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)

Two groups of specifically presensitized Macaca speciosa monkeys received renal allografts via anastomosis to an indwelling arteriovenous (A-V) shunt. One group was pretreated with heparin (2 mg/kg) intravenously and the other was also treated with constant heparin infusion (1 mg/kg/hr) directly into the renal artery. These studies were performed to evaluate the effects of heparin within the kidney on total and compartmental blood flow, complement (C3) levels, sequestration of formed elements, and activation of the coagulation, fibrinolytic, and kinin-forming systems during the initial 3 hours of hyperacute rejection. The results are compared with those previously reported in unmodified control allografts. Heparin prolonged blood clotting time to infinity, markedly prolonged total renal venous blood flow, and normalized compartmental distribution in both groups despite antibody deposition similar to that in controls. With heparin pretreatment only, initial morphologic injury was much reduced but then progressed rapidly. Marked initial cortical cyanosis with mottling appeared to change constantly and was associated with fluctuations in renal turgor, total blood flow, and sequestration of formed elements, all of which suggested repetitive local cortical arterial spasm and incremental destruction of the grafts. Activation of coagulation Factors II and XII was also revealed and marked net Factor VIII activity was observed in the venous effluent. The latter reflects either formation and release of this factor by the injured kidney, or provides in vivo documentation of the "hyperactivation" of Factor VIII by thrombin known to occur in vitro. The addition of intrarenal artery heparin infusion resulted in greater improvement in early total blood flow rates and more uniformly progressive cyanosis and loss of turgor, but the diffuse initial morphologic injury suggested more uniform perfusion of injured areas. Intrarenal consumption of C3 and sequestration of formed elements was similar to that in controls. Paradoxically, prompt activation and consumption of all coagulation factors, plasminogen, and prekallikrein were observed, but formed fibrin was sparse. The exess amount of Factor XIIa present during heparin blockade may have been diverted to production of plasminogen activator and kallikrein formation. The enormous numbers of neutrophils observed within vessels of grafts which showed the greatest kallikrein activation provide the probable in vivo demonstration of the chemotactic properties of kallikrein noted by others in vitro. Heparin-induced platelet aggregation may have played an important role in the failure of these grafts. These studies elucidate the intrarenal effects of heparin during hyperacute rejection and again suggest that vasoconstriction is the most important early determinant of graft failure, as blood flow appeared unrelated to the degree of vascular injury and apparent obstruction. Also, heparin may exer a beneficial effect on blood flow by other than its known action on coagulation.
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PMID:Hyperacute renal allograft rejection in the primate. Intrarenal effects of heparin and associated net release of factor VIII activity and kallikrein activation. 109 75

Simultaneous platelet and fibrinogen survival with 75Se selenomethionine was determined in eight patients with acute infectious hepatitis of intermediate severity. Fibrinogen survival alone was estimated in another nine patients, seven of whom were receiving heparin treatment. Platelet survival was found to be normal (7-9 days) in seven of the 8 patients; it was reduced 4,6 days) only in one patient, who was also affected by measles. Fibrinogen survival was markedly reduced (1-3.7 days) and fibrinogen turnover sharply increased (0.59-2.80 mg/ml/day) in all but one patient, who had thalassaemia major, with normal fibrinogen survival and fibrinogen turnover. Heparin treatment did not affect either platelet survival or fibrinogen turnover. In all patients the coagulation defect was mild and no sign of disseminated intravascular coagulation or of increased fibrinolytic activity could be demonstrated by routine tests. These results are consistent with the hypothesis that in acute infectious hepatitis the decreased survival and increased turnover of fibrinogen might be due to a pathological pathway of defibrination in dependent of thrombin of plasmin.
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PMID:Platelet and fibrinogen survival with 75Se selenomethionine in acute infectious hepatitis. 115 8

Currently, heparin therapy is rarely extended for periods required for the onset of chronic complications. Thus, alopecia and skeletal defects are infrequently encountered. However, during pregnancy, prolonged therapy with heparin may be used. Heparin does not cross the placental barrier, whereas the warfarin class of anticoagulants is freely transported across the barrier. Thus, if extended anticoagulation is required during pregnancy, heparin is preferred to provide maternal anticoagulation while protecting against fetal hemorrhage. Hemorrhage, the most frequent and most feared complication of heparin therapy, does not occur spontaneously in all patients receiving large doses of heparin. However, in certain populations, hemorrhage must be anticipated and appropriate modifications made in the heparin dosage. Elderly women, persons with thrombocytopenia or drug induced platelet dysfunction, or persons who have undergone recent surgical treatment or trauma are sensitive to standard heparin dosages and may bleed during heparin therapy. In these situations, the initial heparin dosage must be appropriately decreased and subsequent dosages carefully determined by frequently monitored coagulation studies. a well maintained, functional coagulation laboratory is imperative in these situations. By careful monitoring of coagulation parameters and by the selection of the smallest effective heparin dosage, complications can be minimized. The clinical cognizance of heparin induced thrombocytopenia is increasing. This disorder must be considered when hemorrhage and low platelet numbers appear during heparin therapy. Discontinuance of heparin therapy causes a rapid increase in platelet counts and diminution of bleeding. The indiscriminate use of protamine sulfate to neutralize heparin must be discouraged. One must resist the temptation to administer multiple extra doses of protamine to assure achievement of hemostasis. The precise dosage of protamine sulfate calculated to neutralize a given heparin dosage must be used. Additional doses of protamine must be determined by coagulation studies, such as whole blood clotting time, protamine titration test, or thrombin time with toluidine blue correction. If proper attention is directed to the dosage of protamine, relative to heparin, the complications of neutralization rarely will occur. Heparin is a basic drug in the armamentarium of the contemporary surgeon. Successful clinical use of heparin requires fundamental knowledge of coagulation mechanisms, the manner in which heparin alters these mechanisms, and the factors which predispose to complications. The complications of heparin therapy can be minimized by strictest attention to selection of initial dosage and by careful subsequent determination of the precise coagulation status of the patient.
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PMID:Complications of heparin therapy. 117 Jun 48

Heparin cofactor, a thrombin inhibitor, is purified from human plasma by affinity chromatography on heparin-agarose. The nature of the binding between thrombin and the inhibitor is studied by treatment of the complex with 6 M guanidinium chloride, hydroxylamine, and dilute alkali. The complex is not dissociated during gel chromatography in 6 M guanidinium chloride. This result supports an earlier proposal that formation of the complex includes the formation of a covalend bond. Treatment of dodecylsulfate-denatured complex with hydroxylamine results in dissociation of the complex to yield free thrombin and heparin cofactor. The complex is also dissociated in dilute NaOH (pH 12) solutions. These results indicate that the covalent bond between thrombin and the inhibitor is a carboxylic ester.
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PMID:Evidence for the formation of an ester between thrombin and heparin cofactor. 118 Sep 62

The treatment of thrombophlebitis in pregnancy with streptokinase is reviewed. Four personal cases are reported. In 3 cases the streptokinase treatment of thrombosis was carried out in the first trimester of pregnancy. Two pregnancies ended in spontaneous term deliveries of well infants without malformations. In one case the pregnancy ended by a spontaneous abortion two weeks following the treatment of the thrombosis. It is suggested that the abortion was much more likely due to a severe state of shock with pulmonary embolism following laparotomy in early pregnancy. The authors are of the opinion that the thrombolytic therapy with streptokinase should also be carried out in the first trimester of pregnancy to prevent embolization of thrombotic material and to prevent a post-thrombotic syndrome. In each case, streptokinase treatment should be followed up with subcutaneous prophylactic treatment with Heparin until term to prevent recurrent thrombophlebitis in pregnancy. With the onset of labour Heparin medication should be interrupted and the thrombin time should be normal with the beginning of the second stage of labour or the Heparin effect should be neutralized by protamine chloride. At the earliest six hours postpartum, the subcutaneous Heparin prophylaxis can be resumed in order to prevent recurrent thrombo-embolism during the postpartum stay.
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PMID:[The treatment of thrombosis in pregnancy (author's transl)]. 121 58

1. The effectiveness of 3 X 5000 IU s. c. heparin daily (starting preoperatively) for the prevention of postoperative deep vein thrombosis was evaluated in a prospective, controlled, randomized study including general surgical and urological patients. 125I-fibrinogen test was performed daily in all patients. 2. 178 patients fulfilled the conditions of the protocol. 35.8% of the 95 patients in the control group developed deep vein thrombosis, but only 13.3% of 83 subjects in the heparin group did so. The difference is statistically highly significant (p less than 0.001). 3. The vast majority of all thrombi in both groups appeared before the 3rd postoperative day. 4. With 1 exception, all deep vein thrombi in the heparin group started in the mid-calf region. In the control group 5 deep thrombi originated in the popliteal vein. 5. Heparin displays a better effect in males (n = 34; p less than 0.01) than in females (n = 49; p less than 0.025). 6. In patients undergoing surgery for malignant disease heparin does not reduce the incidence of deep vein thrombosis. 7. Heparin is far more effective in patients under 60 years of age than in those over 60 (p less than 0.005). 8. Heparin is more effective in obese patients than in those of normal body build. 9. Heparin prophylaxis also reduces the incidence of deep vein thrombosis in patients who exhibit predisposing factors. In patients of the control group with preexisting disease of the venous system, there were significantly more deep vein thrombi (p less than 0.01) than in those without predisposing factors. 10. In the heparin group 29% of all thrombin time determinations show a definite prolongation of more than 26 sec (normal value 15 sec). 11. In 14 patients (=16.9%) of the heparin group, 21 side effects or complications were seen. Bleeding complications were the main problem, comprising 5 wound hematomas and hematomas at the injection site, 4 postoperative bleeding episodes and 2 reoperations. There were no complications in the control group. 12. According to the results of 10 well controlled studies, there is no doubt that in general surgery small doses of subcutaneous heparin, commencing preoperatively, do reduce the incidence of postoperative deep vein thrombosis to a significant degree. However, whether this form of prophylaxis is also effective in patients with fractures of the hip and in elective hip surgery cannot, on the evidence available, be decided. In the fields of gynecological surgery and urology as well, more data are needed before this form of heparin prophylaxis can be recommended.
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PMID:[Subcutaneous small heparin doses for the prevention of thrombosis in general surgery and urology]. 121 80

Heparin has been advocated for the treatment of poisoning by Echis carinatus, a snake whose venom causes disseminated intravascular coagulation. Fourteen patients with proven E. carinatus bite who had incoagulable blood were treated with specific Echis antivenom. Seven of them were also given low-dose heparin, initially 50 units/kg body weight by i.v. injection, followed by 10 units/kg/h by i.v. infusion for 22 h. Response to treatment was assessed clinically and by repeated tests of blood coagulation. All patients showed a rapid return to normal blood coagulability after treatment and the heparinized group were not significantly different in any respect from the group given antivenom alone. Heparin did not reduce the local effects of envenoming. There appears to be no place for heparin in the treatment of E. carinatus poisoning provided that potent antivenom is available. The in vivo results were supported by in vitro studies in which it was found that Echis-induced thrombin was less sensitive to the inhibitory effect of heparin than physiological thrombin.
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PMID:Disseminated intravascular coagulation caused by the carpet viper (Echis carinatus): trial of heparin. 127 79

I. v. administration of N-acetyl-thrombin, similar to thrombin, increases the fermentative fibrinolytic potency of the plasma, although to a lesser extent. This is also expressed in the increased esterase activity of the plasma and euglobulin fraction. When blocking the forming plasmin, esterase activity is observed in kallekreine. (The inhibitory effect of plasma after N-acetyl-thrombin administration tells also on the nonfermentative fibrinolytic activity of the Fibrinogen-Heparin complex, activity of the latter dropping practically to the zero level. Warming up at 60 degrees C decreases the nonfermentative fibrinolytic activity of the complex N-acetyl-thrombin (thrombin-esterase) does not provoke the activation of the second anticoagulang system, while the native thrombin does it.
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PMID:[The state of anticoagulant system of animals following injections of purified thrombin and N-acetyl-thrombin]. 127 33

Disseminated intravascular coagulation (DIC) is a syndrome caused by the systemic generation of thrombin. Most cases are due to pathological activation of the intrinsic coagulation systems (e.g. in sepsis), and/or the extrinsic system (e.g. in malignancy and head trauma). Diagnosis is made by finding abnormalities in at least 3 of 4 laboratory values, namely prothrombin time, platelet count, fibrinogen and fibrinogen/fibrin degradation products. The most common clinical manifestation of DIC is bleeding, with thrombosis in less than 10% of acute cases but more frequently encountered in chronic DIC associated with malignancy. Acute DIC must first be treated by specific therapy of the underlying disease and general support measures. If serial clinical and laboratory monitoring improves, no further treatment is required. If severe or life-threatening haemorrhage occurs or a thrombotic event ensues, heparin anticoagulation followed by aggressive replacement with platelets, fresh plasma and possibly cryoprecipitate is indicated. Heparin doses should be 'therapeutic' (i.e. adequate to overcome the coagulant forces that may have produced a relative heparin-resistant state in the blood). Chronic DIC with haemorrhage, or more usually thrombosis, should also be treated with heparin; warfarin is ineffective. If DIC persists because, for example, a tumour does not regress, long term outpatient subcutaneous heparin therapy may be required.
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PMID:Disseminated intravascular coagulation. Approach to treatment. 128 66

The synthetic peptide, SFLLRNPNDKYEPF, has been recently described as a peptide mimicking the new amino-terminus created by cleavage of the thrombin receptor, therefore acting as an agonist of the thrombin receptor. This peptide was a potent mitogen for rabbit arterial smooth muscle cells (SMC) and exhibited the same activity as that of native alpha-thrombin. Both compounds stimulated the proliferation of growth-arrested SMCs with half-maximum mitogenic responses at 1 nM. NAPAP, a synthetic inhibitor of the enzymatic activity of thrombin, specifically inhibited thrombin-induced SMC growth (IC50 = 0.35 +/- 0.04 microM) but was without effect on the mitogenic effect of the agonist peptide. These results therefore demonstrate that the mitogenic effect of alpha-thrombin for SMCs is intimately linked to its esterolytic activity. Heparin, which inhibited fetal calf serum-induced SMC growth, was without effect on thrombin-induced SMC growth but strongly reduced the mitogenic effect of the agonist peptide (IC50 = 32 +/- 5 micrograms/ml). This effect was not related to the anti-coagulant activity of heparin but was highly dependent on molecular mass and on the global charge of the molecule and was also observed for other sulphated polysaccharides such as pentosan polysulphate.
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PMID:Induction of vascular smooth muscle cell growth by selective activation of the thrombin receptor. Effect of heparin. 131 39


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