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)

Factor VIII (antihemophilic factor) is the protein that is deficient or defective in patients with classical hemophilia and Von Willebrand syndrome. Factor VIII in plasma is thought to be associated in a complex with the highest molecular weight multimers of another glycoprotein, Von Willebrand protein. Highly purified human factor VIII appears to have an Mr of between 200,000 and 300,000 and to consist of several polypeptide chains. The concentration of factor VIII in plasma is around 100-200 ng/ml, equivalent to around 1 nM. The purified proteins retain one or more of the known properties of factor VIII, including the acceleration of factor IXa-mediated activation of factor X, ability to be activated by thrombin and factor Xa, inactivation by activated protein C, and by human antibodies to factor VIII. Among the known clotting factors, factors VIII and V are exceptional in not possessing enzymatic activity. Factors IXa and VIII and X appear to form a functional complex, all of which need to be present and active simultaneously for optimal activation of factor X. The mechanism by which factor VIII promotes activation of factor X by factor IXa is not known, but the major effect is to increase the rate of the reaction. Following treatment of factor VIII with thrombin, a new and smaller polypeptide Mr around 70,000 +/- 5,000 is produced. Factors IXa and Xa also have been reported to activate factor VIII. It is not known whether limited proteolytic cleavage is required absolutely for the expression of factor VIII activity or if it only increases an activity already expressed by the uncleaved protein. Factor VIII is inactivated by thrombin and by activated protein C. Thus, factor VIII can be modulated by at least four of the serine proteases in the clotting system. A major goal for future research is to increase our understanding of the role in blood clotting played by factor VIII, and to apply this information to clinical problems which result from inherited abnormalities of factor VIII.
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PMID:Factor VIII: structure and function in blood clotting. 642 37

Thrombokinetograms are graphic depictions of the optical changes occurring in plasma during the clotting process and provide information, not only on the time required for clotting to begin, but also on the way in which the clot forms. We studied thrombokinetic profiles in plasmas from normal dogs, and dogs with varying degrees of factor VIII deficiency. Clotting was induced through intrinsic, extrinsic and common coagulation pathways [activated partial thromboplastin time, prothrombin time and thrombin time, respectively]. The thrombokinetograms for the various clotting tests were qualitatively similar in normal canine plasmas. After activation of the clotting system there was a period in which no change in optical density occurred. This period was represented by the left base line and corresponded to the duration of the clotting time. When fibrin production commenced there was a rapid increase in the rate of optical density change (DeltaOD) to a maximum (V(max)DeltaOD) in time t(1). This was followed by a more gradual reduction in DeltaOD in time t(2). The activated partial thromboplastin time thrombokinetograms for von Willebrand's disease plasmas were characterized by a reduced V(max)DeltaOD and prolonged t(1). In severe hemophilic plasma [factor VIII coagulant (F VIII:C)<1% of normal] there was a very slow increase in DeltaOD following a prolonged left baseline. The V(max)DeltaOD, t(1) and t(2) could not be determined since a peak was not attained in one minute. The prothrombin and thrombin time thrombokinetograms for von Willebrand's disease plasmas were normal. The prothrombin time thrombokinetogram for hemophilic plasma had a 2X normal V(max)DeltaOD possibly related to the relatively high fibrinogen concentration of this plasma compared to the normal. Changes in thrombokinetogram profiles may be of value in studying mild to moderate clotting factor deficiencies particularly where the clotting times are not markedly prolonged.
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PMID:Thrombokinetic studies in normal and factor VIII-deficient canine plasmas. 660 92

von Willebrand Factor (vWF) is a high molecular weight multimeric (1-20 X 10(6) daltons) glycoprotein which is absent or inactive in von Willebrand's disease (vWD). It is synthesized by the endothelial cell under the control of an autosome and may be released into the blood stream as well as into the subendothelium (SE). vWF is also synthesized by the megacaryocyte and localized in the alpha granules of platelets. Platelet vWF is released during aggregation. Platelets do not adhere to intact endothelial cells but interact with the SE in case of vessel wall injury. vWF plays a key role in platelet adhesion to the SE, especially at high shear rate conditions which prevail in the microcirculation. This function is confirmed by the decreased platelet adhesion observed in either vWD blood (corrected by vWF) or normal blood in the presence of polyclonal or monoclonal antibodies to vWF. The mechanism of platelet adhesion to the SE is still poorly understood. vWF only acts at high shear, ie when the flow rate is elevated and the time of interaction between platelets and the vessel wall is short. This large protein could serve as a "bridge" between the platelet membrane and the SE. It has been shown to bind first to the SE prior to platelet adhesion. Platelet and endothelial cell vWF probably also interact since they may be released in high concentration at the site of injury. The nature of the SE component to which vWF and platelets bind is unknown. Among the candidates are the basement membrane and the collagen fibers (which adsorb vWF), fibronectin, and the microfibrils (which induce vWF-mediated platelet aggregation). It is thus possible that a receptor for vWF exists on one of these components. The ristocetin-induced platelet membrane receptor for vWF seems to be glycoprotein Ib, platelet adhesion being also abnormal in Giant Platelet Syndrome. The in vivo counterpart for ristocetin is unknown, but it is possible that collagen, microfibrils, thrombin (which also induces the platelet receptor for vWF or sialidases (asialo-human vWF is able to directly bind to the platelet membrane) could replace ristocetin. Several sources of data suggest that carbohydrate is important in vWF-platelet interaction.
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PMID:[Von Willebrand factor and platelet adhesion to the subendothelium of the vascular wall]. 675 79

Partially purified (approx. 5000-fold), low molecular weight human antihemophilic factor, free of detectable Von Willebrand factor (ristocetin cofactor activity or Von Willebrand antigen), was prepared from fresh citrated plasma by limited reduction with 1 mM dithiothreitol and chromatography on Sepharose CL-4B, Sephadex G-100, and polyelectrolyte E-5. The ratio of antihemophilic factor activity to Von Willebrand factor activity or antigen was greater than 27 000 : 1. The antihemophilic factor activity could be neutralized with homologous antibody and could be further increased with thrombin. The Mr (approx. 116 000) was determined by calibrated gel permeation chromatography, electrophoresis in 5% polyacrylamide gels with sodium dodecyl sulfate and by electrophoresis in large-pore acrylamide gels without it. Since the low Mr antihemophilic factor could be prepared by treating fresh rather than fresh-frozen plasma with dithiothreitol, it was concluded that partial reduction of the antihemophilic factor with this reagent helped to maintain the antihemophilic factor in a low Mr form. When iodo[l-14C]acetamide was used to alkylate the reduced plasma proteins prior to purification, the molecular weight of the purified antihemophilic factor remained low despite numerous purification steps. By this means, one of four radioactive proteins (Mr 116 000) in the final preparation was bound specifically to homologous antihemophilic factor antibody and attributed to 14C-labeled antihemophilic factor. While the data suggest that antihemophilic factor in fresh plasma contains one or more dithiothreitol-sensitive intramolecular disulfide bonds, the possibility of disulfide linkages with other proteins(s) cannot be excluded.
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PMID:Partial purification of biologically active, low molecular weight, human antihemophilic factor free of Von Willebrand factor. I. Partial characterization and evidence for disulfide bond(s) susceptible to limited reduction. 678 56

Fibronectin is involved in cell-cell and cell-substratum adhesion processes. Since von Willebrand's disease and thrombasthenia are characterized, respectively, by platelet-substratum and platelet-platelet adhesion anomalies, we investigated the state of fibronectin in platelets and plasma of these two disorders as well as the role of plasma fibronectin in platelet aggregation. The levels of platelet and plasma fibronectin in three cases of von Willebrand's disease and in three cases of thrombasthenia did not show statistically significant differences as compared with the normal controls. Immunofluorescent staining intensity and patterns of disease-derived and normal platelets, studied with anti-fibronectin antibodies, were similar. Furthermore, 125I-labeled protein A binds to anti-fibronectin-treated platelets from the two diseases investigated in the same fashion as in normal controls. No role for plasma fibronectin was detected in platelet aggregation induced by ADP, thrombin, collagen, epinephrine, and arachidonic acid. Thus our results do not indicate a direct quantitative role of fibronectin in the adhesion anomalies encountered in these diseases. However, fibronectin may still be important to platelet adhesion and normal hemostasis processes through interactions with the plasma von Willebrand factor and the membrane glycoproteins IIb and III, which have been shown to be deficient in von Willebrand's disease and thrombasthenia, respectively.
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PMID:Fibronectin in von Willebrand's disease and thrombasthenia: role in platelet aggregation. 696 68

von Willebrand's antigen II (vW AgII), a plasma and platelet antigen immunologically and biochemically distinct from factor-VIII-related antigen (VIIIR:Ag), is decreased in von Willebrand's disease. vW AgII is released from platelets during aggregation and clotting. The release of platelet vW AgII was studied in washed platelets following aggregation by thrombin, collagen, and adenosine diphosphate (ADP). Total platelet vW AgII was 3.39 U/10(9) platelets. Thrombin and collagen yielded release of 85% and 86% of platelet vW AgII, respectively, at the highest concentrations. Release of platelet vW AgII was correlated with the release of 5-hydroxytryptamine (5HT). Release of vW AgII by collagen and thrombin was inhibited by metabolic inhibitors. In addition, collagen release of vW AgII was inhibited by aspirin. In clinical syndromes associated with intravascular platelet destruction, marked elevations of plasma vW AgII were noted. Thus, vW AgII is released by a metabolically active process from platelets during aggregation. In addition, vW AgII appears to be a marker of intravascular platelet destruction.
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PMID:Platelet von Willebrand's antigen II: active release by aggregating agents and a marker of platelet release reaction in vivo. 697 40

A new type of congenital platelet dysfunction was found in a young woman presenting a life-long bleeding disorder. The known types of thrombopathia and von Willebrand's disease were excluded by appropriate investigations. The platelets were morphologically normal, underwent normal shape change and contraction and synthesized thromboxane A2 (TXA2) normally. The release reaction was abnormal and the aggregation response to ADP, adrenalin, collagen, thrombin, sodium arachidonate and vasopressin was depressed due to decreased sensitivity of the platelets to prostaglandin endoperoxides and TXA2. Platelet cAMP content was increased.
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PMID:Constitutional thrombocytopathy with subnormal response to thromboxane A2. 719 74

Recent investigations suggest that microthrombi formation in bowel capillaries could be a determinant factor in inflammatory bowel disease (IBD) pathogenesis. To evaluate the implication of the hemostatic system during these thrombotic events, we analyzed plasmatic values of prothrombotic state markers, physiologic inhibitors of coagulation, and endothelial lesion markers in 112 IBD patients. We found an increase in thrombin-antithrombin complexes and a decrease in antithrombin III, probably due to consumption, demonstrating an increase in thrombin generation. High levels of D-dimer reflect increased fibrin formation, but there is no correlation between thrombin generation markers and D-dimer, possibly suggesting the presence of inadequate fibrinolysis. Levels of tissue factor pathway inhibitor were higher in patients than in controls. Nine patients with Crohn's disease (35% of our sample) had levels of this marker under 70% (range 37-69%). Von Willebrand factor values were increased and those of thrombomodulin only in active patients. Most of the changes were detected in patients with inflammatory activity, and there were no differences between ulcerative colitis and Crohn's disease. In conclusion, these results support the hypothesis that there is an endothelial lesion with sustained coagulation activation in IBD patients.
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PMID:Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease. 755 37

In week 12 of the EICESS 92 protocol a 12-year-old boy with pelvic PNET developed acquired von Willebrand disease: bleeding time was prolonged (> 15 min) and von Willebrand factor antigen (54%) and ristocetin cofactor activity (50) were reduced. Platelet aggregations with thrombin and collagen and the number of major platelet glycoproteins/per platelet did not differ from the controls. After Haemate P (Behring Werke, Marburg, Germany) bleeding time normalized and surgery could be performed without occurrence of bleeding episodes. Three weeks after surgery bleeding time, ristocetin cofactor activity, and von Willebrand factor antigen increased to normal paediatric values. Without occurrence of further bleeding episodes the patient received another 10 courses of polychemotherapy (EICESS 92).
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PMID:Acquired von Willebrand disease in malignant peripheral neuroectodermal tumor (PNET). 760 96

In the early phase of primary hemostasis, platelets adhere to damaged vessel wall by binding via the platelet glycoprotein (GP) Ib-V-IX complex to von Willebrand factor (vWf) exposed on the subendothelium. The complex is composed of four glycoprotein subunits, GPIb alpha, GPIb beta, GPIX and GPV, each with a variable number of leucine-rich repeats. GPIb alpha and GPIb beta are linked by a disulphide bridge while GPIX and GPV associate noncovalently with the complex. The study of defects in the expression of the GPIb-V-IX complex at the platelet surface leading to pathological disorders, like Bernard-Soulier syndrome (BSS), or in the affinity of platelets for vWf, like pseudo-von Willebrand disease, has helped to delineate the binding site for vWf on GPIb alpha. However, the mechanism by which the complex binds to vWf has not yet been elucidated but it must involve changes in the conformation of the molecules as no interaction between platelets and vWf occurs in the plasma. The GPIb-V-IX complex has a binding site for thrombin on GPIb alpha which participates in the platelet activation by that agonist. GPV is also cleaved by thrombin but the function of this proteolysis is not clear. The platelet response to thrombin is slower and weaker when the thrombin binding site on GPIb alpha is blocked or cleaved or when the GPIb-V-IX complex is not expressed on the platelet surface as in classic BSS. At low doses of thrombin, the rapid activation of the platelets via the seven-transmembrane thrombin receptor is dependent on the presence of the GPIb-V-IX complex.
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PMID:Platelet GPIb-V-IX complex. Structure, function, physiology, and pathology. 766 Jan 35


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