Prohemorrhagic and bleeding time activities of recombinant tissue plasminogen activator, heparin, aspirin, and a glycoprotein IIb/IIIa antagonist.

ABSTRACT

Intracerebral hemorrhage (ICH) is the most serious side effect of antithrombotic agents, especially in cases of cerebrovascular disease. In the present study, we compared the exacerbation of ICH and prolongation of bleeding time (BT) in guinea pigs with recombinant tissue plasminogen activator (rt-PA), heparin, aspirin, and FK419, a novel nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor antagonist. ICH was induced by injection of bacterial collagenase into the caudate nucleus; BT was measured with a Simplate R device. Neither heparin nor aspirin prolonged BT. In contrast, rt-PA at the highest dose used in the study did prolong BT, and FK419 caused a dose-dependent prolongation of BT. Moreover, rt-PA and heparin increased the degree of ICH in a dose-dependent manner, leading to death in more than half of the animals treated with higher doses of these drugs. These findings show that the prohemorrhagic mechanisms underlying the prolongation of BT differ from those in collagenase-induced ICH, and that the risk of an agent with antithrombotic effects potentiating hemorrhage in the collagenase-induced model of ICH more closely parallels that in stroke patients than does the effect of the agent on BT. The findings also suggest that antiplatelet agents, including FK419, may be safer than thrombolytic or anticoagulant agents for use in patients at risk for ICH, such as those with stroke or cerebral aneurysm.