Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders

Abstract

The recent availability of eculizumab as the first complement inhibitor renewed the interest for complement-mediated damage in several human diseases. Paroxysmal nocturnal hemoglobinuria (PNH) may be considered the paradigm a disease caused by complement dysregulation specifically on erythrocytes; in fact, PNH is a clonal, non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins, including the two complement regulators CD55 and CD59. As a result, PNH erythrocytes are incapable to modulate on their surface physiologic complement activation, which eventually enables the terminal lytic complement leading to complement-mediated intravascular anemia - the typical clinical hallmark of PNH. In the last decade the anti-C5 monoclonal antibody has been proven effective for the treatment of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis, with a remarkable clinical benefit. Since then, different diseases with a proved or suspected complement-mediated pathophysiology have been considered as candidate for a clinical complement inhibition. At the same time, the growing information on biological changes during eculizumab treatment in PNH have improved our understanding of different steps of the complement system in human diseases, as well as their modulation by current anti-complement treatment. As a result, investigators are currently working on novel strategy of complement inhibition, looking at the second generation of anti-complement agents which hopefully will be able to modulate distinct steps of the complement cascade. Here we review PNH as a disease model, focusing on the observation that led to the development of novel complement modulators; the discussion will be extended to other hemolytic disorders potentially candidate for clinical complement inhibition.