PLATELET/HEPARIN INTERACTIONS IN CARDIOVASCULAR SURGERY

本研究的目的是阐明其基本结构

The aim of this research is to elucidate the fundamental structure- function relations of heparin~s interactions with von Willebrand factor, and blood platelets. Heparin is an essential drug for cardiovascular surgery. The main clinical problem is that the salutary anticoagulant effects of pharmaceutical heparin have been married to hemorrhagic, immunogenic, and platelet stimulating side effects. The clinical use of heparin has been a compromise because it has not been possible to capitalize on the many distinct biological activities now being discovered. The main scientific problem has been a lack of understanding of the fundamental structure-function relations of heparin~s interactions with proteins and cells. In previous work, we have established that heparin binds to a specific domain of von Willebrand factor (V.F.), interfering with its platelet adhesive effects via the platelet receptor Gplb. We have refined subspecies of heparin with 7-8 fold increased potency to inhibit V.F.-dependent platelet function, but with only 10% of normal anticoagulant potency. We have defined important structural features of heparin responsible for direct platelet binding, and begun identification of heparin binding sites on the platelet surface. In our future work, we plan to 1) Define the optimal glycosaminoglycan structure responsible for heparin inhibition of V.F.-mediated thrombosis, using structure-specific modifications and synthetic oligosaccharides, in vitro and in vivo biological assessments, and structural analysis; 2) Elucidate the mechanism(s) by which heparin binds V.F. and exerts its inhibitory effects, through biophysical analyses an photoaffinity labeling; and 3) Define the mechanisms of heparin~s direct effects on platelet function, through structural analysis of heparins and identification of platelet surface proteins that bind heparin. Our long germ goal is the development of novel heparin-based antithrombotic drugs with unique, focussed biological activities applicable to cardiovascular surgery: heparins that inhibit platelet thrombosis at sites of vascular injury and on bioprosthetic surfaces, and conversely, heparins with low platelet reactivity. In the future, the results of this work should provide research tools and insights useful for explorations of heparin's interactions with other adhesive proteins, vascular growth factors, and smooth muscle cells.