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

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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 900,000 IU) 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 (1,500,000–3,000,000 IU) was administered to another baboon. After spiking, fibrinolysis with loss of large VWF multimers was observed at [2200 IU/mL]—roughly equivalent to 1,500,000 IU. 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 ≥ 1500,000 IU. 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.

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Acknowledgements

The authors wish to thank Karen Vanhoorelbeke and Claudia Tersteeg of the IRF Life Sciences Laboratory for Thrombosis Research, Kulak Kortrijk Campus of KU Leuven, Kortrijk, Belgium, for supply of the 3H9 monoclonal antibody used for the induction of TTP, for supply of the method used for the determination of plasmin activity, and for technical and scientific advice on the execution of the low and intermediate dose in vivo experiment, as well as Christie Blaauw for assistance with the in vitro experiments’ laboratory assays and data collection.

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Authors and Affiliations

  1. Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, 205 Nelson Mandela Drive, PO Box 339 (G2), Bloemfontein, 9300, South Africa

    J. Joubert, S. M. Meiring & C. Conradie

  2. Universitas Academic Laboratories, Haematology, National Health Laboratory Service, Bloemfontein, South Africa

    J. Joubert & S. M. Meiring

  3. Animal Experimentation Unit, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

    S. Lamprecht

  4. Human Molecular Biology Unit, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

    W. J. Janse van Rensburg

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  1. J. Joubert
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  4. S. Lamprecht
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  5. W. J. Janse van Rensburg
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Contributions

JJ, SMM, and WJVR designed research, performed experiments, collected, analysed, and interpreted data, and co-wrote the manuscript; CC performed experiments, collected and analysed data, and reviewed the manuscript for technical content; SL designed research and performed experiments.

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Correspondence to J. Joubert.

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Joubert, J., Meiring, S.M., Conradie, C. et al. The effects of streptokinase in a Chacma baboon (Papio ursinus) model of acquired thrombotic thrombocytopenic purpura. Clin Exp Med 21, 663–674 (2021). https://doi.org/10.1007/s10238-021-00711-1

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  • DOI: https://doi.org/10.1007/s10238-021-00711-1

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