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)

Hageman factor (HF, factor XII), adsorbed to negatively charged agents, is transformed to an activated state in which it initiates reactions of the intrinsic pathway of thrombin formation by activating plasma thromboplastin antecedent (PTA, factor XI). High-molecular-weight kininogen (HMWK, Fitzgerald factor) and plasma prekallikrein accelerate these early steps in the clotting process. Questions have been raised about the role of HMWK in the activation of Hageman factor by surfaces. In the present studies, we report that the activation of purified human HF by sulfatides, ellagic acid, kaolin, or glass occurred in the absence of HMWK. Indeed, small amounts of HMWK inhibited activation of HF by ellagic acid. Physiological concentration of HMWK had little or no influence on the activation of HF by sulfatides, kaolin, or glass, but higher concentrations (3 to 6 times more) showed the same inhibitory effect as after activation by ellagic acid. This inhibitory property of HMWK may be attributed to competitive binding of HF and HMWK on the surface of the activating agents. In fact, when HF was added to kaolin or glass that had been incubated with HMWK and then washed, the inhibitory effect persisted, indicating HMWK that was bound to the surface blocked activation of HF. Studies with 125I-HF and 125I-HMWK supported this interpretation. Plasma prekallikrein accelerated activation of the amidolytic properties of HF by sulfatides, kaolin, or glass but did not influence activation of HF by ellagic acid. In the presence of plasma kallikrein, HMWK at moderate concentrations slightly accelerated the rate of activation of HF by activating agents other than ellagic acid. Higher concentrations of HMWK counteracted both the accelerating effect of prekallikrein and the inhibitory effect observed when HF was incubated with an excess of kaolin. These experiments, then, support the view that the procoagulant function of HMWK is localized to a point subsequent to the activation of HF.
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PMID:The role of prekallikrein and high-molecular-weight kininogen in the contact activation of Hageman factor (factor XII) by sulfatides and other agents. 660 70

Binding of 125I-Factor XIa to platelets required the presence of high molecular weight kininogen, was enhanced when platelets were stimulated with thrombin, and reached a plateau after 4-6 min of incubation at 37 degrees C. Factor XIa binding was specific: 50- to 100-fold molar excesses of unlabeled Factor XIa prevented binding, whereas Factor XI, prekallikrein, Factor XIIa, and prothrombin did not. When washed erythrocytes, added at concentrations calculated to provide an equivalent surface area to platelets, were incubated with Factor XIa, only a low level of nonspecific, nonsaturable binding was detected. Factor XIa binding to platelets was partially reversible and was saturable at concentrations of added Factor XIa of 0.2-0.4 microgram/ml (1.25-2.5 microM). The number of Factor XIa binding sites on activated platelets was estimated to be 225 per platelet (range, 110-450). We conclude that specific, high affinity, saturable binding sites for Factor XIa are present on activated platelets, are distinct from those previously demonstrated for Factor XI, and require the presence of high molecular weight kininogen.
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PMID:Blood coagulation factor XIa binds specifically to a site on activated human platelets distinct from that for factor XI. 660 36

Recent studies on the mechanism of initiation and regulation of blood coagulation are reviewed. In the intrinsic blood coagulation pathway, factor XII, prekallikrein (or factor XI) and high molecular weight kininogen from a complex on an anionic surface, such as exposed subendothelium at the site of vascular trauma. In complex, zymogen factor XII activates prekallikrein (or factor XI) by limited proteolysis to initiate the coagulation cascade. A similar initiating mechanism may be operative in the extrinsic pathway, where zymogen factor VII, complexed with a lipoprotein (tissue factor) and calcium ions, converts factor X to factor Xa. Factor Xa converts prothrombin to thrombin which converts soluble fibrinogen to an insoluble fibrin network which physically arrests the flow of blood from the damaged vasculature. In addition, thrombin converts protein C to activated protein C. Activated protein C functions as a negative regulator in the coagulation process by degrading factor VIIIa and factor Va.
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PMID:Enzymological aspects of blood coagulation. 668 3

Fibrin deposition and platelet thrombus dimensions on subendothelium were studied in four groups of patients with coagulation factor deficiencies. Five patients with factor VIII deficiency (APTT 120 +/- 8 sec) and three patients with factor IX deficiency (APTT 125 +/- 11 sec) were severe bleeders, whereas four patients with factor XII deficiency and seven with factor XI deficiency were either asymptomatic or only mild bleeders despite APTT values of 439 +/- 49 and 153 +/- 13 sec, respectively. Everted segments of deendothelialized rabbit aorta were exposed at a shear rate of 650 sec(-1) for 5 and 10 min to directly sampled venous blood in an annular chamber. Blood coagulation was evaluated by measuring fibrin deposition (percent surface coverage) on the subendothelium and post-chamber fibrinopeptide A levels; platelet thrombus dimensions on the subendothelium were evaluated by determining the total thrombus volume per surface area (using an optical scanning technique) and the average height of the three tallest thrombi. Consistent differences were observed among the patient groups for both the 5-min and 10-min exposure times. The larger of the 5- and 10-min exposure-time values was used to calculate group averages. Fibrin deposition in normal subjects was 81% +/- 5% surface coverage, and post-chamber fibrinopeptide A values were 712 +/- 64 ng/ml. Markedly decreased fibrin deposition and fibrinopeptide A levels were observed in factor VIII deficiency (2% +/- 1% and 102 +/- 19 ng/ml) and factor IX deficiency (11% +/- 7% and 69 +/- 11 ng/ml). In contrast, significantly higher values were obtained in patients deficient in factor XI (33% +/- 5% and 201 +/- 57 ng/ml) and factor XII (66% +/- 12% and 306 +/- 72 ng/ml). Differences in thrombus dimensions were also observed. In normal subjects, the value for thrombus volume and average height of the tallest thrombi were 8.3 +/- 1.3 cu micron/sq micron and 145 +/- 11 micron, respectively, and in patients were as follows: FVIII, 2.7 +/- 0.6 and 71 +/- 7; FIX, 4.5 +/- 1.8 and 88 +/- 14; FXI, 11.8 +/- 1.9 and 125 +/- 10; and FXII, 7.9 +/- 3.1 and 130 +/- 25. Platelet thrombus dimensions were normal in a patient with fibrinogen deficiency, indicating that the smaller thrombi in factor VIII and factor IX deficiencies were probably due to impaired evolution of thrombin rather than diminished fibrin formation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrin formation, fibrinopeptide A release, and platelet thrombus dimensions on subendothelium exposed to flowing native blood: greater in factor XII and XI than in factor VIII and IX deficiency. 671 90

Platelets participate in hemostasis in part by their complex interrelationships with coagulation proteins. Several intrinsic platelet proteins are present in alpha-granules (fibrinogen, factor V, factor VIII antigen, platelet factor 4), in the cytosol (factor XIII), or in the membrane fraction (factor XI). Platelets also contribute to surface-mediated zymogen activations of plasma factors XII, XI, X, and prothrombin and bind several coagulation proteins including factor Xa, thrombin, and fibrinogen. Finally, platelets can protect coagulation enzymes (factors XIa and Xa) from inactivation by plasma proteinase inhibitors. Thereby intrinsic coagulation reactions occur preferentially on the platelet surface leading to fibrin formation within and around platelet plugs.
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PMID:Platelets and coagulation proteins. 678 10

Previous studies have suggested that human platelets can promote the activation of factor XI by two different mechanisms, one requiring factor XII and ADP-treated platelets and the other requiring collagen-treated platelets in the apparent absence of factor XII. To investigate these hypotheses, isolated platelets were tested for their capacity to promote the activation and cleavage of purified factors XII and XI in various mixtures of purified factor XII, kallikrein, high molecular weight kininogen, and factor XI. That ADP- or collagen-treated platelets can promote the proteolytic activation of factor XII in mixtures containing kallikrein and HMW kininogen was shown by (1) the proteolytic cleavage of factor XII, (2) the development of factor XIIa coagulant activity, and (3) the proteolytic cleavage of 125I-labeled factor XII. Platelets treated with collagen or thrombin were shown to both coagulant assays and cleavage studies to participate with HMW kininogen and kallikrein in the proteolytic activation of factor XI by mechanisms that are partially dependent upon and partially independent of factor XII. These studies demonstrate that platelets can promote the proteolytic activation of factor XII by kallikrein and of factor XI by both factor XII-dependent and factor XII-independent mechanisms.
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PMID:Platelet-coagulant protein interactions in contact activation. 702 19

Recently, an alternative pathway for factor XI activation has been described in which factor XI is activated by thrombin. Patients with a factor XI deficiency bleed mostly from tissues with high local fibrinolytic activity. Therefore, the role of thrombin-mediated factor XI activation in both fibrin formation and fibrinolysis was studied in a plasma system. Clotting was induced by the addition of tissue factor or thrombin to recalcified plasma in the presence or absence of tissue-type plasminogen activator, after which clot formation and lysis were measured using turbidimetry. Thrombin-mediated activation of factor XI was found to take place in plasma under physiologic conditions in the absence of a dextran sulfate-like cofactor. At high tissue factor concentrations, no effect of factor XI was seen on the rate of fibrin formation. Decreasing amounts of tissue factor resulted in a gradually increasing contribution of factor XI to the rate of fibrin formation. In addition, thrombin-mediated factor XI activation resulted in an inhibition of tissue-type plasminogen activator-induced lysis of the clot. This inhibition occurred even at tissue factor concentrations at which no effect of factor XI was observed on fibrin formation. Trace amounts of activated factor XI (1.25 pmol/L, representing 0.01% activation) were capable of completely inhibiting fibrinolysis in our system. The inhibitory effect was found to be mediated by thrombin that is additionally generated in a factor XI-dependent manner via the intrinsic pathway and is capable of protecting the clot against lysis. We also observed that formation of additional thrombin continued after the clot had been formed. We conclude that thrombin-mediated factor XI activation can take place in plasma. The presence of factor XI during coagulation results in the formation of additional thrombin within the clot capable of protecting this clot from fibrinolytic attack. The large amounts of thrombin that are formed by the intrinsic pathway via factor XI may play an important role in the procoagulant and thrombogenic state of clots and may therefore have important clinical and therapeutic implications.
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PMID:Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. 757 97

Excess activated factor XI (FXIa) in plasma indicates increased activation during the contact phase of blood coagulation. To investigate the relationship between such elevations and coronary atherosclerosis, we examined FXIa values in patients with coronary artery disease (CAD) by an enzyme-linked immunosorbent assay method that we developed that detects FXIa in plasma samples as an FXIa-alpha 1-antitrypsin complex (FXIa-alpha 1AT). The presence and extent of CAD were documented by coronary angiography and assessed by a recently developed scoring system for semiquantitative estimation of coronary atherosclerosis. Plasma FXIa-alpha 1AT levels were significantly increased in patients with angiographically proven CAD (13.9 +/- 3.0 micrograms/L, n = 42) compared with age-matched, healthy control subjects (11.9 +/- 1.7 micrograms/L, n = 20) as well as patients with angiographically normal coronary arteries (12.0 +/- 2.3 micrograms/L, n = 25). Moreover, in the total patient population, the FXIa-alpha 1AT level was related to the number of significant coronary artery stenoses as well as to the total coronary score. FXIa-alpha 1AT showed a positive correlation with thrombin-antithrombin III complex, fibrinogen, and Lp(a) and an inverse correlation with apo A-I, as determined by multi-variate analysis. Our studies provide evidence that increased activation of the contact pathway occurs in patients with CAD and is related to the severity of the disease. Although it is unknown whether this abnormality is the cause or the result of the vascular lesion, it may be important for progression of the underlying atherosclerosis or for propagation of the atherosclerotic process itself.
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PMID:Evaluation of factor XIa-alpha 1-antitrypsin in plasma, a contact phase-activated coagulation factor-inhibitor complex, in patients with coronary artery disease. 762 3

A 9-year-old female Kerry Blue Terrier with postoperative hemorrhage and prolonged activated partial thromboplastin and activated clotting times was determined to have factor XI deficiency. Transfusions of fresh-frozen plasma given on 4 consecutive days transiently returned the values for activated clotting time and plasma factor XI activity to within reference range limits and controlled the hemorrhage. Analysis of data from 10 other factor XI-deficient Kerry Blue Terriers with a tendency for mild posttraumatic or postoperative bleeding was suggestive of an autosomal mode of inheritance, with a mild tendency for posttraumatic or postoperative bleeding in homozygous and heterozygous dogs. Factor XI deficiency is the only contact phase protein defect that causes a bleeding disorder in animals, which can be explained by the fact that thrombin is more efficient than factor XIIa in activating factor XI. Factor XIa plays a key role in sustaining coagulation.
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PMID:Factor XI deficiency in Kerry Blue Terriers. 773 Jan 23

Amyloid precursor protein forms that contain Kunitz protease inhibitor domains are released from activated platelets, T-lymphocytes, and leukocytes and inhibit trypsin, plasmin, and activated factor XI. We investigated the effects of amyloid precursor protein isoforms on activated Hageman factor (factor XII), activated factor X (Stuart factor), and thrombin. Recombinant amyloid precursor proteins with or without the Kunitz domain, 770 and 695 amino acids, respectively, were produced in insect cells by Baculovirus expression (BAC770 and BAC695). Neither BAC695 nor BAC770 inhibited human alpha-thrombin or activated factor X. The partial thromboplastin time was prolonged by both amyloid precursor proteins, only one of which, BAC770, contains the Kunitz protease inhibitor domain. Both forms of amyloid precursor proteins inhibited ellagic acid-induced activation of Hageman factor but did not inhibit activated Hageman factor. Bismuth subgallate, which is an insoluble analog of ellagic acid, lost its ability to activate Hageman factor on being exposed to BAC770. Inhibition of ellagic acid-induced activation of Hageman factor by both forms of amyloid precursor protein was enhanced by heparin. These findings suggested that the heparin-binding domain of amyloid precursor proteins is not in the Kunitz domain. This heparin-binding domain may block the activation of Hageman factor by negatively charged agents. Thus, amyloid precursor proteins may be involved in the control of hemostasis, properties not all dependent on the Kunitz domain.
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PMID:Inhibitory action of amyloid precursor protein against human Hageman factor (factor XII). 784 73


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