Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this report cultured bovine capillary endothelial cells are demonstrated to specifically bind factors IX and X and also their activated forms. Bound factor IXa and cell-associated factor VIII can activate factor X. The product of this reaction, factor Xa, can then interact with a factor V-like molecule expressed by capillary endothelial cells promoting thrombin formation. The thrombin formed can cleave fibrinogen leading to release of fibrinopeptide A and clot formation. Endotoxin-treatment of capillary endothelial cells leads to induction of tissue factor activity which, in the presence of factor VIIa, promotes activation of factors IX and X. The amount of factor Xa formed endotoxin-treated endothelial cells incubated with factors VIIa, IX, VIII and X, is 8 times greater than cells incubated with factors VIIa and X alone. This indicates that on the perturbed endothelial cell surface factors VIII and IX do play an important role in factor X activation by the tissue factor pathway. The perturbed capillary endothelial cell can thus provide a model of the thrombotic state promoting initiation and propagation of a procoagulant pathway leading to thrombin formation. This pathway of coagulation is endothelial cell-dependent, since it requires expression of tissue factor and factor V by capillary endothelial cells, as well as interaction of coagulation factors with the surface of capillary endothelial cells.
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PMID:A pathway of coagulation on bovine capillary endothelial cells. 308 7

Stimulation with thrombin or the calcium ionophore, A23187 caused human platelets to release a coagulation inhibitor similar to the Lipoprotein Associated Coagulation Inhibitor (LACI). This was documented functionally, with clotting assays measuring tissue factor inhibition and factor Xa inhibition, as well as immunologically, in a competitive immunoassay. The total amount of LACI released by 3 x 10(8) platelets after two hours stimulation was 7% to 8% of the amount found in 1 mL of serum. Half of the LACI was released by five minutes. The LACI was present in the platelet supernatant and was not associated with the platelet membrane or shed vesicles. The tissue factor and factor Xa inhibitory activities that were released were neutralized by preincubating the platelet supernatants with specific rabbit polyclonal anti-LACI IgG. On Western blot, platelet LACI appeared to run as a doublet with a molecular weight (mol wt) 45,000 to 47,000. Blood samples obtained from the site of a wound (template bleeding time) demonstrated a progressive increase in LACI concentration. A cDNA probe, derived from endothelial cell LACI cDNA, hybridized selectively to 4.0 and 1.4 kb transcripts in a preparation of platelet mRNA.
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PMID:Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. 314 29

We have investigated concomitantly the pro-aggregating and pro-coagulant activities of 11 breast and 2 colon human carcinomas. Tumor tissues, obtained at surgery, were immediately processed to prepare tumor-cell suspensions for the study of aggregating activity and tissue extracts for the study of procoagulant capacity. Nine carcinomas (8 breast and 1 colon) possessed a high, dose-dependent platelet-aggregating activity, which was present in the cell-free supernatant and was inhibited by HgCl2 and iodoacetic acid, specific cysteine proteinase inhibitors, while apyrase and hirudin had no significant effect; in contrast, the other tumors did not aggregate platelets. All the tumor extracts tested from 12 carcinomas (11 breast and 1 colon) were able to activate blood coagulation in both the presence and the absence of F VII. The activity was inhibited by HgCl2 and iodoacetamide, while Con A was less effective. Therefore, these tumors do not aggregate platelets through the production of ADP or thrombin, nor promote blood coagulation through the production and release of tissue factor; a tumor-associated cysteine proteinase plays a major role in both pro-aggregating and pro-coagulant activities.
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PMID:Human breast and colon carcinomas express cysteine proteinase activities with pro-aggregating and pro-coagulant properties. 317 28

A 66-year-old man with homozygous deficiency of factor VII (less activity than 4 percent of normal) had a minimal hemorrhagic tendency and severe coronary atherosclerosis, and underwent aortocoronary saphenous vein bypass surgery. Although plasma factor VII coagulant activity and cross-reacting material were markedly reduced, comparable amounts of factor VII antigen were detected in peripheral blood mononuclear cells of both the patient and of a normal subject by Western blotting techniques. Accelerated coagulation was observed following brief exposure of the patient's phytohemagglutinin-stimulated peripheral blood mononuclear cells to low concentrations of ambient factor VII in vitro. Evidence indicates that factor VII plays a role in vivo in both hemostasis and atherogenesis and it might be assumed that factor VII deficiency would both predispose to excessive bleeding and forestall atherosclerosis. However, these observations suggest that factor VII-mediated thrombin generation may proceed by partitioning of small amounts of factor VII on tissue factor-expressing cells and that factor VII contained within monocytes may facilitate tissue factor-induced coagulation by these cells. These features may provide efficient coagulation activation despite a deficiency of the plasma coagulant protein. The current results may explain, at least in part, the minimal bleeding tendency, and also the occurrence of thrombosis and atherosclerosis in certain persons with factor VII deficiency.
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PMID:Atherosclerosis and coronary bypass surgery in hereditary factor VII deficiency. 325 74

The normal hemostatic system is complex yet exquisitely well regulated. Interrelationships exist between responses of the vasculature, circulating platelets, coagulation proteins, and fibrinolytic mechanism. These relationships serve to limit blood loss, preserve tissue perfusion, and stimulate local repair processes. Natural inhibitors of coagulation and fibrinolysis modulate these systems to prevent uncontrolled thrombosis or hemorrhage following pathologic stimuli. Vascular endothelial cells play an important role in the maintenance of a thromboresistant luminal interface with circulating cells and proteins. Normal hemostasis also requires the synthetic, metabolic, and repair processes of the vascular endothelium. The initial vascular response to injury produces brief vasoconstriction and exposes subendothelial substances that attract circulating platelets and activate coagulation proteins. Platelets respond by adherence and aggregation at the site of injury, with subsequent release of substances that mitigate blood loss. Platelet adherence to collagen requires von Willebrand's factor, fibrinogen, fibronectin, and specific glycoprotein receptors on platelet surfaces. Platelet-to-platelet interactions (aggregation) recruit additional platelets to the primary hemostatic plug. Aggregation requires fibrinogen, energy, and calcium. Release of ADP, serotonin, and the contents of intracellular granules as well as generation of prostaglandins prepares platelet surfaces for reactions with the coagulation proteins. Activation of the intrinsic or extrinsic coagulation pathway, or of both, causes formation of fibrin from fibrinogen by means of an elaborate and intricate system that also entraps platelets and activated coagulation proteins. The intrinsic system is activated by the contact of factor XII with a negatively charged surface, most likely collagen. Through a series of reactions with prekallikrein, HMWK, and factors XI, IX, and VIII, the common coagulation pathway is propagated. The extrinsic, or tissue factor, system stimulates both the common pathway and factor IX the intrinsic pathway. Discovery of this stimulation of the intrinsic pathway by factor VII in the extrinsic pathway has stimulated reassessment of the biologic importance of the extrinsic system. The common pathway includes factors X and V and causes thrombin to convert fibrinogen to fibrin. Calcium and platelet phospholipids are substances that have important roles in steps in the coagulation scheme. Once fibrin is formed, factor XIII interacts with the substance, providing a stabilizing effect.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An overview of hemostasis. 328 84

The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.
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PMID:Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds. 334 42

Highly sensitive automated methods for the evaluation of the extrinsic coagulation reactions in human plasma were developed by the combination of fluorogenic peptide substrate (MCA) for thrombin and a centrifugal autoanalyzer (Cobas Bio). Prothrombin time (PT) was measured by the reaction time to reach 0.1 relative fluorescence which was caused by the action of thrombin generated after the activation of 3 microliters plasma with human placental tissue factor (Thromborel S). Factors X and VII contents in plasma were measured by the same method after mixing diluted plasma with each factor deficient plasma, tissue factor, calcium and MCA in which 10-800% of each factor was quantitatively measured. Prothrombin content in plasma was quantitated by measuring thrombin activity after the activation with human activated Factor X in the presence of phospholipid and calcium in which 10-160% of prothrombin was measured. By the application of these fluorogenic methods to the patients with cardiovascular diseases, it was demonstrated that these methods are highly sensitive not only to hypocoagulable state, but also to hypercoagulable state, particularly to the increase of Factors X and VII concentrations in plasma.
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PMID:Automated fluorogenic methods for the evaluation of the extrinsic coagulation reactions in human plasma. 340 87

Previous studies demonstrated that endothelial cells participate actively in both anticoagulant and procoagulant reactions. Although anticoagulant mechanisms predominate on the surface of quiescent endothelial cells, perturbed endothelial cells can promote coagulation through the coordinated induction of procoagulant activity and suppression of anticoagulant mechanisms. Purified recombinant interleukin 1 was infused intravenously into rabbits and coagulant properties of the native aortic endothelium were subsequently studied. Interleukin 1 infusion resulted in a time- and dose-dependent induction of the procoagulant cofactor tissue factor, while concomitantly blocking the protein C anticoagulant pathway. Tissue factor activity increased greater than 10-fold by 3-5 hr after the infusion, while endothelial cell-dependent thrombin-mediated protein C activation decreased by 72% and assembly of functional activated protein C-protein S complex on the vessel surface was decreased by greater than 90%. Scanning electron microscopy of major arteries demonstrated fibrin strands closely associated with the luminal endothelial cell surface with a predilection for bifurcations. Interleukin 1, a mediator of the inflammatory response, can shift the balance of procoagulant and anticoagulant reactions on the endothelium unidirectionally favoring clot formation. The surface of perturbed endothelium can thus provide a template, facilitating the development of a prethrombotic state, and provides a model for the early stages of thrombosis.
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PMID:Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. 348 18

Platelet consumption is a prominent feature of disseminated intravascular coagulation. We investigated whether monocyte procoagulant activity (PCA) might play a role in platelet consumption associated with gram-negative septicemia. Human mononuclear cells exposed in vitro to lipopolysaccharide demonstrated parallel dose-dependent increases in PCA and ability to induce platelet aggregation. Induction of platelet aggregation required the generation of thrombin dependent on coagulation Factors VII, X, and II, and calcium. This is consistent with monocyte tissue factor initiating thrombin generation. A specific monoclonal antimonocyte antibody was used to identify monocytes via indirect immunofluorescence, and demonstrated that all monocytes were included in platelet aggregates. Mononuclear cells that did not express PCA did not induce platelet aggregation and monocytes were not surrounded by platelet clumps. These data suggest that monocytes induced to express tissue factor on their surface may be important mediators of endotoxin-induced platelet, as well as fibrinogen, consumption.
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PMID:Human platelet aggregation is initiated by peripheral blood mononuclear cells exposed to bacterial lipopolysaccharide in vitro. 353 97

Tumour cell induced platelet aggregation (TCIPA) may facilitate haematogenous tumour metastasis. In this study of the aggregatory responses of human platelets to human tumour cell lines, we have found two distinct mechanisms of TCIPA. Colon carcinoma lines Colo 205 and Colo 397 produced TCIPA which was dependent upon thrombin generated through the activation of clotting factor VII, consistent with the expression of tissue factor activity by these cells. This mechanism was calcium dependent and was partially mediated by platelet ADP release as it was inhibited by apyrase. A uterine carcinosarcoma line (Colo 526) produced TCIPA by a novel mechanism which was dependent upon calcium, but was independent of thrombin generation and of the presence of plasma proteins, indicating that this aggregatory response is initiated by a direct platelet-tumour cell interaction.
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PMID:Plasma-dependent and -independent mechanisms of platelet aggregation induced by human tumour cell lines. 362 45


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