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
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)
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]])
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]])
