Paroxysmal nocturnal hemoglobinuria

1)PNH originates from an acquired mutation ( frame-shift that creates a premature stop codon) in a myeloid stem cell, the acquired mutation in PNH occurs in the PIGA gene which is responsible for the first step in the synthesis of the GPI anchor that attaches CD55 and CD59 to the cell surface.

2)Complement detects self vs nonself cells by these complement inhibitors. Function of these complement inhibitors is to:

3)In the absence of these inhibitors, complement proteins bind cell membranes of our own cells and through the alternative complement pathway can lyse self-cells.

4)CD55/DAF decrease → More C3 convertase→Increase C3b→Increase opsonization→Extra Vascular Hemolysis.

   CD59/MIRL decrease→More MAC→Intra Vascular Hemolysis.


5)Why nocturnal hemoglobinuria- hemolysis occurs throughout day but its more at night because:   (a)Increased hemolysis in night due to respiratory acidosis(Shallow breathing).
 (b)Overnight concentration of urine is more and hemoglobinuria is clearly evident.

6)Diagnosis:(a)Flow cytometry- decrease CD55 and CD59 levels.
                     (b)HAM test-confirmatory.
                     (c)Direct coombs test-Negative (Helps to differentiate PNH and AIHA- its positive in AIHA)                                                                           

7)Treatment: 

(a)Ravulizumab- long acting C5 complement inhibitor

(b)Eculizumab- It is an Antibody to C5 and prevents its clevage to C5a and C5b, so no MAC. Ravulizumab has a half life that is three to four times longer than eculizumab.

-Srikar Sama

SOURCE: UpToDate, Uworld.