Sandbox:PNH
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Historical Perspective
Discovery
Although some question the diagnostic importance of nocturnal haemoglobinuria [Dacie and Lewis (1972) reported it to be the presenting symptom in only 26% of patients], it was this symptom that defined PNH as a distinct clinical entity and ignited the curiosity of early investigators (Table I). Further, the nocturnal aspect of the paroxysms suggested to Strübing (1882) a mechanism for the haemoglobinuria. He hypothesized that this symptom was a consequence of the abnormal sensitivity of PNH erythrocytes to systemic acidosis resulting from accumulation of CO2 during sleep. Although the validity is still debated, systematic investigation of this hypothesis by Strübing (1882), Hijmans van den Berg (1911) and Ham (1937) lead directly to the development of a specific diagnostic test for PNH (the acidified serum lysis test of Ham) and to the discovery by Ham of the fundamental role of complement in the lysis of PNH erythrocytes (Ham, 1939; Ham & Dingle, 1939).
In a 1953 review, Crosby reported the high incidence of thrombosis‐related deaths in PNH, and subsequent clinical studies have confirmed that thromboembolic events are a major cause of morbidity and mortality (Crosby, 1953a). Thus, in addition to being classified as a haemolytic anaemia, PNH is included on the list of thrombophilic conditions. The fundamental basis of the thrombophilia of PNH is undefined and represents one of two major unsolved mysteries of PNH (Table I) (Dacie, 1963).
PNH is also included among the bone marrow failure syndromes because, at some point during the course of their illness, almost all patients have (in addition to anaemia) thrombocytopenia, leucopenia or both. Further, there is a clear, albeit incompletely understood, connection between PNH and acquired aplastic anaemia. PNH is also a stem cell disorder because platelets and leucocytes share, with erythrocytes, the deficiency of GPI‐anchored proteins (the exact stage of differentiation in which the genetic mutation occurs is undefined, but it must be effected in a very primitive stem cell because mutant PIG‐A is found in erythroid, myeloid and lymphoid elements from the same patient).
PNH is remarkable because it is a clonal disease but not a malignant disease, and the bone marrow and peripheral blood are mosaics of normal and abnormal cells. Further, individual patients often have multiple abnormal clones that are phenotypically and genotypically discrete. The abnormal stem cells are a consequence of somatic mutation and the mutant gene is located on the X‐chromosome. Thus, inactivation of only one gene in somatic tissues is necessary for manifestation of the phenotype, explaining why all cases of PNH are due to mutant PIG‐A (this hypothesis assumes that all other genes that could cause the phenotype are autosomal). Genetically, females and males are equally susceptible because only one X‐chromosome is active in the somatic tissue of females.
The mutant gene, PIG‐A, is an essential component of the pathway required for synthesis of the GPI moiety that serves as an anchor for a functionally diverse group of membrane proteins. Of the 20 or so proteins that are deficient on the haematopoietic cells of PNH, only DAF (CD55) and MIRL (CD59) share an obvious functional relationship (they are both complement regulatory proteins). Absence of these two proteins accounts for the marked susceptibility of PNH erythrocytes to complement‐mediated lysis. The PIG‐A mutation is necessary for the development of PNH, but it appears insufficient to result in clonal expansion in the absence of some other selective pressure. Defining the nature of the selective process that results in the expansion and clonal dominance of the PIG‐A mutant stem cells is currently the most active area of investigation and represents Dacie's ultimate problem –‘the aetiology of the disease and its relationship to marrow hypoplasia’ (Dacie, 1963). Whatever the solution to this problem, it must somehow depend on the absence of one or more GPI‐anchored proteins.
After reviewing Table I, I hope it is apparent why this elegant, complex disease is a source of continuing fascination for haematologists. This history of PNH is intended to chronicle the landmark events that defined the disease over the past century.