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)

We have investigated whether or not tissue factor (TF) which is present in the supernatant of isolated glomeruli, is responsible for the stimulatory activity of TXB2 production by isolated human platelets. Reconstituted TF stimulated TXB2 synthesis in platelets in a dose-dependent manner. This effect was potentiated in the presence of a mixture of the major fatty acids found in glomerular supernatants. Addition of a neutralizing anti-TF monoclonal antibody abolished both the procoagulant activity and the platelet-TXB2 stimulatory activity of reconstituted TF and of glomerular supernatants. Anti-factor VII/VIIa (F VII/VIIa) Fab inhibited in a dose-dependent manner the platelet-TXB2 stimulatory activity of an identical dilution of reconstituted TF and of glomerular supernatants, providing evidence that the functional complex TF. VIIa and not TF itself was the active agent. Pretreatment of platelets, TF or glomerular supernatant by hirudin, an inhibitor of thrombin, as well as by antithrombin III heparin, which inhibits both activated factor X and thrombin also markedly inhibited the synthesis of TXB2 by platelets in the presence of either TF or glomerular supernatant. Taken together, these results demonstrate that the stimulatory activity for TXB2 production by platelets which is released by the glomerular cells is attributable to TF. TF does not act directly. Its effect is mediated by thrombin which is formed de novo at the platelet surface in the presence of even traces of the plasma coagulation proteins associated with platelets. TXB2 formation in platelets correlates well with TF concentration in the glomerular supernatant. The possibility of a similar set of mechanisms associated with glomerular injury may require consideration.
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PMID:Glomerular tissue factor stimulates thromboxane synthesis in human platelets via thrombin generation. 155 9

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.
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PMID:Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. 156 31

The antitrypanosomal drug suramin, which has recently been under investigation as a cancer chemotherapeutic agent, has previously been found to induce heparin-like anticoagulants in treated patients. In the currently reported work suramin is shown to have an additional anticoagulant activity that is due to direct effects of the drug on procoagulant proteins. The studies were conducted with pooled normal plasma treated in vitro with suramin and with plasma samples obtained from patients who had received the drug intravenously for 2 weeks. It is demonstrated that in plasma suramin inhibits factors V, VIII, IX, X, XI, and XII, while thrombin, prothrombin, and factor VII are unaffected. The inhibition of factor V is virtually irreversible, although the effect of suramin on the other factors is readily reversed by dilution.
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PMID:The effect of suramin on laboratory tests of coagulation. 163 91

The effect of burn wound size on the activation of fibrinolysis, coagulation, and contact factors was analyzed in 60 thermal injury patients. Blood samples from 47 male patients and 13 female patients, (average age 37 years; range 1.5-70 years) were collected within the first 36 hours and at 5-7 days following injury. The patient population was categorized by percentage of burn (second degree and/or third degree): less than 20%, n = 22; 20%-40%, n = 18; greater than 40%, n = 20. The average percentage of burn was 32% (range, 4%-95%). The mechanism of injury was by flame (25), explosion and flame (19), scald (12), electric (3), or chemicals (1). An associated inhalation injury was present in 12 patients. The overall mortality rate was 13% (8). Sepsis or serious infection occurred in 23% (14) of the patients. On admission, 83% of the patients had normal prothrombin times (PT) and activated partial thromboplastin times (APTT). However, specific hemostatic variables showed marked changes. Admission hemostatic markers that correlated with the severity of injury were: tissue-plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimer (D-di), plasminogen (Plg), proteins C and S (PrC and PrS), antithrombin III (ATIII), thrombin-antithrombin complex (TAT), kallikrein (Kal:c), kinin (Kin), C1 esterase inhibitor (C1Inh), and factor VII clotting and antigen (FVII:c, FVII:ag). These data suggest that during the early course following burn injury, thrombogenicity is increased (TAT increases) because of a decrease in ATIII, PrC, and PrS; and fibrinolysis activation (D-di increases) occurs via an increase in tPA with a p value increase in PAI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of burn wound size on hemostasis: a correlation of the hemostatic changes to the clinical state. 163 6

The occurrence and distribution of components of coagulation pathways in situ were determined using immunohistochemical techniques applied to 10 cases of primary carcinoma of the breast, normal breast tissue obtained from two patients undergoing reductive mammoplasty, and three patients with benign breast tumors. Tumor cells stained for factor X and thrombomodulin but not for tissue factor, factor V, factor VII, or factor XIII. Rare nonneoplastic duct epithelial cells stained for thrombomodulin, but these tissues did not otherwise stain for any of these antigens. Macrophages within the tumor stroma stained for tissue factor, factor VII, and factor XIII but not for factor V or factor X. These features of macrophages were the same in malignant and nonmalignant breast tissue. Fibrinogen was present in abundance throughout the connective tissue in breast cancer but not in nonmalignant tissues. By contrast, no staining was observed using fibrin-specific antibodies. These results suggest that an intact coagulation pathway does not exist in breast cancer tissue and that thrombin capable of transforming fibrinogen to fibrin is not generated in significant amounts in this tumor type. While fibrin is not a feature of the connective tissue stroma in breast cancer, it is conceivable that the abundant fibrinogen present in the tumor connective tissue (and factor XIII present in connective tissue macrophages) might contribute to the structural integrity of breast tumor tissues.
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PMID:Fibrinogen deposition without thrombin generation in primary human breast cancer tissue. 167 Sep 92

Nonmalignant lymphoid tissue and tissue from patients with nodular sclerosis, Hodgkin's disease, and large cell lymphocytic lymphoma was examined by immunohistochemical techniques for the occurrence in situ of components of coagulation and fibrinolysis reaction pathways. Staining for material interpreted as fibrinogen was observed in abundance in both malignant and reactive lymphoid tissue. Fibrin also occurred to a variable extent but focally in all tissues. Components of coagulation pathways, including tissue factor, factor VII, factor X, and factor XIII ("a" subunit), were restricted to tissue macrophages. Double-labeling techniques revealed fibrin in direct apposition to tissue macrophages. We conclude that fibrinogen and fibrin occur in both benign and malignant lymphoid tissue and that the transformation of fibrinogen to fibrin is attributable to macrophage-initiated thrombin formation. We postulate that both systemic and local hypercoagulability associated with these disorders may be attributable to macrophage activation resulting in expression of procoagulant activity.
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PMID:Fibrinogen deposition and macrophage-associated fibrin formation in malignant and nonmalignant lymphoid tissue. 174 Jun 24

Purer factor IX concentrates, containing very little or no factor II or X, have been developed in an attempt to avoid the thromboembolic complications that occur with prothrombin complex concentrates (PCC), which also contain factors II and X and variable amounts of factor VII. To evaluate ex vivo the thrombogenic potential of one of these purer concentrates, we studied whether large single doses produced signs of activation of the coagulation cascade in patients with haemophilia B, and compared the results with those obtained after infusion of a PCC. Seven patients were infused with 50 IU/kg of factor IX concentrate and seven additional patients were subsequently infused with 100 IU/kg of the same concentrate. After the infusions, factor IX levels rose in proportion to the administered dose while the concentrations of factor II and factor X did not rise at all. At both doses of concentrate, we did not observe significant post-infusion increments in the levels of the factor X activation peptide (a measure of the activity of the factor VIIa-tissue factor complex and/or the factor IXa-VIIIa-activated surface complex), prothrombin fragment 1 + 2 (a measure of factor Xa activity), and fibrinopeptide A (a measure of thrombin activity). We also infused 10 patients with a PCC (50 IU/kg). After the infusions, significant rises in the concentrations of the factor X activation peptide and prothrombin fragment were observed. Therefore, it appears that the infusion of a PCC to patients with haemophilia B can augment factor X activation and subsequently thrombin generation in vivo and that this process can be abrogated by the administration of more pure factor IX concentrate.
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PMID:No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate. 177 82

Activation of the extrinsic plasmatic clotting system was simulated in a computerized analysis. The results were compared with previously described experimental investigations in plasma with isolated clotting factor deficiency, which led to the conclusion that the sequence of patterns for constants of a function describing the extinction curves is related to the sequence of steps of clotting factor activation. The kinetics of activation resulting in extinction curves that correspond to the curves obtained from experimental measurements are described by sets of stiff coupled linear differential equations. The set of functions can be numerically solved without further approximations. As for experimental extinction curves the simulated extinction curves are characterized by an empirical function with three constants. The distribution patterns for the constants are qualitatively similar to experimental patterns, if the following assumptions are made: (1) feedback reaction occurs from factor IIa via factor V, and (2) the conversion of factor II by factor Xa occurs at a rate considerably slower than the conversion of factor II by the prothrombinase complex. A feedback reaction by factor Xa via factor VII accelerates the formation of factor X, although the distribution pattern remains similar to the distribution pattern for a mechanism without the feedback reaction, provided that the initial activation of factor X occurs at a fast rate. A feedback reaction by factor Xa via factor V in addition to the feedback reaction by factor IIa via factor V accelerates the activation, while the pattern distribution remains unchanged. The simultaneous inhibition of factor Xa and factor IIa by antithrombin III does not change the pattern distribution, while the formation of activated factor II is decelerated.
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PMID:Simulation of the extrinsic pathway of the plasmatic clotting system. 182 78

To examine the relationship between diabetic vascular disease and haemostasis, a set of sensitive assays has been used to assess in vivo activation of coagulation in 62 diabetic patients (41 Type 1 and 21 Type 2), aged 19-68 years, who had been screened for the presence of complications. Fibrinopeptide A, an index of thrombin activity, was significantly increased in diabetic patients compared with control subjects (p less than 0.05), in both plasma (with complications mean 8.04 +/- 11.87 (+/- SD); without complications 7.21 +/- 10.13; control subjects 2.11 +/- 1.40 micrograms l-1) and urine (with complications mean 1.48 +/- 0.74; without complications 1.35 +/- 0.62; control subjects 0.98 +/- 0.39 micrograms l-1). Activated factor VII (VIIa ratio 1.21 +/- 0.39; 1.13 +/- 0.23; 1.01 +/- 0.11) and fibrinogen (3.15 +/- 0.59; 3.11 +/- 0.69; 2.70 +/- 0.57 g l-1) were also elevated in diabetic patients with and without complications (VIIa p less than 0.05, fibrinogen p less than 0.01). The only difference between Type 1 and Type 2 patients was in fibrin degradation products (Type 1 0.28 +/- 0.18; Type 2 0.40 +/- 0.18 mg l-1, p less than 0.01). Plasma levels of fibrin degradation products were elevated in diabetic patients (p less than 0.05 vs control subjects), and correlated with age (r = 0.44, p less than 0.01) but were unrelated to the presence of complications. There were no significant differences in any coagulation variables between diabetic patients with and without complications.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of coagulation in diabetes mellitus in relation to the presence of vascular complications. 183 Feb 55

Haemostatic changes may explain the paradoxical observations that regular exercise helps to prevent ischaemic heart disease but the risk of myocardial infarction and sudden death is actually increased during exercise. This study measured relevant haemostatic variables in 100 athletes before and after races of 10-26.2 miles duration and compared resting levels in athletes with 25 non-exercising controls. Prothrombin time, kaolin cephalin clotting time, fibrinogen, factor VII, factor VIII clotting (one and two stage), von Willebrand factor antigen, euglobulin clot lysis time, fibrin degradation products, full blood count, mean platelet volume, and platelet aggregation to collagen, adrenalin and adenosine diphosphate were measured. The immediate post-race results showed the familiar rise in platelet count and factor VIII clotting but there was no evidence of consumption or thrombin modification of factor VIII clotting. Platelet aggregation to adrenalin was reduced after the race and fibrinolysis was increased (P less than 0.05). The athletes at rest showed no significant differences from controls in their coagulation factor levels but showed increased fibrinolytic activity and reduced platelet aggregation to adrenalin (P less than 0.05). These results suggest a hypocoagulable rather than a hypercoagulable state during running and are consistent with the epidemiological evidence that such exercise is beneficial in the prevention of ischaemic heart disease.
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PMID:Haemostatic changes in long-distance runners and their relevance to the prevention of ischaemic heart disease. 189 55


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