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Heparins designed to specifically inhibit platelet interactions with von Willebrand factor

, : Heparins designed to specifically inhibit platelet interactions with von Willebrand factor. Circulation 93(5): 992-999

Background: Platelet interactions with the injured vessel wall may contribute significantly to the early and late failures of many cardiovascular interventions: the adhesive protein von Willebrand factor (vWF) is thought to play an important role. Previously, we demonstrated that heparin interfered with platelet/vWF hemostatic mechanisms by binding to vWF within the protein's domain responsible for binding the platelet vWF receptor, glycoprotein Ib. The purpose of the present study was to develop and refine heparins with greater potency to inhibit platelet/vWF interactions. Methods and Results: Immobilized synthetic peptides based on a known heparin-binding domain of vWF were used to yield novel fractions of standard heparin that demonstrated a seven-fold increase in their ability to inhibit vWF-dependent platelet agglutination and vWF/platelet binding. The high vWF affinity heparin showed enhanced anti-factor Xa activity but comparable activated partial thromboplastin time activity. Chemical modification of a standard heparin by periodate oxidation and borohydride reduction enhanced its ability to inhibit platelet/vWF interactions by threefold, while eliminating more than 90% of its activated partial thromboplastin time and anti-factor Xa activity. Affinity chromatography of the chemically modified heparin yielded a heparin with an eight-fold higher inhibitory potency than the original heparin. Conclusions: Subspecies of heparin can be developed with significantly enhanced potency to inhibit vWF/platelet interactions. The vWF-inhibiting property of heparin can be dissociated from its antithrombin-binding activity. Based on a growing understanding of heparin/vWF interactions, combinations of affinity separations and chemical modifications could be designed to yield heparins uniquely suitable for prevention of arterial thrombosis.


PMID: 8598091

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