PLATELET/HEPARIN INTERACTIONS IN CARDIOVASCULAR SURGERY

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For 50 years, heparin has been the anticoagulant of choice in cardiovascular surgery and extracorporeal circulation, albeit a compromise choice. The doses of heparin that provide adequate conventional anticoagulation may cause harmful activation of platelets through direct and immune-mediated effects. Most failures in cardiovascular surgery are caused by acute, platelet- dominated thrombosis, or later intimal hyperplasia due to vascular smooth muscle cell proliferation and migration. Yet it has been difficult to capitalize on heparin's anti-platelet or antiproliferative promise. The investigative challenge has been dissecting the different biological effects of heparin from each other, especially considering the structural heterogeneity of heparins, and the multiplicity of its interactions with cells and proteins. The Chief Aim of this research proposal is to understand the fundamental structure-function relations and basic mechanisms of heparin interaction with vascular cells and proteins. Our long- term goals are to devise novel heparin-based drugs to control platelet dependent thrombosis and neointimal hyperplasia. To date we have refined novel heparins that inhibit platelet adhesion under high shear, by blocking von Willebrand factor (vWf), but have low conventional anticoagulant potency. We have begun to define the precise heparin structure responsible for this activity. We have identified the platelet integrin alphaIIb/beta3 as a potentially important site for heparin's direct modulation of platelet function (and by extension, heparin modulation of other vascular integrins). To further this work, we have developed or assembled critical tools. Precisely defined synthetic oligosaccharides and multimeric constructs, as well as molecular modeling and biophysical analyses are being used to identify the structural features of heparin that dictate its binding to platelets and vascular smooth muscle cells. Unique heparin crosslinkers and probes are engaged to identify cellular heparin binding sites. And we are employing recombinant vWf proteins and cell lines that ectopically express recombinant integrin and vWf receptors (and mutants) to elucidate precisely how heparin modulates integrin-dependent signalling and function, and vWf adhesive function. These studies will advance our fundamental understandings of how heparins modulate hemostasis, angiogenesis, and vascular repair, and lay the foundations for the development of novel anti-platelet and anti-proliferative heparin-based drugs.