IMPORTANCE OF PLATELETS IN THE PROCESS LEADING TO PAI-1 INCREASE FOLLOWING ENDOTOXEMIA IN-VIVO

Endotoxin producing bacteria cause disseminated intravascular coagulat ion, The mechanism of endotoxin action is still unclear but impairment of the fibrinolytic system has been suggested as a contributing mecha nism. A single injection of endotoxin (1 mu g/kg, i.v.) dramatically i ncreased the circulating activity of plasma PAI-1 in the rabbit, This effect occurred in time-dependent manner, the maximum activity of circ ulating PAI-1 being observed 4 h after the administration of endotoxin . In order to determine the importance of platelets in this phenomenon , we administered and-platelet antiserum which reduced platelet counts to 6% of the basal value, Antiserum-induced thrombocytopenia did not alter the effect of endotoxin showing that PAI-1 increase resulting fr om the injection of endotoxin did not depend on platelet release direc tly or indirectly. This observation was further confirmed by the effec t of various antithrombotic agents, known for their effects on platele ts, tested for their ability to affect endotoxin-induced PAI-1 increas e. Indeed, neither antiplatelet agents like clopidogrel, an ADP antago nist, SR 27417, a selective PAF receptor antagonist, SR 46349, a 5-HT2 receptor antagonist, L-NAME a nitric oxide synthase inhibitor or aspi rin nor anticoagulants like heparin of hirudin, administered intraveno usly before the administration of endotoxin showed any activity with r egard to PAI-1 increase, Therefore, we show that PAI-1 increase result ing from the injection of endotoxin do not depend on platelet release directly or indirectly.