The effects of streptokinase in a Chacma baboon (Papio ursinus) model of acquired thrombotic thrombocytopenic purpura

Abstract

TTP is a life-threatening disorder with limited pharmaceutical treatment options. Recently, the potential of streptokinase in the treatment of acquired TTP was demonstrated in humans in vitro, and in vivo in a mouse model. We aimed to determine the in vitro and in vivo effects of streptokinase in an established Papio ursinus model of acquired TTP. In vitro: VWF activities & multimer patterns and thromboelastograms were assessed with increasing concentrations of streptokinase. In vivo: After induction of TTP, escalating streptokinase doses (ranging from 50,000 to 900,000IU) were administered, and the effects of streptokinase assessed on peripheral blood counts, fibrinolysis, VWF activities & multimer patterns and thromboelastograms. In an extension of the study, high-dose streptokinase (1,500,000-3,000,000IU) was administered to another baboon. After spiking, fibrinolysis with loss of large VWF multimers was observed at [2200IU/mL]-roughly equivalent to 1,500,000IU. However, administration of escalating intravenous streptokinase doses had no in vivo effect on the TTP phenotype, and in vivo increases in plasmin activity were mild when compared with baseline, even at high doses. Minimal effect on VWF multimer patterns was observed but only at doses ≥ 1500,000IU. Streptokinase is not effective in resolving TTP in a Papio ursinus model of TTP, possibly due to limited activation of the baboon fibrinolytic system. Modifications to this model, the use of alternative higher animal models, or alternative thrombolytics, should be considered to establish proof-of-concept.