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.