In vivo Effects of Low Molecular Weight Heparins on Experimental Thrombosis and Bleeding
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Recent studies with heparin fractions indicate that it is possible to dissociate the antithrombotic and hemorrhagic effects of heparin and so improve its therapeutic potential. Heparin inhibits blood coagulation by 3 independent mechanisms by augmenting the effect of antithrombin III (the major effect), by augmenting the inhibitory effect of thrombin or heparin cofactor II, and by disrupting the activation of blood coagulation on the platelet surface; it has an additional effect on hemostasis through its interaction with blood platelets. Some insight into the mechanism of heparin-induced bleeding has been provided by studies with low molecular weight heparins. These heparins have reduced antithrombin activity but retain anti-Xa activity and have antithrombotic properties in animals with a reduced risk of bleeding. There is evidence that the reduction in the bleeding risk is unrelated to the anticoagulant effect of these low molecular weight heparins, but that it may be related to the observation that they inhibit platelet function less than standard heparin. The very low molecular weight heparins (molecular weight 3,000 daltons), have virtually no anti-IIa activity and are relatively weaker antithrombotic agents than low molecular weight heparins of 5,000 daltons. A minimal amount of anti-IIa activity is required for full expression of the antithrombotic activities of these low molecular weight heparins.
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