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)

A wide variety of haemostatic variables were measured in healthy male subjects predominantly blood donors residing in Riyadh, the capital city of Saudi Arabia. Subjects were divided according to ethnic origin: Saudi Arabs n = 487, Westerners (Europeans and Americans) n = 300, South East Asians (Koreans and Filipinos) n = 360, and West Africans n = 82. There were no significant differences in prothrombin time, partial thromboplastin time, thrombin time, reptilase time, plasma fibrinogen, antithrombin, plasminogen and platelet count between Saudis, Westerners and Asians. Africans exhibited significantly lower plasma levels of fibrinogen, platelet count and plasminogen than other ethnic groups. Arabs and Africans had higher levels of FVIII:C and vWF:ristocetin cofactor than Westerners. On the other hand, FX was significantly higher in Westerners than in other ethnic groups. Smokers had higher fibrinogen levels than non-smokers. These variations, which could not be related to blood group distribution, physical parameters of height and weight, may be due to genetic and/or dietary habits. In conclusion, this study established the existence of racially determined variations in haemostatic variables, with Black Africans showing changes consistent with a lesser tendency towards atherosclerosis and cardiovascular disease than other ethnic groups. These variations should be taken into account when investigating the haemostatic system in patients.
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PMID:Ethnic variations in the haemostatic system: comparison between Arabs, Westerners (Europeans and Americans), Asians and Africans. 757 95

Activated factor VIIa (FVIIa), von Willebrand factor antigen (vWF:Ag), D-dimer and thrombin-antithrombin III complex (TAT) were measured to monitor coagulation status in patients with juvenile chronic arthritis (JCA). Subjects included 14 patients with systemic JCA, 16 with pauciarticular JCA and 16 with polyarticular JCA without disseminated intravascular coagulopathy, thrombosis or liver dysfunction. All types of JCA showed an increase of FVIIa, D-dimer and TAT, indicating enhanced activation of coagulation. In systemic JCA only there was also characteristically an elevation of vWF:Ag. We conclude that all types of JCA constitute a state of subclinical hypercoagulopathy caused by tissue damage and that additionally systemic JCA involves a prothrombotic state associated with or precipitated by vasculitis.
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PMID:Increase of activated factor VIIA and haemostatic molecular markers in juvenile chronic arthritis. 778 78

Healthy endothelium is a metabolically active interface between the blood and extravascular tissues. Its intimal surface is anticoagulant and antithrombotic, and it secretes a variety of molecules involved in regulating platelet function and blood coagulation. The rapid interactions between platelets, their secreted components, or thrombin and endothelial cells at sites of vessel damage ensure the local secretion of mediators such as prostacyclin and nitric oxide that limit the intravascular growth of the haemostatic plug. There is considerable evidence that a decreased ability of endothelial cells to synthesize NO contributes to the pathogenesis of arterial disease. Local deficiency of PGI2 synthesis has also been implicated in the thrombotic problems in haemolytic uraemic syndrome. Endothelium is also the source of circulating von Willebrand factor, important for efficient platelet adhesion. Chronically elevated plasma levels of vWF in a series of diseases where there is vascular pathology apparently reflect endothelial cell damage or activation, and may contribute to the prothrombotic tendency they exhibit. They may be compounded by decreased levels of the surface anticoagulant thrombomodulin, if the increased concentrations of the soluble forms of thrombomodulin detected in the circulation under similar conditions are a reflection of loss from the endothelium. Further alterations of function in a procoagulant/prothrombotic direction take place when endothelial cells are exposed to certain cytokines or lipopolysaccharide. Tissue factor synthesis is induced, thrombomodulin expression is decreased, and there is enhanced sensitivity of vWF secretion. In addition, the balance of tissue-type plasminogen activator and plasminogen activator inhibitor type I secretion is changed in favour of the latter. These processes are each likely to contribute to the occurrence of disseminated intravascular coagulation which can accompany septic shock.
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PMID:Endothelial cell function and thrombosis. 784 94

Various levels of thrombin generation were induced by the infusion of a combination of factor Xa (F.Xa) and phosphatidylcholine/phosphatidylserine (PCPS) vesicles into normal dogs and non-human primates. In the dog, an immediate loss of von Willebrand factor antigen (vWF:Ag) with a progressive recovery to normal levels by 45 min was observed. Multimeric assay demonstrated a selective loss of high molecular weight multimers (HMWM) with subsequent replacement. At low doses, in non-human primates (chimpanzees), identical changes to those seen in the dog were observed and this was associated with an equivalent loss of ristocetin co-factor activity (vWF:RCoF). At high dose a reversal of the wWF response occurred with levels increasing to twice that of baseline values by 2 min and multimeric analysis demonstrated the presence of abnormally large multimers and increased vWF:RCoF specific activity, suggesting that the response at each dosage reflected a net balance of consumption over release. This was supported by in vitro simulation where increasing thrombin generation was associated with a selective loss of HMWM without replacement. In both species, an immediate fall in platelet count occurred and this was directly correlated with the amount of thrombin generated. Full recovery occurred within 45 min and isotopic labelling studies demonstrated that platelet sequestration rather than consumption was occurring. These studies demonstrate that thrombin generation in vivo is associated with a selective loss of the multimeric forms of vWF known to interact with platelets and this may provide an in vivo model to characterize the physiology/pathophysiology of this primary event in haemostasis.
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PMID:The generation of thrombin in vivo induces the selective loss of high molecular weight multimers of von Willebrand factor and the reversible sequestration of platelets. 791 40

We attempted to determine if a hypercoagulability state exists in patients with polycythemia vera (PV) and essential thrombocythemia (ET). We studied the hematocrit level, platelet count, use of any antiaggregant drugs, thrombotic or bleeding accidents and plasma levels of antithrombin III, protein C, total protein S, free protein S, vWF:Ag (Von Willebrand's factor related antigen), thrombin-antithrombin complexes, D-dimer, fibrinolytic activity, tissue plasminogen activator, plasminogen and PAI-1 in 33 patients (19 with ET and 14 with PV). PAI-1 plasma concentration was significantly higher in, both ET and PV patients than in the control group, and were higher in those patients with previous thrombotic episodes than in asymptomatic patients or with previous bleeding episodes. Increasing age was associated to more thrombotic episodes while younger patients presented with more hemorrhagic complications. A linear correlation between platelet count and PAI-1 levels in PV patients (r = 0.44, p < 0.05) and ET patients (r = 0.30, p < 0.05) was found. Fibrinolytic activity in patients with ET was significantly decreased when compared to the control group. A hypofibrinolytic state could be an additional factor which could be used as a predictive index of the thrombotic or bleeding tendency in each patient.
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PMID:High plasma levels of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis. 799 52

Thrombin and the 7-mer agonist peptide from its receptor (SFLLRNP) were compared for their ability to promote the binding of vWF to platelets. Identical Ca(2+)-dependence and kinetics of activation were observed. Studies of inhibition of the binding by a series of monoclonal antibodies to GPIb, GPIIb/IIIa and vWF and experiments performed using platelets from patients with Glanzmann thrombasthenia or Bernard-Soulier syndrome enabled to identify GPIIb/IIIa as the receptor of vWF. Binding isotherms of vWF in the presence of an excess of either agonist yielded a similar number of binding sites but an apparent dissociation constant slightly but consistently higher with the 7-mer peptide than with thrombin. The latter point was confirmed by studying the binding of limiting amounts of vWF to platelets as a function of the agonist concentration. The lower affinity in the presence of 7-mer peptide was not corrected by adding increasing amounts of FPR-thrombin, a derivative with irreversibly blocked active site but retaining the binding properties of the active enzyme. Conversely, the higher affinity observed with thrombin was decreased when platelets were treated with Serratia protease which selectively cleaved GPIb but did not affect the function of the thrombin receptor and GPIIb/IIa. Our data thus suggest that both the 7-mer peptide and thrombin are able to induce the assembly of functional GPIIb/IIIa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of von Willebrand factor with platelets activated by thrombin or a synthetic 7-amino acid peptide derived from the cleaved thrombin receptor. 800 Sep 16

Factor VIII functions as an essential cofactor in the blood coagulation cascade for the factor IXa-mediated activation of factor X. Factor VIII contains 6 tyrosine residues at positions 346, 718, 719, 723, 1664, and 1680 that are modified by post-translational sulfation. This modification is required for full factor VIII procoagulant activity. We have employed site-directed mutagenesis to identify the individual sulfated tyrosines within factor VIII that influence activity. The molecules were expressed in COS-1 monkey cells by transient transfection, and the resultant proteins were characterized. Metabolic incorporation of [35S]sulfate demonstrated that all 6 tyrosine residues are sulfated in factor VIII. Sulfation at residues 346 and 1664 was required for full activity in a factor VIII clotting assay but did not affect factor VIII activity monitored by a factor Xa generation assay. The Tyr346-->Phe and Tyr1664-->Phe mutants displayed delayed thrombin activation that correlated with delayed cleavage at residues 372 and 1689, respectively. In contrast, these mutants were efficiently activated by factor Xa. A triple Tyr to Phe mutant at residues 718, 719, and 723 displayed both reduced factor VIII clotting activity and factor Xa generation activity. Finally, a Tyr1680-->Phe mutant factor VIII displayed a 5-fold reduced affinity for von Willebrand factor. The results demonstrate that 1) sulfation at tyrosine residues 346 and 1664 increases factor VIII activity by increasing the rate of thrombin activation and cleavage; 2) sulfation at tyrosine residues 718, 719, and 723 increases the intrinsic activity of factor VIIIa; and 3) sulfation at tyrosine residue 1680 increases the affinity for vWF. In addition, the results implicate that thrombin interacts with three distinct sites within factor VIII, two of which are required for proteolytic activation. The results demonstrate that the six sites of tyrosine sulfation modulate factor VIII activity through different mechanisms.
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PMID:Identification of individual tyrosine sulfation sites within factor VIII required for optimal activity and efficient thrombin cleavage. 805 Oct 97

Platelet membrane glycoproteins Ib (GPIb) and IIb/IIIa (GPIIb/IIIa) bind soluble von Willebrand factor (vWf) after stimulation with ristocetin (GPIb) or with thrombin or ADP (GPIIb/IIIa). In fluid-phase, vWf does not bind to these platelet receptors without stimulation. In contrast, platelets adhere to solid-phase vWf without stimulation by ristocetin, adenosine diphosphate (ADP), or thrombin, and adhesion increases after stimulation by these agonists. The effect of monoclonal antibodies specific for GPIb (6D1) and GPIIb/IIIa (10E5 and HP1-1D) on platelet adhesion to solid-phase vWF was studied. Adhesion of radiolabeled, washed platelets (with washed red blood cells) aspirated at a constant wall shear rate of 1000 sec-1 through glass capillary tubes coated with purified human vWf was quantified. Unstimulated platelet adhesion was decreased 80% to 90% by blocking either the GPIb site or the GPIIb/IIIa site with 6D1 or 10E5, respectively, or with 6D1 and 10E5 together. Adhesion was not reduced significantly by HP1-1D (anti-GPIIb/IIIa). After stimulation with ADP or thrombin, the platelet adhesion was reduced by prior incubation with saturating concentrations of either 6D1 (61% reduction) or 10E5 (80% reduction), as well as with both 6D1 and 10E5 (80% reduction). After stimulation with ristocetin, the adhesion was reduced with either 6D1 (90% reduction) or 10E5 (90% reduction) or both 6D1 and 10E5 (90% reduction). Prior incubation with HP1-1D had minimal effect on platelet adhesion to vWF after stimulation with thrombin, ADP, or ristocetin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal antibodies to platelet glycoproteins Ib and IIb/IIIa inhibit adhesion of platelets to purified solid-phase von Willebrand factor. 805 92

There is a need for viable small diameter vascular grafts, the luminal surface of which could be seeded by endothelial cells (ECs) to prevent thrombosis. In order to select candidates for EC seeding before implantation, the in vitro cytocompatibility of three different Pellethanes (polyetherurethanes) using human ECs was investigated. The methodology included two stages depending on either direct contact between cells and materials or contact between cells and material extracts, obtained under standardized conditions. By the latter method, we observed a cytotoxic effect on cell growth with 2363-55 D Pellethane extract at a 50% (v/v) concentration in the nutrient medium, likely provoked by leachables and correlated with the lowest levels of tPA, PAI1, and vWF antigens in the supernatants. By the former method, we studied EC attachment and growth. Morphology was studied by classical means and completed by scintigraphy and microautoradiography after 111Indium-labeling of the EC monolayer. Differentiation was determined by the release of vWF antigen and measurement of vWF activity (multimeric organization) after human thrombin stimulation. Despite an inhibition of proliferation for both 55 D and 75 D types (compared to the control), a functional monolayer of ECs was obtained on 75 D. Pellethane 75 D could be the best support for in vitro endothelization.
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PMID:Endothelial cell compatibility testing of three different Pellethanes. 826 99

Effect of blood-air contact in the venous line air-trap chamber on blood clotting was studied. Fourteen chronic hemodialysis patients (six men, eight women; mean age, 49 years) with elevation of thrombin-antithrombin III were studied. To prevent blood-air contact, triglyceride (NOF-005) was floated over the blood in the chamber. Control hemodialysis was performed for 4 weeks and hemodialysis using NOF-005 followed for the next 4 weeks. Clot formation in the circuit was examined after each hemodialysis and clotting factors including thrombin-antithrombin III, FXII Antigen, vWF Antigen, PF4 and beta-thromboglobulin were measured before and after the last hemodialysis of each control and NOF-005 hemodialysis. Clotting in the chamber was improved when NOF-005 was used. Thrombin-antithrombin III increase during hemodialysis was suppressed to about 30% of control values by using NOF-005. blood-air contact seems to promote thrombin generation and accelerate clot formation.
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PMID:Suppression of thrombin formation during hemodialysis with triglyceride. 826 4


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