Mechanisms for the anticoagulant effect of heparin and related polysaccharides.
The anticoagulant actions of heparin and related polysaccharides can best be addressed by answering the following 2 questions: to what extent do unfractionated heparin, low molecular weight heparins, dermatan sulfate and heparan sulfate inhibit the activation of prothrombin in plasma depleted of antithrombin III and heparin cofactor II? What roles do antithrombin III and heparin cofactor II play in the expression of the overall anticoagulant effects of heparin, low molecular weight heparins, dermatan sulfate and heparan sulfate? Since only heparin can, but only weakly at best, inhibit the activation of prothrombin in plasma depleted of both antithrombin III and heparin cofactor II, it is obvious that the anticoagulant effects of heparin, low molecular weight heparins, dermatan sulfate and heparan sulfate are mediated primarily by their catalytic effects on the antiprotease actions of antithrombin III (heparin, low molecular weight heparins and heparan sulfate) and heparin cofactor II (dermatan sulfate). The catalytic efficiencies of various glycosaminoglycans (GAGs) on the inhibition of thrombin by undiluted plasma follow in the order of the ability of each GAG to inhibit the intrinsic pathway activation of prothrombin. The reasons for this observation probably follow from the effects of GAGs on the 2 positive amplification reactions of thrombin during blood coagulation. Factor VIIIa and factor Va, which directly or indirectly contribute to the rapid formation of prothrombinase, arise from the limited proteolysis of factor VIII and factor V by thrombin and/or factor Xa. On depletion of thrombin by enhanced formation of thrombin-antithrombin III or thrombin-heparin cofactor II, factor Xa provides the only mechanism by which factor VIII and factor V activation in plasma will proceed.(ABSTRACT TRUNCATED AT 250 WORDS)
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Canadian Red Cross Society, Blood Transfusion Service, Hamilton, Ontario.
D000925:Anticoagulants; D000990:Antithrombin III / Q000037:antagonists & inhibitors; D002807:Chondroitin / Q000031:analogs & derivatives*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006493:Heparin / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D013917:Thrombin / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D000990:Antithrombin III; D002807:Chondroitin; D003871:Dermatan Sulfate; D006025:Glycosaminoglycans; D006493:Heparin; D006497:Heparan Sulfate; D013917:Thrombin