Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombomodulin (TM), a membrane-bound receptor for thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of thrombin, but also the thrombin generation via accelerating the thrombin-catalyzed protein C activation. In rat disseminated intravascular coagulation (DIC) models, intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on heparin-resistant DIC models with low AT III level in rats. Intravenous injection of MR-33 prevented the endotoxin-induced increases in TAT, TNF-alpha and IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage, and this drug also has anti-inflammatory effects. Clinical trials of MR-33 for the treatment of DIC are now in progress in Japan.
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PMID:[Thrombomodulin]. 1121 78

To determine the presence of a 'hypercoagulable state' as assessed by indices of thrombin and plasmin generation and of the amount of fibrin that is lysed, in patients with stable coronary, cerebral and peripheral arterial disease a population-based cross-sectional study was performed. From a population-based cohort comprising 7983 men and women aged 55 years and over, we randomly selected 127 subjects with a history of myocardial infarction, 124 with a history of stroke and/or transient ischemic attack, 131 patients with peripheral arterial disease and 263 control subjects in the same age group without arterial disease. Subjects using anticoagulant drugs were not selected. F1+2, TAT, and PAP were not associated with a history of cardiovascular events, nor with peripheral arterial disease. In contrast, positive associations were found for D-Dimer. Mean D-Dimer level was 40 microg/l (95% CI 35, 44) in control subjects; 53 microg/l (47, 61) in those with a history of myocardial infarction and 51 microg/l (45, 58) in those with a history of stroke and or transient ischemic attack. D-Dimer increased gradually with increasing severity of peripheral atherosclerosis; a decrease in ankle/arm systolic blood pressure ratio of 0.1 was associated with an increase in D-Dimer of 3.9 microg/l (p<0.01). This was more pronounced in subjects with higher F1+2, TAT and PAP concentration. In conclusion, the markers of onset of coagulation F1+2, TAT and PAP are not associated with the presence of arterial disease, but increased levels of these markers are necessary for the positive association between D-Dimer and arterial disease.
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PMID:Activation products of the haemostatic system in coronary, cerebrovascular and peripheral arterial disease. 1124 39

Surgery induces immediate hypercoagulability by direct alteration of the vascular bed, release of procoagulant substances from the extravascular spaces and blood flow decrease, and delayed hypercoagulation in response to tissue damage which triggers inflammatory responses. Thus, the postoperative period represents a high-risk time for thrombosis. Recognition of high-risk individuals would make it possible to improve thromboembolism prevention. We studied in women undergoing laparoscopic surgery a series of markers known to be related to the thrombotic risk and confronted their results with those of a global test, the thrombin generation test (TGT) described by Hemker's group. Our results show that two groups of patients can be distinguished according to usual risk markers (PAI-1, TAT, body mass index): the higher risk group demonstrates higher initial TGT values, but also a postoperative decrease of the TGT values whose mechanisms remain to be defined.
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PMID:Changes in haemostasis after laparoscopic surgery in gynaecology: contribution of the thrombin generation test. 1140 47

Thrombin related coagulatory effects of a heparin-coated cardiopulmonary bypass system combined with full and low dose systemic heparinization were investigated in a prospective, randomized study in coronary bypass surgery patients. One hundred nineteen patients were divided into 3 groups. Group A (n = 39) had a standard uncoated extracorporeal circulation (ECC) set, and systemic heparin was administered in an initial dose of 400 IU/kg body weight. During ECC activated clotting time (ACT) was maintained at > or =480 s. Group B (n = 42) had the same ECC set completely coated with low molecular weight heparin. Intravenous heparin was given in the same dose as in Group A, and ACT was kept at the same level. Group C (n = 38) had the same coated ECC set as Group B, but intravenous heparin was reduced to 150 IU/kg, and during ECC, ACT was set to be > or =240 s. The same ECC components were used in all 3 groups including roller pumps, coronary suction, and an open cardiotomy reservoir. Thrombin generation as indicated by F1/F2 was significantly elevated at an ECC duration >60 min if heparin-coated ECC combined with low dose systemic heparinization was employed. Complexed thrombin (TAT) was significantly elevated after administration of protamine. Release of D-dimers indicating fibrinolysis was not significantly different between groups. Signs of clinical thromboembolism, i.e., postoperative neurological deficit, occurred in 2 patients in Group A and 1 patient in Group C. We conclude that heparin-coated extracorporeal circulation combined with reduced systemic heparinization intraoperatively leads to significantly increased thrombin generation, but not to increased fibrinolysis.
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PMID:Heparin-coated extracorporeal circulation with full and low dose heparinization: comparison of thrombin related coagulatory effects. 1145 79

The stent to be examined (Wiktor-Stent, Medtronic ESTC, Kerkrade, NL) was mounted into a closed-loop tubular-system and perfused with platelet-rich plasma (PRP). As controls the tubular-system without stent (as non-thrombogenic control) and secondly the tube filled with glassbeads (as thrombogenic control) were evaluated. A decrease in the number of singularly circulating thrombocytes correlated well with an increases in circulating platelet aggregates. The increasing activation of thrombocytes was demonstrated by immunolabelling of surface structures (CD 62) which become prominent on activation of thrombocytes. The increase in case of the non-thrombogenic controls is thought to be due to the action of the roller-pump. This increase was coincident with an increase in immunologically labelled GPIIb/IIIa receptors and well correlated with an increase in platelet activation as demonstrated by the elevated CD 62 label. In spite of the use of anticoagulation principles in the perfusion model, thrombin was generated (measured by the TAT-complex) in all three cases and the completed coagulation (measured by the occurrence of fibrin D-dimers) also happened. The amount of D-dimers was small, however, in the cases of non-thrombogenic controls and of tubes equipped with stents. Only after the contact of PRP with tubes filled with glass-beads a significant increase in D-dimers followed. In conclusion the implantation of a stent led to an activation, adherence and aggregation of thrombocytes to a somewhat greater extent as in the control-system. It has, however, a much less thrombogenic surface than glass-beads.
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PMID:Haemocompatibility of endovascular coronary stents: Wiktor GX. 1155 1

Coagulation and fibrinolysis activities in relation to trauma, surgery and thrombosed microanastomoses were studied during free-flap surgery in eight patients with lower-extremity defects due to recent trauma or chronic ulcers. One patient had an intraoperative thrombosis, and three more patients required reoperations on the same day due to postoperative thromboses; one of these also required a second reoperation due to flap failure. The baseline level of fibrinogen was slightly elevated in all patients except one, and was significantly higher in the patients who underwent reoperation. At the end of the primary surgery, distinct thrombin generation (TAT and F1+2) was seen in three patients with excessive bleeding, and all three later underwent reoperations. One of these patients generated excessive thrombin on the eighth postoperative day, upon removal of a necrotic flap. Thrombin generation (F1+2) was also seen at baseline in the patient with the intraoperative thrombosis, and persisted on the first postoperative day. D-dimer at baseline was higher in patients with recent trauma, and in two of these, both of whom underwent reoperations on the same day, D-dimer remained high perioperatively. Resistance to fibrinolysis with increased PAI-1 levels was seen in these two patients at the time of reoperation. In all, TAT and F1+2 were associated with the threat of flap failure. A preoperative hypercoagulable state and excessive bleeding during the operation were predictors of reoperation. The markers for coagulation and fibrinolysis could be used preoperatively to target antithrombotic control, and postoperatively to detect the threat of flap failure. Meticulous haemostasis during surgery might help to diminish the need for reoperations.
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PMID:Activation of coagulation and fibrinolysis in microsurgical reconstructions in the lower extremities. 1158 96

Complex pertubations of hemostasis occur in sickle cell disease (SCD). Although the procoagulant property of sickle erythrocytes in vitro is tied to exposure of phosphatidylserine (PS), no study has directly linked this PS positivity to in vivo thrombin generation. This study was designed to determine if thrombin generation in SCD correlates with erythrocyte PS, or whether platelets play a significant role. PS was quantified on erythrocytes and platelets from 40 patients with SCD (SS genotype = 25; SC genotype = 15) and 11 controls. Markers of thrombin generation (prothrombin fragment F1.2; thrombin-antithrombin or TAT complexes) and fibrin dissolution (D-dimer; plasmin-antiplasmin or PAP complexes) were also evaluated. Thrombin generation and activation of fibrinolysis occurred with elevations in F1.2, TAT, and D-dimer. Although numbers of both PS-positive erythrocytes and platelets were elevated, there was no correlation between PS-positive platelets and any hemostatic markers. In contrast, correlations were noted between PS-positive erythrocytes and F1.2 (P <.0002), D-dimer (P <.000002), and PAP (P <.01). Correlations between F1.2 and D-dimer (P <.0001) demonstrated that fibrinolysis was secondary to thrombin generation. In patients with the SC genotype, abnormalities in coagulation, although present, were of a lesser magnitude than in SS disease. This study suggests that the sickle erythrocyte is the cell responsible for the thrombophilic state in SCD because associations between erythrocyte PS and thrombin generation were observed. No such relationship with platelet PS was noted. The use of erythrocyte PS as a surrogate marker in trials testing new therapeutic modalities may provide insights into the vascular complications of SCD.
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PMID:Thrombophilia in sickle cell disease: the red cell connection. 1171 58

The administration of menaquinone-4 (MK-4), one of subclasses of vitamin K2, significantly reduces bone loss in postmenopausal osteoporotic women. However, concerns have been raised about whether vitamin K administration alters the hemostatic balance by inducing a thrombotic tendency. We investigated were whether the administration of vitamin K in the form of MK-4 induced a thrombotic tendency in 29 elderly patients with osteoporosis (5 men, 24 women; age range 78.7+/-5.1 years). Patients were administered 45 mg/day (three times a day, 30 min after each meal) of MK-4 for 12 weeks. Blood samples were obtained from the patients at 0, 4 and 12 weeks after the start of MK-4 administration. A number of hemostatic parameters remained stable under the markedly increased plasma levels of MK-4. However, in patients with suspected vitamin K deficiency, whose plasma levels of vitamin K or factor VII were low, vitamin-K-dependent clotting factors such as factor VII and prothrombin were gradually increased after administration of MK-4. No changes in the sensitive molecular markers such as TAT and F1+2, which reflect the amount of thrombin generated in the blood stream, were observed, even in those patients with suspected vitamin K deficiency. These results indicate that MK-4 can be administered safely, with regard to maintaining the hemostatic balance, to osteoporotic patients receiving no anticoagulant therapy.
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PMID:Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency. 1184 34

Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis and recurrent miscarriage. We assessed levels of coagulation activation markers and aPL during normal pregnancy and in women with the antiphospholipid syndrome (aPS). Fluctuations in aPL levels were observed in all patients with aPS. No particular pattern of antibody positivity, or fluctuation in aPL level, was associated with poor pregnancy outcome. A significant increase was observed in levels of factor Xlla (FXIIa; P < 0.001), factor VIIa (FVIIa, P < 0.001), thrombin antithrombin complexes (TAT; P < 0.001), prothrombin fragment F1.2 (F1.2; P < 0.001) and D-dimer (DD; P < 0.05) during normal pregnancy. Factor VIIa, TAT, F1.2 and DD increased significantly before 20 weeks gestation, while a statistically significant increase in FXIIa levels was first detected between weeks 20 and 30 of gestation. In pregnant women with aPS, increases in FXIIa were similar to those in normal pregnancy, but increased FVIIa levels were not observed until after 30 weeks gestation. Similar to normal pregnancy, increased levels of TAT and F1.2 were detected in aPS pregnancies before 20 weeks gestation, but increased DD were not observed until after week 20. Surprisingly, women with aPS receiving low molecular weight heparin prophylaxis had significantly higher (P = 0.02) levels of TAT (median 8.6; interquartile range (IQR) 6.5-20.8) between weeks 20 and 30 of gestation compared to the normal pregnant population (median 5.9; IQR 4.7-7.9), thus indicating increased thrombin generation in women with aPS in mid-pregnancy.
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PMID:Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal and heparin-treated antiphospholipid syndrome pregnancies. 1189 13

For rehabilitation training it is recommended that the intensity of exercise should be distinctly below the individual anaerobic threshold (IAT). We investigated platelet activity, reactivity and platelet-leukocyte conjugate formation following a stardardized treadmill (TR) ergometer test at 90% IAT for 60-120 min. Seventeen healthy male non-smokers underwent TR. Blood samples were taken after a 30-min rest, immediately after exercise, and 2 h after exercise completion. Platelets were detected flow cytometrically by CD41 in whole blood, activated platelets by CD62P. In addition, stimulation of platelets in vitro with 7.5 microM TRAP-6 was performed. For testing platelet-leukocyte conjugates, antibodies against CD45 and CD41 were used. After TR the percent of non-stimulated CD62P-positive platelets (%PC) remained unchanged (1.65 +/- 0.56 to 1.73 +/- 0.79%PC) (mean +/- SD). In contrast, an increase (P<0.05) from 31.9 +/- 13.5 to 37.4 +/- 15.0 %PC in CD62P, TRAP-6 stimulated and enhanced (P<0.01) platelet-leukocyte conjugates (11.7 +/- 3.7 to 16.1 +/- 6.9, CD41-%PC) after TR were observed. Both changes were independent of thrombin generation measured by F1+2 and TAT, and reversible after 2 h. Long-term exercise (90% IAT) on a treadmill ergometer only leads to a moderate increase of platelet reactivity and platelet-leukocyte conjugates. The determination of platelet-leukocyte conjugates may offer the possibility to detect an early activation stage of platelets in vivo.
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PMID:Platelet activity, sensitivity to agonist, and platelet--leukocyte conjugate formation after long-term exercise. 1218 12


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