Nejm 2006;355:1048; 1991;325:991

Cause:A somatic mutation of PIG-A gene on the X chromosome in a hematopoietic stem cell (Nejm 1994;330:249)

Pathophys:

(Ann IM 1999;131:467; Nejm 1990;323:1184) Somatic mutation clonal deficiency in rbc membranes as well as megakaryocyte and myeloid series; 2 cell populations, lysed cells are young, survivors are normal. Rbc's of normals transfused into PNH patients survive; PNH cells transfused to normal, lyse. Lysis due to C'3 inhibitor absence (DAF or decay acceleration factor) from cell surface because the absent protein normally glues C' inhibitor and other proteins to cell surface membrane (Nejm 1994;330:249).

Periodic massive hemolysis causes hemoglobinuria; correlates with sleep and with local acidosis (increased C'3 activity with slight decreases in pH).

Thrombosis, multiple microscopic and gross, perhaps due to lipid from rbc broken down membrane (thromboplastin) or platelets lysed and/or activated by C'3 system (Nejm 1972;286:180)

Rare; onset usually age 20-40 yr

Sx:

Weakness; pain (microthrombi) in lumbar back, chest, abdomen

Dark urine in the morning from hemoglobinuria; present initially in 50% adults, 15% under age 20 yr; eventually 65% under age 20 yr develop it. Aspirin can precipitate attack

Si:Unexplained hemolytic anemia or Fe deficiency; occasionally splenomegaly; occasionally icterus

(Nejm 1995;333:1253) Chronic, median survival = 10 yr, 15% spontaneously remit; death from venous thrombosis, bleeding, or renal failure

• Marrow failure present on presentation in 25% of adults and 60% under age 20 yr. Eventually most manifest marrow aplasia, which is not caused by PNH, rather immune aplasia allows PNH clones to proliferate (Ann IM 1999;131:401, 467). May present as an aplastic crisis or as infection (agranulocytosis). Fe and folate deficiencies also develop from losses in urine
• Venous thrombi (50% at postmortem) in bowel, extremities, and liver causing liver failure and varices
• Di Guglielmo's syndrome (Nejm 1970;283:1329) or CML

r/o cold hemoglobinuria (IgG antibody fixes to rbc in cold and lyses when warmed, causing gangrene of digits and extremities; common in tertiary syphilis)

Lab:

Chem:LDH elevated, from rbc's; AST (SGOT) increased, from liver damage

Hem:Plasma brown with methemalbumin; pancytopenia with low alk phos in polys; macrocytosis (decreased folate); hypochromia (Fe loss in urine); retics increased to 10-16%

• Ham test: a diagnostic test; patient's rbc's broken down by normal serum acidified to pH 5.5-6.0. Thrombin worsens, Mg worsens (Nejm 1973;288:705)
• Sugar water test: a screening test; PNH cells lyse in isosmolar sugar water with no lytes, normals don't (C'3 activated more easily in absence of lytes)
• Flow cytometry and PIG-A gene product assays much more sens now than Ham and sugar water tests (Ann IM 1999;131:401, 467)

Path: Renal biopsy shows Fe deposits

Urine:Intermittent hemoglobinuria, persistent hemosiderinuria from tubular cells; positive for Fe by nitroprusside blue; UUB >1/64

Rx:

• Avoid heparin since increased C'3 activation; warfarin can be used. Acutely can transfuse with washed rbc's (avoid wbc antigens, which when combined with antibody can activate C'3). Replace folate and Fe; but not too much, since iron can worsen because it increases retics, which themselves are more sensitive to hemolysis
• Eculizumab (Soliris), a recombinant human monoclonal antibody that inhibits C' activation; iv q 1-2 wk; prevents transfusions in 50% by RDBCT (Nejm 2006;355:1233); costs $35 000/mo (Med Let 2007;49:79)
• Androgens may help
• Marrow transplants work (Ann IM 1984;101:193) but risks compared to natural crs may not be worth it (Nejm 1995;333:1253)
• Streptokinase for acute venous thrombosis, eg, Budd-Chiari and inferior vena cava, can be used safely (Ann IM 1985;103:539)