1. Paroxysmal Nocturnal Hemoglobinuria Paul M. Johnson Department of Internal Medicine University of North Carolina Hospitals April 6, 2010

2. Overview Pathophysiology – back to med school Common presentations Diagnosis – hemolytic anemia, marrow failure, thrombophilia Prognosis Management

3. Pathophysiology nonmalignant clonal expansion of hematopoietic stem cells with somatic PIG-A mutation progeny cells lack GPI-APs deficiency of CD55 and CD59 (GPI-anchored complement regulatory proteins) leads to intravascular hemolysis

4. Nature Biotechnology, 2007; 25: 1256

5. Presentation Signs and symptoms No. of patients (%) Symptoms of anemia 28 (35) Hemoglobinuria 21 (26) Hemorrhagic signs and symptoms 14 (18) Aplastic anemia 10 (13) Gastrointestinal symptoms 8 (10) Hemolytic anemia and jaundice 7 (9) Iron-deficiency anemia 5 (6) Thrombosis or embolism 5 (6) Infections 4 (5) Neurologic signs and symptoms 3 (4) Blood. 2005 Dec 1;106(12):3699-709.

6. Diagnosis Anemia – coombs-negative, intravascular hemolysis – quantitation of CD 55 and CD 59 by flow cytometry Marrow failure – granulocytopenia, thrombocytopenia, aplastic anemia, MDS Thrombosis

7. Prognosis Survival – 65% at 10 years – 48% at 15 years Risk factors for poor outcome – thrombosis relative risk 10.2 [95% CI 6-17], p<0.0001 – evolution to pancytopenia 5.5 [2.8-11], p<0.0001 – age over 55 years 4 [2.4- 6.9], p<0.0001 – myelodysplastic syndrome or acute leukemia 19.1 [7.3-50], p<0.001 Lancet 1996 Aug 31;348(9027):573-7

8. Management Anemia: hemolysis vs. impaired erythropoesis – steroids – iron replacement – Transfusion – -folate – treatment of MDS or aplastic anemia – monitor LDH

9. Management Thrombosis – for each 10% increase in GPI-AP deficient cells, odds ratio for thrombosis was 1.64 – higher in US/Europe than Japan, China, Mexico – NO RCT for prophylaxis – heparin, then indefinite therapy for thrombosis – thrombolysis for Budd-Chiari

10. Management Eclizumab – binds C5 component and inhibits MAC activation – decreased transfusions, improved quality of life, decreased LDH – $400,000/year – vaccinate for N. meningitidis HCT – for patients with poor prognosis, refractory

11. Key Points complement mediated Coombs-negative hemolytic anemia thrombocytopenia, thrombophilia flow cytometry (CD55, CD59) indefinite anticoagulation for thrombosis eclizumab acts against C5

12. References Socie J, Mary JY, et al. Paroxysmal nocturnal hemoglobinuria: long-term follow up and prognostic factors. Lancet 1996; 348: 573. Parker C, Omine, M, et al. Diagnosis and management on paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 3669. Ristano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natrual history, and treatment options in the era of biologics. Biologics: Targets and Therapy 2008; 2008: 205. Paroxysmal nocturnal hemoglobinuria (clinical manifestations and diagnosis and treatment). Accessed at www.uptodate.com on April 5, 2010. Rollins SA, Roth RP. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nature Biotechnology, 2007; 25: 1256