Paroxysmal nocturnal hemoglobinuria

Background

• Intravascular hemolysis caused by increased sensitivity of RBCs to hemolytic action of complement

Pathophysiology

• Abnormal PIG-A gene > defect in GPI-linked anchor > partial/complete absence of GPI-linked proteins (mainly CD55 and CD59) > increased sensitivity of RBCs to hemolytic action of complement
• Hemolysis precipitated by stresses that activate complement (eg infection)
  • Nocturnal hemolysis attributed to intestinal absorption of lipopolysaccharide (strong activator of complement) at night

Clinical Features

• Intravascular hemolysis
• Renal failure (both from intravascular hemolysis causing AKI and chronic hemolysis causing iron deposition in kidneys)
• DVT, thrombosis of hepatic/intraabdominal/cerebral veins, arterial thrombosis
• Bone marrow failure leading to aplastic anemia
• Myelodysplastic (MDS) or myeloproliferative disorders
• Acute leukemia
• Esophageal spasm
• Crampy abdominal pain
• Impotence/ED

Differential Diagnosis

Microangiopathic Hemolytic Anemia (MAHA)

• Disseminated Intravascular Coagulation (DIC)
• Thrombotic Thrombocytopenic Purpura (TTP)
• Hemolytic Uremic Syndrome (HUS)
• HELLP syndrome
• Heparin-Induced Thrombocytopenia (HIT)
• Hereditary spherocytosis
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Malignant hypertension
• Scleroderma
• Antiphospholipid Syndrome (APS)
• Other medical causes: malignancy, renal allograft rejection, vasculitides like polyarteritis nodosa and Wegener's granulomatosis
• Drugs: chemotherapy; Clopidogrel (Plavix) associated with TTP
• Nonvascular causes: prosthetic valve (more common with mechanical, more common at aortic valve), LVAD, TIPS, coil embolization, patched AV shunt, AVM

Diagnosis

• Anemia
• Negative Coombs test
• Hemoglobinuria
• Elevated LDH
• Decreased haptoglobin
• Positive sucrose lysis test or Ham test (both test sensitivity of RBCs to lysis by complement)
• Other clues: granulocytopenia/thrombocytopenia, venous thrombosis, aplastic anemia, MDS, dysphagia or abdominal pain

Treatment

• Eculizumab (C5 antibody): stops hemolysis in PNH
• Iron/folate supplements
• RBC transfusion PRN
• Prednisone may decrease RBC destruction
• For severe hematopoietic dysfunction w/ marked cytopenias: hematopoietic cell transplant or immunosuppression (cyclosporine or antithymocyte globulin)
• Anticoagulation for thrombosis