Clinical Medicine Insights: Therapeutics

Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired clonal stem cell disorder resulting in hemolysis and thrombosis. A somatic mutation in the phosphatidylinositol glycan A gene in hematopoietic stem cells results in a deficiency of the complement regulatory proteins, CD55 and CD59. There is a consequent increased sensitivity to complement mediated lysis. Eculizumab is a recombinant, humanized monoclonal antibody directed against C5 of the complement system. It blocks terminal complement activation and the formation of the membrane attack complex. It has been demonstrated in 3 clinical studies that this blockade of the terminal complement system effectively and significantly prevents intravascular hemolysis thereby abolishing or reducing the need for transfusions, reduces thromboses, improves quality of life and appears to prevent renal damage and improve pulmonary pressures. The drug is very well tolerated with few safety concerns. Case reports of the use of eculizumab in pregnancy, cold agglutinin disease and atypical hemolytic syndrome are also described.