Summary
Intraoperative high-dose aprotinin administration has been shown to reduce the intra-and
postoperative blood loss in cardiac surgery. The haemostatic effect has been attributed
to platelet preserving properties and to inhibition of contact activation reducing
thrombotic and fibrinolytic activity during and after cardiopulmonary bypass (CPB).
Here we report on the effects of aprotinin on urokinase-type plasminogen activator,
especially on the protection of the zymogen singlechain urokinase-type plasminogen
activator (scu-PA). scu-PA occurs cell associated as well as free in the circulation
(concentration 50 pM, half-life 5 min), and is potentially activated by kallikrein
and plasmin, both potent targets for aprotinin. The generated active two-chain u-PA
(tcu-PA) is a powerful activator of fibrinolysis.
Sixteen male patients undergoing myocardial revascularization were randomly assigned
to aprotinin 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
hours postoperatively. After an initial drop due to haemodilution at the onset of
CPB, the concentrations of circulating u-PA forms restored intraoperatively in A,
but remained subnormal in C until the end of the observation period. The concentration
of total u-PA antigen of shed mediastinal blood was both in A and C two-fold higher
than in the circulation, but the antigen was preserved as the zymogen scu-PA in A
and largely converted to an inactive, non activatable form in C. Intra- and postoperative
blood losses were less than half the amount in A as compared to C.
It is concluded that without aprotinin administration activation of circulatory scu-PA
occurs, accompanied by stimulation of fibrinolysis and bleeding, finally resulting
in elimination of tcu-PA complexed with endogenous inhibitors. Furthermore, cellular
release of scu-PA occurs at or near the bleeding sites, as evidenced by the two-fold
higher u-PA antigen concentration in the shed mediastinal blood. The released scu-PA
is also activated and subsequently converted to an inactive form unless aprotinin
is administered. High-dose aprotinin application during CPB effectively protects circulating
and released scu-PA from activation and attenuates bleeding consequences.
