title: An experimental model of intracranial hemorrhage during thrombolytic therapy with t-PA.
abstract: 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 24h was observed, by combining 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.
authors.affiliation: Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Paoni
authors.forename: H G
authors.initials: HG
authors.lastname: Steinmetz
authors.forename: N
authors.initials: N
authors.lastname: Gillett
authors.forename: C J
authors.initials: CJ
authors.lastname: Refino
authors.forename: J M
authors.initials: JM
authors.lastname: Badillo
authors.forename: S
authors.initials: S
authors.lastname: Bunting
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage; D002543:Cerebral Hemorrhage / Q000209:etiology; D004195:Disease Models, Animal; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000008:administration & dosage; D006801:Humans; D006973:Hypertension / Q000150:complications*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013300:Streptokinase / Q000008:administration & dosage*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D005343:Fibrinolytic Agents; D006629:Hirudins; D000990:Antithrombin III; D006493:Heparin; D013300:Streptokinase; D010959:Tissue Plasminogen Activator