Paroxysmal nocturnal hemoglobinuria pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.
It is thought to be an acquired disease with the clonal expansion of pluripotent stem cells containing the somatic mutation of an X-linked (short arm of X-chromosome) PIG-A (for phosphatidylinositol glycan class A) gene.[1] The gene that codes for PIG-A is inherited in an X-linked fashion. This gene is involved in the first step of the synthesis of the glucosylphosphatidyl-inositol anchor of GPI membrane proteins such as CD55, CD59, CD14 and others (CD is an acronym for 'cluster of differentiation'). Mutations in the PIG-A gene cause a deficiency of the glucosylphophatidylinositol-anchored proteins in PNH hematopoietic cells (all 3 cell lines can be affected). Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of this disease. The complement system is the part of the immune system that helps to destroy invading microorganisms. The presence of CD55 and CD59 confers resistance to the body's blood cells from lysis by complement. CD55 inhibits C3 convertase and CD59 blocks the formation of the membrane attack complex (MAC) by inhibiting the incorporation of C9 into the MAC. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis but it is the intravascular hemolysis that contributes to much of the morbidity of this disease.
The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets. They are also made by the bone marrow stem cells and will have the same GPI anchor defect as the red blood cells. The proteins which use this anchor are needed for platelets to clot properly, and their absence leads to a hypercoagulable state.
References
- ↑ Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood 2005;105:3848-54. PMID 15687243.