Paroxysmal nocturnal hemoglobinuria (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. PNH is the paradigm of diseases implying
complement dysregulation as main pathogenic mechanism; in fact, PNH erythrocytes are uncapable to modulate on their surface physiologic complement activation, which eventually leads to the typical clinical hallmark of PNH - the chronic
complement-mediated intravascular
anemia. Indeed, due to the lack of CD55
complement is continuously activated on erythrocyte surface, which subsequently enables the terminal lytic
complement because of the lack of CD59, finally resulting in erythrocyte lysis. The availability of
eculizumab as the first
complement inhibitor for clinical use renewed the interest for this rare
hematological disease. Indeed, in the last decad the anti-C5
monoclonal antibody has proven effective for the treatment of PNH, resulting in a sustained control of
complement-mediated
intravascular hemolysis, with a remarkable clinical benefit. Anti-
complement treatment allowed transfusion independence in at least half of PNH patients receiving
eculizumab, with adequate control of all
hemolysis-associated symptoms even in almost all remaining patients. In addition, the risk of thromboembolic events - an other clinical hallmark of PNH, which significantly affects prognosis and survival - seems substantially reduced on
eculizumab treatment, apparently resulting in improved survival. Even with all these remarkable effects,
eculizumab treatment does not result in
hemoglobin normalization, and most patients remain anemic. It has been demonstrated that this is due to persistent activation of the early phases of complement activation (upstream the C5), leading to
complement-mediated
extravascular hemolysis. Ongoing researches are focusing on possible strategies to improve current anti-
complement therapies, aiming to develop second-generation
complement therapeutics. Here we review PNH and its
complement-mediated pathophysiology, summarizing available data on anti-
complement treatment; we'll also discuss recent pathogenic insights which drive the development of novel strategies of
complement inhibition.