolism or patient clinical characteristics, including recent chemotherapy regimens. Thus, we aimed to address this in a Japanese cohort of 197 patients and 41 healthy volunteers. Plasma tissue factor levels were measured by ELISAs preevaluated by tissue factor specificity. Multivariable analysis was used to identify independent predictors of cancer-associated thromboembolism. We found that the cancer-associated thromboembolism rate in the patient cohort was 6.6% (4.6%, venous thromboembolism; 2.0%, arterial thromboembolism). Tissue factor levels of 100 pg/mL or higher at patient registration were predictive of cancer-associated thromboembolism, with positive and negative predictive values of 23.1% and 94.6%, respectively. Multivariable analysis showed that plasma tissue factor levels were an independent predictive factor for cancer-associated thromboembolism, with a risk ratio of 5.54 (95% confidence interval, 1.02-30.09). Unlike in healthy volunteers and patients without cancer-associated thromboembolism, tissue factor levels were highly correlated with extracellular vesicles' procoagulant activity in patients developing cancer-associated thromboembolism. Taken together, our data show that the tissue factor levels at patient registration were a predictive factor for cancer-associated thromboembolism in this cohort of patients with pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Confidence Intervals; Enzyme-Linked Immunosorbent Assay; Extracellular Vesicles; Female; Humans; Japan; Male; Middle Aged; Multivariate Analysis; Pancreatic Neoplasms; Predictive Value of Tests; Risk; Thromboembolism; Thromboplastin; Venous Thromboembolism

The relationship between cancer and venous thromboembolic disease (VTD) are complex because the activated coagulation factors are not only involved in thrombosis but also in malignant processes, such as angiogenesis and metastasis.. To compare phenotypes of extracellular vesicles (EVs), and levels of D-dimer, soluble P-selectin (sP-selectin) and antigenic tissue factor (TF) between unprovoked VTD patients, who did not develop cancer during one-year follow-up, and those with advanced stage of cancer but not associated with VTD.. A prospective study in which we included 138 unprovoked VTD patients and 67 advanced cancer patients, who did not develop thrombosis. Levels of EVs of different cellular origin (platelet, endothelium and leukocyte), EVs positive for tissue factor (TF) and P-selectin glycoprotein ligand 1 were quantified by flow cytometry. D-dimer, soluble P-selectin (sP-selectin) and antigenic TF were determined by ELISA.. TF-positive EVs, D-dimer, and sP-selectin were markedly elevated in unprovoked VTD patients compared to cancer patients without association with thrombosis.. Levels of TF-positive EVs, D-dimer and sP-selectin are able to discriminate between unprovoked VTD patients not related to cancer and cancer patients not associated with VTD. These results could lead to the application of EVs as biomarkers of both diseases.

Topics: Aged; Biomarkers; Case-Control Studies; Extracellular Vesicles; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Membrane Glycoproteins; Middle Aged; Neoplasms; Prospective Studies; Thromboembolism; Thromboplastin

Thromboembolism is one of the most common complications during induction therapy of pediatric acute lymphoblastic leukemia (ALL). Procoagulant microparticles in the circulation may cause thromboembolic events. The aim of our study was to determine the levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microparticles of children with ALL at diagnosis and during induction therapy.. Sixteen precursor B-cell ALL cases and 30 healthy children between 1 and 18 years of age were included. Microparticle levels were analyzed from peripheral blood samples at initial diagnosis, on days 12 and 13 (before and after the first L-asparaginase administration), and on day 33 of ALL-BFM 2000 treatment protocol. Microparticle levels were analyzed by using flow cytometry.. At initial diagnosis, platelet, endothelial-derived, and tissue factor-positive microparticle levels were significantly high in children with ALL. They increased significantly after prednisone and L-asparaginase administration. Apoptotic microparticle levels were not elevated at diagnosis, but remained high during all induction therapy period. None of the patients had evidence of thromboembolism during induction therapy.. Our study demonstrated that children with ALL have increased levels of apoptotic, platelet-derived, endothelial-derived, and tissue factor-positive microprticles during induction therapy. Further studies are needed in larger groups of patients in order to evaluate the risk of elevated microprticles for development of thromboembolism during induction therapy period in children with ALL.

Topics: Adolescent; Apoptosis; Asparaginase; Blood Platelets; Cell-Derived Microparticles; Child; Child, Preschool; Endothelial Cells; Female; Humans; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Remission Induction; Thromboembolism; Thromboplastin

Thromboembolic complication occurs frequently in β-thalassaemia/HbE patients, particularly in splenectomised patients. Endothelial cells play an important role in thrombosis. There is strong evidence of endothelial cell activation and dysfunction in β-thalassaemia. Microparticles (MPs) are associated with thrombosis and endothelial cell dysfunction in many diseases including β-thalassaemia. However, the effect of thalassaemic-MPs on endothelial cells mediating thrombus formation has not been elucidated. In this study, the effects of circulating MPs from β-thalassaemia/HbE patients on endothelial cell functions were investigated. The results showed that MPs directly induce tissue factor, interleukin (IL)-6, IL-8, intracellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin expression in human umbilical vein endothelial cells (HUVECs). Notably, the levels of these endothelial cell activation markers were significantly increased in HUVECs treated with MPs obtained from splenectomised β-thalassaemia/HbE patients when compared to MPs from non-splenectomised patients or normal subjects. The increased endothelial cell activation ultimately lead to increased monocyte-endothelial cell adhesion. THP-1 and HUVECs adhesion induced by MPs from normal subjects, non-splenectomised and splenectomised patients increased to 2.0 ± 0.4, 2.3 ± 0.4 and 3.8 ± 0.4 fold, respectively when compared to untreated cells. This finding suggests that MPs play an important role on thrombosis and vascular dysfunction in β-thalassaemia/HbE disease, especially in splenectomised cases.

Topics: Cell Adhesion; Cell Adhesion Molecules; Cell-Derived Microparticles; Cytokines; Hemoglobinopathies; Human Umbilical Vein Endothelial Cells; Humans; THP-1 Cells; Thromboembolism; Thromboplastin

Topics: Humans; Lung; Thromboembolism; Thromboplastin

Thromboembolic events (TEE) in patients receiving infusions of intravenous immunoglobulin (IVIG) products have recently been associated with contaminating factor XIa. We studied whether platelet and monocyte activation could also be involved.. Twenty IVIG samples from five manufacturers were tested for the induction of visible whole blood clot formation. A selection of TEE-associated and not associated lots was further analyzed for effects on thromboelastometry, platelet activation and adhesion, as well as monocyte tissue factor surface expression. Pure factor XIa was included for comparison. Western blotting was applied to analyze anti-CD154-reactive proteins in IVIG.. In whole blood, IVIG enhanced macroscopic clotting additively with factor XIa. In monocytes, all IVIG products induced the FcγRII-dependent tissue factor expression to a similar extent, which was not affected by addition of factor XIa. Testing platelet aggregation, IVIG strengthened the ADP and TRAP-6-elicited response. Furthermore, IVIG increased platelet-monocyte adhesion and annexin V binding to platelet microvesicles, and promoted platelet adhesion to IVIG-coated surfaces. The strongest effects were observed with TEE-associated lots. CD154-related proteins were detected in all IVIG products. CD154-related high molecular weight complexes were particularly found in the TEE-associated IVIG. In platelet aggregation, recombinant soluble CD154 enhanced aggregate formation and stability.. Our data demonstrate that IVIG modulate platelet and monocyte activation and can thereby affect the hemostatic balance. These effects are either additive to or independent from factor XIa. CD154-related proteins are assumed to be involved in these interactions, the mechanism of which needs to be elucidated in further studies.

Topics: Administration, Intravenous; Blood Coagulation; Blood Platelets; Factor XIa; Humans; Immunoglobulins; Monocytes; p38 Mitogen-Activated Protein Kinases; Platelet Activation; Platelet Adhesiveness; Thromboembolism; Thromboplastin

Tissue factor (TF), the physiologic initiator of coagulation, is over-expressed in pancreatic cancer, and is associated with a pro-coagulant and pro-angiogenic state. We hypothesized that in patients with pancreaticobiliary cancers (PBC), elevated circulating microparticle-associated TF (MP-TF) activity would be associated with thrombosis and worsened survival.. Clinical data and plasma were obtained for consecutive patients with PBC seen at Roswell Park Cancer Institute from 2005-08. MP-TF activity levels were measured using a TF-dependent FXa generation assay.. The study population comprised 117 patients, including pancreatic (n=80), biliary (n=34) or unknown primary histologically consistent with PBC (n=3). Of these, 52 patients (44.5%) experienced thromboembolism, including pulmonary embolism (n=15), deep venous thrombosis (n=21) and other arterial or venous events (n=32). Mean TF was 2.15 (range 0.17- 31.01) pg/mL. Median survival was 98.5 days for MP-TF activity ≥ 2.5 pg/mL versus 231 days for MP-TF activity<2.5 pg/mL (p<0.0001). In multivariate analysis, elevated MP-TF activity was associated with both VTE (OR 1.4, 95% CI 1.1-1.6) and mortality (HR 2.5, 95% CI 1.4-4.5).. Elevated circulating MP-TF activity is associated with thrombosis and worsened survival in patients with PBC. MP-TF activity as a prognostic biomarker warrants further prospective evaluation.

Topics: Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell-Derived Microparticles; Cohort Studies; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Survival Analysis; Thromboembolism; Thromboplastin

Earlier reports have indicated that patients with endometrial clear cell carcinoma (CCC) may have an increased risk for thromboembolic events. Tissue factor is a 47-Kd transmembrane glycoprotein that plays a critical role in platelet activation, fibrinogenesis, blood clot formation, and as such, general hemostasis. The mammalian heparanase is an endo-β-glucuronidase that can cleave heparan sulfate at specific molecular sites, resulting in structural modification of the extracellular matrix barrier, facilitating cancer cell invasion, and eventual metastasis. Recent reports indicate that heparanase may also induce tissue factor expression. The purpose of this study is to assess the clinicopathologic significance of tissue factor and heparanase expression, especially as they relate to the risk of thromboembolic events, in endometrial CCC and selected other endometrial cancers. Eighty-four endometrial carcinomas, including 17 CCC, 20 endometrial serous carcinomas, 15 grade 1 endometrial endometrioid carcinomas (EEC), 15 grade 2 EEC, 10 grade 3 EEC, and 7 mixed endometrial carcinomas with at least a 10% clear cell component (mixed CCC) were evaluated for the immunophenotypic expression of heparanase and tissue factor, and their associated frequency of thromboembolic events. Seven of the 84 patients experienced 8 thromboembolic events during the follow-up period. By multivariate analysis, the pure CCC histotype [odds ratio 5.2; 95% confidence interval (CI): 2.4523-13.6754; P=0.026] was significantly associated with an elevated risk for thromboembolic events. Tissue factor expression was present in 12 (14.28%) of the 84 endometrial carcinomas, including in 7 (41.17%) of 17 pure CCC, 2 (10%) of 20 endometrial serous carcinomas, 1 (14.3%) of 7 mixed CCC, 2 (13.3%) of 15 grade 1 EEC, and in 0% of grade 2 and 3 EEC. Tissue factor expression was significantly more likely to be seen in pure CCC than in all other cancers as a group (P=0.0018) and in all other high-grade endometrial cancers (P=0.007). By multivariate analysis, tissue factor expression was significantly associated with the risk of thromboembolic events [odds ratio 4.8 (95% CI: 1.9196-11.93), P=0.013]. Tissue factor expression was not associated with patient outcome or any other clinicopathologic parameter. Heparanase expression was present in 57 (67.8%) of the 84 endometrial carcinomas, and was significantly associated with the endometrioid histotype, but not outcome or the risk of thromboembolic events.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Aged, 80 and over; Endometrial Neoplasms; Female; Glucuronidase; Humans; Immunohistochemistry; Middle Aged; Risk Factors; Thromboembolism; Thromboplastin

Ischemia is a leading causes of morbidity in giant cell arteritis (GCA). We studied circulating platelets and leukocytes in patients with GCA and with polymyalgia rheumatica. Normal healthy donors (>60 a) served as controls. Patients had a significantly greater fraction of platelets expressing P-selectin, of platelet-Nph and platelet-Mo aggregates, and of Nph and Mo expressing tissue factor. These differences were correlated with the percentage of platelets expressing P-selectin and were not influenced by clinical features or by systemic inflammation. Activated circulating leukocytes and platelets could contribute to indolent vessel inflammation and possibly to thromboembolic events in patients with systemic large vessel vasculitis.

Topics: Aged; Blood Platelets; Giant Cell Arteritis; Humans; Inflammation; Leukocytes; Middle Aged; P-Selectin; Platelet Activation; Polymyalgia Rheumatica; Risk Factors; Thromboembolism; Thromboplastin

Our aim was to clarify the role of anti-phospholipid antibodies in the pathogenesis of monocyte tissue factor (TF) expression and thromboembolic complications (TE) in patients with SLE. We examined cell surface expression of TF on monocytes in 93 SLE patients. Monocyte TF expression was significantly higher in SLE patients who had TE than in other SLE patients, and confirmed that the high expression of monocyte TF was a strong risk factor for TE. Furthermore, the presence of anti-cardiolipin/beta2-glycoprotein I antibodies (anti-CL/beta2-GPI) was strongly associated with the high expression of monocyte TF. We therefore studied the in vitro effect of IgG anti-CL/beta2-GPI on lipopolysaccharide (LPS)-induced expression of TF on monocytes in healthy peripheral blood and found that purified IgG containing anti-CL/beta2-GPI significantly enhanced LPS-induced monocyte TF expression. These results suggest that anti-CL/beta2-GPI cause persistently high TF expression on monocyte, which may contribute to the risk of thromboembolic events in SLE patients.

Topics: Adolescent; Adult; Aged; Antibodies, Antiphospholipid; Child; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Monocytes; Risk Factors; Thromboembolism; Thromboplastin

Topics: Adult; Age Factors; Age of Onset; Aged; Drug Interactions; Endpoint Determination; Female; Fibrinolytic Agents; Humans; Middle Aged; Randomized Controlled Trials as Topic; Risk; Thromboembolism; Thromboplastin; Vitamin E

Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis.. We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects.. Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TF-activity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19- 0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model.. Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Antigens, Neoplasm; Blood Coagulation; Breast Neoplasms; Case-Control Studies; Cell Differentiation; Cytoplasmic Vesicles; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Likelihood Functions; Male; Middle Aged; Mucin-1; Mucins; Neoplasm Invasiveness; Neoplasm Staging; Pancreatic Neoplasms; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Risk Assessment; Thromboembolism; Thromboplastin; Time Factors; Venous Thrombosis

Ovarian cancer, and clear cell carcinoma in particular, reportedly increases the risk of venous thromboembolism (VTE). However, the mechanisms remain unclear. Tissue factor (TF) supposedly represents a major factor in the procoagulant activities of cancer cells. The present study examined the involvement of TF expression in VTE for patients with ovarian cancer. Subjects comprised 32 consecutive patients (mean age 49.8 years) with histologically confirmed ovarian cancer. Presence of VTE was examined using a combination of clinical features, D-dimer levels and venous ultrasonography. Immunohistochemical analysis was used to evaluate TF expression into 4 degrees. Venous thromboembolism was identified in 10 of the 32 patients (31%), including five of the 11 patients with clear cell carcinoma. Tissue factor expression was detected in cancer tissues from 24 patients and displayed significant correlations with VTE development (P=0.0003), D-dimer concentration (P=0.003) and clear cell carcinoma (P<0.05). Multivariate analysis identified TF expression as an independent predictive factor of VTE development (P<0.05). Tissue factor (TF) expression is a possible determinant of VTE development in ovarian cancer. In particular, clear cell carcinoma may produce excessive levels of TF and is more likely to develop VTE.

Topics: Adolescent; Adult; Aged; Female; Humans; Immunohistochemistry; Middle Aged; Ovarian Neoplasms; Thromboembolism; Thromboplastin

Pulmonary tumor thrombotic microangiopathy is an unusual malignancy-related respiratory complication characterized by multiple microthrombi and intimal myofibroblast proliferation. Its clinical manifestation is subacute respiratory failure with pulmonary hypertension. Herein is reported a case of pulmonary tumor thrombotic microangiopathy associated with gastric signet ring cell carcinoma. A 51-year-old woman with gastric cancer died of subacute respiratory failure. Autopsy showed gastric signet ring cell carcinoma with diffuse metastasis of pulmonary lymphatics and pleurae; every organ examined lacked a space-occupying tumor mass. Histologically, proliferated intimal myofibroblasts obliterated most of the pulmonary vascular lumen, and a few stenosed vascular lumina contained cancer cells. In addition, pulmonary vasculature associated with intimal proliferation contained microthrombi. Most cancer cells in the stomach and pulmonary lymphatics were typical signet ring cells, whereas those in vascular lesions were cells of poorly differentiated adenocarcinoma without mucous production. Consistent with a previous report, the latter expressed vascular endothelial growth factor (VEGF) and tissue factor (TF). The proliferated intimal myofibroblasts also expressed type 2A serotonin receptor (5-HT(2A)). These findings suggest that local expression of VEGF, TF, and 5-HT(2A) may be linked to the pathogenesis of this unusual pulmonary complication.

Topics: Carcinoma, Signet Ring Cell; Endothelium, Vascular; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Lung; Lung Neoplasms; Microcirculation; Middle Aged; Neoplastic Cells, Circulating; Receptor, Serotonin, 5-HT2A; Respiratory Insufficiency; Stomach Neoplasms; Thromboembolism; Thromboplastin; Vascular Endothelial Growth Factor A

Topics: Cardiac Surgical Procedures; Drug Interactions; Factor VIIa; Heart-Assist Devices; Hemostatics; Humans; Recombinant Proteins; Risk Factors; Thromboembolism; Thromboplastin

Collagen and thrombin are the strongest physiological platelet agonists, acting through different receptors, among which glycoprotein VI (GPVI) and protease-activated receptors, respectively, are the essential ones. In mice, targeting of GPVI with the monoclonal antibody JAQ1 induces depletion of the receptor from circulating platelets, resulting in abolished collagen responses and long-lasting antithrombotic protection.. Mice were treated with JAQ1, and the early effects of this treatment were analyzed. In addition to the known abolition of the collagen reactivity, this treatment also affected platelet response to thrombin but not other agonists. In platelets from JAQ1-treated mice, thrombin-induced activation of integrin alphaIIbbeta3, the surface expression of P-selectin, and the procoagulant activity were decreased on days 1 and 2, then progressively recovered and returned to normal on day 5. In parallel, the mice were transiently protected from lethal tissue factor-induced pulmonary thromboembolism (100% survivors versus 40% in control group), which appeared to be based on a decreased generation and activity of intravascular thrombin.. Anti-GPVI treatment induces 2-phase antithrombotic protection in mice consisting of a partial and transient inhibition of thrombin responses in platelets and a prolonged and complete loss of the collagen response.

Topics: Animals; Antibodies, Monoclonal; Blood Platelets; Male; Mice; Mice, Inbred Strains; P-Selectin; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Pulmonary Embolism; Thrombin; Thromboembolism; Thromboplastin; Thrombosis

Recently, our laboratory devised a dynamic whole blood (WB) thrombelastographic coagulation model employing activation with minute amounts of tissue factor. A series of studies were conducted to validate the feasibility of the model to illustrate hypocoagulation in various bleeding disorders and its usefulness in detecting the haemostatic effect of pro-coagulants by ex vivo titration experiments. In this context, the present study hypothesized that the thrombelastographic model also can reveal hypercoagulation. Hence, the objective of the present study was to record dynamic WB coagulation profiles in a series of patients (n=76) who had previously suffered from a venous (n=34) or arterial (n=42) thrombo-embolic event and to compare the results with those of a group of healthy reference subjects (n=60).. Patients receiving vitamin K antagonist treatment were not enrolled in the study. Forty-four of the patients had no known thrombophilia risk factor and 32 patients had at least one thrombophilia risk factor.. The most commonly found risk factors were mild hyperhomocysteinaemia and heterozygosity for the factor V Leiden polymorphism. The data showed that, as compared with the healthy controls, patients with a history of venous or arterial thromboembolism had a significantly greater hypercoagulant WB coagulation clot signature as defined by a shortened clotting time together with an accelerated maximum velocity of clot propagation.. In future studies with ex vivo dose titration assessment of pro-coagulant components mixed with blood from a patient suffering from compromised haemostasis, observation of a significantly shortened clot initiation concomitant with a distinctly accelerated clot propagation is likely to indicate an increased risk of thrombosis.

Topics: Adolescent; Adult; Aged; Factor V; Feasibility Studies; Female; Humans; Hyperhomocysteinemia; Male; Middle Aged; Risk Factors; Thrombelastography; Thromboembolism; Thrombophilia; Thromboplastin

To study expression of tissue factor (TF) in pancreatic cancer and its role in the development of thromboembolism.. TF expression was studied in eight human pancreatic carcinoma cell lines by Northern blot and indirect immunofluorescence. Expression of alternatively spliced TF (asTF) was assessed by RT-PCR. In addition, TF expression was determined by immunofluorescence in pancreatic tissues of 19 patients with pancreatic adenocarcinoma (PCa), 9 patients with chronic pancreatitis (CP) and 20 normal controls. Plasma samples (30 PCa-patients, 13 CP-patients and 20 controls) were investigated for soluble TF levels and coagulation activation markers [thrombin-antithrombin III complex (TAT), prothrombin fragment 1 + 2 (F1 + 2)].. All pancreatic carcinoma cell lines expressed TF (8/8) and most of them expressed asTF (6/8). TF expression at the protein level did not correlate with the differentiation of the carcinoma cell line. All but two pancreatic cancer tissue samples stained positive for TF (17/19). In all samples of CP weak staining was restricted to pancreatic duct cells, whereas only a few subendothelial cells were positive in 9/20 of normal controls. TF and TAT levels in PCa patients were significantly elevated compared to controls whereas elevated F1 + 2 levels did not reach statistical significance compared to controls. In CP patients TAT and F1 + 2 levels proved to be significantly elevated compared to controls, although TAT elevation was less pronounced than in PCa patients.. We conclude that in addition to the upregulated expression of TF on the cell membrane, soluble TF might contribute to activation of the coagulation system in pancreatic cancer.

Topics: Adenocarcinoma; Aged; Blood Coagulation; Cell Line, Tumor; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Thromboembolism; Thromboplastin

Tissue factor (TF) exposure is a potent pro-thrombotic trigger that initiates activation of the coagulation cascade, while thrombomodulin (TM) is a potent anticoagulant protein that limits the extent of activation. Both TF neutralizing antibodies and soluble TM (sTM) are effective anticoagulants. We have developed a novel anticoagulant fusion protein, Ab(TF)-TM, by fusing a TFneutralizing single-chain antibody, Ab(TF), to an active fragment of TM. Ab(TF)-TM is a novel anticoagulant targeting to sites of TF exposure with a dual mechanism of action. The Ab(TF) portion of the molecule inhibitsTF/factorVIIa mediated activation of FIX and FX, and the TM portion of the molecule acts as a cofactor for activation of protein C. In-vitro coagulation assays show that Ab(TF)-TM more potently inhibits TF-initiated coagulation (prothrombin time) than can its individual components, Ab(TF) (20-fold) and sTM (80-fold) alone, or in combination (10-fold). In contrast, the potency of Ab(TF)-TM in the activated partial thromboplastin and thrombin clotting time assays was similar to sTM alone. In a rat model of disseminated intravascular coagulation (DIC), intravenous injection of a human TF-containing thromboplastin reagent (0.5 ml/kg) resulted in an immediate death in approximately 60% of the animals and a clinical score of approximately 2.5. Pre-injection of Ab(TF)-TM or Ab(TF) and sTM, given alone or in combination, showed dose-dependent efficacy. At a dose of 0.7 nmol/kg, Ab(TF)-TM completely prevented death and reduced clinical scores by 79%, while neitherAb(TF) nor sTM, given alone or in combination, showed significant therapeutic effects. Calculated effective doses that reduced mortality by 50% relative to that in the control group (ED(50), nmol/kg) were 0.21 for Ab(TF)-TM, 3.2 for an equimolar mixture of Ab(TF) and sTM, 4.3 for sTM and 20 for Ab(TF). Thus, Ab(TF)-TM presented 10- to 100-fold enhancement of the anticoagulant potency, relative to the ED(50) in Ab(TF) and sTM given either alone or in combination, in a rat DIC model.

Topics: Animals; Anticoagulants; Blood Coagulation; Dimerization; Dose-Response Relationship, Drug; Humans; Male; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Thromboembolism; Thrombomodulin; Thromboplastin; Time Factors

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinicopathological entity causing severe pulmonary hypertension. Its histological features include widespread tumor emboli along with fibrocellular intimal proliferation and thrombus formation in the small arteries and arterioles of the lungs. The result is occlusion or stenosis of the pulmonary vasculature, but the detailed pathogenesis has yet to be clarified in spite of the serious clinical manifestations. Herein is described the case of a 62-year-old man with a gastric adenocarcinoma who died of sudden cardiopulmonary arrest. The autopsy revealed advanced cancer disease as well as findings of PTTM, which seemed to be the cause of his unexpected death. The carcinoma cells were immunohistochemically positive for vascular endothelial growth factor (VEGF) and also for tissue factor (TF). There is another report suggesting that TF might play an important role in the pathogenesis of PTTM. Also, VEGF has been reported to be involved in a variety of forms of pulmonary hypertension and to be upregulated by TF. These findings suggest that VEGF and TF may be involved in the pathogenesis of PTTM. The present PTTM case, in which the tumor cells demonstrate the coexpression of VEGF and TF, is important in facilitating understanding of the lethal disorder in the future.

Topics: Adenocarcinoma; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Male; Microcirculation; Middle Aged; Neoplastic Cells, Circulating; Stomach Neoplasms; Thromboembolism; Thromboplastin; Vascular Endothelial Growth Factor A

Topics: Anticoagulants; Humans; Indicators and Reagents; International Normalized Ratio; Prothrombin Time; Thromboembolism; Thromboplastin

Thromboembolism secondary to atrial fibrillation accounts for approximately one-fourth of all strokes. Although considerable resources have been targeted to pharmacologic prophylaxis, neither the cellular nor the biochemical composition of atrial thrombi is known. Quantitative immunohistochemistry was undertaken to define the composition of atrial thrombi and to explore morphological differences between atrial appendage thrombi and those that embolize.. Serial sections of thrombi obtained during valve replacement surgery or embolectomy from 22 patients with atrial fibrillation were stained with antibodies against fibrin, integrin beta3, or tissue factor and analyzed with NIH-image.. Thrombi showed distinct regions staining for either fibrin or platelets and on average, the fibrin-rich regions predominated (P < 0.0001). The platelet content of embolized thrombi was nearly twice that of atrial thrombi (P = 0.02). Non-staining amorphous material comprised nearly half of atrial thrombi in situ, but was rare in embolized thrombi (P < 0.001). Tissue factor colocalized to areas rich in platelets and granulocytes.. The abundance of fibrin relative to platelets underscores the enhanced efficacy of warfarin prophylaxis in clinical trials. The finding of tissue factor localized to platelet-leukocyte clusters suggests its blood-borne origin. Compositional differences between in situ and embolized thrombi suggest directions for investigating propensity for embolization.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Platelets; Female; Fibrin; Heart Valve Prosthesis; Humans; Immunohistochemistry; Integrin beta3; Male; Thromboembolism; Thromboplastin; Thrombosis; Warfarin

Fondaparinux and enoxaparin are both effective and safe in preventing post-operative venous thromboembolism. However, neither of them significantly influence the conventional clotting tests. We compared the influence of clinically relevant concentrations of fondaparinux and enoxaparin on normal whole blood (WB) thromboelastographic profiles after triggering TF-pathway with minimal amount of thromboplastin. Diluted thromboplastin was added to WB samples supplemented with buffer (control), fondaparinux (0.25; 0.5; 1 microg/ml), or enoxaparin (0.1; 0.5; 1 anti-Xa IU/ml). Four parameters were analyzed, R: clotting time, K: time required to reach an amplitude of 20 mm, alpha angle: measurement reflecting clot development kinetics and MA: maximal amplitude. At concentrations used in prophylaxis, both enoxaparin (0.1 anti-Xa IU/ml) and fondaparinux (0.25 microg/ml which correspond to 0.27 anti-Xa IU/ml) significantly prolonged the R and K times, but did not significantly modify the alpha angle as compared to the control. At concentrations observed after administration of curative doses for the treatment of DVT (> or = 0.5 anti-Xa IU/ml for enoxaparin and > or = 0.5 microg/ml for fondaparinux) both drugs induced a significant increase of R and K times, and a significant decrease of the alpha angle (p < 0.05). In contrast to fondaparinux, enoxaparin at concentrations equal to or higher than 0.5 anti-Xa IU/ml significantly reduced MA. The present study provides evidence that the whole blood TF-triggered TEG assay is sensitive to the presence of clinically relevant concentrations of enoxaparin or fondaparinux. Moreover, the angle may be used in order to distinguish the effect of prophylactic and therapeutic concentrations, since it was significantly reduced by the later ones. Further studies are needed to evaluate the clinical usefulness of whole blood TF-triggered TEG assay for the monitoring of treatment with enoxaparin or fondaparinux.

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Dose-Response Relationship, Drug; Enoxaparin; Fondaparinux; Humans; In Vitro Techniques; Kinetics; Polysaccharides; Thrombelastography; Thrombin; Thromboembolism; Thromboplastin; Time Factors; Venous Thrombosis

Activated protein C resistance (APCR), high tissue factor (TF) expression, and hyper-homocysteinemia are associated with thromboembolic diseases. Thromboembolism is a frequent complication of systemic lupus erythematosus (SLE). In this study, we evaluated the prevalence of APCR, high TF, and homocysteine with correlation of the thrombotic tendency in SLE. Ninety-four SLE patients and 28 normal controls were included. APC ratio and TF antigen were measured using commercial kits. Plasma homocysteine level was measured using HPLC. The prevalence of APCR, high TF antigen level, and hyper-homocysteinemia in our SLE patients were 21.3%, 66.0%, and 23.4%, respectively. The median plasma level of TF antigen in SLE patients was 145.23 pg/mL (range, 31.00-778.50 pg/mL), which was significantly higher than the control value of 39.83 pg/mL (range, 1.55-168.50 pg/mL). The median APC ratio in SLE patients was 2.76 (range, 1.48-13.47), which was significantly lower than the control value of 3.59 (range, 0.26-5.66). The plasma level of homocysteine was not significantly different from that of control. A significant association was observed between the presence of APCR (OR = 8.59, P < 0.0001) but not with the presence of high plasma TF antigen level (OR = 1.24, P = 0.67) and thrombotic complications in SLE patients. In conclusion, APCR and high plasma TF levels are common in SLE, but a significant association was observed only between the presence of APCR and thrombosis in SLE patients.

Topics: Activated Protein C Resistance; Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Homocysteine; Humans; Hyperhomocysteinemia; Lupus Erythematosus, Systemic; Male; Middle Aged; Prevalence; Retrospective Studies; Thromboembolism; Thromboplastin; Thrombosis

Tissue factor (TF) is an essential enzyme activator that forms a catalytic complex with FVII(a) and initiates coagulation by activating FIX and FX, ultimately resulting in thrombin formation. TF is found in adventitia of blood vessels and the lipid core of atherosclerotic plaques. In unstable coronary syndromes, plaque rupture initiates coagulation by exposing TF to blood. Biologically active TF has been detected in vessel walls and circulating blood. Elevated intravascular TF has been reported in diverse pro-thrombotic syndromes such as myocardial infarction, sepsis, anti-phospholipid syndrome and sickle-cell disease. It is unclear how TF circulates, although it may be present in pro-coagulant microparticles. We now report identification of a form of human TF generated by alternative splicing. Our studies indicate that alternatively spliced human tissue factor (asHTF) contains most of the extracellular domain of TF but lacks a transmembrane domain and terminates with a unique peptide sequence. asHTF is soluble, circulates in blood, exhibits pro-coagulant activity when exposed to phospholipids, and is incorporated into thrombi. We propose that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.

Topics: Alternative Splicing; Antibodies; Blood Coagulation; Blood Platelets; Electrophoresis; Humans; Immunohistochemistry; Molecular Sequence Data; Phospholipids; Recombinant Proteins; Thromboembolism; Thromboplastin

Concentrations of non-cell-bound (NCB; soluble) tissue factor (TF) are elevated in blood collecting in the pericardial cavity of patients during cardiopulmonary bypass (CPB). Previously, we reported microparticles supporting thrombin generation in such blood samples. In this study we investigated the extent of microparticle association of the NCB form of TF in pericardial and systemic blood, and whether this microparticle-associated form is active in thrombin generation compared with non-microparticle-bound, (fluid-phase) TF.. Systemic and pericardial blood samples were collected before and during CPB from six patients undergoing cardiac surgery. Microparticles were isolated by differential centrifugation and their thrombin-generating capacity measured in a chromogenic assay. Microparticle-associated and fluid-phase forms of NCB TF were measured by ELISA. Microparticle-associated TF was visualized by flow cytometry.. In pericardial samples, 45-77% of NCB TF was microparticle-associated, and triggered factor VII (FVII)-mediated thrombin generation in vitro. Microparticles from systemic samples triggered thrombin generation independently of FVII, except at the end of bypass (P = 0.003). The fluid-phase form of TF did not initiate thrombin generation. Both forms of NCB TF were, at least in part, antigenically cryptic.. We demonstrate the occurrence of two forms of NCB TF. One form, which is microparticle-associated, supports thrombin generation via FVII. The other form, which is fluid-phase, does not stimulate thrombin formation. We hypothesize that the microparticle-associated form of NCB TF may be actively involved in postoperative thromboembolic processes when pericardial blood is returned into the patients.

Topics: Blood Circulation; Coronary Artery Bypass; Coronary Circulation; Factor VII; Humans; Octoxynol; Particle Size; Postoperative Complications; Solubility; Thrombin; Thromboembolism; Thrombophilia; Thromboplastin

The leflunomide metabolite analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK) which plays an important role in platelet physiology by regulating the glycoprotein GPVI-FcRgamma-coupled collagen receptor signaling pathway. At low micromolar concentrations, LFM-A13 inhibited collagen-induced ultrastructural changes indicative of activation. LFM-A13 inhibited collagen (but not thrombin, TRAP-6, or ADP)-induced platelet aggregation in a concentration-dependent fashion with an IC50 value of 2.8 microM. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 1 to 100 mg/kg. At nontoxic dose levels, LFM-A13 prolonged the tail bleeding times of mice and improved event-free survival in two mouse models of agonist-induced invariably fatal pulmonary thromboembolism. To our knowledge, LFM-A13 is the first anti-thrombotic agent which prevents platelet aggregation by inhibiting BTK.

Topics: Adenosine Diphosphate; Agammaglobulinaemia Tyrosine Kinase; Amides; Animals; Aspirin; Bleeding Time; Catalytic Domain; Collagen; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fibrinolytic Agents; Humans; Janus Kinase 3; Male; Mice; Mice, Inbred ICR; Nitriles; Peptide Fragments; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Protein-Tyrosine Kinases; Pulmonary Embolism; Quinazolines; Receptors, Collagen; Signal Transduction; Thrombin; Thromboembolism; Thromboplastin

ADP plays a key role in hemostasis, acting through 2 platelet receptors: the P2Y(1) receptor and an unidentified P2 receptor, called P2cyc, coupled to adenylyl cyclase inhibition, which is the target of the antiplatelet drug clopidogrel. We showed that the P2Y(1) receptor is an essential cofactor in thrombotic states induced by intravenous infusion of collagen and epinephrine. The aim of the present study was to assess the role of this receptor in thrombin-dependent tissue factor-induced thromboembolism.. Human thromboplastin was injected intravenously into wild-type or P2Y(1)-deficient mice, and the effects on platelet count and mortality were determined and plasma thrombin-antithrombin III (TAT) complexes were quantified. P2Y(1)-deficient mice were resistant to the thromboembolism induced by injection of thromboplastin. Whereas the platelet count decreased sharply in wild-type mice, there was no significant drop in platelets in P2Y(1)-knockout mice. The platelet consumption in wild-type mice was probably due to thrombin generation, because it was abolished by hirudin. Thromboplastin also led to a rise in TAT complexes in plasma, again reflecting thrombin formation. This effect, however, was less important in P2Y(1)-knockout mice than in wild-type mice, indicating that less thrombin was generated in the absence of P2Y(1). Similar results were obtained after intravenous administration of N:(6)-methyl-2'-deoxyadenosine-3':5'-bisphosphate, a selective antagonist of the P2Y(1) receptor, to wild-type mice.. Our results demonstrate a role of the P2Y(1) receptor in thrombotic states involving thrombin generation and provide further evidence for the potential relevance of this receptor as a target for antithrombotic drugs.

Topics: Acute Disease; Adenosine Diphosphate; Animals; Antithrombin III; Disease Models, Animal; Fibrinolytic Agents; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Hydrolases; Platelet Count; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y1; Thrombin; Thromboembolism; Thromboplastin

Liver cirrhosis is associated with alterations of the coagulation system commonly causing bleeding as well as thromboembolic complications. The potential pathophysiological roles of tissue factor (TF) (the initiator of the extrinsic coagulation pathway) and thrombomodulin (TM) (an initiator of the anticoagulatory protein C pathway) are unknown. We therefore measured plasma concentrations of TF and TM in 111 patients with liver diseases who were evaluated for liver transplantation. We could demonstrate that the levels of both molecules increased with the Child's class of liver cirrhosis, independently of aetiology. TM was significantly elevated in Child A, B and C patients compared with patients without cirrhosis; TF only in Child C patients. The plasma TM and TF concentrations correlated with prothrombin time, activated partial thromboplastin time, and inversely with factor VII activity, cholinesterase serum activity, and serum albumin concentration. TM was elevated in patients with a bleeding tendency, but TM and TF did not differ between patients with or without prior thrombotic events. Further studies are warranted to clarify the underlying mechanisms that raise TM and TF plasma levels in liver disease with possible clinical consequences.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; Female; Hemorrhage; Humans; Liver Cirrhosis; Male; Middle Aged; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Reference Values; Thromboembolism; Thrombomodulin; Thromboplastin

Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in monocytes and endothelial cells and is present in atherosclerotic plaque to initiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced the 5' domain of the gene up to nucleotide 2732 and found 6 different polymorphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patients with myocardial infarction in a case-control study involving 2354 subjects showed no association between the polymorphisms and nonfatal coronary thrombosis. In another study involving 255 patients with venous thromboembolism and 1204 controls, allele D was less common in the cases (P=0.022). The odds ratio associated with the presence of at least 1 D allele was 0.72 (P=0. 031). Comparison of subgroups of control subjects who were homozygous for the D or I allele demonstrated a lower plasma TF concentration in DD homozygotes. These results indicate that the TF gene promoter exists in 2 major forms differing at 4 sites. The 1208 D haplotype is not associated with coronary thrombosis but is associated with reduced plasma TF levels and a lower risk of venous thrombosis.

Topics: 5' Untranslated Regions; Adult; Aged; Base Sequence; Case-Control Studies; DNA Primers; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Molecular Sequence Data; Myocardial Infarction; Polymorphism, Genetic; Prevalence; Promoter Regions, Genetic; Risk Factors; Thromboembolism; Thromboplastin; Venous Thrombosis

Lupus anticoagulant (antiphospholipid antibodies) is associated with venous and arterial thrombosis in patients with and without autoimmune disorders. Vitamin K antagonists are the treatment of choice in patients with thrombosis, of which the dose is titrated by INR monitoring. Several recent reports suggest that the presence of the lupus anticoagulant disturbs the INR test and may lead to unreliable results with a large variation in INR values, dependent on the reagents used.. We studied 11 lupus anticoagulant positive patients and 11 lupus anticoagulant negative patients, all using vitamin K antagonists. The INR value was determined using seven different tests and the variation in INR values was compared between the two groups. The amidolytic Factor X levels were used as an phospholipid independent measure for intensity of warfarin therapy. Factor VII and X activity were measured to assess the stability of warfarin therapy.. The variation of the results with different INR tests within one patient was minimal and comparable in the two groups for INR's in the therapeutic range. The coefficient of variation for the cases and control group was 10.43 and 9.35, respectively. Variation in both groups increased at supratherapeutic levels of anticoagulation and when the anticoagulation was unstable (measured with Factor X/Factor VII ratio). The relationship between INR values and Factor X analysis revealed no influence of the lupus anticoagulant.. In this study, lupus anticoagulant antibodies do not disturb INR laboratory tests. Differences in INR measurements are seen in patients with a high intensity of anticoagulation and in patients who either just started or in whom no stable anticoagulation has been achieved. Abbreviated Abstract. This study investigates the influence of lupus anticoagulant on INR determination tests in patients treated with warfarin. Eleven cases and eleven lupus anticoagulant negative control patients, also on warfarin therapy, were included. Seven INR results per patient were obtained using different laboratory tests. A factor X assay was performed to obtain an independent measure for the intensity of warfarin therapy. The variation of INR results between the cases and controls revealed no difference in these groups. In addition, the relationship between INR values and Factor X analysis indicated no influence of the lupus anticoagulant. What was observed was an increased difference in INR values in patients with a high intensity of anticoagulation and in patients who either just started or in whom no stable anticoagulation has been achieved

Topics: Factor VII; Factor X; Humans; International Normalized Ratio; Lupus Coagulation Inhibitor; Reagent Kits, Diagnostic; Statistics, Nonparametric; Thromboembolism; Thromboplastin; Venous Thrombosis; Vitamin K; Warfarin

Anti-beta 2-glycoprotein I antibodies bind to endothelial cells through beta 2-GPI. The antibodies are present in patients with systemic lupus erythematosus and antiphospholipid syndrome and are associated with the pathogenesis of the disease. Anti-endothelial cell antibodies that react with constitutive antigens on ECs are present in patients with vasculiditis and other diseases. Both types of antibodies can activate ECs. Frequent findings in APLS and vasculitis are fibrin deposits and thromboembolic phenomena. These indicate that the coagulation system is activated. However, the mechanism of activation is not clear. ECs generate tissue factor upon stimulation with various substances. In the present study we report that monoclonal anti-beta 2-GPI antibodies and AECAs, derived from a patient with primary APLS and a patient with Takayasu's arteritis, respectively, induce a potent tissue factor in ECs. The production of TF activity, TF antigen and TF mRNA is dose and time dependent. The TF activity was induced also by F(ab)2 but not by Fc fragments and was abolished completely by pre-incubation with ant-TF antibodies. The TF that is induced in ECs by AECAs with and without beta 2-GPI specificity may activate the coagulation and thereby play a major role in the pathogenesis of fibrin deposition and thrombus formation in diseases that are associated with the presence of these antibodies.

Topics: Antibodies; Antigens; Antiphospholipid Syndrome; Apolipoproteins; beta 2-Glycoprotein I; Binding Sites, Antibody; Cells, Cultured; Endothelium, Vascular; Fibrin; Glycoproteins; Humans; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Lupus Erythematosus, Systemic; Membrane Glycoproteins; RNA, Messenger; Takayasu Arteritis; Thromboembolism; Thromboplastin; Vasculitis

The association between cancer and thromboembolic disease has been known for over a century. Increased tissue factor expression by endothelial cells, monocytes or macrophages is implicated. Thus, monocyte tissue factor measurements may reflect disease presence or progression.. Using a 2 stage kinetic chromogenic assay, monocyte tissue factor levels were assessed in normal controls (n=60), patient controls (hernia or cholecystectomy, n=60) and in patients with benign and malignant disease of the bladder (n=73), prostate (n=81), breast (n=83) and colorectum (n=62). This was performed as baseline (resting cells) and after 6 hours incubation with (stimulated) and without (unstimulated) lipopolysaccharide. Each benign disease group was sub-divided into inflammatory and non-inflammatory categories.. The relative operating characteristic curve for the lipopolysaccharide-stimulated monocyte tissue factor assay showed sensitivity and specificity for cancer, the area under the curve being 0.71. The control groups and the benign non-inflammatory groups gave similar results and were pooled for further analysis. Each malignant group showed higher monocyte tissue factor levels than the control groups for baseline (P< 0.05) and lipopolysaccharide-stimulated cells (P< 0.05). All benign inflammatory groups apart from breast, showed increased monocyte tissue factor levels over controls for baseline (P< 0.05) and lipopolysaccharide-stimulated cells (P< 0.05). In all cases there was no significant difference between the malignant and the benign inflammatory groups. Monocyte tissue factor levels were related to tumor grade or stage, patients' survival time, serum prostate specific antigen and static bone scan images. Levels were also higher in patients with bladder cancer recurrence and in those who subsequently died.. Lipopolysaccharide-stimulated monocyte tissue factor assay showed sensitivity and specificity for cancer compared to controls. Monocyte tissue factor levels are raised in malignant groups compared to controls and non-inflammatory diseases but not when compared with inflammatory conditions. Stimulated cells give better discrimination between the groups and may be useful in identifying high risk individuals. Monocyte tissue factor levels were related to tumor progression.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Diseases; Breast Neoplasms; Case-Control Studies; Colonic Diseases; Colorectal Neoplasms; Discriminant Analysis; Disease Progression; Female; Humans; Inflammation; Male; Middle Aged; Monocytes; Prostatic Diseases; Prostatic Neoplasms; Risk Factors; Sensitivity and Specificity; Thromboembolism; Thromboplastin; Urinary Bladder Diseases; Urinary Bladder Neoplasms

Topics: Abortion, Habitual; Adult; Animals; Antibodies, Antiphospholipid; Anticoagulants; Antiphospholipid Syndrome; Autoimmune Diseases; Drug Monitoring; Female; Humans; International Normalized Ratio; Intracranial Embolism; Intracranial Thrombosis; Male; Middle Aged; Pregnancy; Recombinant Proteins; Recurrence; Risk; Seizures; Thromboembolism; Thrombophilia; Thrombophlebitis; Thromboplastin; Warfarin

The anticoagulant and antithrombotic effects of YM-75466 (N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)methyl]sulfamoyl acetic acid monomethanesulfonate), a novel orally-active factor Xa (FXa) inhibitor, and warfarin were compared in mice. Both agents were orally administered in all studies. In ex vivo studies, the peak effects of YM-75466 occurred 1 hr after administration while the peak of warfarin activity occurred 18 hr after administration. At each peak, both YM-75466 and warfarin prolonged coagulation time dose-dependently. The dose response curve of warfarin for prothrombin time was steeper than that of YM-75466. In a thromboplastin-induced thromboembolism model, administration of 30 mg/kg YM-75466 or 3 mg/kg warfarin significantly improved the lethality ratio. In blood loss studies, YM-75466 did not increase blood loss from the tail even at 30 mg/kg, while warfarin markedly increased blood loss at 3 mg/kg. Agents that interfere with warfarin action did not interfere with YM-75466 action. In conclusion, this study shows that YM-75466 has advantages over warfarin: i) rapid onset of anticoagulant activity, ii) wide therapeutic range, iii) little effect on bleeding and iv) lack of drug interaction with agents that interfere with warfarin. These results suggest that YM-75466 may be promising as a novel oral anticoagulant agent.

Topics: Administration, Oral; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Anticoagulants; Anticonvulsants; Antifibrinolytic Agents; Blood Coagulation; Carbamazepine; Cimetidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Erythromycin; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Male; Mice; Mice, Inbred ICR; Partial Thromboplastin Time; Phenytoin; Piperidines; Prothrombin Time; Rifampin; Sulfonamides; Thromboembolism; Thromboplastin; Vitamin K 1; Warfarin

Recommended therapeutic international normalized ratios (INRs) for oral anticoagulation in patients with lupus anticoagulants who sustain a thromboembolic event are controversial. Patients with lupus anticoagulants often have a prolonged prothrombin time, which may complicate management of anticoagulant therapy.. To determine the validity of the INR as a monitor for warfarin therapy in patients with lupus anticoagulants and to investigate alternate approaches to monitoring warfarin therapy in these patients.. Prospective case series.. Tertiary care hospital.. 34 patients with lupus anticoagulants.. Prothrombin times were determined by using several thromboplastins, and INRs were calculated for the patients receiving warfarin. Factor II levels, chromogenic factor X levels, and prothrombin-proconvertin times were determined for patients receiving warfarin.. For patients with lupus anticoagulants who were not receiving warfarin, prothrombin times were often elevated and varied significantly with different thromboplastins. Individual thromboplastins differed in sensitivity to the presence of a lupus anticoagulant. For patients receiving warfarin, INRs obtained by using different thromboplastins greatly varied and often overestimated the extent of anticoagulation. Chromogenic factor X levels and prothrombin-proconvertin times correlated well with each other and with established therapeutic ranges.. Lupus anticoagulants can influence prothrombin times and lead to INRs that do not accurately reflect the true level of anticoagulation. Use of the INR to standardize prothrombin times is invalid for some patients with lupus anticoagulants. To prevent supratherapeutic or subtherapeutic anticoagulation, these patients must be individually monitored with a test that is insensitive to lupus anticoagulants.

Topics: Adolescent; Adult; Aged; Anticoagulants; Blood Coagulation Tests; Female; Humans; Lupus Coagulation Inhibitor; Male; Middle Aged; Monitoring, Physiologic; Prospective Studies; Prothrombin Time; Reference Values; Thromboembolism; Thromboplastin; Warfarin

The international normalized ratio, or INR, was introduced in 1983 by the World Health Organization, or WHO, Committee on Biological Standards to more accurately assess patients receiving anticoagulation therapy. The INR mandates the universal standardization of prothrombin time. This article describes the method used to calculate INR, as well as its clinical relevance to the practice of dentistry.

Topics: Anticoagulants; Blood Coagulation; Calcium; Dental Care; Half-Life; Heparin; Humans; Prothrombin Time; Reference Standards; Reproducibility of Results; Thromboembolism; Thromboplastin; Time Factors; United States; Warfarin; World Health Organization

To investigate whether monocyte expression of tissue factor is increased by plasma from patients with severe ovarian hyperstimulation syndrome (OHSS).. Prospective longitudinal study.. Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting.. Nine IVF patients with severe OHSS.. Pretreatment with leuprolide acetate was followed by gonadotropin treatment for ovarian follicular stimulation. After administration of hCG, a standard IVF-ET procedure was performed.. Measurement during the syndrome and 4 to 5 weeks after recovery of induced monocyte tissue factor expression.. In each of the nine patients, plasma obtained during the syndrome induced a significantly higher proportion of monocytes expressing tissue factor and a significantly higher intensity of tissue factor expression on monocytes than plasma obtained after recovery and control plasma.. Procoagulant activity of blood monocytes, which is mediated principally by tissue factor expression, is increased in patients with severe OHSS. This fact may be important in thrombotic events associated with the syndrome.

Topics: Adult; Capillary Permeability; Female; Hemostasis; Humans; Monocytes; Ovarian Hyperstimulation Syndrome; Thromboembolism; Thromboplastin

The neutralization by protamine sulfate of bleeding enhancement induced by the potent anti-factor Xa pentasaccharide SR 90107A/Org 31540 and by heparin has been studied in rats and mice. Bleeding, as measured by transection of the tail of anaesthetised rats or mice, was increased following the administration of heparin and very high doses of SR 90107A/Org 31540. In rats, i.v. doses of 0.6 mg/kg heparin or 15 mg/kg SR 90107A/Org 31540 were required to enhance bleeding time to approximately the same extent (5- or 7-fold increase), whereas in mice a 13-fold increase in blood loss was observed with i.v. doses of 3 mg/kg heparin or 10 mg/kg SR 90107A/Org 31540. Protamine sulfate (10 mg/kg i.v.) reduced bleeding in rats and mice induced by both compounds. It also neutralized the anti-factor Xa activity as well as the antithrombotic activity of heparin as observed in venous thrombosis models in both species. However, protamine sulfate neither affected the anti-factor Xa activity nor the antithrombotic activity of SR 90107A/Org 31540 in rats and mice. The present results suggest that protamine sulfate may be regarded as a potential antidote to neutralize bleeding side-effects in cases of SR 90107A/Org 31540 overdosing.

Topics: Animals; Bleeding Time; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Heparin; Heparin Antagonists; Humans; Male; Mice; Oligosaccharides; Protamines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Species Specificity; Thromboembolism; Thromboplastin

Tissue injury following trauma and surgery may induce alterations in blood coagulation and fibrinolysis. Hypercoagulable state after surgery can be associated with the risk of postoperative thromboembolic complications. The contact of coagulation factors with TF after injury of vessel wall and organ tissues may contribute to the development of thrombosis after surgery (1). TF, the cell surface receptor and cofactor of factor VII/VIIa is normally not expressed by cells within the vasculature. Only monocytes and endothelial cells can be stimulated to express TF transiently by a variety of inflammatory and immunological reactions (for review see 2,3). Also surgical treatment was reported to induce TF synthesis in monocytes (4,5,6). TF is present in many extravascular tissues as vascular adventitia, organ capsules, epidermis, colonic mucosal epithelium, liver stroma, pancreas stroma and also on tumor cells (7-12). In this study, we investigated, whether we can detect the release of TF from the traumatized tissues and from activated monocytes into the circulation following abdominal surgery. To test the dependence of the extension of tissue injury during surgery we segregated the patients into group A with major abdominal operations and group B consisting of patients with appendectomy and cholecystectomy. No relationship could be established between changes of TF and postoperative thromboembolic complications.

Topics: Abdomen; Adult; Aged; Aged, 80 and over; Factor VII; Female; Humans; Male; Middle Aged; Monocytes; Postoperative Complications; Thromboembolism; Thromboplastin

Endothelins (ET) are the most important vasoconstrictors known, and administration results in contraction of vascular strips in man and experimental animals in vitro. We examined the effects of ET-1 on thrombus formation in rabbits. We used vasoconstrictor and thrombus forming agents and we selected an animal model, the vena jugularis thrombus model. In addition, intravascular endothelium was examined ultrastructurally. The ET-1 level is known to be high in patients with hypertension; if these patients also have atherosclerosis, then intravascular thrombus formation may increase. In the vena jugularis thrombus model, thromboplastin and ET-1 act synergistically to increase intravascular thrombus formation. On injection of ET-1 dose dependent vasoconstriction was shown in the vessel wall. Although similar maximal contraction is achieved, a decrease in vessel diameter is associated with increased potency of ET-1 and thromboplastin. The results suggest that ET-1 may regulate vascular tone through constriction of vessels.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Endothelins; Jugular Veins; Male; Rabbits; Thromboembolism; Thromboplastin

Patients receiving long-term anticoagulant therapy may be subject to unnecessary risks of bleeding or thromboembolism because of variability in the commercial thromboplastins used to determine prothrombin time and consequent uncertainty about the actual intensity of anticoagulation.. We explored the effect of this uncertainty on the benefits and risks of anticoagulation in patients with prosthetic heart valves, using models of thromboembolic and hemorrhagic complications as a function of the intensity of anticoagulation, with quality-adjusted life expectancy and average variable costs used to describe outcomes.. Anticoagulation provides a striking benefit for patients whose treatment is conducted within the recommended range of the international normalized ratio (INR)--i.e., 2.5 to 3.5--but if uncertainty about the laboratory results causes the intensity of anticoagulation to fall outside this range, the gain becomes smaller. Uncertainty about the true intensity of anticoagulation may reduce the potential gain in life expectancy, adjusted for quality of life, by more than half and may increase the ratio of costs to effectiveness to almost five times the optimal value. Variability in the intensity of anticoagulation is even greater if older recommendations advocating a higher level of anticoagulation are followed.. Uncertainty about the sensitivities of the commercially available thromboplastins used in the United States can have important clinical and economic effects. This problem could be eliminated if clinical laboratories uniformly reported the intensity of anticoagulation as the INR, by adjusting prothrombin-time ratios for variability in thromboplastins.

Topics: Cost-Benefit Analysis; Decision Support Techniques; Drug Monitoring; Heart Valve Prosthesis; Hemorrhage; Humans; Markov Chains; Prothrombin Time; Quality of Life; Reference Values; Risk Factors; Sensitivity and Specificity; Thromboembolism; Thrombolytic Therapy; Thromboplastin

Primary antiphospholipid syndrome (PAPS) is an autoimmune disorder manifested by recurrent thrombosis in the venous and arterial system. We report a group of seven patients with lower limb ischaemia associated with PAPS. Four were male patients and three were females, with a mean age of 37 years. All had a previous deep vein thrombosis and the majority, five out of seven, had a prior cerebrovascular accident (CVA). Prolonged activated thromboplastin time was demonstrated in all our patients and PAPS was established by positive thromboplastin titration index, circulating anticoagulant index and increased anticardiolipin levels. Symptoms included claudication in three, rest pain in four and gangrene in five patients. Angiography demonstrated thrombosis of various segments of the arterial tree including: aorta, iliac, femoral and popliteal arteries. Two patients were treated conservatively and one by percutaneous transluminal angioplasty (PTA) of the distal aorta. A total of eleven vascular surgical procedures were performed in four patients resulting in early postoperative thrombosis (2h-30 days) in 10 cases. Only one graft remained patent, when full heparinisation (1000 units/h) was used perioperatively. We conclude that PAPS patients are at high risk for graft thrombosis and should only be operated upon on full anticoagulation, starting at operation and proceeding indefinitely.

Topics: Adolescent; Adult; Aged; Antiphospholipid Syndrome; Female; Graft Occlusion, Vascular; Humans; Ischemia; Leg; Male; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Thrombectomy; Thromboembolism; Thromboplastin; Ultrasonography; Whole Blood Coagulation Time

Patients with cancer experience a much higher than expected incidence of thromboembolic disorders, commonly referred as Trousseau syndrome. Although this association has been well documented, the etiology of the hypercoagulable state is not known. The expression on tumor cells of tissue factor (TF), a membrane-bound lipoprotein that functions as a cofactor to factor VIIa in the initiation of the extrinsic pathway of blood coagulation, has been postulated as a possible mechanism. Whereas the distribution of TF in normal tissues is known, no large survey of TF expression in malignant tissues has been reported. In this study a polyclonal, monospecific rabbit anti-human TF IgG was used for immunohistochemical localization of TF antigen in 85 different tumor specimens. In general, cell types which normally express TF continued to do so after malignant transformation (41 of 60 epithelial tumor specimens were positive for TF). Tumors of nonepithelial origin frequently lacked TF, with only 3 of 19 specimens containing evidence of TF antigen. In addition five of six benign tumors did not express TF. Many tumor types commonly associated with Trousseau syndrome, for example lung, pancreatic, breast, colon and gastric carcinomas, stained positively for TF. Based on this survey, it appears that TF expression by tumors may be an important factor in the pathogenesis of a hypercoagulable state in some patients with cancer.

Topics: Antigens, Neoplasm; Cell Transformation, Neoplastic; Humans; Immunohistochemistry; Neoplasms; Staining and Labeling; Thromboembolism; Thromboplastin

Thrombin production in plasma in contact with various materials was consistent with a first-order autocatalytic model (d[T]/dt = kp[T]; [T] = thrombin concentration, t = time, kp = thrombin production rate constant) since the initial portion of a semilogarithmic plot of thrombin concentration against time was linear. Thrombin concentration was measured in clotting plasma (phospholipid enhanced or platelet-rich plasma) using a fluorogenic substrate (BMCA) by aliquot sampling at various intervals or more conveniently by monitoring cumulative fluorescence. The latter was generated by the action, on BMCA incubated in the clotting plasma, of the thrombin as it was generated. The thrombin concentration was determined from the first derivative of the S-shaped cumulative fluorescence curve. kp was greater for glass (7.92 x 10(-3) cm/s) than for the other materials (polypropylene, polystyrene, polyethylene and PVA; kp approximately 3.1 x 10(-3) cm/s) in plasma with cephalin without flow. A kp for heparin-PVA could not be determined since the thrombin concentration was too low to be quantified. A larger difference between polyethylene and PVA was noted with platelet-rich plasma without flow while lower values (1.0 x 10(-3) cm/s) were noted in a flow system but at a higher surface to volume ratio. The first-order rate constant can be used in simple models relating production of thrombin at a wall of a tube to its mass transfer away from the wall in flowing blood. One such model predicts that the concentration of thrombin at the wall should become infinite at the point in the tube when the mass transfer coefficient equals kp. According to this model, kp on the order of 10(-4) cm/s would be a useful target for a nonthrombogenic material.

Topics: Amino Acid Sequence; Animals; Biocompatible Materials; Blood; Calibration; Coumarins; Enzyme Activation; Glass; Heparin; Humans; Kinetics; Materials Testing; Models, Theoretical; Molecular Sequence Data; Oligopeptides; Phosphatidylethanolamines; Platelet Activation; Polypropylenes; Polystyrenes; Polyvinyl Alcohol; Prothrombin; Rabbits; Rheology; Spectrometry, Fluorescence; Thrombin; Thromboembolism; Thromboplastin

Topics: Humans; Laboratories; Male; Prothrombin Time; Thromboembolism; Thromboplastin; Warfarin

Topics: Abortion, Habitual; Autoimmune Diseases; Blood Coagulation Factors; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lupus Coagulation Inhibitor; Male; Partial Thromboplastin Time; Phospholipids; Pregnancy; Reagent Kits, Diagnostic; Thromboembolism; Thromboplastin

Topics: Administration, Oral; Animals; Humans; Indicators and Reagents; Prothrombin Time; Rabbits; Thromboembolism; Thromboplastin; United Kingdom; United States; United States Food and Drug Administration; Warfarin

Activation of coagulation occurs at inflammatory sites following the ingress of mononuclear cells, and may result from alterations in the vessel wall. Since the monokine, interleukin 1, initiates diverse responses to inflammation, its ability to enhance vascular procoagulant activity was studied. Interleukin 1-treated cultured human endothelial cells acquired elevated levels of the procoagulant, tissue factor. This required de novo protein synthesis, was maximal at 2 h after exposure to interleukin 1, and resulted in persistently elevated cellular procoagulant activity. Tissue factor was later expressed (6-24 h) on the surface of uninjured endothelial cells. Endothelial cell procoagulant production and expression in response to interleukin 1 could be dissociated from endogenous prostaglandin metabolism, being insensitive to hydrocortisone, indomethacin, eicosatetrayionic acid and exogenous arachidonic acid. In addition, no increase in prostaglandin synthesis occurred during the interval in which tissue factor was synthesized. We therefore conclude that interleukin 1 stimulates endothelial synthesis and surface expression of tissue factor by a prostaglandin-independent mechanism.

Topics: Cells, Cultured; Dose-Response Relationship, Drug; Endothelium; Female; Humans; Interleukin-1; Prostaglandins; Receptors, Cell Surface; Thromboembolism; Thromboplastin; Time Factors

The thromboplastin activity in blood monocytes from 13 women on oral contraceptives and from a reference group of 20 women not on oral contraceptives has been compared. The thromboplastin activity in endotoxin-stimulated monocytes from the oral contraceptive (OC) users was on average 54% of the activity in the reference group (p less than 0.05). The thromboplastin activity in unstimulated monocytes was also lower in the OC group than in the reference group although not statistically significant. Factor VII was significantly higher (p less than 0.05) in the OC group, whereas no difference was observed in fibrinogen and factor V levels.

Topics: Adult; Contraceptives, Oral, Combined; Endotoxins; Female; Humans; In Vitro Techniques; Monocytes; Thromboembolism; Thromboplastin

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation Tests; Heparin; Humans; Partial Thromboplastin Time; Platelet Aggregation; Prothrombin Time; Rabbits; Thromboembolism; Thromboplastin; Thrombosis; Vitamin K; Warfarin

This study describes the use of a modified dilute thromboplastin assay for demonstration of the lupus coagulation inhibitor in plasma. A one-stage clotting inhibition assay is used in which the ability of the test plasma to prolong the clotting time of normal plasma is measured. The method is easy to perform and suitable for routine use. Clinical and laboratory data from five patients with the inhibitor but without systemic lupus erythematosus are presented. Thromboembolic manifestations were observed in three patients and obstetric complications possibly due to placenta thrombosis in two. One patient showed a bleeding tendency, associated with prothrombin deficiency. A number of pathological coagulation analyses and other laboratory data may be due to affinity of the lupus inhibitor for negatively charged phospholipids in vitro.

Topics: Abortion, Spontaneous; Adult; Anticoagulants; Blood Coagulation Factors; Blood Coagulation Tests; Female; Fetal Death; Humans; Lupus Coagulation Inhibitor; Pregnancy; Pregnancy Complications, Cardiovascular; Thromboembolism; Thromboplastin

Topics: Autoantibodies; Blood Coagulation Factors; Blood Coagulation Tests; Humans; Preoperative Care; Risk; Surgical Procedures, Operative; Thromboembolism; Thromboplastin

Topics: Adolescent; Adult; Aged; beta-Thromboglobulin; Female; Fibrinopeptide A; Fibrinopeptide B; Humans; Leg; Lung; Male; Middle Aged; Platelet Factor 4; Postoperative Complications; Radionuclide Imaging; Thrombin; Thromboembolism; Thrombophlebitis; 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

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

Thromboembolic complications are often a common pathological consequence of severe soft tissue trauma. Recent demonstration that monocytes (M0) produce tissue factor (TF) has led to the suggestion that these TF producing M0 might play a role in coagulopathy. We have previously demonstrated that trauma patients with splenectomy develop aberrant monocyte function and this patient group is also known to be at high risk of hypercoagulability episodes. This paper is an initial report on the use of M0 TF as an indicator of and/or correlated to clotting episodes. Monocytes isolated form the Ficoll-Hypaque purified mononuclear cells of 46 normal individuals, 17 trauma patients and 6 surgical controls were assayed at 3 day post-injury intervals for their levels of TF activity. Changes in monocyte TF activity were correlated to increases in the fractional catabolic rate (FCR) of 125 I-fibrinogen. Trauma patients were retrospectively divided into those whose FcR was elevated to a level indicative of coagulopathy and those whose FCR levels were not associated with coagulation abnormalities. All trauma patients who exhibited significantly increased FCR experienced thromboembolic episodes and had monocytes whose TF activity was increased an average of 300% (mean = 47 units vs mean = 12 units) over surgical controls. These increase in monocyte TF activity occurred at 6-13 days post injury and preceded clinical manifestation of coagulopathy by 4-6 days. The increased monocyte TF activity demonstrated in this study was significantly correlated to detection of pathologically increased FCR (R = 0.850) and compared to other indices of hypercoagulability.

Topics: Blood Coagulation; Fibrinogen; Humans; Monocytes; Postoperative Complications; Splenectomy; Thromboembolism; Thromboplastin; Wounds and Injuries

Topics: Animals; Blood Coagulation Tests; Cattle; Heparin; Humans; Infusions, Parenteral; Thromboembolism; Thromboplastin

Activated coagulation time (ACT) for protamine reversal was monitored in 28 consecutive patients (Group 1) and a standard heparin-protamine protocol was used for an earlier series of 28 patients (Group 2). Although Group 1 received a significantly higher total heparin dose than Group 2 (p less than 0.01), the protamine dose for reversal was significantly less for the ACT group than for the controls (p less than 0.0005). The mean ratio of protamine to total heparin was 1 : 1 (range, 0.33 to 1.44) for the ACT group and 2 : 1 (range, 1.42 to 2.59) for the controls. There were no significant differences between the two groups in operative and postoperative blood loss, transfusion requirements, hematocrit, and partial thromboplastin time. This study shows that the ACT test did not reduce postoperative bleeding significantly when compared with our standard protocol. It also indicates that there is wide individual sensitivity to heparin and that significantly less protamine is required for reversal.

Topics: Blood Coagulation Tests; Blood Transfusion; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Evaluation Studies as Topic; Hematocrit; Hemorrhage; Heparin; Humans; Middle Aged; Monitoring, Physiologic; Postoperative Complications; Protamines; Thromboembolism; Thromboplastin

Topics: Adult; Aged; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Lung; Middle Aged; Radionuclide Imaging; Recurrence; Thromboembolism; Thromboplastin; Time Factors

A total of 41 patients with ischaemic heart disease and 30 normal donors were subjected to examinations of the biochemical indices of the blood coagulation system in its coagulation and anticoagulation links, as well as to tests reflecting the fibrinolytic and inhibitory activity of the urine. In the presence of thromboembolic complications in myocardial infarction patients a sharp elevation of "residual fibrinogen" and antiplasmins is noted along with a reduction of the urokinase activity of the urine.

Topics: Adult; Blood Coagulation Tests; Chromatography, Paper; Factor XIII; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Fibrinolysis; Humans; Middle Aged; Myocardial Infarction; Plasminogen Activators; Plasminogen Inactivators; Serum Globulins; Thromboembolism; Thromboplastin; Time Factors; Urokinase-Type Plasminogen Activator

Topics: Humans; Prothrombin Time; Thromboembolism; Thromboplastin

Topics: Antithrombins; Blood Coagulation Tests; Chromatography, Affinity; Chromatography, Gel; Factor IX; Factor XIII; Humans; In Vitro Techniques; Isoflurophate; Thrombin; Thromboembolism; 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 new centrifugal blood pump system has been developed for left ventricular bypass by the addition of non-thrombogenic blood surface materials and an ultrathin-walled cannula for the retrograde cannulation of the left ventricle. Partial LV bypass at 3 to 6 L/min was undertaken in 55 calves without thoracotomy. In 20 it was continued for 24 hours, with 13 survivors who were eventually sacrificed. Eleven of the last 14 experiments were completed without mishap. Heparin was employed only during pump insertion. Hematologic changes were limited to moderate platelet depression, and tolerable hemolysis (average serum level 21 mg% in the last 13 experiments). Normal clotting parameters and the absence of significant fibrin split product formation correlated with the absence of gross thrombosis and few minor renal emboli observed at autopsy. This pump system appears to have several advantages over previously described equipment for LV bypass.

Topics: Animals; Assisted Circulation; Blood Cell Count; Blood Platelets; Blood Pressure; Cattle; Fibrinogen; Hematocrit; Hemoglobins; Hemolysis; Leukocyte Count; Oxyhemoglobins; Prothrombin Time; Thromboembolism; Thromboplastin

Topics: Blood Coagulation; Cesarean Section; Female; Humans; Postoperative Complications; Pregnancy; Thromboembolism; 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: Adult; Antibody Formation; Blood Cell Count; Blood Coagulation Tests; Blood Platelets; Complement Fixation Tests; Hemorrhage; Heparin; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Adhesiveness; Prothrombin Time; Thrombocytopenia; Thromboembolism; Thromboplastin; Thrombosis

A prospective, randomized trial is described in which the usefulness of two tests in the control of anticoagulant therapy is compared. Fifty-two patients were controlled by the one-stage prothrombin time and 55 by the activated partial thromboplastin time. There was no significant difference in the incidence of bleeding between the two groups. When bleeding did occur, it was more often reflected by prolongation of the prothrombin time than of the activated partial thromboplastin time. The prothrombin time was found to have some practical advantages over the activated partial thromboplastin time.

Topics: Adult; Age Factors; Aged; Anticoagulants; Blood Coagulation Tests; Hemorrhage; Humans; Methods; Middle Aged; Prothrombin Time; Thromboembolism; Thrombophlebitis; Thromboplastin

Current methods of assessment of heparinization are either inconvenient as bedside procedures or lack correlation with the Lee-White whole blood clotting time over the therapeutic range. A new thromboplastin time (CAT time) has been developed to overcome these disadvantages by offering uniform contact activation. The test makes use of a partial thromboplastin activated by celite-adsorbed "contact factor", thus eliminating the activation phase of the activated partial thromboplastin time. Preliminary experiments suggest that this modification will be helpful in the study of "contact factor" deficiencies.

Topics: Blood Coagulation Tests; Drug Stability; Evaluation Studies as Topic; Heparin; Humans; Methods; Temperature; Thromboembolism; Thromboplastin; Time Factors

Topics: Blood Coagulation Tests; Heparin; Humans; Methods; Thromboembolism; Thromboplastin; Time Factors

Topics: Adolescent; Adult; Aged; Blood Coagulation Tests; Female; Hemorrhage; Heparin; Humans; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Radiography; Radionuclide Imaging; Recurrence; Thromboembolism; Thrombophlebitis; Thromboplastin; Time Factors

Topics: Anticoagulants; Humans; Prothrombin Time; Thromboembolism; Thromboplastin

Topics: Adolescent; Adult; Aged; Blood Coagulation Tests; Female; Heparin; Humans; Injections, Intravenous; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Thromboembolism; Thrombophlebitis; Thromboplastin

Topics: Animals; Blood Coagulation; Chickens; Cholesterol; Chromatography, Gel; Chromatography, Thin Layer; Erythrocytes; Esters; Lipids; Phospholipids; Snakes; Thromboembolism; Thromboplastin; Time Factors; Venoms

Topics: Animals; Blood Coagulation; Dogs; Fibrinogen; Heart, Artificial; Platelet Adhesiveness; Prothrombin Time; Thrombin; Thromboembolism; Thromboplastin

Commercially available thromboplastin reagents and two human brain preparations have been compared using the one-stage prothrombin time and plasma samples from patients receiving long-term oral anticoagulant therapy. Considerable variation is noted between various thromboplastins using the same plasma sample. The commercially available thromboplastins give shorter prothrombin times than do human brain preparations. With the latter, the "therapeutic range" is represented by a prothrombin time of about 1.8 to 3.0 times the normal control value, whereas with commercial preparations the "therapeutic range" is about 1.25 to 1.75 times normal. The implications of these observations are discussed; the desirability of standardization of the one-stage prothrombin time is emphasized.

Topics: Anticoagulants; Brain; Humans; Indicators and Reagents; Methods; Prothrombin Time; Thromboembolism; Thromboplastin

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

Difficulties associated with the whole blood clotting time (W.B.C.T.) as a method of monitoring heparin therapy have led to the investigation of the activated partial thromboplastin time (A.P.T.T.) as an alternative. The conclusion is reached that the latter procedure possesses several advantages. Using the method described and a citrate-preserved blood sample collected just prior to the administration of the next serial dose of heparin, the suggested therapeutic duration of the A.P.T.T. is 70 seconds or twice the mean control value. A practical range for this method is 60 to 70 seconds.

Topics: Administration, Oral; Blood Coagulation; Blood Coagulation Tests; Citrates; Coumarins; Heparin; Humans; Injections, Intravenous; Oxalates; Prothrombin Time; Thromboembolism; Thromboplastin; Time Factors

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; Blood Flow Velocity; Blood Transfusion; Fibrinogen; Humans; Prothrombin Time; Shock, Traumatic; Thromboembolism; Thromboplastin

Topics: Blood Coagulation Tests; Heparin; Humans; Methods; Plasma; Thromboembolism; Thromboplastin

Topics: Blood Coagulation Tests; Heparin; Humans; Statistics as Topic; Thromboembolism; Thromboplastin; Time Factors

Topics: Animals; Blood; Blood Coagulation Tests; Female; Fibrinolysin; Injections, Intravenous; Lung; Mice; Placenta; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy, Animal; Thromboembolism; Thromboplastin; Tissue Extracts

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: 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: Animals; Blood Coagulation Tests; Hemostasis; Heparin; Male; Rabbits; Thromboembolism; Thromboplastin; Thrombosis; Time Factors

Topics: Arteriosclerosis; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Extracorporeal Circulation; Fibrin; Fibrinolysis; Hemorrhage; Heparin; Heparin Antagonists; Humans; Hyperlipidemias; Hypersensitivity; Natriuresis; Osteoporosis; Protamines; Prothrombin Time; Thromboembolism; Thrombophlebitis; Thromboplastin

Topics: Animals; Blood Coagulation; Blood Platelets; Catecholamines; Humans; Hypoxia; Microscopy, Electron; Shock; Shock, Septic; Thromboembolism; Thromboplastin; Wounds and Injuries

Topics: Adolescent; Adult; Aged; Blood Coagulation Factors; Blood Coagulation Tests; Chronic Disease; Colitis, Ulcerative; Factor IX; Factor VII; Factor VIII; Factor X; Factor XII; Female; Fibrinogen; Humans; Male; Middle Aged; Thromboembolism; Thromboplastin

Topics: Catheterization; Child, Preschool; Humans; Hydrocephalus; Male; Pulmonary Heart Disease; Thromboembolism; Thromboplastin; Vascular Surgical Procedures

Topics: Adenocarcinoma; Blood Coagulation Tests; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Coumarins; Female; Heparin; Humans; Male; Smoking; Thromboembolism; Thrombophlebitis; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Tests; Coumarins; Erythrocytes; Hematuria; Heparin; Humans; Postoperative Care; Postoperative Complications; Thromboembolism; Thromboplastin

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

Topics: Ethyl Biscoumacetate; Hemorrhage; Heparin; Humans; Streptokinase; Thromboembolism; Thromboplastin

Topics: Coumarins; Thromboembolism; Thromboplastin

Topics: Blood Coagulation Tests; Diagnosis; Drug Therapy; Embolism; Heparin; Oxyphenbutazone; Pharmacology; Phenylbutazone; Preventive Medicine; Prothrombin; Pyrazoles; Thromboembolism; Thromboplastin; Thrombosis

Topics: Adult; Aged; Anticoagulants; Humans; Middle Aged; Myocardial Infarction; Thromboembolism; Thromboplastin; Thrombosis

Topics: Animals; Anticoagulants; Biological Assay; Heparin; Lagomorpha; Rabbits; Research; Thromboembolism; Thromboplastin; Thrombosis

Topics: Anticoagulants; Capillaries; Drug Therapy; Humans; Thromboembolism; Thromboplastin

Topics: Anticoagulants; Blood Coagulation Factors; Blood Coagulation Tests; Esophageal Neoplasms; Factor VII; Fibrinogen; Heparin; Humans; Postoperative Complications; Prothrombin; Stomach Neoplasms; Thromboembolism; Thromboplastin

Topics: Arteries; Disease; Humans; Pulmonary Artery; Thromboembolism; Thromboplastin; Vascular Diseases

Topics: Anticoagulants; Thromboembolism; Thromboplastin