Nishimura Jun-Ichi
Osaka University Graduate School of Medicine, Department of Hematology and Oncology.
Rinsho Ketsueki. 2018;59(8):1042-1047. doi: 10.11406/rinketsu.59.1042.
Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of clonal expansion of hematopoietic stem cells that have acquired a somatic mutation in the PIGA gene. The resulting hematopoietic cells have deficiencies in the GPI-anchored complement regulatory proteins CD55 and CD59, which account for the intravascular hemolysis that is the primary clinical manifestation of PNH. Thromboembolism is a major cause of morbidity and mortality in PNH, particularly in Caucasian patients. In a previous report on the clinical course of PNH patients in the United States and Japan, we showed that thrombosis was significantly more prevalent in white PNH patients than in Asian PNH patients. The pathophysiological mechanisms underlying thrombosis in PNH have not been fully clarified, and multiple factors are likely to be involved. Eculizumab, a humanized monoclonal antibody, targets the terminal complement protein C5 and inhibits terminal complement-mediated hemolysis associated with PNH. Brodsky et al. reported that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. These facts strongly suggest that the main cause of thrombosis in PNH is complement activation and/or hemolysis. In this review, the pathophysiology of thrombosis in PNH is discussed in the context of observations in PNH patients treated with eculizumab.
阵发性睡眠性血红蛋白尿（PNH）是由于造血干细胞克隆性扩增所致，这些造血干细胞在PIGA基因中发生了体细胞突变。由此产生的造血细胞缺乏糖基磷脂酰肌醇（GPI）锚定的补体调节蛋白CD55和CD59，这导致了血管内溶血，而血管内溶血是PNH的主要临床表现。血栓栓塞是PNH发病和死亡的主要原因，在白种人患者中尤为明显。在之前一份关于美国和日本PNH患者临床病程的报告中，我们发现白种人PNH患者的血栓形成明显比亚洲PNH患者更为普遍。PNH中血栓形成的病理生理机制尚未完全阐明，可能涉及多种因素。依库珠单抗是一种人源化单克隆抗体，作用于补体终末蛋白C5，抑制与PNH相关的终末补体介导的溶血。布罗德斯基等人报告称，依库珠单抗治疗可降低PNH患者临床血栓栓塞的风险。这些事实有力地表明，PNH中血栓形成的主要原因是补体激活和/或溶血。在这篇综述中，我们将结合接受依库珠单抗治疗的PNH患者的观察结果，讨论PNH中血栓形成的病理生理学。
