PROTECTION OF SINGLE-CHAIN UROKINASE-TYPE PLASMINOGEN-ACTIVATOR (SCU-PA) IN APROTININ TREATED CARDIAC SURGICAL PATIENTS UNDERGOING CARDIOPULMONARY BYPASS

Intraoperative high-dose aprotinin administration has been shown to re duce the intra and postoperative blood loss in cardiac surgery. The ha emostatic effect has been attributed to platelet preserving properties and to inhibition of contact activation reducing thrombotic and fibri nolytic activity during and after cardiopulmonary bypass (CPB). Here w e report on the effects of aprotinin on urokinase-type plasminogen act ivator, especially on the protection,of the zymogen single-chain uroki nase-type plasminogen activator (scu-PA), scu-PA occurs cell associate d as well as free in the circulation (concentration 50 pM, half-life 5 min), and is potentially activated by kallikrein and plasmin, both po tent targets for aprotinin. The generated active two-chain u-PA (tcu-P A) is a powerful activator of fibrinolysis. Sixteen male patients unde rgoing myocardial revascularization were randomly assigned to aprotini n treatment (A) or control group (C). Plasma concentration of total u- PA antigen and of the specific forms scu-PA(zymogen) and tcu-PA(active enzyme) were measured at different stages intraoperatively and two ho urs postoperatively. After an initial drop due to haemodilution at the onset of CPB, the concentrations of circulating u-PA forms restored i ntraoperatively in A, but remained subnormal in C until the end of the observation period. The concentration of total u-PA antigen of shed m ediastinal blood was both in A and C two-fold higher than in the circu lation, but the antigen was preserved as the zymogen scu-PA in A and l argely converted to an inactive, non activatable form in C. Intra- and postoperative blood losses were less than half the amount in A as com pared to C. It is concluded that without aprotinin administration acti vation of circulatory scu-PA occurs, accompanied by stimulation of fib rinolysis and bleeding, finally resulting in elimination of tcu-PA com plexed with endogenous inhibitors. Furthermore, cellular release of sc u-PA occurs al or near the bleeding sites, as evidenced by the two-fol d higher u-PA antigen concentration in the shed mediastinal blood. The released scu-PA is also activated and subsequently converted to an in active form unless aprotinin is administered. High-dose aprotinin appl ication during CPB effectively protects circulating and released scu-P A from activation and attenuates bleeding consequences.