HEPARIN-BINDING PROTEINS - CONTRIBUTION TO HEPARIN REBOUND AFTER CARDIOPULMONARY BYPASS

Background. Heparin rebound, the reappearance of anticoagulant activit y after adequate neutralization with protamine, can lead to excessive postoperative bleeding after cardiac surgery. We investigated the mech anism of heparin rebound by using chemically modified heparin that lac ks anticoagulant activity (low-affinity heparin) but that is able to d isplace protein-bound anticoagulantly active heparin. Methods and Resu lts. Sixteen patients undergoing elective cardiac surgery were given h eparin (400 U/kg) to achieve an activated clotting time (ACT) >400 sec onds. After cardiopulmonary bypass, protamine sulfate was given (by he parin-ACT dose-response curve) to return the ACT to prebypass times (p re operative, 160+/-9 seconds; postoperative, 156+/-17 seconds). Blood samples were obtained serially for 24 hours and assayed for thrombin clotting time (TCT) and heparin activity using an anti-factor Xa assay . The TCT and anti-factor Xa activity were consistently and abnormally elevated for the first 6 hours after surgery. The anti-factor Xa acti vity increased fourfold after the addition of low-affinity heparin (es sentially free of anti-factor Xa activity), indicating that anticoagul antly active heparin persisted in the circulation after protamine neut ralization bound nonspecifically to plasma proteins. Blood loss correl ated with postoperative TCTs. Conclusions. Our findings demonstrate th at heparin anticoagulant activity persists for up to 6 hours after sur gery despite apparent protamine neutralization. The observation of the marked increase in plasma anti-factor Xa activity after the addition of low-affinity heparin suggests that after its administration, a larg e proportion of the heparin binds to plasma proteins and is incomplete ly removed by protamine. After protamine is cleared, the protein-bound heparin dissociates slowly and binds to anti-thrombin III to produce an anticoagulant effect.