Effect of heparin on fibrinolytic activity and platelet function in vivo

Abstract

Heparin, a polyanionic glycosaminoglycan, is used routinely before the induction of cardiopulmonary bypass. Earlier observations in our laboratory suggested that the postoperative bleeding that occurs, despite neutralization of heparin with protamine, 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 min. 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 vitro. 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.

Multifactorial Comparison of Modified and Conventional Perfusion Strategies in A Porcine Model of Cardiopulmonary Bypass

“…However, this decrease was significantly worse when conventional NHB circuits were utilized for CPB (Table 3). These alterations in hematological parameters are consistent with what has been observed by others [1,4,22].…”

“…The conventional practice of using a nonthromboresistant extracorporeal circuit in cardiac surgery has been shown to induce a variety of hematological and inflammatory adverse events [1][2][3]. These effects are the result of the foreign surfaces of the cardiopulmonary bypass (CPB) circuit, high-dose heparin anticoagulation, systemic hypothermia, hemodilution, and the open perfusion bypass system that allows air to interface with blood as a foreign surface during surgery [3][4][5][6].…”

Strategies to prevent intraoperative lung injury during cardiopulmonary bypass

“…On the other hand, studies have shown that heparin administration a), results in a rapid release of t-PA from its body sources, which may induce fibrinolysis [79], b) causes (in vitro) inhibition of platelet function in more than 30% of patients, thus leading to increased postoperative blood loss [80], c) has pro-activating properties on granulocytes and platelets [81], and finally d), heparin after its neutralization with protamine, is inducing an activation of the complement system, action which is correlated with postoperative pulmonary shunt fraction [82]. To avoid these adverse effects of heparin, some possible alternatives have been proposed.…”

Hemostatic Defect in Baboons Autotransfused Treated Plasma to Simulate Shed Blood

“…A previous study from our laboratory has documented that heparin produced a platelet dysfunction and fibrinolysis in patients before cardiopulmonary bypass surgery 25 . In another study from our laboratory infusion of heparin into the baboon induced fibrinolytic activity, 100 units per kg of heparin produced a heparin level of 7.8 units per mL and a plasmin level of 72.7 units per liter 50 minutes following the infusion into baboons 26 …”