Platelet agggregation and adhesion are primary events in normal hemostasis and in the contact of blood with artificial surfaces. Because heparin is a potent inhibitor of the plasma coagulation system, it is widely used to treat or prevent thrombosis during cardiovascular surgery and extracoporeal circulation. However, heparin does not significantly inhibit platelet activation and may paradoxically stimulate platelets. The interactions between heparin and platelets may produce the serious complications of bleeding or immune thrombocytopenia. Many artificial surfaces bonded with heparin are not truly non-thrombogenic, and remain platelet reactive. We hypothesize that platelets have specific heparin binding sites which determine many of the unique interactions between heparin and platelets. Our own preliminary research does suggest the presence of heparin binding sites on the platelet surface, and indicates that platelet activation may enchance heparin binding. Our work, and that of others indicate that certain regions of the heparin molecule are preferentially bound, and that heparin binding affects platelet behavior. We propose to characterize the platelet surface receptors for heparin and to determine the physiologic and biochemical conditions which influence heparin binding, using a novel platelet- heparin binding assay. We plan to identify these binding sites using photoaffinity labelling techniques. We will study the binding of precisely characterized heparin fractions to determine the distinctive regions of the heparin molecule which promote binding. Finally, using these fractions we will study heparin- mediated platelet aggregation and correlate heparin binding with the functional effects of heparin on platelets. Our long range goals are to apply these basic scientific techniques to the study of platelet-heparin interactions in clinical patients, and to identify heparin species which are less platelet reactive, but are effective antithrombotic agents.
| Yagi, Mayumi; Murray, Jacqueline; Strand, Kurt et al. (2012) Heparin modulates the conformation and signaling of platelet integrin ?IIb?3. Thromb Res 129:743-9 |
| Reichman, W; Nichols, B; Toner, J et al. (1990) Strategies in the treatment of major tissue loss and gangrene: results of 100 consecutive vascular reconstructions. Ann Vasc Surg 4:233-7 |
