• PNH arises as a result of nonmalignant clonal expansion of one or several hematopoietic stem cells that have acquired a somatic mutation of phosphatidylinositol glycan class A (PIG-A).
  • The PIGA gene is located on the X-chromosome, and it encodes an enzyme that is an essential component of the complex biosynthetic pathway that generates glycosyl phosphatidylinositol (GPI).
  • The GPI moiety serves as a membrane anchor for more than 20 proteins of diverse function that are normally expressed on hematopoietic cells. As a consequence of somatic mutation of PIGA, progeny of affected stem cells are deficient in all GPI-anchored proteins (GPI-APs).
  • Among the GPI-APs normally expressed on hematopoietic cells are the complement regulatory proteins CD55 (decay accelerating factor [DAF]) and CD59 (membrane inhibitor of reactive lysis [MIRL]), and it is the deficiency of these two proteins that accounts for the complement-mediated intravascular hemolysis that is the primary clinical manifestation of the disease.

• Patients with PNH often have more than one PIGA mutant clone.
• In addition to complement-mediated intravascular hemolysis, an element of bone marrow failure (BMF) is present in all patients, and PNH frequently arises in association with a defined BMF process, particularly aplastic anemia and, to a lesser extent, low-grade myelodysplastic syndrome (MDS).

• A defining feature of PNH is phenotypic mosaicism based on sensitivity of the erythrocytes to complement-mediated lysis.
  • PNH III was 15 to 25 times more susceptible to lysis. Half-life is approximately 6 days (compared with 60 days for normal erythrocytes).
  • PNH II was of intermediate sensitivity, about three to five times more susceptible than normal cells.
  • Most patients have a mixture of type I and type III cells, but mosaics of type I, type II, and type III, as well as type I and type II, are also observed.

• The threshold for biochemical evidence of intravascular hemolysis is crossed when the population of GPI-deficient neutrophils (as a measure of the PNH clone size) is 20% to 25% or greater.
  • Patients with a clone size of 20% to 25% usually have 3% to 5% PNH erythrocytes (the population of PNH III cells is smaller than the clone size because the complement-sensitive red cells are quickly and selectively destroyed intravascularly).
• Visible hemoglobinuria is absent when PNH III erythrocytes constitute less than 20% of the red cell population (corresponding to a PNH clone size of 40%-60%). Paroxysms of gross hemoglobinuria occur when the PNH III population ranges from 20% to 50% of the population (corresponding to a PNH clone size of 60%-90%), and constant hemoglobinuria is associated with greater than 50% PNH III erythrocytes (PNH clone size > 90%).
• PNH II cells (the erythrocytes with intermediate sensitivity to complement), even when present in high proportions, are associated with no visible hemoglobinuria unless an intervening factor such as stress, infection, surgery, or trauma that activates complement supervenes.

• The only nonrandom chromosomal aberrations specific for PNH involves rearrangement of the HMGA2 locus on 12q13-15. The presence of karyotypically abnormal bone marrow cells is not a negative prognostic factor in PNH.
• The incidence of acute leukemia in association with PNH appears to be approximately 1%, although higher (7.7% in a study of Japanese patients) and lower (0 of 80 patients in a study from England) rates of incidence have been reported. The rate of myelodysplastic disease in association with PNH is on the order of 5%.

Clinical Presentations

• The diagnosis of PNH must be considered in any patient who has the following: (1) signs and symptoms of intravascular hemolysis (manifested by an abnormally high LDH) of undefined cause (ie, Coombs-negative), with or without macroscopic hemoglobinuria often accompanied by iron deficiency; (2) pancytopenia in association with hemolysis; (3) venous thrombosis affecting unusual sites, especially intraabdominal, cerebral, or dermal locations accompanied by evidence of hemolysis; (4) unexplained recurrent bouts of abdominal pain, low backache, or headache in the presence of chronic hemolysis; and (5) Budd–Chiari syndrome.

• When intravascular hemolysis occurs at night, while the patient is asleep, hemoglobin accumulates in the bladder, and the patient becomes alarmed the following morning by the startlingly abnormal appearance of the first voided urine.

• PNH is associated with a striking predisposition toward intravascular thrombosis, especially within the venous circulation.

  • The pathogenesis is incompletely understood.
  • Propensity toward thrombosis appears roughly proportional to the size of the PNH clone.
  • Sites of thrombosis that are disproportionately represented: hepatic vein (Budd–Chiari syndrome), mesenteric veins, portal vein, cerebral veins and dermal veins.
  • Thrombotic disease accounts for about 50% of all deaths in patients with PNH. Fatal thrombosis usually involves the portal system or the brain.
  • The risk of thromboembolic disease appears higher in white and African-American patients than in patients of Asian/Pacific Island or Hispanic ancestry.
  • Anticoagulation is required, including cerebral vein thrombosis. Platelet count > 50000/μl is not a contraindication. Patients who have experienced a thromboembolic event should remain anticoagulated indefinitely, even if under treatment with eculizumab.

• Acute renal insufficiency is associated with hemoglobinuric crises and may resolve without residual damage.

• The red cells may appear hypochromic and microcytic because of iron deficiency resulting from chronic and acute hemoglobinuria with consequent urinary loss of hemoglobin iron. Moderate anisocytosis and poikilocytosis are common, but spherocytes and schistocytes are not observed in the peripheral blood film.

• Polychromatophilia, reflecting reticulocytosis, is observed unless BMF is severe. Relative reticulocytosis may be marked, but the absolute reticulocyte count is often lower than that found in association with other hemolytic disorders at comparable degrees of anemia.

Treatment