Paroxysmal nocturnal hemoglobinuria and the age of therapeutic complement inhibition

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells due to a mutation in the PIG-A gene leading to a deficiency of GPI-anchored proteins. Lack of two specific GPI-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that result in both intravascular and extravascular hemolysis. Free hemoglobin leads to nitric oxide depletion that mediates the pathophysiology of some of the common clinical signs of PNH. Clinical symptoms of PNH include evidence of hemolytic anemia, bone marrow failure, smooth muscle dystonias and thromboses. Treatment options for patients with PNH include bone marrow transplantation, a therapy associated with high morbidity and mortality, or treatment with the complement inhibitor eculizumab. Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life (QoL) of patients.

Keywords::

• complement inhibition
• eculizumab
• paroxysmal nocturnal hemoglobinuria

Financial & competing interests disclosure

RA Brodsky serves on the scientific advisory board for Alexion pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells due to a mutation in the PIG-A gene leading to a deficiency of GPI-anchored proteins.

• • Central to the pathophysiology of PNH is uncontrolled activation of the alternative pathway of complement due to lack of CD55 and CD59, both GPI-anchored proteins that normally function to regulate complement.

• • Uncontrolled complement activation leads to both intravascular and extravascular hemolysis. Free hemoglobin leads to nitric oxide depletion that mediates the pathophysiology of some of the common clinical signs of PNH.

• • PNH can arise de novo or in the setting of aplastic anemia.

• • Clinical symptoms of PNH include evidence of hemolytic anemia, bone marrow failure, smooth muscle dystonias and thromboses.

• • Treatment options for patients with PNH include bone marrow transplantation or treatment with the complement inhibitor eculizumab.

• • Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life of patients.

• • While use of eculizumab has been shown to be safe and have few adverse effects more data is needed to evaluate the consequences of long-term complement inhibition in patients with PNH.