Paroxysmal nocturnal hemoglobinuria and thrombosis

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal hematopoiesis disorder caused by a somatic mutation in the PIGA (phosphatidylinositol glycan, class A) gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)anchored complement regulatory proteins on blood cell surface. Dysregulation of the complement system leads to chronic intravascular hemolysis, anemia, endothelial dysfunction as well as development of prominent acquired thrombophilic state, clinically manifested by venous thromboembolism, frequently involving atypical vascular sites. Thrombotic complications represent the leading cause of adverse outcomes and mortality in patients with PNH. This review summarizes current evidence on PNH etiology, molecular genetics and pathophysiological mechanisms including complement dysregulation, nitric oxide depletion, intraand extravascular hemolysis, and the multifactorial pathogenesis of thrombosis. The clinicopathogenetic relationship between PNH, aplastic anemia, and myelodysplastic syndromes is discussed in the context of immune-mediated bone marrow failure. Special emphasis is put on PNH course in women of reproductive age. Physiological changes associated with pregnancy and the postpartum period, including complement activation and hypercoagulability, are shown to be associated with increased risk of hemolytic crises and thromboembolic complications in women with PNH, thereby defining the disease as a condition of extremely high obstetric risk. Contemporary principles for multidisciplinary management aimed at improving maternal and perinatal outcomes are reviewed.

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