Clinical guidelines for the management of patients with paroxysmal nocturnal hemoglobinuria

Introduction. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disease of the blood system characterized by intravascular hemolysis, bone marrow dysfunction and an increased risk of thrombotic and organ complications.

Aim — to provide relevant clinical recommendations for the provision of medical care to adults and children with PNH.

Basic information. Experts from the National Hematological Society association which is focused on the promotion of hematology, transfusiology and bone marrow transplantation along with experts from the public organization, National Society of Pediatric Hematologists and Oncologists, have developed current clinical recommendations for providing medical care to adults and children with PNH. The recommendations address in detail the issues of etiology, pathogenesis, epidemiology, and clinical manifestations of the disease. Special attention is paid to the diagnosis, differential diagnosis, and treatment of PNH based on the principles of evidence.

1. Bessler M., Mason P.J., Hillmen P., et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994; 13(1): 110–7. DOI: 10.1002/j.1460-2075.1994.tb06240.x.

2. Takeda J., Miyata T., Kawagoe K., et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993; 73(4): 703–11. DOI: 10.1016/0092-8674(93)90250-t.

3. Medof B.Y.M.E., Kinoshita T., Nussenzweig V. Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med. 1984; 160(5): 1558–78. DOI: 10.1084/ jem.160.5.1558.

4. Lublin D.M., Atkinson J.P. Decay-accelerating factor: Biochemistry, molecular biology, and function. Annu Rev Immunol. 1989; 7: 35–58. DOI: 10.1146/annurev.iy.07.040189.000343.

5. Rollins S.A., Sims P.J. The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9. J Immunol. 1990; 144(9): 3478–83.

6. Noris M., Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013; 33(6): 479–92. DOI: 10.1016/j.semnephrol.2013.08.001.

7. Tegla C.A., Cudrici C., Patel S., et al. Membrane attack by complement: The assembly and biology of terminal complement complexes. Immunol Res. 2011; 51(1): 45–60. DOI: 10.1007/s12026-011-8239-5.

8. Serna M., Giles J.L., Morgan B.P., Bubeck D. Structural basis of complement membrane attack complex formation. Nat Commun. 2016; 7: 10587. DOI: 10.1038/ncomms10587.

9. Sun X., Funk C.D., Deng C., et al. Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting. Proc Natl Acad Sci USA. 1999; 96(2): 628–33. DOI: 10.1073/pnas.96.2.628.

10. Brodbeck W.G., Kuttner-Kondo L., Mold C., Medof M.E. Structure/function studies of human decay-accelerating factor. Immunology. 2000; 101(1): 104–11. DOI: 10.1046/j.1365-2567.2000.00086.x.

11. Farkas I., Baranyi L., Ishikawa Y., et al. CD59 blocks not only the insertion of C9 into MAC but inhibits ion channel formation by homologous C5b-8 as well as C5b-9. J Physiol. 2002; 539(2): 537–45. DOI: 10.1113/jphysiol.2001.013381.

12. Bessler M., Hiken J. The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. Am Soc Hematol Educ Program. 2008: 104–10. DOI: 10.1182/asheducation-2008.1.104.

13. Hill A., Kelly R.J., Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013; 121(25): 4985–96. DOI: 10.1182/blood-2012-09-311381.

14. Rother R.P., Bell L., Hillmen P., Gladwin M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA. 2005; 293(13): 1653–62. DOI: 10.1001/jama.293.13.1653.

15. Olsen S.B., Tang D.B., Jackson M.R., et al. Enhancement of platelet deposition by cross-linked hemoglobin in a rat carotid endarterectomy model. Circulation. 1996; 93(2): 327–32. DOI: 10.1161/01.cir.93.2.327.

16. Simionatto C.S., Cabal R., Jones R.L., Galbraith R.A. Thrombophlebitis and disturbed hemostasis following administration of intravenous hematin in normal volunteers. Am J Med. 1988; 85(4): 538–40. DOI: 10.1016/s00029343(88)80092-5.

17. Studt J.-D., Hovinga J.A.K., Antoine G., et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood. 2005; 105(2): 542–4. DOI: 10.1182/blood-2004-06-2096.

18. Seregina E.A., Tsvetaeva N.V., Nikulina O.F., et al. Eculizumab effect on the hemostatic state in patients with paroxysmal nocturnal hemoglobinuria. Blood Cells Mol Dis. 2015; 54(2): 144–50. DOI: 10.1016/j.bcmd.2014.11.021.

19. Ritis K., Doumas M., Mastellos D., et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol. 2006; 177(7): 4794–802. DOI: 10.4049/jimmunol.177.7.4794.

20. Wojta J., Kaun C., Zorn G., et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood. 2002; 100(2): 517–23. DOI: 10.1182/blood.v100.2.517.

21. Yu F., Du Y., Han B. A comparative analysis of clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria between Asia and Europe/America. Int J Hematol. 2016; 103(6): 649–54. DOI: 10.1007/s12185-016-1995-1.

22. Hill A., DeZern A.E., Kinoshita T., Brodsky R.A. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Prim. 2017; 3: 17028. DOI: 10.1038/nrdp.2017.28.

23. Hill A., Platts P.J., Smith A., Richards S.J., et al. The incidence and prevalence of paroxysmal nocturnal hemoglobinuria (PNH) and survival of patients in Yorkshire. Blood. 2006; 108(11): 985. DOI: 10.1182/blood.V108.11.985.985.

24. Kulagin A.D., Klimova O.U., Dobronravov A.V., et al. Clinical manifestation and diagnostic errors of classic paroxysmal nocturnal hemoglobinuria: An analysis of 150 cases. Clinical oncohematology. 2017; 10(3): 333–41. DOI: 10.21320/2500-2139-2017-10-3-333-341. (In Russian).

25. Hillmen P., Elebute M., Kelly R., et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol. 2010; 85(8): 553–9. DOI: 10.1002/ajh.21757.

26. Hill A., Sapsford R.J., Scally A., et al. Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: Raised pulmonary pressure and reduced right ventricular function. Br J Haematol. 2012; 158(3): 409–14. DOI: 10.1111/j.1365-2141.2012.09166.x.

27. Sahin F., Akay O.M., Ayer M., et al. Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res. 2016; 6(2): 19–27.

28. Brodsky R.A. Paroxysmal nocturnal hemoglobinuria. Blood. 2014; 124(18): 2804–11. DOI: 10.1182/blood-2014-02-522128.

29. Kulagin A.D., Lisukov I.A., Ptushkin V.V., et al. National clinical guidelines for the diagnosis and treatment of paroxysmal nocturnal hemoglobinuria. Onkogematologiya. 2014; 9(2): 20–8. (In Russian).

30. 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. Cytom Part B Clin Cytom. 2010; 78(4): 211–30. DOI: 10.1002/cyto.b.20525.

31. Manivannan P., Ahuja A., Pati H.P. Diagnosis of paroxysmal nocturnal hemoglobinuria: Recent advances. Indian J Hematol Blood Transfus. 2017; 33(4): 453–62. DOI: 10.1007/s12288-017-0868-y.

32. Movalia M.K., Weitz I., Lim S.H., Illingworth A. Incidence of PNH clones by diagnostic code utilizing high sensitivity flow cytometry. Blood. 2011; 118(21): 1033. DOI: 10.1182/blood.V118.21.1033.1033.

33. Sipol A.A., Babenko E.V., Borisov V.I., et al. An inter-laboratory comparison of PNH clone detection by high-sensitivity flow cytometry in a Russian cohort. Hematology. 2015; 20(1): 31–8. DOI: 10.1179/1607845414Y.0000000162.

34. Dezern A.E., Borowitz M.J. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 1 — clinical utility. Cytom Part B Clin Cytom. 2018; 94(1): 16–22. DOI: 10.1002/cyto.b.21608.

35. Sutherland D.R., Illingworth A., Marinov I., et al. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 2 — reagent selection and assay optimization for high-sensitivity testing. Cytom Part B Clin Cytom. 2018; 94(1): 23–48. DOI: 10.1002/cyto.b.21610.

36. Brubaker L.H., Essig L.R.J., Mengel C.E. Neutrophil life span in paroxysmal nocturnal hemoglobinuria. Blood. 1977; 50(4): 657–62.

37. Patriquin C.J., Kiss T., Caplan S., et al. How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol. 2019; 102(1): 36–52. DOI: 10.1111/ejh.13176.

38. Bokeria L.A., Zatevakhin I.I., Kirienko A.I., et al. Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications (VTEC). Flebologiya. 2015; 9(4-2): 1–52. (In Russian).

39. Villegas A., Arrizabalaga В., Bonanad S., et al. Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal hemoglobinuria. Med Clin (Barc). 2016; 146(6): 278e1–7. DOI: 10.1016/j.medcli.2015.12.012.

40. Hill A., Hillmen P., Richards S.J., et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106(7): 2559–65. DOI: 10.1182/blood-2005-02-0564.

41. Hillmen P., Young N.S., Schubert J., et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006; 355(12): 1233–43. DOI: 10.1056/NEJMoa061648.

42. 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. DOI: 10.1182/blood-2007-06-094136.

43. Hillmen P., Hall C., Marsh J.C.W., et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004; 350(6): 552–9. DOI: 10.1056/NEJMoa031688.

44. Reiss U.M., Schwartz J., Sakamoto K.M., et al. Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria. Pediatr Blood Cancer. 2014; 61(9): 1544–50. DOI: 10.1002/pbc.25068.

45. McNamara L.A., Topaz N., Wang X., et al. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. MMWR Morb Mortal Wkly Rep. 2017; 66(27): 734–7. DOI: 10.15585/mmwr.mm6627e1.

46. Brodsky R.A. Stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica. 2010; 95(6): 855–6. DOI: 10.3324/haematol.2010.023176.

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. DOI: 10.3324/haematol.2012.062828.

48. Shasheleva D.A., Maschan A.A., Shelikhova L.N., et al. Hematopoietic stem cell transplantation with alpha/beta T-lymphocyte depletion and short course of eculizumab in adolescents and young adults with paroxysmal nocturnal hemoglobinuria. Terapevticheskii arkhiv. 2018; 90(7): 57–64. DOI: 10.26442/terarkh201890757-64. (In Russian).

49. Young N.S., Meyers G., Schrezenmeier H., et al. The management of paroxysmal nocturnal hemoglobinuria: Recent advances in diagnosis and treatment and new hope for patients. Semin Hematol. 2009; 46(1 Suppl 1): S1–16. DOI: 10.1053/j.seminhematol.2008.11.004.

50. Brecher M., Taswell H. Paroxysmal nocturnal hemoglobinuria and the transfusion of washed red cells. A myth revisited. Transfusion. 1989; 29(8): 681–5. DOI: 10.1046/j.1537-2995.1989.29890020439.x.

51. Parker C. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106(12): 3699–709. DOI: 10.1182/blood-2005-04-1717.