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Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria. Paul M. Johnson Department of Internal Medicine University of North Carolina Hospitals April 6, 2010. Overview. Pathophysiology back to med school Common presentations Diagnosis hemolytic anemia, marrow failure, thrombophilia Prognosis Management.

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Paroxysmal Nocturnal Hemoglobinuria

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  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 somaticPIG-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 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-termfollow up and prognosticfactors. 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

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