Snapshot A 29-year-old woman presents to the emergency room with a high fever and cough. She has been feeling fatigued for a year prior to presentation. Chest radiography reveals a lower lobe pneumonia. Labs reveal Hb 6.7 g/dL, leukocyte count of 5,000/mm3, platelets of 100,000/mm3,high reticulocyte count, and high LDH. Coombs test was negative. Concerned with the apparent intravascular hemolysis, a bone marrow biopsy showed hypercellularity and normal cytogenetics. Flow cytometry was positive for CD55/CD59-negative RBCs. Introduction Clonal stem cell defect from mutation in hematopoietic stem cell May cause aplastic anemia myelodysplasia acute leukemia ETIOLOGY Pathogenesis mutation in PIGA gene defect in glycosylphosphatidylinositol (GPI) anchors CD55 (decay-accelerating factor) and CD59 on RBC membrane these protect RBC from complement DAF inhibits C3 convertase complement-mediated destruction of RBCs activation of platelets and WBCs "PNH Thrombosis" Pancytopenia Nocturnal build up of dark urine Coombs negative Hemolytic anemia (complement-mediated) venous Thrombosis from pro-coagulant and pro-inflammatory state formed by complement activation Presentation Symptoms/physical exam episodic dark urine with first urine of the day caused by hemoglobin chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria acute hemolytic episodes from activators of complement surgery infection stress alcohol thrombocytopenia: mucosal bleeding, petechiae, and ecchymoses leukemia: infections thrombosis abdominal pain, fever, and rectal bleeding (mesenteric vein thrombosis) headache, vomiting, and seizures (cerebral venous sinous thrombosis) fever, jaundice, hepatomegaly (Budd-Chiari syndrome) renal impairment STUDIES Flow cytometry – most accurate test CD55/59-negative RBCs Labs anemia thrombocytopenia leukopenia Differential Diagnosis Aplastic anemia Myelodysplasia DIAGNOSIS Diagnosis often made during pregnancy Treatment Best initial therapy – eculizumab (or ravulizumab) inactivates C5 in complement pathway decreases red cell destruction complement inhibitor must vaccinate all against Neisseria due to increased risk Best curative therapy – allogeneic bone marrow transplant Supportive therapy folic acid transfusions as needed Complications Renal insufficiency Thromboembolism 5% develop myelodysplasia 2.5% develop acute leukemias Prognosis Improved with use of eculizumab