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)

Numerous investigators have postulated that a hypercoagulable state exists in humans for a period of time before the development of thrombotic episodes. A clear biochemical definition of the prethrombotic state, however, has proved elusive due in part to the lack of reliable techniques for monitoring pertinent changes in blood coagulability. Based on recent advances in our knowledge of the biochemistry of the coagulation system, a series of highly sensitive and specific immunochemical tools has been developed that can quantitate the activities of various steps of the hemostatic mechanism in vivo at the subnanomolar level. We have established assays for F1+2 and the protein C activation peptide, which measure the cleavage of the prothrombin molecule by factor Xa and the scission of protein C by the thrombin-thrombomodulin complex, respectively. Nossel and coworkers had previously constructed similar assays for fibrinopeptide A (FPA) and fragment B beta 1-42, which monitor the cleavage of fibrinogen by thrombin and the proteolysis of fibrin I by plasmin, respectively. Substantial elevations in the levels of these markers have been found in patients with disseminated intravascular coagulation and many subjects with acute deep venous thrombosis. The F1+2 and FPA assays have been used to demonstrate that significant increments in factor Xa activity but not thrombin activity regularly occur in the blood of nonanticoagulated individuals with congenital deficiencies of antithrombin or protein C. These two disorders are known to be correlated with the subsequent development of thrombosis. Patients with protein C deficiency have also been noted to have significantly reduced plasma levels of protein C activation peptide. By using the immunoassays for FPA and B beta 1-42 in studies of postoperative patients, it has been shown that an imbalance between the procoagulant action of thrombin and the anticoagulant effect of plasmin on fibrin I polymer may induce an acquired thrombotic diathesis. Finally, we have recently demonstrated that prothrombin activation as measured by the F1+2 assay is suppressed by oral anticoagulants in the blood of patients with thrombotic diatheses. These investigations suggest that these assay techniques can be used to improve our understanding of the hypercoagulable state as well as to develop more effective treatment strategies for the prevention of thromboembolic events.
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PMID:The pathophysiology of the prethrombotic state in humans: insights gained from studies using markers of hemostatic system activation. 360 75

To define the role of activated platelets we have attempted to prepare monoclonal antibodies specific for activated platelets. The IgG2b antibody of one of the clones, designated 2.28, was studied in more detail. Native platelets from normal individuals bound 650 125I-2.28 molecules/platelet, whereas thrombin-activated platelets bound 12,600 molecules/platelet with high affinity (4.6 nmol/L). Immunoelectrophoretic analysis revealed that 2.28 reacted with a 53,000-mol wt protein. Immunocytochemistry showed that the antigen is located in a special subclass of platelet granules in unstimulated platelets and is exposed on the surface of thrombin-activated platelets. Double-labeling studies with immunogold labels disclosed simultaneous localization of 2.28 binding sites and cathepsin D in the same granules both in megakaryocytes and endothelial cells, thereby indicating that the antigen may be localized in lysosomes. By using flow cytofluorometry, in vivo platelet activation was studied in patients undergoing cardiac surgery with cardiopulmonary bypass. Increased numbers of platelets that expressed the 2.28 antigen on their surface were observed after extracorporeal perfusion. The percentage of 2.28-positive platelets in the circulation was 3.9% +/- 2.7% (SD) in controls (n = 20), 5.5% +/- 3.0% in patients (n = 10) before cardiopulmonary bypass surgery, 24.6% +/- 13.5% after the bypass, and 8.5% in two patients with acute deep venous thrombosis. These data indicate that 2.28 may serve as a useful probe of in vitro and in vivo platelet activation.
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PMID:Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000-molecular weight lysosome-like granule protein is exposed on the surface of activated platelets in the circulation. 362 Jul 3

The cause of postoperative DVT is considered to be changes in blood coagulation, stasis of blood within the veins, and injury to the vein wall. The coagulation changes have been investigated and documented and involve platelet activation, stimulation of the coagulation cascade, and blunting of endogenous fibrinolytic activity. Stasis has been objectively identified by retention of contrast material in soleal sinuses and marked changes in venous flow velocity in patients in the supine position and in those under general anesthesia. Vein wall injury is more controversial, but has been shown to be directly related to venodilation. Such dilation of veins occurs in response to operative trauma, hence venous endothelial damage most likely plays a part in the milieu responsible for postoperative DVT. The prophylaxis provided by the combination of dihydroergotamine and heparin appears to affect each of the three limbs of Virchow's triad. Heparin achieves its prophylactic benefit by activating antithrombin III. Activated antithrombin III affects numerous sites in the coagulation cascade. It has been shown that 1 micrograms of antithrombin III inhibits the formation of 1 unit of thrombin; however, in the presence of heparin, 1 micrograms of activated antithrombin III inhibits 750 units of thrombin. Dihydroergotamine increases venous smooth muscle tone without affecting arteriolar smooth muscle. Hence, it has the effect of preventing stasis without increasing blood pressure. It also affects the platelet membrane, prostaglandin synthesis, and blood distribution, although these findings need to be elucidated. The combination of dihydroergotamine and heparin seems to have a synergistic prophylactic effect in preventing postoperative DVT. Heparin modifies the coagulation changes, whereas dihydroergotamine minimizes stasis and potentially prevents the endothelial damage caused by excessive operative venodilation. Such a combination of effects can explain the synergistic prophylactic efficacy found when dihydroergotamine and heparin were employed in combination in the multicenter trial [42].
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PMID:Combined dihydroergotamine and heparin prophylaxis of postoperative deep vein thrombosis: proposed mechanism of action. 390 91

The diagnostic efficiency of autologous 111In-labelled platelets (ILP) as a scanning agent in deep vein thrombosis (DVT) was investigated in 24 South African baboons (Papio ursinus). Thrombi were surgically induced by stasis, intimal injury and the injection of thrombin in the common femoral veins of adult baboons. The thrombi were allowed to age for 1, 2, 4, 8, 24, 48 and 72 h before injecting the ILP. Scanning was done with a large field gamma camera at 10 min post injection and again at 2, 4, 6, 8, 10, 14, 24, 48 and 72 h. Time-activity curves were thus obtained and it was possible to establish an optimal time after injection of the ILP to scan for each group of thrombi. The results indicate that only the younger thrombi (1-8 h after thrombus formation) were detected. Twenty-four hour and older thrombi were not visualised. A favourable time to scan in the case of the younger thrombi appeared to be approximately 20 h after the injection of ILP. However, the thrombus age limitation still impairs the diagnostic efficiency of the procedure.
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PMID:Evaluation of the diagnostic efficacy of autologous 111In-labelled platelets as a scanning agent for deep vein thrombosis in the chacma baboon. 400 84

An abnormal variant of antithrombin III is reported in a young male with deep vein thrombosis. The heparin cofactor, progressive thrombin inhibition, and factor Xa inactivation are decreased. The abnormality seems to be a mutation which is transmitted in an autosomaldominant way. The half-life and fractional catabolic rate of 125I antithrombin III concentrate is the same in this patient as in patients with the classic type of antithrombin III deficiency and in a control.
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PMID:A Swedish family with abnormal antithrombin III. 401 20

Bleeding complications occurred in 30 (11%) out of 280 patients who received continuous heparin infusion for deep venous thrombosis (DVT). 22 (8%) had minor while 8 patients (3%) had major bleeding complications (1 intrathoracic [fatal], 2 gastrointestinal and 5 retroperitoneal). Heparin activity, in daily drawn blood samples, was determined by four assays (chromogenic substrate [CS] assay, activated partial thromboplastin time [APTT], thrombin time with citrated plasma [CiTT] and thrombin time with recalcified plasma [CaTT]). The differences in median heparin activity between patients with minor bleeding and patients with no bleeding did not reach significance for any of the tests. In patients with major bleeding, the differences were significant with the CS (p = .011) and the CaTT (p = .030) assays. Patients with retroperitoneal bleeding had significantly increased median activity judged by all four assays: CS (p = .002), CaTT (p = .003), APTT (p = .010), CiTT (p = .029). The difference was most pronounced after four days of heparin treatment, but there was a considerable overlap with patients without bleeding.
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PMID:Heparin assays and bleeding complications in treatment of deep venous thrombosis with particular reference to retroperitoneal bleeding. 402 37

Human plasma containing the Australia (hepatitis-associated) antigen was fractionated by the cold ethanol method of Cohn, Strong, Hughes, Mulford, Ashworth, Melin, and Taylor (1946) and small aliquots were examined for the presence of this antigen by immunodiffusion and by electron microscopy. The findings were in general agreement with the postulated risk of transmitting hepatitis by blood derivatives. The Australia (hepatitis-associated) antigen was detected in fibrinogen, thrombin, and antihaemophilic globulin as well as in other fractions. The antigen was not found in gamma globulin (immunoglobulin fraction) nor in albumin.The use of radioiodinated fibrinogen for the diagnosis of deep vein thrombosis is discussed and it is concluded that the use of fibrinogen for diagnostic procedures should be assessed against the possible risk of hepatitis.
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PMID:The Australia (hepatitis-associated) antigen in fibrinogen and other fractions of human plasma. 499 77

Plasma concentrations of thrombin sensitive peptide fibrinopeptide A (FpA), plasmin sensitive fibrinogen fragment B beta 1-42 and the platelet release product beta-thromboglobulin (beta TG) have been measured in 36 patients before and after total hip replacement. Statistically significant elevations of all three activation products were observed in the days following operation. There were small differences in plasma concentrations of FpA, B beta 1-42 and beta TG in patients who did (n = 13) and did not (n = 23) develop post operative deep vein thrombosis, as assessed by ascending venography on post operative day 10, but these differences were not statistically significant. It is concluded that coagulation and fibrinolytic systems and also blood platelets are activated following total hip replacement operations. However, the formation of post operative deep vein thrombosis can not be effectively monitored by measurement of the activation products.
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PMID:Plasma concentrations of fibrinopeptide A, fibrinogen fragment B beta 1-42 and beta-thromboglobulin following total hip replacement. 618 May 1

In a prospective study, 280 patients with phlebographically proven deep venous thrombosis received intravenous heparin infusion; 224 of the patients were subjected to control phlebography after 5-8 days of treatment. Females above 70 years showed least phlebographic improvement despite similar heparin dosage and heparin activity. Heparin activity in daily drawn blood samples was determined by four different assays. Chromogenic substrate (CS) assay (Coatest heparin), activated partial thromboplastin time (Cephotest), and thrombin time with recalcified plasma (CaTT) showed weak but significant correlations with thrombus resolution judged by phlebography (p = 0.004, 0.003 and 0.018, respectively). A linear prediction equation showed that the phlebographic result was about equally influenced by the mean dose and by the result of any of the three heparin assays. Thrombin time with citrated plasma showed no correlation. CS assay and CaTT showed significantly lower mean heparin activity in patients with (n = 13) than without clinically diagnosed pulmonary embolism (p = 0.012 and 0.001, respectively).
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PMID:The antithrombotic effect of heparin in deep venous thrombosis: relation to four heparin assays. 649 86

The assay of fibrinopeptide A (FPA) has stimulated particular interest because of its high sensitivity and unique specificity for the action of thrombin. It has proved to be an extremely useful tool in research studies concerning the pathophysiology of thrombotic disease. Use of FPA in the diagnosis and treatment of deep venous thrombosis and pulmonary embolism is reviewed, and the potential usefulness of measuring FPA in the monitoring of the effectiveness of anticoagulant therapy is discussed.
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PMID:Fibrinopeptide A in the diagnosis and treatment of deep venous thrombosis and pulmonary embolism. 649 99


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