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
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
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]])
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]])
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]])
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]