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)

Alterations of platelet, coagulation, and fibrinolysis markers were investigated to determine the indications for antithrombotic therapy in patients with different clinical categories of acute cerebral infarction. Marked platelet activation was observed in platelet function tests, including measurements of platelet-specific proteins and platelet survival, platelet scintigraphy in the brain, and platelet fibrinogen binding assay, in patients with atherothrombotic stroke. Among patients with atherothrombotic stroke, increases of thrombin-antithrombin III complex (TAT) and D-dimer were frequent in addition to the findings of platelet activation in patients showing progressing stroke. Patients with cardioembolic stroke demonstrated marked elevation of coagulation markers, TAT and fibrinopeptide A, and fibrinolysis markers, D-dimer and plasmin-alpha2-plasmin inhibitor complex, as well as platelet activation. In contrast, neither activation was seen in patients with lacunar stroke. On the basis of these findings, antiplatelet therapy is indicated for stable or improving stroke, whereas anticoagulant therapy is indicated for progressing stroke among patients with atherothrombotic stroke. In patients with cardioembolic stroke, anticoagulant therapy should be started as soon as possible, or should be followed by thrombolytic therapy in the hyperacute phase. However, further investigation appears necessary for recommendations for patients with lacunar stroke.
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PMID:Alterations of platelet, coagulation, and fibrinolysis markers in patients with acute ischemic stroke. 946 26

In order to clarify the coagulation profile accompanying ischemic stroke, which may have implications on therapeutic strategies, we performed a prospective study to evaluate the hemostatic parameters in the first 24 h after the onset of cortical atherothrombotic infarct and lacunar infarction. Twenty-seven patients with cortical atherothrombotic infarction and 27 patients with lacunar infarction, diagnosed on clinical and CT-scan criteria, had blood samples taken within the first 24 h after onset of the stroke, and before anticoagulant treatment had been started. Levels of fibrinogen, von Willebrand factor, D-dimers, prothrombin factors 1 + 2, anti-thrombin III, and C-protein and S-proteins, were measured. Laboratory tests detected the following abnormalities: a protein C deficiency was observed in 1 case of cortical infarction and in 1 case of lacunar infarction; a decrease in S-protein was observed in 1 case of cortical infarction, and the presence of lupus anticoagulant in 4 cases (2 in cortical and 2 in lacunar infarction). Various degrees of coagulation activation were observed. Statistically significant activation of the coagulation was observed in the patients with cortical infarction, compared to normal patients adjusted for age: the levels of DDI were significantly raised (2298 +/- 2221 ng ml-1 vs. 750 +/- 400 ng ml-1) (p < 0.03) as were F1 + 2 levels (3.9 +/- 2.8 nmol l-1 vs. 1.5 +/- 0.9 nmol l-1). (p < 0.01). In the lacunar infarction group, there was a significant rise in F1 + 2 compared with normal patients adjusted for age (2.2 +/- 1.7 nmol l-1 vs. 1.5 +/- 0.9 nmol l-1) (p < 0.01), while the DDI level was in the normal range, when age was taken into account. In the cortical infarction group, we observed a significantly raised fibrinogen level (4.8 +/- 1.7 g l-1 vs. 3.7 +/- 1.0 g l-1) (p < 0.05) and von Willebrand factor level (271 +/- 104% vs. 178 +/- 103%) (p < 0.01) compared to the lacunar infarction group. In addition, we observed a significantly low level of S-protein in the cortical infarction group (105 +/- 29%) compared to the lacunar infarction group (127 +/- 28%) (p < 0.01). Confirmation of the role of enhanced thrombin activity in the pathogenesis of acute stroke may be an important determinant in its therapeutic management.
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PMID:Coagulation abnormalities in lacunar and cortical ischemic stroke are quite different. 947 Oct 97

From injury through healing, thrombin has several important functions in blood clotting, subsequent clot lysis, and tissue repair. These include edema, inflammation, cell recruitment, cellular releases, transformations, mitogenesis, and angiogenesis. Thrombin also participates in disease states, such as venous thrombosis, coronary thrombosis, stroke, and pulmonary emboli, among others and is implicated in atherosclerosis, the growth and metastasis of certain cancers, Alzheimer's disease, and perhaps other conditions. Thrombin must be continually generated to sustain normal and pathogenic processes. This is because of a variety of consumptive mechanisms. Unlike other activated factors in thrombotic and fibrinolytic pathways, and because thrombin promotes its own generation (feedback and cellular activation), thrombin is a primary target for therapeutics. Besides recombinant hirudins, Argatroban (Novastan) and Bivalirudin (Hirulog) are promising thrombin-directed inhibitors for antithrombotic intervention.
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PMID:Thrombin and antithrombotics. 957 30

Activation of blood coagulation and fibrinolysis has previously been detected in stroke patients. It is unknown, however, what factors contribute to the acceleration of coagulation reactions, especially in cases where no obvious predisposing factors exist. We therefore postulated and tested the hypothesis that in such patients monocytes may trigger the pathway leading to thrombosis by expressing tissue factor (TF). TF antigen was determined in 48 patients and 40 controls by flow cytometry using an indirect immunofluorescent technique. TF antigen expression was significantly increased on monocytes in young stroke patients in both the acute (p < 0.01) and chronic (p < 0.05) phases of the disease. The TF antigen also possessed functional activity, quantitated by a one-stage clotting assay. TF expression on monocytes was not associated with an elevation in C-reactive protein values. In both acute and chronic phases, blood coagulation activation markers, e.g. the thrombin-antithrombin complex and F1 + 2 fragments, were significantly elevated. However, in the acute phase D-dimer levels were similar to those in controls and were only elevated in the chronic phase of the disease (p < 0.05). In conclusion, in cerebral ischemia TF expression on monocytes suggests enhanced activation of blood coagulation and subsequent fibrinolysis.
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PMID:Monocytes express tissue factor in young patients with cerebral ischemia. 968 64

Hydroxyethyl starch (HES) is often used for volume therapy. Since bleeding complications have been reported repeatedly, a strict dose limitation of a maximum of 1,500 ml 6% solution per day is recommended. However, many indications require higher dosages. Bleeding complications are known to be caused by an acquired von Willebrand syndrome. It has been shown that the accumulation of large molecules and their impairment in the coagulation system can be avoided by using HES preparations with a low in vivo molecular weight. However, the effects of a high-dose therapy have not been studied yet. We have investigated, how a 4-day high-dose therapy, using 3,000 ml 6% HES 70/0.5 on the 1st day and 1,500 ml on days 2-4, affects the coagulation system and hemorheological parameters of acute stroke patients. Thromboplastin time, activated partial thromboplastin time and thrombin time showed no significant changes, except for a slight, clinically irrelevant change due to dilution. The subunits of von Willebrand factor VIII showed no significant change. Hematocrit decreased from 42.3 +/- 4.6 to 37.4 +/- 3.9% (p < 0.05) after day 1, reaching 35.3 +/- 4.2% (p < 0.01) at the end of the therapy, demonstrating a substantial volume effect. Plasma viscosity and erythrocyte aggregation decreased slightly, however not significantly. Our study shows that even a high-dose therapy with 6% HES 70/0.5 has no influence on the coagulation system.
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PMID:No coagulation disorders under high-dose volume therapy with low-molecular-weight hydroxyethyl starch. 969 Apr 84

Anticoagulant therapy has changed dramatically during the past two years. Low molecular weight heparin has substantially replaced unfractionated heparin as the parenteral anticoagulant of choice. The use of warfarin has substantially increased, especially for prevention of stroke in the setting of atrial fibrillation. It has become clear that warfarin cannot be administered effectively in an unmonitored fixed-dose fashion. The parenteral direct thrombin inhibitor desirudin was shown to be efficacious in the prevention of deep vein thrombosis in man. Small thrombin and factor Xa inhibitors with in vivo oral anticoagulant activity have been identified.
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PMID:Cardiovascular chemotherapy: anticoagulants. 973 18

The relationship between echocardiographic variables and the incidence of ischemic stroke in patients with atrial fibrillation was investigated by transthoracic and transesophageal echocardiography in 67 patients with chronic nonvalvular atrial fibrillation. Hematologic variables were also measured simultaneously, including plasma levels of D-dimer and thrombin-antithrombin III complex in these patients. There was a prior history of ischemic stroke in 13 patients (stroke group), but not in the other 54 patients (nonstroke group). There were no significant differences in age, sex, left ventricular ejection fraction, left ventricular end-diastolic diameter, left atrial diameter or hematologic parameters between the groups. The left atrial appendage emptying flow velocity was lower in the stroke group than in the nonstroke group (21 +/- 5 vs 32 +/- 3 cm/sec, p < 0.05), and the incidence of left atrial spontaneous echo contrast was significantly higher in the stroke group than in the nonstroke group (69% vs 26%, p < 0.01). There was no significant difference in the incidence of left atrial thrombi between the groups (23% vs 12%). These findings suggest that transesophageal echocardiographic variables are correlated with the risk of ischemic stroke in patients with chronic nonvalvular atrial fibrillation.
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PMID:[Echocardiographic and hematological variables as a risk factor for stroke in chronic nonvalvular atrial fibrillation]. 973 13

Worldwide, streptokinase continues to be used widely in the treatment of myocardial infarction because it is inexpensive and causes fewer intracranial hemorrhages than other thrombolytic regimens. However, in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-I) trial, the 90-minute angiographic Thrombolysis in Myocardial Infarction (TIMI) trial grade 3 flow rate with streptokinase was 43% lower than that with accelerated tissue plasminogen activator, and there was a higher incidence of death or disabling stroke with streptokinase (7.8% vs 6.9%, p <0.01). In the first Hirulog and Early Reperfusion/Occlusion (HERO-1) trial, 48% of patients given the direct thrombin inhibitor bivalirudin (formerly Hirulog, The Medicines Company) after streptokinase had TIMI 3 patency at 90 minutes, compared with 35% of patients given intravenous heparin (p <0.05). Other angiographic and clinical studies and animal research have shown that early infarct artery blood flow may be increased markedly if a direct thrombin inhibitor is administered before the thrombolytic agent. In the HERO-2 trial, 17,000 patients presenting within 6 hours after the onset of acute myocardial infarction will be given aspirin and randomized to receive either intravenous heparin or bivalirudin before streptokinase is administered. The primary endpoint will be 30-day mortality, and secondary endpoints will include death or myocardial infarction within 30 days, and death or nonfatal disabling stroke. If the thrombin hypothesis is supported by improved clinical outcomes with bivalirudin in the HERO-2 trial, large-scale clinical trials will be needed to evaluate the administration of direct thrombin inhibitors before other thrombolytic regimens.
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PMID:Direct thrombin inhibition and thrombolytic therapy: rationale for the Hirulog and Early Reperfusion/Occlusion (HERO-2) trial. 980 93

The authors studied whether haemostatic abnormalities connected with the development of cerebral circulatory disturbances can be demonstrated in young stroke patients in whom Doppler and angiographic examination failed to reveal deviations indicative of stroke. They determined the in vivo activation of the coagulation system (TAT, F 1 + 2), the degree of secondary fibrinolysis (D-dimer), the plasma levels of the markers of fibrinolysis, with special regard to inhibitors: plasminogen activator inhibitor (PAI-1), alpha 2 antiplasmin (alpha 2 AP), alpha 2 macroglobulin (alpha 2 M), the frequency of pathologic serum lipoprotein (a)-Lp(a)-values and the association of PAI-1 and Lp(a) with the fibrinolytic system. They conclude that in the acute phase of the disease, the TAT and F 1 + 2 values were significantly elevated compared to the control, without change in the D-dimer value. The results suggest that in the tested period increased thrombin generation dominated and it significantly surpassed plasmin activity since the D-dimer values of that period did not indicate substantial increase in secondary fibrinolysis. The results of the study were separately analyzed in acute, chronic TIA and stroke groups. In the TIA and acute group the F 1 + 2 values, while in stroke the TAT values were more elevated. The in vitro fibrinolytic capacity of the patients significantly decreased compared to controls, showing significant correlation with the Lp(a) level, but not with the PAI value. Examination of the marker molecules renders possible to assess the degree of hypercoaguability and of endogenous lysis. Their knowledge is held important for judging the progression of the disease and the therapeutic consequences.
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PMID:[Hemostatic abnormalities in ischemic stroke]. 981 Jan 64

The anticoagulant transmembrane glycoprotein thrombomodulin (TM) is expressed at the luminal surface of vascular endothelial cells. Recently, we showed that TM antigen and TM mRNA are expressed in brain microvessels in several species and that brain capillaries have the capability to activate protein C. The activation of protein C in brain microcirculation was greatly impaired by major stroke risk factors in rats due to downregulation of TM. In this study, a partial sequence of TM was determined from TM mRNA from brain capillaries examined in brain capillaries of the rat, a species that provides a useful model to investigate stroke mechanisms in relation to brain hemostasis. The predicted deduced amino acid sequences for rat TM were compared with other TM sequences. Particularly high homology (77-100%) among functional domains of the protein, i.e., the epidermal growth factor repeats (EGFRs) 1-6 and the transmembrane region, was observed between mice and rats. Somewhat less degree of homology was observed for bovine and human EGFRs 1-6, while the homology of the transmembrane region was 92-96%. All cysteine residues were conserved among the TM sequences, and specific amino acids previously suggested to be essential for activation of protein C by thrombin TM were highly conserved. We conclude that the highly conserved mRNA and protein sequences may reflect a similar anticoagulant role of TM in brain endothelial and systemic vascular endothelial cells across different species.
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PMID:Rat brain capillary thrombomodulin: structure and function. 985 12


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