Office of Naval Research Contract N00014-88-c-0118 Contract N00014-94-c-0149 Technical Report 95-07 the Effect of Heparin on Fibrinolytic Activity and Platelet Function

Heparin, a polyanionic glycosaminoglycan, is used routinely prior to the induction of cardiopulmonary bypass. Earlier observations in our laboratory suggested that the postoperative bleeding which occurs, despite neutralization of heparin with prdtamine, is secondary to hypothermia and dilutional anemia during bypass. An additional, potential mechanism for excessive bleeding following cardiopulmonary bypass is that heparin activates the fibrinolytic system, which may, in turn, adversely affect hemostasis. To understand better the effects of heparin administration on the fibrinolytic system in vivo, we simulated the anticoagulant regimen of cardiopulmonary bypass by administering increasing doses of intravenous heparin to five adult baboons over 60 minutes. We measured fibrinolytic parameters serially following heparinization, and demonstrated that heparin induces activation of the fibrinolytic system. We showed that the fibrinolytic system was activated in vivo as evidenced by an increase in plasmin activity and immunoreactive plasmin light chain, as well as an increase in immunoreactive fibrinogen fragment E in yjtro. These results demonstrate that the fibrinolytic system is activated in vivo by the administration of heparin during cardiopulmonary bypass. These data suggest that, despite administration of a neutralizing agent such as protamine, heparin may contribute to postoperative bleeding complications following cardiopulmonary bypass surgery owing principally to its longer-lived effects on the fibrinolytic system. Introduction The generalized hemorrhagic tendency accompanying cardiopulmonary bypass has been recognized for over a decade. An abnormality in platelet function is believed to be the principal hemostatic defect underlying this hemorrhagic^tendency (16,42,17,7); however, abnormalities in the coagulation and fibrinolytic systems have also been reported (26,22). We have recently attempted to characterize the specific defect in platelet function that accompanies cardiopulmonary bypass, and concluded that the defect is extrinsic to the platelet (21); intrinsic platelet function appears to be preserved. The high circulating concentrations of heparin used during cardiopulmonary bypass are likely to account in part for platelet dysfunction. Inactivation of circulating thrombin, the most important platelet agonist in vivo (15,8,20), by antithrombin III is dependent upon heparin. In addition, the relative protection of thrombin from antithrombin III afforded by fibrin binding is overcome by the high concentrations of heparin used during cardiopulmonary bypass (40) [4.5 U/ml with an activated clotting time > 999 seconds in our original study (21)]. Coupled with the direct inhibitory effects of hypothermia on platelet activation (21,36,28), the inhibition of thrombin by heparin provides a rational mechanism for attenuated platelet responses during bypass. Heparin, however, has a number of profibrinolytic effects that have