Thrombotic complications in paroxysmal nocturnal haemoglobinuria: a literature review.

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, clonal haematopoietic stem cell disease caused by mutations in an X-linked gene called phosphatidylinositol glycan class A (PIG-A). The disease can present with bone marrow failure, haemolytic anaemia, smooth muscle dystonia and thrombosis. The PIG-A gene product is necessary for the first step in the biosynthesis of glycosylphosphatidyinositol (GPI) anchors - the transfer of GlcNAc from UDP-GlcNAc to form N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI) - where expansion and differentiation of the PIG-A mutant stem cell leads to clinical manifestations of the disease1. PNH may occur de novo (classical PNH) or in the setting of aplastic anaemia (hypoplastic PNH); the absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders these cells susceptible to terminal complement-mediated haemolysis2. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but the range is wide. Thrombosis is the leading cause of death, and an initial thrombotic event increases the relative risk of death by 5- to 10-fold in PNH3. Haemolysis most likely contributes to thromboembolism, as patients with larger PNH clones have a higher incidence of thromboembolism and events have been temporally associated with increased haemolysis. Although the mechanism is not fully understood, haemolysis has been implicated in the initiation of platelet activation and aggregation4. This review discusses the underlying mechanisms that lead to thrombosis in PNH and therapeutic approaches.