Harker L A
Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Semin Hematol. 1998 Jul;35(3):241-52.
Endogenous thrombopoietin (TPO) stimulates platelet production in nonhuman primates by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. In nonhuman primates, recombinant human TPO, nonpegylated or pegylated rHu megakaryocyte growth and development factor produce log-linear responses in peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number, and mass. Mpl ligands can support normal peripheral platelet concentrations after myelosuppressive chemotherapy in baboons, and correct the thrombocytopenia in human immunodeficiency virus-infected chimpanzees. Whereas mpl ligands do not induce platelet aggregation in vitro, mpl ligands enhance aggregatory responsiveness of platelets to physiologic agonists both in vitro and transiently ex vivo after treatment with mpl ligands in nonhuman primates. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet concentration, per se. These findings indicate that appropriate dosing of mpl ligands prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications.
内源性血小板生成素（TPO）通过诱导早期骨髓造血祖细胞产生剂量依赖性的巨核细胞发育以及随后的增殖和核内复制，刺激非人类灵长类动物的血小板生成。在非人类灵长类动物中，重组人TPO、非聚乙二醇化或聚乙二醇化的重组人巨核细胞生长和发育因子在外周血小板计数峰值（或外周血小板质量周转率）以及骨髓巨核细胞体积、倍性、数量和质量方面产生对数线性反应。Mpl配体可在狒狒骨髓抑制化疗后维持正常的外周血小板浓度，并纠正人类免疫缺陷病毒感染的黑猩猩的血小板减少症。虽然Mpl配体在体外不诱导血小板聚集，但在非人类灵长类动物中，Mpl配体在体外以及在用Mpl配体处理后的短暂体内均增强血小板对生理性激动剂的聚集反应性。然而，在血小板依赖性血栓形成的定量兔或狒狒模型中评估时，除了血小板浓度本身的影响外，这些药物不会增加形成血栓的血小板募集。这些发现表明，适当剂量的Mpl配体可预防血小板减少症，而不会增加血小板依赖性血栓闭塞性并发症的风险。
