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A. Characteristics navigator

  1. Acquired disorder of red blood cells (RBCs) and platelets
    1. Affected cells originate from abnormal hematopoietic stem cell
    2. Mutation in gene required for expression of many surface proteins
  2. Epidemiology
    1. Averge age of onset 33-40 years; 1-2 cases per million persons in USA
    2. Male to female ratio ~1:1
    3. Survival 65% at 10 years and 48% at 15 years from diagnosis [2]
    4. Development of a thrombotic episode was main predictor for poor prognosis
    5. Treatments are now highly effective and lifespan has increased
  3. Pathophysiology [2,3]
    1. Initial observation that PNH RBCs are highly susceptible to complement (C') mediated lysis
    2. PNH is due to mutations in gene for glycosyl-phosphatidylinositol (GPI) linking enzyme
    3. PIG-A (phosphatidylinositol glycan class A) genetic mutation is responsible
    4. Hematopoietic stem cells which acquire mutations in this X-linked gene expand more than normal cells
    5. A number of proteins which require GPI links for activity are not expressed
    6. Result is abnormal surface protein composition of hematopoietic cells
    7. Erythrocytes are the major cell type affected
  4. Effects of PIG-A Mutations [2]
    1. PNH cells have deficient surface expression of decay-accelerating factor (DAF, CD55)
    2. They also have deficiency in cell surface CD59
    3. Both CD55 and CD59 protect cells from complement C' mediated lysis
    4. These lipids are the membrane anchors for CD55 and CD59 (and other surface proteins)
    5. Other proteins are missing from lymphocytes (LFA-3) and Neutrophils (FcgRIII, others)
    6. C8 binding protein is also absent from PNH cells
    7. Blockade of the complement system reduces signs and symptoms of PNH [5]

B. Symptoms and Signs navigator

  1. Nocturnal hemoglobinuria - due to chronic hemolysis
  2. Fatigue, Malaise
  3. Chronic or subacute hemolytic anemia
    1. Intravascular hemolysis
    2. Elevated lactate dehydrogenase (LDH) levels
    3. Reduced haptogloblin levels (due to binding to hemoglobin and clearance)
    4. Indirect hyperbilirubinemia
  4. Thrombosis - abnormal activation of platelets
  5. Abdominal Pain
  6. Renal failure - due to hemoglobin deposition in kidneys (often reversible)
  7. Complications
    1. Pancytopenia
    2. Thrombosis - including Budd-Chiari Syndrome
    3. Evolution to bone marrow failure syndromes (below)
    4. Infection - associated with neutropenia
    5. Hemorrhage - associated with thrombocytopenia
  8. Bone Marrow Failure Syndromes [4]
    1. PNH may evolve to, or be associated with, bone marrow failure syndromes
    2. Myelodysplasia (MDS)
    3. Aplastic Anemia [3]
    4. Acute Leukemia
    5. About 25% of patients with MDS or AA have GPI-anchored protein deficiency
    6. Patients with chemotherapy or transplant induced marrow failure have normal GPI

C. Diagnosis [2]navigator

  1. History and Physical Examination
    1. Thrombotic events are most common severe complication
    2. Abdominal Pain
    3. Nocturnal Hemoglobinuria
    4. Rule out myoglobinuria
  2. Laboratory Findings
    1. Chronic Hemolytic Anemia (>90%)
    2. Thrombocytopenia and leukopenia may be present
    3. Iron deficiency is not uncommon, and often severe
    4. Pancytopenia occurred in 15% of patients over 8 years [2]
  3. Flow cytometric evaluation of DAF, CD59, and/or C8 Binding protein levels now standard [1,2]

D. Treatment navigator

  1. Supportive Care
    1. Transfusions are mainstay of therapy in ~50% of patients
    2. Iron replacement therapy may be required
    3. Anti-platelet Agents - for thrombotic episodes
    4. Antibiotics - low threshhold for use in PNH patients, especially with neutropenia
    5. Alkalinization of urine to reduce hemoglobin toxicity
  2. Complement Blockade [1,5,6,7]
    1. Eculizumab (Soliris®) is a recombinant antibody against complement protein C5
    2. Blocks terminal complement activation by inhibiting C5 cleavage to C5a and C5b
    3. Eculizumab 600mg IV weekly x 4 then 900mg IV biweekly through week 12 or 26
    4. Safe and well tolerated in PNH patients
    5. Reduces intravascular hemolysis and hemoglobinuria
    6. Improves quality of life in randomized trial
    7. No transfusions were required for patients on eculizumab over 26 weeks in randomized trial, versus 10 units red blood cells on placebo arm [6]
    8. All patients should receive immunization against Neisseria before treatment starts
    9. Most effetive for PNH patients with high levels of intravascular hemoloysis (LDH >1.5X normal)
    10. Lifelong therapy required; cost >$300,000 per year
  3. Histone deacetylase inhibitor butyrate activates GPI expression and reduced intractable seizures in one child with a non-PNH GPI-deficiency syndrome [8]
  4. Glucocorticoids and androgens have been used with some success
  5. Allogeneic Bone Marrow Transplantation is definitive therapy

References navigator

  1. Brodsky RA. 2008. Ann Intern Med. 148(8):587 abstract
  2. Nguyen JS, Marinopoulos SS, Ashar BH, Flynn JA. 2006. NEJM. 355(10):1048 (Case Discussion) abstract
  3. Young NS. 2002. Ann Intern Med. 136(7):534 abstract
  4. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. 1999. Ann Intern Med. 131(6):401 abstract
  5. Hillmen P, Hall C, Marsh JCW, et al. 2004. NEJM. 350(6):552 abstract
  6. Hillmen P, Young NS, Schubert J, et al. 2006. NEJM. 355(12):1233 abstract
  7. Eculizumab. 2007. Med Let. 49(1270):79 abstract
  8. Almeida AM, Murakami Y, Baker A, et al. 2007. NEJM. 356(16):1641 abstract