Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes: clonal expansion of PIG-A-mutant hematopoietic cells in bone marrow failure.

C lones of paroxysmal nocturnal hemoglobinuria (PNH) cells – glycosylphosophoinositol (GPI)-anchored protein-deficient hematopoietic cells – can be detected by flow cytometry in patients with myelodysplastic sydromes (MDS). While the etiology of PNH is known to be a somatic mutation in the X-linked PIG-A gene, which abrogates GPI synthesis, the patho-physiology of PNH clonal expansion is not well understood. In frank PNH with clinical symptoms and signs of intravascular hemolysis and venous thrombosis, PNH cells dominate in the peripheral blood. Very small PNH clones can also be detected efficiently and routinely in patients with aplastic anemia and MDS. PNH clones emerge almost always in the setting of marrow failure, presumably immune-mediated hematopoietic destruction. Possible mechanisms for clonal expansion and clinical implications for the diagnosis, prognosis, and treatment of MDS are discussed. A short history of paroxysmal nocturnal hemoglobinuria PNH, despite its rarity, has intrigued physicians since its description in the 19 th century. 1-3 Progressive understanding of the disease has paralleled advances in biochemistry , cell biology, and molecular biology; as problems in etiology and pathophysiology have been resolved, however, new questions have arisen. In the current era, treatments beyond simple blood transfusion have proven effective, particularly stem cell trans-plantation and the novel monoclonal antibody eculizumab; as both are expensive and entail risk, a clear description of the pathophysiology of PNH has become more important. Early in the history of the study of PNH, interest centered on the episodic and often dramatic appearance in the morning urine of an abundant red pigment, rather than red blood cells as occurs in the far more prevalent renal pathologic processes. Once biochemical investigations identified this pigment as hemoglobin, the focus became the origin of the intravascular hemolysis that released erythrocyte contents directly into the circulation. Unlike in the more common extravascular hemoly-sis of transfusion reactions and in autoimmune hemolyt-ic anemia, an antibody could not be implicated. While the erythrocytes themselves seemed defective, this intrinsic susceptibility to lysis in vitro could only be elicited in the presence of a non-immunoglobulin component of serum. Ham discovered that the serum component was complement, thus creating a laboratory assay for PNH cells and also initiating further research on the specific complement reaction responsible as well as the ery-throcyte defect. Multiple proteins were missing from the red blood cell surface; some [decay accelerating factor (CD55) and membrane inhibitor of reactive lysis (CD59)] acted to inactivate complement, explaining the intravas-cular …