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 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 May cause aplastic anemia myelodysplasia acute leukemia Diagnosis often made during pregnancy 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 Evaluation Flow cytometry – most accurate test CD55/59-negative RBCs Labs anemia thrombocytopenia leukopenia Differential Diagnosis Aplastic anemia Myelodysplasia Treatment Best initial therapy – eculizumab 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 Prognosis, Prevention, and Complications Prognosis improved with use of eculizumab Complications renal insufficiency thromboembolism 5% develop myelodysplasia 2.5% develop acute leukemias