One in a million – nocturnal paroxysmal hemoglobinuria – a rare interdisciplinary problem Review article
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Published:
Mar 31, 2023
Keywords:
paroxysmal nocturnal hemoglobinuria, hematopoietic stem cell defect, diagnosis, FLAER
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Abstract
Paroxysmal nocturnal hemoglobinuria is a very rare disease associated with an acquired somatic mutation in the PIGA gene of the bone marrow stem cell. This mutation leads to the lack of protective proteins on the surface of leukocytes, erythrocytes and platelets. Excessive action of the complement system on erythrocytes lacking membrane proteins GPI(-) leads to continuous haemolysis with numerous atypical symptoms. It is the most severe acquired thrombophilia and thromboembolic episodes are the most common cause of death in patients with paroxysmal nocturnal hemoglobinuria. Patients with paroxysmal nocturnal hemoglobinuria may suffer from cardiovascular, gastrointestinal, neurological or hematologic symptoms. Very often they are referred to several specialists. The aim of this article is to review the diagnosis and management of patients with paroxysmal nocturnal hemoglobinuria, with particular emphasis on identifying high-risk groups.
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How to Cite
Kozińska, J. (2023). One in a million – nocturnal paroxysmal hemoglobinuria – a rare interdisciplinary problem. Medycyna Faktow (J EBM), 16(1(58), 74-81. https://doi.org/10.24292/01.MF.0123.14
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References
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9. Hill A, DeZern AE, Kinoshita T et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017; 3: 17028. http://doi.org/10.1038/nrdp.2017.28.
10. Nicholson-Weller A, March JP, Rosenfeld SI et al. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulator protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983; 80: 5066-70.
11. Zipfel PF, Hallstrom T, Riesbeck K. Human complement control and complement evasion by pathogenic microbes – tipping the balance. Mol Immunol. 2013; 56: 152-60.
12. Richards SJ, Rawstron AC, Hillmen P. Application of flow cytometry to the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry. 2000; 42: 223-33.
13. Spychalska J, Brojer E. Nocna napadowa hemoglobinuria – patofizjologia, klasyfikacja i nowoczesna diagnostyka (Paroxysmal nocturnal hemoglobinuria – pathophysiology, classification and modern diagnostics). Hematology in Clinical Practice. 2013; 4(4): #37127.
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16. Nair RK, Khaira A, Sharma A et al. Spectrum of renal involvement in paroxysmal nocturnal hemoglobinuria: report of three cases and a brief review of the literature. Int Urol Nephrol. 2008; 40: 471-5.
17. Ballarin J, Arce Y, Balcells RT et al. Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression. Nephrol Dial Transplant. 2011; 26: 3408-11.
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21. DeCobelli F, Pezzetti G, Margari S et al. New insights in abdominal pain in Paroxysmal Nocturnal Hemoglobinuria (PNH): a MRI study. PLoS One. 2015; 10(4): e0122832.
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25. Hoekstra J, Leebeek FWG, Plessier A et al.; European Network for Vascular Disorders of the Liver. Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study. J Hepatol. 2009; 51: 696-706.
26. Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal haemoglobinuria. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 208‐16.
27. Kim JS, Jang JH, Yoon SS et al. Distinct subgroups of paroxysmal nocturnal hemoglobinuria (PNH) with cytopenia: results from South Korean National PNH Registry. Ann Hematol. 2016; 95(1): 125‐33.
28. Robak T, Warzocha K. Hematologia. Nocna napadowa hemoglobinuria. Via Medica, Gdańsk 2016: 579-89.
29. Borowitz MJ, Craig FE, DiGiuseppe JA et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2010; 78: 211-28.
30. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106: 3699-709.
31. Windyga J. Profilaktyka i leczenie żylnej choroby zakrzepowo-zatorowej u chorych na nowotwór złośliwy. Omówienie wytycznych American Society of Hematology 2021. Med Prakt. 2021; 7-8: 8-15.
32. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Ravulizumab. 2022 May 15.
33. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019; 133(6): 530-9. http://doi.org/10.1182/blood-2018-09-876136.
34. Brodsky RA, Peffault de Latour R, Rottinghaus ST et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021; 106(1): 230-7. http://doi.org/10.3324/haematol.2019.236877.
35. Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003; 77: 113-20.
36. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106: 3699-709.
37. Żupańska B, Spychalska J, Pyl H et al. Nocna napadowa hemoglobinuria – wieloletnie obserwacje. Charakterystyka kliniczna i analiza wielkości klonu z defektem kotwicy glikozylofosfatydyloinozytolowej (GPI). Acta Haematologica Polonica. 2012; 43(1): 75-82.
38. Pulini S, Marando L, Natale A et al. Paroxysmal nocturnal hemoglobinuria after autologous stem cell transplantation: extinction of the clone during treatment with eculizumab – pathophysiological implications of a unique clinical case. Acta Haematol. 2011; 126(2): 103-9. http://doi.org/10.1159/000327251.
2. Socié G, Mary JY, de Gramont A et al. Paroxysmal Nocturnal Haemoglobinuria: Long-Term Follow-Up and Prognostic Factors. French Soc Haematology. Lancet. 1996; 348: 573-7. http://doi.org/10.1016/S0140-6736(95)12360-1.
3. Nishimura JI, Kanakura Y, Ware RE et al. Clinical Course and Flow Cytometric Analysis of Paroxysmal Nocturnal Hemoglobinuria in the United States and Japan. Med (Baltimore). 2004; 83: 193-207. http://doi.org/10.1097/01.md.0000126763.68170.46.
4. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014; 124: 2804-11.
5. Curran KJ, Kernan NA, Prockop SE et al. Paroxysmal nocturnal hemoglobinuria in pediatric patients. Pediatr Blood Cancer. 2012; 59: 525-9.
6. Krawitz PM, Höchsmann B, Murakami Y et al. A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood. 2013; 122: 1312-5.
7. Brodsky RA. How do PIG-A mutant paroxysmal nocturnal hemoglobinuria stem cells achieve clonal dominance? Expert Rev. Hematol. 2009; 2: 353-6.
8. Wysoczynski M, Reca R, Ratajczak J et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood. 2005; 105: 40-8.
9. Hill A, DeZern AE, Kinoshita T et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017; 3: 17028. http://doi.org/10.1038/nrdp.2017.28.
10. Nicholson-Weller A, March JP, Rosenfeld SI et al. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulator protein, decay accelerating factor. Proc Natl Acad Sci USA. 1983; 80: 5066-70.
11. Zipfel PF, Hallstrom T, Riesbeck K. Human complement control and complement evasion by pathogenic microbes – tipping the balance. Mol Immunol. 2013; 56: 152-60.
12. Richards SJ, Rawstron AC, Hillmen P. Application of flow cytometry to the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry. 2000; 42: 223-33.
13. Spychalska J, Brojer E. Nocna napadowa hemoglobinuria – patofizjologia, klasyfikacja i nowoczesna diagnostyka (Paroxysmal nocturnal hemoglobinuria – pathophysiology, classification and modern diagnostics). Hematology in Clinical Practice. 2013; 4(4): #37127.
14. Brodsky RA. Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiency. J Clin Invest. 2019; 129(12): 5074-6.
15. Wong EKS, Kavanagh D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl Res. 2015; 165(2): 306-20.
16. Nair RK, Khaira A, Sharma A et al. Spectrum of renal involvement in paroxysmal nocturnal hemoglobinuria: report of three cases and a brief review of the literature. Int Urol Nephrol. 2008; 40: 471-5.
17. Ballarin J, Arce Y, Balcells RT et al. Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression. Nephrol Dial Transplant. 2011; 26: 3408-11.
18. Bessler M, Hiken J. The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2008; 104-10.
19. Lee JW, Jang JH, Kim JS et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean Registry. Int J Hematol. 2013; 97(6): 749‐57.
20. de Latour RP, Mary JY, Salanoubat C et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008; 112(8): 3099‐106.
21. DeCobelli F, Pezzetti G, Margari S et al. New insights in abdominal pain in Paroxysmal Nocturnal Hemoglobinuria (PNH): a MRI study. PLoS One. 2015; 10(4): e0122832.
22. Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003; 77: 113-201.
23. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013; 121: 4985-96.
24. Ziakas PD, Poulou LS, Rokas GI et al. Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview. J Thromb Haemost. 2007; 5: 642-5.
25. Hoekstra J, Leebeek FWG, Plessier A et al.; European Network for Vascular Disorders of the Liver. Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study. J Hepatol. 2009; 51: 696-706.
26. Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal haemoglobinuria. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 208‐16.
27. Kim JS, Jang JH, Yoon SS et al. Distinct subgroups of paroxysmal nocturnal hemoglobinuria (PNH) with cytopenia: results from South Korean National PNH Registry. Ann Hematol. 2016; 95(1): 125‐33.
28. Robak T, Warzocha K. Hematologia. Nocna napadowa hemoglobinuria. Via Medica, Gdańsk 2016: 579-89.
29. Borowitz MJ, Craig FE, DiGiuseppe JA et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2010; 78: 211-28.
30. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106: 3699-709.
31. Windyga J. Profilaktyka i leczenie żylnej choroby zakrzepowo-zatorowej u chorych na nowotwór złośliwy. Omówienie wytycznych American Society of Hematology 2021. Med Prakt. 2021; 7-8: 8-15.
32. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006–. Ravulizumab. 2022 May 15.
33. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019; 133(6): 530-9. http://doi.org/10.1182/blood-2018-09-876136.
34. Brodsky RA, Peffault de Latour R, Rottinghaus ST et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021; 106(1): 230-7. http://doi.org/10.3324/haematol.2019.236877.
35. Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol. 2003; 77: 113-20.
36. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106: 3699-709.
37. Żupańska B, Spychalska J, Pyl H et al. Nocna napadowa hemoglobinuria – wieloletnie obserwacje. Charakterystyka kliniczna i analiza wielkości klonu z defektem kotwicy glikozylofosfatydyloinozytolowej (GPI). Acta Haematologica Polonica. 2012; 43(1): 75-82.
38. Pulini S, Marando L, Natale A et al. Paroxysmal nocturnal hemoglobinuria after autologous stem cell transplantation: extinction of the clone during treatment with eculizumab – pathophysiological implications of a unique clinical case. Acta Haematol. 2011; 126(2): 103-9. http://doi.org/10.1159/000327251.