Paroxysmal Nocturnal Hemoglobinuria

Today we discussed a very rare cause of anemia and thrombosis, PNH.

This disease results from an acquired mutation in DNA encoding components of complement system, which leads to several clinical manifestations:

1) Hemolysis, which is episodic ("paroxysmal"). The degree of hemolysis depends on how many RBCs are abnormal. Unclear why it is sometimes nocturnal, as shown above. Chronic hemolysis can cause severe anemia, and renal failure from myoglobin-induced tubular damage

2) Thrombosis. It is unclear why patients with PNH are hypercoagulable; it may have to do with platelet abnormalities in PNH (all hematopoietic stem cells can be involved). Thrombosis is usually venous, but can be arterial. The hallmark is thromboses in relatively unusual places, most commonly portal vein or other intra-abdominal veins and cerebral venous sinus thrombosis.

3) Diminished hematopoiesis. Because marrow stem cells are involved, pancytopenia can be ther presenting manifestation.

Diagnosis: "PNH assay", which is flow cytometry for the clone of cells with abnormal complement-related proteins.

Therapy:

1) For hemolysis:
-supportive measures include transfusion, iron supplementation, folic acid supplementation.
-specific therapy is Eculizumab, a monoclonal antibody that inhibits complement activation, and significantly reduces hemolysis. Limiting factor is cost, estimated at $400,000 / year

2) For thrombosis:
-anticoagulation with heparin then warfarin as secondary prevention
-there may be lower risks of thrombosis on Eculizumab
-there is retrospective evidence supporting prophylactic anticoagulation with warfarin in selected patients

Stem cell transplant is also an option reserved as a last resort

Links:

Click here for the paper showing the effect of Eculizumab in PNH