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)

Coumarin drugs or vitamin K absence cause a decrease of factor II, VII, IX and X activities and the appearance of pre-factors into the circulation. Such pre-factors have been postulated to inhibit thrombin conversion. The current of research on the alleged activity of such "inhibitors" is taken into consideration. Thrombotest discrepancy, mixing experiments etc.) speak against the inhibitor theory. So far the only sure demonstration of the presence of coumarin induced pre-factors has been obtained by immunological means. However, this does not say anything about their biological activity. These pre-factors could well be "inert" as far as clotting is concerned. Until new, unequivocal data on the subject will be available, any method or technique claiming to be able to detect or monitor the "inhibitory" effect should be accepted with extreme caution. Too many unjustified views have been put forward in recent years.
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PMID:Evidence against the presence of "inhibitors" in coumarin treated patients. 8 74

Warfarin and other 4-hydroxycoumarins are effective antithrombotic agents. They affect four blood coagulation proteins that act sequentially to produce thrombin. Coumarin therapy decreases the biological activity of these proteins, and therefore decreases the rate at which blood clots. As the mechanism by which these drugs act has become clear, it has also been found that vitamin K will overcome the effects of coumarin anticoagulation and can be used to control bleeding side effects of coumarin therapy. Vitamin K is necessary for activity of a liver enzyme, the vitamin K-dependent carboxylase. A second enzyme that recycles an inactive to an active form of the vitamin is inhibited by coumarins. The ability of other liver enzymes to bypass the coumarin-sensitive step greatly enhances the safety of 4-hydroxycoumarins.
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PMID:Warfarin and vitamin K. 219 10

BACKGROUND AND DESIGN--Protein C is a vitamin K-dependent plasma protein that is converted to the serine protease activated protein C by the thrombin-thrombomodulin complex. Activated protein C functions as a natural anticoagulant by inactivating the cofactors of the coagulation cascade, factors Va and VIIIa. Coumarin (warfarin)-induced skin necrosis is thought to be due to a rapid elimination of protein C relative to other vitamin K-dependent factors during the initial phase of oral anticoagulation. We have used a highly purified protein C concentrate to treat a patient with acquired protein C deficiency who developed skin necrosis during the initial phase of oral anticoagulant therapy. OBSERVATIONS AND CONCLUSIONS--During protein C concentrate therapy, no further skin lesions appeared, and the healing process of necrotic areas was facilitated. Replacement therapy with protein C concentrate appears to be safe and effective as an adjunctive treatment for coumarin-induced skin necrosis.
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PMID:Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. 850 82

The interaction of novel series of synthetic inhibitors with various serine proteases (leukocyte elastase, thrombin, cathepsin G, chymotrypsin, plasminogen activators and plasmin) and an aspartic protease (HIV-1 protease) were studied. Various aspects were analyzed: mechanism of action, structure-activity relationships, and in some cases, molecular modelling and biological evaluation. Functionalized cyclopeptides and N-aryl azetidin-2-ones behaved as suicide substrates acting specifically on trypsin-like proteases (thrombin or urokinase) and elastases, respectively. Novel hydrazinopeptides acted as reversible inhibitors of elastases. Coumarin derivatives inactivated very efficiently chymotrypsin-like proteases (k(inact)/K(I) = 760,000 M(-1) .s(-1)). Inhibitors of HIV-1 protease acting either as inactivators or dimerization inhibitors are under investigation. The inhibitors described above are useful for elucidating the biological roles of the target enzymes and constitute potential drugs.
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PMID:[Synthetic inhibitors targeting serine and aspartic acid proteases]. 877 49

Coumarin-induced skin necrosis is believed to be due to a transient hypercoagulable state resulting from a more rapid decline of the protein C activity relative to that of coagulation factors (F) II, IX and X during initiation of oral anticoagulant therapy. We studied hemostatic system activation during early oral anticoagulant treatment with a technique that investigates coagulation activation in the microcirculation. We determined in 10 healthy volunteers the concentrations of prothrombin fragment F1 + 2 (f1.2) and thrombin-antithrombin complex (TAT) in blood emerging from an injury of the microvasculature (bleeding time incision) before and after initiation of both high-intensity and low-intensity coumarin therapy. In addition, f1.2, TAT, activated F VII (F VIIa) and the activities of F II, F VII, F X and protein C were measured in venous blood. A rapid decline of F VII and protein C was observed in venous blood with activities at 24 h of 7 +/- 1% and 43 +/- 2%, respectively, during the high-intensity regimen. A 20 to 30% reduction of f1.2 and TAT was seen in venous blood at 72 h with no major difference between the high- and the low-intensity regimen. F VIIa levels were substantially affected by anticoagulation with a > 90% reduction at 48 h during the high-intensity regimen. Following high-intensity coumarin, a > 50% decrease in the f1.2 and TAT levels was found in shed blood at 48 h suggesting substantial inhibition of thrombin generation during early oral anticoagulation. An increase in the f1.2 and TAT levels was seen neither in shed blood nor in venous blood. Our data do not support the concept of a transient imbalance between generation and inhibition of thrombin as the underlying pathomechanism of coumarin-induced skin nekrosis.
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PMID:Inhibition rather than enhancement of hemostatic system activation during initiation of oral anticoagulant treatment. 913 43

Coumarin poisoning in dogs is not unusual and is in most cases caused by warfarin, a coumarin derivative which is used as a rodenticide. Competitive inhibition of vitamin K with an incomplete synthesis of the coagulation factors II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3-year old male West Highland White Terrier with a reduced general condition and dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3 mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT with uncharacteristic thrombin time (TT); factor II, VII and X activities were reduced while factor V activity was normal, all of which are characteristic for coumarin poisoning. HPLC did not reveal the presence of warfarin but of phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This observation has not been described for dogs to date.
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PMID:[Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for coumarin poisoning in a dog]. 1259 69

Cutaneous reactions have been reported during anticoagulant therapy with coumarin derivatives, unfractionated and low molecular weight heparins, heparinoids, danaparoid and hirudins. Anticoagulant-induced skin reactions vary from local allergic manifestations to skin necrosis. In patients with allergic reactions, diagnosis and crossreactions between anticoagulants can be confirmed by intracutaneous testing. Coumarin- and heparin-induced skin necrosis are rare, but are important side effects due to their high morbidity and occasional mortality. Cutaneous tests are contraindicated in these patients. In the future, anticoagulant strategies may include direct synthetic thrombin inhibitors (argatroban and melagatran/ximelagatran) and the Factor Xa inhibitor, pentasaccharide (fondaparinux).
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PMID:Anticoagulant-related skin reactions. 1290 44

Anticoagulants and antiplatelet agents are currently used during pregnancy as treatment or prophylaxis for thromboembolic disease. Main adverse events of these agents are bleeding episodes, which put the pregnancy at risk. Unfractionated and low molecular weight heparins are first-line treatment or prophylaxis for thromboembolism. If an antiplatelet agent is needed, aspirin alone or in combination with heparins can be safely administered. Coumarine derivatives are still contraindicated during pregnancy because of teratogenicity and/or bleeding. No adequate data are yet available on the safety profile of the new antiplatelet agents or the direct thrombin inhibitors. Special considerations are discussed on the risks of regional anesthesia, as well as on nursing during anticoagulation.
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PMID:[Anticoagulants and antiplatelet agents in pregnancy]. 1570 3

Heparin-induced thrombocytopenia, or HIT, can present in many ways, ranging from common-isolated thrombocytopenia, venous thromboembolism, acute limb ischemia-to less common but specific presentations-necrotizing skin lesions at heparin injection sites, post-bolus acute systemic reactions, and adrenal hemorrhagic necrosis (secondary to adrenal vein thrombosis). Many patients with HIT have mild or moderate thrombocytopenia: the median platelet count nadir is 60 x 10(9)/L, and ranges from 15 to 150 x 10(9)/L in 90% of patients, most of whom evince a 50% or greater fall in the platelet count. HIT that begins after stopping heparin ("delayed-onset HIT") is increasingly recognized. Factors influencing risk of HIT include type of heparin (unfractionated heparin > low-molecular-weight heparin), type of patient (surgical > medical), and gender (female > male). Since timely diagnosis and treatment of HIT may reduce the risk of adverse outcomes, this review focuses on those clinical circumstances that should prompt the clinician to "think of HIT." Coumarin anticoagulants such as warfarin are ineffective in acute HIT and can even be deleterious by predisposing to micro-thrombosis via protein C depletion (venous limb gangrene and skin necrosis syndromes). Thus, it is important to avoid or postpone coumarin while managing HIT hypercoagulability, focusing on agents that inhibit thrombin directly (lepirudin, argatroban) or that inhibit its generation (danaparoid, fondaparinux). Post-marketing experience suggests that standard dosing of lepirudin is too high; current recommendations are to avoid the initial lepirudin bolus and to begin with lower infusion rates, even in patients without overt renal dysfunction.
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PMID:Think of HIT. 1712 91

Umckaloabo is a herbal drug for the treatment of respiratory tract infections. It contains an aqueous ethanolic extract from roots of Pelargonium sidoides DC (EPs) 7630) as the active ingredient. Polymeric polyphenols and coumarins have been identified as the principal ingredients of EPs 7630. In view of the coumarin content, it has been suggested that the administration of Umckaloabo could possibly be associated with an increased risk of bleeding. This study, therefore, investigated whether a change in blood coagulation parameters or an interaction with coumarin-type anticoagulants occurred after administration of EPs 7630 to rats. No effect on thromboplastin time (TPT), partial TPT (PTPT) or thrombin time (TT) was observed after oral administration of EPs 7630 (10, 75, 500 mg/kg) for 2 weeks, while treatment with warfarin (0.05 mg/kg) for the same period resulted in significant changes in TPT and PTPT. If EPs 7630 (500 mg/kg) and warfarin (0.05 mg/kg) were given concomitantly, the anticoagulant action of warfarin was not influenced. Similarly, the pharmacokinetics of warfarin were unchanged after pre-treatment with EPs 7630 for 2 weeks. Coumarin-type anticoagulants inhibit the synthesis of vitamin K-dependent coagulation factors via an identical mechanism in rat and man, and have a similar pattern of metabolism in both species. Moreover, as the coumarins so far identified in EPs 7630 do not posses the structural characteristics needed for anticoagulant activity, it appears unlikely that an increased tendency to haemorrhage arises in patients after intake of Umckaloabo.
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PMID:Treatment of rats with the Pelargonium sidoides extract EPs 7630 has no effect on blood coagulation parameters or on the pharmacokinetics of warfarin. 1718 79


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