Newland Adrian
Department of Haematology, Centre for Haematology, The Royal London Hospital, London, UK.
Semin Hematol. 2007 Oct;44(4 Suppl 5):S35-45. doi: 10.1053/j.seminhematol.2007.11.005.
Thrombopoietin (TPO) is a potent endogenous cytokine and the principal regulator of platelet production. Advances in the understanding of the structure of TPO enabled development of the first generation of thrombopoietic growth factors, recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF). Clinical results showed that these agents were effective in promoting increases in platelet counts in a variety of thrombocytopenic disorders. However, clinical development was halted when studies demonstrated risk for autoantibody formation with cross-reactivity to endogenous TPO. A second generation of thrombopoietic growth factors, including TPO peptide and nonpeptide mimetics and TPO agonist antibodies, utilizing different mechanisms from recombinant growth factors to promote platelet production, are currently in development. The TPO peptide mimetic AMG 531 and the nonpeptide mimetic eltrombopag are in advanced clinical trials and have both resulted in dose-dependent increases in platelets in healthy subjects and in significant increases in platelets in patients with chronic immune thrombocytopenic purpura (ITP). Clinical trials are also being conducted to examine the efficacy and safety of eltrombopag to treat thrombocytopenia in hepatitis C virus (HCV)-infected individuals. These agents appear to be well tolerated and the formation of autoantibodies appears to be limited to first-generation growth factors. Increases in marrow reticulin have been demonstrated with some growth factors, but this appears to be a reversible phenomenon and is not associated with formation of collagen fibrosis. There appears to be no increased incidence of thrombotic events in patients who achieve high platelet counts with growth factor treatments, and although occasional thrombotic events have been reported, their association to the treatment is uncertain. While there is evidence that activation of signaling pathways involved in platelet production may result in reduction in the threshold for platelet activation, this appears to have minimal clinical relevance for the use of thrombopoietin growth factors.
血小板生成素（TPO）是一种强效内源性细胞因子，也是血小板生成的主要调节因子。对TPO结构认识的进展促成了第一代血小板生成生长因子的研发，即重组人血小板生成素（rhTPO）和聚乙二醇化人重组巨核细胞生长和发育因子（PEG-rHuMGDF）。临床结果表明，这些药物在多种血小板减少性疾病中能有效促进血小板计数增加。然而，当研究证明存在与内源性TPO交叉反应的自身抗体形成风险时，临床研发就停止了。目前正在研发第二代血小板生成生长因子，包括TPO肽和非肽模拟物以及TPO激动剂抗体，它们利用与重组生长因子不同的机制来促进血小板生成。TPO肽模拟物AMG 531和非肽模拟物艾曲泊帕正在进行后期临床试验，两者都已使健康受试者的血小板呈剂量依赖性增加，并使慢性免疫性血小板减少性紫癜（ITP）患者的血小板显著增加。也正在进行临床试验以检验艾曲泊帕治疗丙型肝炎病毒（HCV）感染个体血小板减少症的疗效和安全性。这些药物似乎耐受性良好，自身抗体的形成似乎仅限于第一代生长因子。已证明某些生长因子会使骨髓网硬蛋白增加，但这似乎是一种可逆现象，且与胶原纤维化的形成无关。接受生长因子治疗使血小板计数升高的患者中，血栓事件的发生率似乎并未增加，尽管偶尔有血栓事件的报告，但其与治疗的关联尚不确定。虽然有证据表明参与血小板生成的信号通路激活可能导致血小板激活阈值降低，但这似乎对血小板生成素生长因子的使用没有太大临床意义。
