Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening and debilitating clonal blood disorder caused by an acquired mutation in the
phosphatidylinositol glycan (PIG)-A gene. In pluripotent hematopoietic stem cells, this leads to a deficiency of
glycosylphosphatidylinositol (GPI)-anchors and
GPI-anchored proteins, including the
complement regulators CD55 and CD59, on the surface of affected blood cells. PNH red blood cells are highly vulnerable to activation of
complement and the formation of the
membrane attack complex (MAC). The resulting chronic
intravascular hemolysis is the underlying cause of PNH morbidities and mortality. Until recently, the treatment of PNH has been largely empirical and symptomatic with
blood transfusions, anticoagulation, and supplementation with
folic acid or
iron. The only potentially curative treatment is allogeneic
stem cell transplantation, but this has severe complications and high mortality and morbidity rates. A new targeted and disease-modifying treatment strategy is the inhibition of the terminal
complement cascade with the humanized monoclonal anti-C5 antibody,
eculizumab. This effectively inhibits MAC formation and
intravascular hemolysis.
Eculizumab has shown significant efficacy in controlled studies, with a marked decrease in
anemia,
fatigue, transfusion requirements, renal impairment,
pulmonary hypertension, and risk of severe thromboembolic events, ultimately resulting in improving quality of life and survival.