PRETREATMENT WITH A BLOCKING MONOCLONAL-ANTIBODY TO P-SELECTIN ACCELERATES PHARMACOLOGICAL THROMBOLYSIS IN A PRIMATE MODEL OF ARTERIAL THROMBOSIS

It has been established that the fibrin content of a developing thromb us can be dramatically reduced with the use of the GA6 monoclonal anti body, which is directed against P-selectin (CD62p). This effect is pro bably related to diminished tissue factor activity on monocytes in the presence of P-selectin antagonism. Therefore, we hypothesized that an occlusive arterial thrombus formed in the presence of a P-selectin mo noclonal antibody would be more susceptible to lysis with standard thr ombolytic therapy. To test this hypothesis, 22 male cynomolgus monkeys were anesthetized and instrumented for induction of thrombosis of a f emoral artery. Endothelial injury was induced by passing a 150-mu A an odal current through a small electrode that was placed in the femoral artery. Blood flow through the artery was continuously monitored using an ultrasonic transit-time flowmeter. The GA6 monoclonal antibody (1 mg/kg) or control, isotype matched mouse IgG(1) (P23 or P7) was admini stered i.v. 1 hr before electrolytic endothelial injury. In the P23 gr oup (n = 11), an occlusive thrombus formed in 52.1 +/- 8.5 min, and in the GA6 group (n = 11), an occlusive thrombus formed in an average ti me of 52.0 +/- 8.1 min. After formation of an occlusive thrombus, the current was terminated and intravenous heparin (100 U/kg + 50 U/kg/hr) was administered to prevent clot extension. After the thrombus had be en aged for 1 hr, thrombolytic therapy with i.v. streptokinase (5000 U /kg loading dose + 500 U/kg/min infusion for 120 min) was initiated. I n the P23 group, clot lysis occurred in 8 of 11 experiments (73%), whi ch was not appreciably different from lysis in the GA6 group (9 of 11; 82%). Of those vessels that were successfully recanalized, the mean t ime to lysis was 61.1 +/- 12.9 min in the GA6 group, which was approxi mately 39% faster than the time to lysis in the P23 control of 100.7 /- 10.4 min (P = .033). Thus we conclude that the reduced fibrin conte nt, which results from P-selectin antagonism, yields a thrombus that i s lysed more rapidly in response to pharmacological thrombolysis.