Paroxysmal nocturnal hemoglobinuria and thrombosis in the era of eculizumab

Abstract

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.