Summary
Multiple clinical trials have proven that thrombolytic therapy is an effective treatment
for acute myocardial infarction. Spontaneous intracranial hemorrhage (ICH) occurs
in a small percentage of patients as a result of the treatment. The etiology of the
ICH is unknown and there is currently no established experimental model for this side
effect. A model of ICH during thrombolytic therapy has been developed using spontaneously
hypertensive rats (SHR). The SHR were made susceptible to ICH during thrombolytic
therapy by bilateral ligation of the external jugular veins. This procedure produced
asymptomatic hemorrhagic lesions in the brains of the animals in the hours preceding
the administration of t-PA/heparin. The incidence of ICH following the administration
of test substances was assessed by histological examination and by measuring the red
blood cell count in a sample of cerebrospinal fluid taken from the atlanto-occipital
space. t-PA administration produced a low frequency of ICH in this model. The incidence
and severity of ICH were dramatically increased, and significant mortality at 24 h
was observed, by combining heparin with the t-PA. No fewer hemorrhages were observed
if the t-PA and heparin were administered sequentially rather than simultaneously.
Furthermore, ICHs were observed whether the t-PA dose was administered over 4 h, 1
h, or as a double bolus 30 min apart. The potentiation of ICH by heparin was dose
dependent and proportional to the prolongation of the aPTT. Although the precise mechanism
of ICH during thrombolytic therapy is unknown, many similarities exist between the
observations made in this model and in the human clinical experience.
