Ivplateletrelated Prohemorrhagic Effects Of Heparin

Paradoxically, despite the in vitro evidence that heparin stimulates platelets, there is evidence that heparin causes bleeding partly because of its effects on platelet function (Hirsh, 1984; John et al., 1993). Heparin, for example, causes prolongation of the skin bleeding time unrelated to any effects on platelet counts. Also, the structural characteristics of heparin that enhance platelet stimulation in vitro (i.e., increased heparin size or sulfation; decreased affinity for antithrombin) are associated with enhanced bleeding in animal models (Hjort et al., 1960; Carter et al., 1982; Ockelford et al., 1982; Fernandez et al., 1986; Borowska et al., 1988; Van Ryn-McKenna et al., 1989).

The apparent inhibition of platelet function in vivo may be related to two specific actions of heparin: inhibition of thrombin-induced platelet activation and reduction of von Willebrand factor (vWf)-dependent platelet function. Thrombin is a "strong" platelet activator (i.e., it stimulates platelet secretion without intermediate platelet aggregation [Ware and Coller, 1995]). However, in the presence of antithrombin, heparin essentially eliminates stimulation of platelets by thrombin (Westwick et al., 1986; Cofrancesco et al., 1988). This effect is likely responsible for the marked prolongation of bleeding time seen in patients receiving high doses of heparin during heart surgery (Kestin et al., 1993). Heparin also binds to vWf, preventing vWf binding to platelets (Sobel et al., 1991, 1992). This reduces vWf-mediated subendothelial adhesion of platelets flowing at high shear rates, perhaps also contributing to the heparin-related prolongation of the bleeding time.

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