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)

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.
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PMID:Exercise-induced myocardial ischemia in patients with coronary artery disease: lack of evidence for platelet activation or fibrin formation in peripheral venous blood. 633 91

Among extracellular biological processes the spatial control of blood clotting is a unique phenomenon. Localization in space has very important consequences in both normal and pathological conditions. Under physiological circumstances a clot is formed only in the vicinity of injury, albeit the prerequisites of coagulation are almost completely given in the whole circulation. The local character of blood clotting is secured by the following major conditions: The regulatory signal initiating coagulation-the damaged vascular wall-is itself a surface on which the majority of clotting reactions take place. The first enzyme, factor XII, of the intrinsic coagulation pathway is activated on the collagen fibers exposed in the damaged vascular wall, although the significance of this reaction in respect of the clotting process is ambiguous. On the membrane of platelets adhered to the damaged blood vessel is activated factor XI, too, which is a well-established participant of the intrinsic clotting process. The further consecutive reactions of coagulation are confined to the surface produced by injury, because the enzymes involved contain gamma-carboxyl-glutamyl side chains which are anchored through calcium bridges to the phospholipids of the platelet membrane. The last enzyme of the sequence is thrombin, which is released from the surface. The reactions taking place on the surface form an enzyme cascade, which amplifies the relatively weak triggering signal by several orders of magnitudes. Amplification is ensured not only by the enzyme-substrate relationship of the consecutive reaction partners, but also by spatial confinement, which endows the process with higher efficacy than could be expected on a statistical basis from reactions in solution. It contributes to the efficiency of enzyme cascade that the non-enzymatic regulatory proteins increase the activity of factors IXa and Xa, and thereby the overall process. While the partner of factor IXa, factor VIII, is captured from plasma, factor V, the partner of factor Xa, is derived from the platelets adhered to the damaged surface and orients the binding of factor Xa. The surface localization ensures the protection of the members of clotting system: In the activator complexes found on the surface, the spatial arrangement of clotting factors prevents the inactivation of factors by physiological inhibitors or by proteolytic enzymes and specific antibodies that appear in the circulation in pathological conditions. Platelet factor 4, derived from platelets, binds heparin and thereby markedly decreases the reactivity of antithrombin III, the physiological inhibitor of clotting factors. The above two circumstances are
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PMID:Surface-governed molecular regulation of blood coagulation. 636 61

Ristocetin, protamine and Polybrene promote factor VIII:vWF binding and agglutination of formalinized platelets. It has been suggested that these polycations neutralize platelet negative surface charges and promote the attachment of VIII:vWF to platelets. Platelet factor 4 (PF4), protamine, and Polybrene inhibit heparin activity by neutralizing heparin negative charges. We tested the hypothesis that PF4, which is bound to the platelet surface after platelet activation and secretion, could promote the binding of VIII:vWF and subsequent platelet agglutination. Purified PF4 in concentrations comparable to those of ristocetin did not agglutinate formalinized platelets or induce the disappearance of VIII:vWF from the suspending plasma. Platelets were thrombin-treated in order to induce the release of PF4, and then formalinized and resuspended in normal plasma. These platelets did not agglutinate spontaneously, or at lower ristocetin concentrations than platelets that were not treated with thrombin before formalin fixation. Platelets were also activated by thrombin in the presence of EDTA to prevent surface binding of VIII:vWF or secreted PF4, and then formalinized. These platelets did not bind VIII:vWF in the presence of purified PF4. We conclude that even though PF4 binds to both polyanions and the platelet membrane, it does not promote the attachment of VIII:vWF.
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PMID:Platelet factor 4 does not promote von Willebrand factor binding to human platelets. 644 Mar 7

AGEPC (PAF), at 1.9 x 10(-8) M or higher, induced concentration-dependent aggregation and release in human platelet-rich plasma. Comparative studies with arachidonate, collagen, ionophore, and ADP suggested that AGEPC was a strong stimulus for platelet aggregation and probably a moderate agonist for release, as well as a relatively weak inducer of TXA2 production. The initial phase of AGEPC-induced aggregation was independent of ADP release and TXA2 formation, since it was not inhibited by ASA, apyrase, or CP/CPK. Whereas irreversible aggregation always required ADP release, TXA2 formation was not essential in each instance. Thus, in several experiments, full aggregation responses took place in AGEPC-stimulated platelets that had been pretreated with ASA. AGEPC-induced release of 5-HT, beta -thromboglobulin and PF-4 occurred in parallel and were inhibited by both apyrase and ASA. Washed human platelets did not respond to exogenous AGEPC in the absence of ADP and did not appear to generate significant quantities of AGEPC upon stimulation with thrombin or ionophore.
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PMID:Effects of acetyl glyceryl ether phosphorylcholine on human platelet function in vitro. 645 58

Heparin cofactor II is a glycoprotein present in human plasma at a concentration of approximately 1.2 microM. It inhibits thrombin by forming a stable, 1:1 complex with the protease. The rate of complex formation is increased approximately 1,000-fold by heparin or dermatan sulfate. Heparin cofactor II appears to be the only thrombin inhibitor in plasma that can be activated by dermatan sulfate. Platelet factor 4 abolishes the activation of heparin cofactor II by dermatan sulfate, but plasma histidine-rich glycoprotein does not. Heparin cofactor II is activated by dermatan sulfate oligosaccharides that are at least 12-14 sugar residues in length and contain a high-affinity binding site for the inhibitor protein.
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PMID:Activation of heparin cofactor II by heparin and dermatan sulfate. 654 14

Platelet factor 4 (PF4) is a potent antiheparin in vitro. In view of the large amount of PF4 secreted from platelet alpha-granules during routine blood collection and processing techniques, the potential significance of this release was investigated using three measurements of heparin activity: the activated partial thromboplastin time (aPTT), the thrombin time, and factor Xa inactivation using the chromogenic substrate S2222 for assay of factor Xa. The results demonstrate that purified PF4 neutralizes heparin activity when added in increasing amounts to normal platelet-poor plasma containing a fixed concentration of commercial porcine gut mucosal heparin. This effect was seen when assaying heparin activity by all three methods. In addition, when heparin was added in increasing concentrations to pooled plasma samples that were collected from normal volunteers, there was neutralization of heparin activity in blood samples collected by routine citrate anticoagulation (CIT60) in comparison to blood samples collected simultaneously with platelet secretion inhibiting agents added to the anticoagulant (CIT+). This effect was seen when assaying heparin by the aPTT and thrombin time. These data confirm that both purified and secreted PF4 have significant antiheparin activity when heparin is added in vitro to normal plasma. Neutralization of circulating heparin by PF4 secreted during blood collection from anticoagulated patients could result in underestimation of the actual in vivo heparin concentration. In order to evaluate the significance of this effect, purified PF4 was added to plasma collected from heparinized patients and again PF4 neutralized heparin activity. This was seen, however, only when heparin activity was measured by the thrombin time or Xa inactivation assays. There was minimal shortening of the aPTT when PF4 was added in final concentrations up to 1000 ng/ml. When blood samples were simultaneously collected from anticoagulated patients by both routine and special collection methods, these results were confirmed. There was a significant difference between heparin activities measured in the CIT+ (secreted PF4 58 ng/ml) and CIT60 (secreted PF4 1074 ng/ml) plasma samples by both thrombin time and Xa inactivation. There was no difference, however, in the aPT when both types of plasma samples were simultaneously collected and assayed for each anticoagulated patient. This suggests that there may be circulating heparin fractions which can prolong the aPTT but which do not interact with PF4.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of platelet factor 4 (PF4) on assays of plasma heparin. 674 73

Two in vitro systems were used to identify an antithrombin III cofactor activity on vascular endothelium. Langendorff rat heart preparations or columns packed with endothelium cultured on microcarrier beads were perfused with mixtures of purified thrombin and antithrombin III. With each preparation, accelerated inhibition of thrombin by antithrombin III occurred during passage over endothelium. Platelet factor 4, protamine sulfate and diisopropylphosphoryl thrombin, all antagonists of the antithrombin III cofactor activity of heparin, significantly reduced the capacity of the preparation to inhibit thrombin. It is concluded that a substance with the functional properties of a stationary phase cofactor for antithrombin III is present on the microvascular endothelium and there catalyzes the inactivation of circulating free thrombin.
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PMID:Identification in vitro of an endothelial cell surface cofactor for antithrombin III. Parallel studies with isolated perfused rat hearts and microcarrier cultures of bovine endothelium. 706 10

To determine the relationship between platelet secretion and prothrombin conversion in whole blood, the release of platelet factor 4 and the generation of a X(a)-specific cleavage product of prothrombin, fragment 1 + 2, were measured during the coagulation of whole blood. There was a parallel increase in the concentration of the two proteins. Over the first 5 min of incubation, platelet factor 4 concentration increased 6 ng/ml per min, and after 6-7 min, the rate of release increased to 750 ng/ml per min. Over the initial 5-7 min of incubation, fragment 1 + 2 concentration increased 1.5 pmol/ml per min with a subsequent increase of 45 pmol/ml per min. Incubation with 10 muM prostaglandin E(1) or 15 muM prostaglandin I(2) inhibited secretion of platelet factor 4 and delayed the onset of the rapid phase of fragment 1 + 2 generation by 8 min, while stimulation of platelet secretion with 1 mug/ml collagen suspension enhanced production of fragment 1 + 2. The addition of either 10 muM epinephrine or 100 ng/ml collagen suspension to whole blood did not affect either platelet factor 4 release or fragment 1 + 2 generation, although the combination of 3 muM epinephrine and 100 ng/ml collagen suspension enhanced platelet release and prothrombin cleavage. The relationship between platelet factor 4 release and prothrombin cleavage was also studied in Factor VIII-deficient blood. When 0.001 U/ml factor VIII activity was present, <80 ng/ml platelet factor 4 were released, and no fragment 1 + 2 was generated after 30 min of incubation. The addition of 0.008-0.08 U/ml Factor VIII activity progressively increased platelet factor 4 release and prothrombin cleavage. Platelet factor 4 release was normal at 0.08 U/ml Factor VIII activity, whereas prothrombin cleavage was still delayed. Very little thrombin, the amount generated by the cleavage of 3-5 nM fragment 1 + 2, was needed to induce release of platelet factor 4.
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PMID:Relationship between platelet secretion and prothrombin cleavage in native whole blood. 726 60

The purpose of this study was to investigate whether or not the systems of coagulation and fibrinolysis are activated after human recombinant erythropoietin therapy in patients with end-stage renal failure and renal anemia. Six thousand IU of human recombinant erythropoietin (EPOCH) were administered intravenously to 11 patients once a week for 8 weeks. Coagulation, fibrinolysis and platelet as well as renal functions were investigated before and after the EPOCH therapy. Platelet count did not increase in spite of improvement in anemia. No changes in prothrombin time, activated partial thromboplastin time, concentrations of fibrinogen, fibrinopeptide A, thrombin antithrombin III complex, fibrin/fibrinogen degradation products (FDP), FDP-E, FDP-D dimer, plasmin alpha 2-plasmin inhibitor complex were observed. Platelet factor 4 and beta-thromboglobulin also were unchanged. Reciprocal changes in serum creatinine concentrations over the duration of therapy were compared before and after therapy. There was no significant difference between the reciprocal changes in serum creatinine concentrations before and after therapy. The increases in hemoglobin did not correlate with the changes in coagulation, fibrinolysis and the other parameters, except for the change in prothrombin time. These results indicate that coagulation, fibrinolysis and platelet systems in end-stage renal failure patients were not affected by EPOCH administration, in spite of increase in hemoglobin.
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PMID:Effects of recombinant human erythropoietin (EPOCH) on the coagulation and fibrinolytic systems and platelet function in pre-dialysis patients with chronic renal failure. 825 11

In a randomized crossover study twelve healthy male volunteers (23.5 +/- of 4.8 years, 73.0 +/- 6.4 kg, 180.8 +/- 5.7 cm) received one subcutaneous injection of either enoxaparin (EN) at 40 mg or 1 mg kg-1, or unfractionated heparin (UH) at 5,000 IU at one week intervals. Area under curves (AUC) of Anti-Xa and Anti-IIa activities correlated with EN dose. The relative effectiveness of EN versus UH 5,000 U as assessed by AUC ratio (EN/UH) was 7 and 15 for Anti-Xa activity, 1.3 and 3.1 for Anti-IIa activity after sc injection of EN 40 mg (4,000 Anti-Xa IU and 1,200 Anti-IIa U) and 1 mg kg-1 (7,300 +/- 640 Anti-Xa IU and 2,190 +/- 290 Anti-IIa IU) respectively. In volunteers receiving EN, a dose dependent inhibition of thrombin generation rate in platelet depleted plasma (PDP), measured with a new and simple chromogenic thrombin generation assay, was observed when compared with baseline values. Similarly, intrinsic prothrombin activation in whole blood, evidenced by measuring residual factor II in serum 2 hours after clotting (prothrombin consumption test: PC), was inhibited in a dose dependent manner. In UH treated volunteers, although the inhibition of thrombin generation rate in PDP was similar to that observed with EN 40 mg, prothrombin consumption in whole blood was not significantly modified. Tissue factor pathway inhibitor (TFPI) activity release was increased similarly for UH and EN 40 (1.4 fold increase above baseline values) and 1.9 fold for the higher dose of EN. The discrepancy between prothrombin consumption in whole blood and inhibition of thrombin generation rate in PDP in the UH and not in the EN group strongly suggests that UH and not EN is influenced by the presence of a platelet component. This could be formed during thrombin induced platelet activation. Platelet factor 4 is a possible candidate. Another hypothesis involves the role of TFPI-UH complex anticoagulant activity which might be inhibited more during whole blood coagulation than the TFPI-EN complex.
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PMID:Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor. 838 83


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