Paroxysmal Nocturnal Hemoglobinuria (PNH) (Marchiafava–Micheli Syndrome)

Epidemiology

  • Prevalence: rare (1-5 per million)
    • May have higher prevalence in Southeast Asia and Far East
  • Age: most patients are young adults (although may occur in children or in 70’s)
  • Sex: M = F

Physiology

  • X-Linked Phosphatidylinositol Glycan Anchor Biosynthesis, Class A (PIGA) Somatic Gene Mutation: mutation is unique in each affected patient
    • Deficiency of the glycolipid, glycosylphosphatidyl-inositol (GPI), which anchors CD55 and CD59 to membrane -> decreased surface expression of CD55 and CD59 (CD59, predominantly, and to a lesser extent CD55, normally protect the RBC from complement-mediated lysis) -> leads to intravascular hemolysis + granulocyte lysis + platelet lysis
    • PNH cells are sensitive to complement-mediated lysis whether activated by the alternative pathway (explaining intravascular hemolysis) or via an antigen-antibody reaction (explaining why some cases may be exacerbated by a viral or bacterial infection)
    • Risk of Thrombosis: may be related to inadequate platelet surface CD59 -> inappropriate platelet activation

Diagnosis

Ham Acid Lysis Test

  • No Longer Used: only performed in a few labs

Sucrose Lysis Test

  • No Longer Used: unreliable

Thrombin Lysis Test

  • No Longer Used

Flow Cytometry of Peripheral Blood with CD55 + CD59 Antibodies

  • Gold Standard for Diagnosis: flow demonstrates of mosaic of normal and abnormal cells in distinct populations
  • Advantages
    • Useful to determine the degree of GPI anchor deficiency (PNH type I, II, or III)
  • CD55-Negative + CD59-Negative RBC: usually comprise at least 5% of RBC
    • Decreased sensitivity may occur due to the short half-life of circulating PNH red blood cells
  • CD55-Negative + CD59-Negative Granulocytes: usually comprise at least 20% of granulocytes

Flow Cytometry of Peripheral Blood with CD59/CD24/CD16 or Any Other GPI-Linked Proteins Expressed on Granulocytes

  • Advantages: the deficiency of at least 2 GPI-linked proteins is sensitive and specific for the diagnosis of PNH
  • Disadvantages: may be difficult to perform in cases with severe aplastic anemia, where the number of circulating granulocytes are low

Flow Cytometry with Fluourescently Labelled Inactive Toxin Aerolysin (FLAER)

  • FLAER binds to the GPI Anchor
  • Advantages: the lack of FLAER binding to granulocytes is sufficient to make the diagnosis of PNH
  • Disadvantages
    • Cannot be used to analyze red blood cells or platelets
    • May be difficult to perform in cases with severe aplastic anemia, where the number of circulating granulocytes are low

PIGA Gene Mutation Analysis

  • May Be Performed

Clinical Manifestations (Classical Clinical Triad of Complement-Mediated Intravascular Hemolytic Anemia + Thrombosis + Bone Marrow Failure)

General Features

  • Usually Chronic Course with Acute Exacerbations
    • Natural history may extend over decades
    • A superimposed viral/bacterial infection may exacerbate episodes

Hematologic Manifestations

Hypercoagulable State (see Hypercoagulable States, [[Hypercoagulable States]])

  • General Comments
    • Incidence: approximately 40% of PNH patients develop a thrombotic event during the course of their disease
    • Correlation Between Number of Circulating PNH Red Blood Cells and Risk of Thrombosis: patients with a large PNH clone are at a higher risk of developing thrombosis than patients with a small PNH clone
    • Thrombosis Usually Follows an Episode of Acute Hemolysis: inhibition of complement activation and inhibition of hemolysis significantly reduce the risk of thrombosis in PNH
    • Possible Mechanisms of Thrombosis
      • Nitric oxide scavenging by cell-free plasma hemoglobin
      • Alterations of platelet and red cell membranes (including the formation of microparticles)
  • Arterial Thrombosis: increased risk
  • Venous Thrombosis: increased risk

Anemia/Hemolytic Anemia (see Anemia, [[Anemia]] and Hemolytic Anemia, [[Hemolytic Anemia]])

  • Epidemiology: anemia is the most common clinical finding in PNH
  • Diagnosis
    • Complete Blood Count (CBC)
      • Usually Normocytic-Macrocytic: if MCV is high, this is usually due to reticulocytosis
      • Occasionally May be Microcytic: in cases where iron deficiency is superimposed (due to chronic hemoglobinuria)
    • Evidence of Hemolysis
      • Decreased Haptoglobin: usually undetectable
      • Increased Lactate Dehydrogenase (LDH): may be in the thousands
      • Indirect (Unconjugated) Hyperbilirubinemia: usually mildly-moderately elevated
    • Reticulocytosis: can be significantly elevated (up to 20% in some cases)
    • Bone Marrow Biopsy: usually cellular with marked erythroid hyperplasia (and mild-moderate dyserythropoetic featres)

Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

  • xxx

Aplastic Anemia/Pancytopenia (see Pancytopenia, [[Pancytopenia]])

  • Epidemiology: may precede or occur after diagnosis of PNH
  • Diagnosis
    • Bone Marrow Biopsy: hypocellular-aplastic

Acute Myeloid Leukemia (AML) (see Acute Myeloid Leukemia, [[Acute Myeloid Leukemia]])

  • Epidemiology: occurs in 1-2% of PNH cases

Renal Manifestations

  • Bilirubinuria (see Bilirubinuria, [[Bilirubinuria]])
  • Hemoglobinuria (see Hemoglobinuria, [[Hemoglobinuria]]): may vary from hour to hour or day to day
  • Hemosiderinuria (see Hemosiderinuria, [[Hemosiderinuria]]): consistent with chronic Intravascular hemolysis

Gastrointestinal Manifestations

Recurrent Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])

  • Physiology: may be related to mesenteric venous thrombosis or smooth muscle spasm caused by red blood cell breakdown products
    • Occurs mainly when the hemolysis is rapid

Dysphagia (see Dysphagia, [[Dysphagia]])

  • Physiology: due to smooth muscle spasm caused by red blood cell breakdown products
    • Occurs mainly when the hemolysis is rapid

Budd-Chiari Syndrome/Hepatic Vein Thrombosis (see Hepatic Vein Thrombosis, [[Hepatic Vein Thrombosis]])

  • Abdominal Pain
  • Ascites
  • Acute Hepatomegaly
  • Elevated LFT’s

Other Manifestations

  • Erectile Dysfunction (ED) (see Erectile Dysfunction, [[Erectile Dysfunction]])
    • Physiology: due to smooth muscle spasm caused red blood cell breakdown products
      • Occurs mainly when the hemolysis is rapid

Treatment

Transfusion of Filtered Packed Red Blood Cells (PRBC) (see Packed Red Blood Cells, [[Packed Red Blood Cells]])

  • Cautions: red blood cell transfusion can exacerbate hemolysis (due to presence of donor complement that acts on patient’s complement-sensitive red blood cells)
    • Measures to Minimize Risk of Hemolysis with Red Blood Cell Transfusion
      • Use washed red blood cells
      • Use packed red blood cells
      • Leukocyte-deplete red blood cells

Folate/Iron Supplementation (see Folate, [[Folate]] and Iron, [[Iron]])

  • Usually Required

Prednisone (see Prednisone, [[Prednisone]])

  • Decreases Complement Activation: can be used at night to decrease nocturnal hemolysis

Androgens

  • Decrease Complement Activation: decreases hemolysis
  • Increase Red Blood Cell Production: decreases hemolysis

Eculizumab (Soliris) (see Eculizumab, [[Eculizumab]])

  • FDA-Approved to Treat PNH in 2007
  • Pharmacology: human monoclonal antibody against complement C5 -> inhibits terminal complement activation
  • Efficacy: demonstrated to decrease need for PRBC transfusions in only 50% of cases (presumably due to extravascular hemolysis of cells opsonized by C3 fragments)
  • Cost: approximate cost of $400k/year
  • Administration: requires lifelong therapy q14 days

Allogeneic Bone Marrow Transplant (BMT)/Stem Cell Transplant (SCT) (see Bone Marrow Transplant, [[Bone Marrow Transplant]])

  • Only Curative Treatment

Anti-Thymocyte Globulin (ATG) or Cyclosporine A (see Anti-Thymocyte Globulin, [[Anti-Thymocyte Globulin]] and Cyclosporine A, [[Cyclosporine A]])

  • Indications: presence of aplastic anemia
    • Mainly used to treat thrombocytopenia and neutropenia (as these agents are poorly effective for the treatment of hemolysis)

Anticoagulation

  • Indications: venous thrombosis or other hypercoagulable state risk factors

Prognosis

  • Median Survival: 8-10 years (without treatment)
    • Most common causes of death
      • Venous Thrombosis
      • Infection (due to neutropenia)
      • Hemorrhage (due to thrombocytopenia)
  • Full Recovery: has been reported in rare cases

References

  • Black mornings, yellow sunsets–a day with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004 Feb 5;350(6):537-8 [MEDLINE]