THE EFFECT OF RECOMBINANT APROTININ ON T-PA-INDUCED BLEEDING IN RATS

High dose aprotinin administered during cardiopulmonary bypass (CPB) h as been shown to reduce post-operative bleeding substantially. The exa ct mechanism of action is still debated. A reduction in fibrinolytic a ctivity by inhibition of plasmin generated during CPB may be the prima ry mode of action. However, this hypothesis has been questioned as the apparent inhibitory constant of aprotinin for plasmin is orders of ma gnitude lower than the clinically effective plasma concentration of ap rotinin. In the present study the effect of various plasma levels of a protinin on a plasmin-induced bleeding in rats was investigated. The m ean time of bleeding was 10 min in rats receiving only saline whereas a prolonged bleeding of up to > 45 min was seen in rats given t-PA and saline. The steady-state plasma concentration of recombinant aprotini n during infusion of 11 mg/kg/h was approximately 2 mu M which roughly corresponds to the clinical use of aprotinin. This dose reduced the t -PA-induced bleeding to a mean value of 11 min, whereas no effects wer e observed with lower doses. The effect of aprotinin in clinical care of blood loss in CPB in man may therefore be caused by direct inhibiti on of plasmin.