Activation of Antithrombin III by Protamine-Bound Heparin a Possible Cause Of Heparin Rebound

There have been a variety of bleeding syndromes associated with the use of cardiopulmonary bypass procedures attributed to such things as platelet function defects, activation of plasmin, thrombocytopenia and consumption coagulopathy. One other cause of bleeding, particularly in the postoperative period, has been that of hyperheparinemia or so-called "heparin rebound". Usually high doses of heparin are used during bypass to prevent not only thrombosis in the patient, but to avoid clot formation within the machine. At the end of the pump run, the heparin is neutralized with either protamine sulfate or protamine chloride. In the United States, protamine sulfate is the only neutralizing agent being used at the present time. By definition then, heparin rebound is the resurgence of anticoagulant or antithrombin activity in a heparinized patient whose blood has been neutralized with protamine. There have been many explanations for this phenomenon offered in the literature 1). On the one side, there is an increase in heparin concentration in the blood due to release from various sites of storage in the vessels such as red cells or endothelial surfaces, or the return of heparin into the circulation from extravascular spaces. An additional possibility is a naturally occurring protaminase which will destroy protamine, thereby releasing heparin from a heparin protamine complex.