Joubert J, Meiring S M, Conradie C, Lamprecht S, Janse van Rensburg W J
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.
Universitas Academic Laboratories, Haematology, National Health Laboratory Service, Bloemfontein, South Africa.
Clin Exp Med. 2021 Nov;21(4):663-674. doi: 10.1007/s10238-021-00711-1. Epub 2021 Apr 22.
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.
血栓性血小板减少性紫癜（TTP）是一种危及生命的疾病，药物治疗选择有限。最近，链激酶在治疗获得性TTP中的潜力在人体体外以及小鼠模型体内得到了证实。我们旨在确定链激酶在已建立的狒狒获得性TTP模型中的体外和体内作用。体外：随着链激酶浓度增加，评估血管性血友病因子（VWF）活性、多聚体模式和血栓弹力图。体内：诱导TTP后，给予递增剂量的链激酶（范围为50,000至900,000国际单位），并评估链激酶对外周血细胞计数、纤维蛋白溶解、VWF活性、多聚体模式和血栓弹力图的影响。在该研究的扩展部分，对另一只狒狒给予高剂量链激酶（1,500,000 - 3,000,000国际单位）。加样后，在[2200国际单位/毫升]时观察到纤维蛋白溶解且大VWF多聚体消失 - 大致相当于1,500,000国际单位。然而，递增静脉注射链激酶剂量对TTP表型没有体内作用，与基线相比，即使在高剂量时，体内纤溶酶活性的增加也很轻微。仅在剂量≥1500,000国际单位时观察到对VWF多聚体模式的最小影响。在狒狒TTP模型中，链激酶对解决TTP无效，可能是由于狒狒纤维蛋白溶解系统的激活有限。应考虑对该模型进行修改、使用替代的高等动物模型或替代溶栓剂，以建立概念验证。
