Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia in which the red cells lack the proteins that protect them from complement.
Why the cells are unprotected
Complement is a set of plasma proteins that can destroy cells, and normal cells carry molecules that hold it in check. In PNH the red cells are deficient in the complement-controlling molecules:
- CD55;
- CD59, which prevents the attachment of the C9 complex to the cell.
The cells that lack CD59 carry no mutation in the CD59 molecule itself. The fault lies in the GPI anchor, the glycosylphosphatidylinositol structure that ties CD59 and a family of other proteins to the cell surface and is built with the help of the PIGA gene. That mutation is somatic, arising in a bone-marrow stem cell, so it is not inherited; the patient is mosaic, carrying a mixture of PNH and non-PNH red cells in the peripheral blood.
Because CD55 and CD59 are absent, the red cells are destroyed intravascularly by either the classical or the alternative pathway of complement.
PNH mostly arises from a de novo mutation, but it can also be secondary to diseases such as myelodysplastic syndromes (MDS), aplastic anemia, and primary myelofibrosis (PMF).
The triad
PNH is an acquired chronic hemolytic anemia with a triad of:
- hemolysis;
- pancytopenia, a reduction in red cells, white cells and platelets together, which suggests an element of bone marrow failure; the neutropenia it brings can cause severe infections and the thrombocytopenia severe bleeding, alongside the thrombosis;
- a distinct tendency to venous thrombosis. Because of this, one of the main complaints is severe abdominal pain, from venous thrombosis in the abdomen; when the thrombosis affects the hepatic vein, hepatomegaly and ascites follow.
The high tendency to thrombosis is not fully explained, but one proposal is that the loss of CD59 on the platelet surface allows complement to act on platelets and promotes clotting.
Laboratory findings
The laboratory findings are:
- anemia, which can be mild to severe and is mostly normocytic normochromic; in the long term the patient can also become microcytic if iron deficiency develops from the iron lost through hemoglobinuria;
- high LDH;
- high unconjugated bilirubin;
- low haptoglobin;
- an erythroid hyperplastic bone marrow aspirate.
Diagnosis
The diagnosis is confirmed by flow cytometry, which measures the GPI-anchored proteins on the surface of red cells and white cells. Staining with fluorescently labeled proaerolysin (FLAER) binds the GPI anchor itself and is more accurate than measuring CD55 or CD59 alone, because it can detect even small PNH clones.
Treatment
Since 2007 a humanized monoclonal antibody, eculizumab, has been available. It is anti-C5 and prevents the intravascular hemolysis of PNH, but it does not prevent the extravascular hemolysis mediated by C3b molecules. By eliminating intravascular hemolysis and preventing thrombosis it has substantially increased the quality of life of patients. Because blocking C5 also weakens the defense against Neisseria, patients are vaccinated against meningococcal disease before treatment.