National clinical guidelines for the diagnosis and treatment of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder caused by somatic mutation of the phosphatidylinositol
glycan complementation group A gene (PIG-A) in a hematopoietic stem cell. PNH is characterized by chronic intravascular hemolysis, bone marrow failure, thrombosis, renal dysfunction and other severe clinical syndromes. These clinical guidelines include definition, classification, methods and diagnostic criteria of PNH, indications for screening, optimal treatment including targeted therapy with eculizumab, bone marrow transplantation and symptomatic therapy.

1. Hillmen P., Lewis S. M., Bessler M. et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253–8.

2. Socié G., Mary J. Y., de Gramont A. et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996;348(9027):573–7.

3. Kelly R., Richards S., Hillmen P., Hill A. The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab. Ther Clin Risk Manag 2009;5:911–21.

4. McKeage K. Eculizumab: a review of its use in paroxysmal nocturnal haemoglobinuria. Drugs 2011;71:2327–45.

5. Hillmen P., Muus P., Dührsen U. et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007;110:4123–8.

6. Hill A., Richards S. J., Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol 2007;137:181–92.

7. Lee J., Jun Ho J., Sung Soo Y. et al. High prevalence and mortality associated with thromboembolism in Asian patients with paroxysmal nocturnal hemоglobinuria (PNH). Haematologica 2010;95:205–6.

8. Figueroa J. E., Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991;4:359–95.

9. Cappellini M. D. Coagulation in the pathophysiology of hemolytic anemias. Hematology Am Soc Hematol Educ Program 2007;74–8.

10. Bessler M., Hiken J. The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program 2008;104–10.

11. Woodruff T. M., Nandakumar K. S., Tedesco F. Inhibiting the C5‑C5a receptor axis. Mol Immunol 2011;48:1631–42.

12. Parker C., Omine M., Richards S. et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005;106:3699–709.

13. Parker C. J. Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy. Hematology Am Soc Hematol Educ Program 2011;2011:21–9.

14. Madkaikar M., Gupta M., Jijina F., Ghosh K. Paroxysmal nocturnal haemoglobinuria: diagnostic tests, advantages & limitations. Eur J Haematol 2009;83:503–11.

15. Borowitz M. J., Craig F. E., Digiuseppe J. A. et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010;78(4):211–30.

16. Schubert J., Alvarado M., Uciechowski P. et al. Diagnosis of paroxysmal nocturnal haemoglobinuria using immunophenotyping of peripheral blood cells. Br J Haematol 1991;79:487–92.

17. Höchsmann B., Rojewski M., Schrezenmeier H. Paroxysmal nocturnal hemoglobinuria (PNH): higher sensitivity and validity in diagnosis and serial monitoring by flow cytometric analysis of reticulocytes. Ann Hematol 2011;90:887–99.

18. Brodsky R. A., Mukhina G. L., Li S. et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000;114:459–66.

19. de Latour R. P., Mary J. Y., Salanoubat C. et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008;112:3099–106.

20. Brodsky R. A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009;113:6522–7.

21. Movalia M. K., Weitz I., Lim S. H., Illingworth A. Incidence of PNH clones by diagnostic code utilizing high sensitivity flow cytometry. Blood (ASH Annual Meeting Abstracts) 2011;118:1033.

22. Wanachiwanawin W., Siripanyaphinyo U., Piyawattanasakul N., Kinoshita T. A cohort study of the nature of paroxysmal nocturnal hemoglobinuria clones and PIG-A mutations in patients with aplastic anemia. Eur J Haematol 2006;76:502–9.

23. Hall C., Richards S., Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 2003;102:3587–91.

24. Nishimura J., Kanakura Y., Ware R. E. et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004;83:193–207.

25. Moyo V. M., Mukhina G. L., Garrett E. S., Brodsky R. A. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 2004;126:133–8.

26. Brubaker L. H., Essig L. J., Mengel C. E. Neutrophil life span in paroxysmal nocturnal hemoglobinuria. Blood 1977;50:657–62.

27. Dunn D. E., Tanawattanacharoen P., Boccuni P. et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999;131:401–8.

28. Wang H., Chuhjo T., Yasue S. et al. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood 2002;100:3897–902.

29. Sugimori C., Chuhjo T., Feng X. et al. Minor population of CD55‑CD59‑blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood 2006;107:1308–14.

30. Kulagin A., Lisukov I., Ivanova M. et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol 2014;164:546–54.

31. Brodsky R. A., Mukhina G. L., Nelson K. L. et al. Resistance of paroxysmal nocturnal hemoglobinuria cells to the glycosylphosphatidylinositol-binding toxin aerolysin. Blood 1999;93:1749–56.

32. Mukhina G. L., Buckley J. T., Barber J. P. et al. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia. Br J Haematol 2001;115:476–82.

33. Sutherland D. R., Kuek N., Davidson J. t al. Diagnosing PNH with FLAER and multiparameter flow cytometry. Cytometry B Clin Cytom 2007;72:167–77.

34. Parker C. J. Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria. Hematol Oncol Clin North Am 2009;23:333–46.

35. Hillmen P., Hall C., Marsh J. C. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004;350:552–9.

36. Hillmen P., Young N. S., Schubert J. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233–43.

37. Brodsky R. A., Young N. S., Antonioli E. et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111(4):1840–7.

38. Kelly R. J., Hill A., Arnold L. M. et al. ong-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117:6786–92.

39. Hillmen P., Muus P., Roth A. et al. Long- term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haemotol 2013;162(1):62–73.

40. Santarone S., Bacigalupo A., Risitano A. M. et al. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Haematologica 2010;95:983–8.

41. Saso R., Marsh J., Cevreska L. et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999;104:392–6.

42. de Latour R. P., Schrezenmeier H., Mary J-Y. et al. Stem cell transplantation for paroxysmal nocturnal haemoglobinuria: an ongoing joint study of the AAWP EBMT Group and the French Society of Haematology (EBMT abstract 316). Bone Marrow Transplant 2009;43(Suppl 1):57–8.

43. Armitage J. O. Bone marrow transplantation. N Engl J Med 1994;330:827–38.

44. Benavides Lopez E. PNH clonal expansion following bone marrow transplant: case report. Haematologica 2011;96:524.

45. Fraser C. J., Bhatia S., Ness K. et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 2006;108:2867–73.

46. Bieri S., Roosnek E., Helg C. et al. Quality of life and social integration after allogeneic hematopoietic SCT. Bone Marrow Transplant 2008;42:819–27.

47. de Latour R. P., Schrezenmeier H., Bacigalupo A. et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012;97(11):1666–73.