Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells that manifests with chronic intravascular hemolysis and bone marrow failure. A mutation in the phosphatidylinositol glycan class A (PIGA) gene causes a deficiency of glycosylphosphatidylinositol (GPI)-anchored complement-regulating proteins, such as CD55 and CD59, on the surface of blood cells, which results in the cellular defects that characterize this fatal disease. 

PNH Patient Populations

Most patients with PNH are diagnosed between the ages of 30 and 40 years. The disease may also affect children, although not frequently.1 In 2012, an examination of 1610 patients enrolled in the International PNH Registry revealed that the median age of all patients was 42 years and that the average duration of disease was 4.6 years. The patients in the registry ranged in age from 3 to 99 years.2 

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Life Expectancy Relative to Treatment

Before the development of complement inhibitors like Soliris® (eculizumab), individuals with PNH generally lived for 10 to 22 years. Thrombotic episodes were the main cause of death. Since the introduction of Soliris and Ultomiris® (ravulizumab), the survival rate of patients with PNH is comparable to that of people who do not have the condition.3 Complement inhibitor therapy enhances patients’ quality of life and extend their average life expectancy to more than 15 to 20 years following the initial diagnosis.1 

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Life Expectancy Relative to Complications and Comorbidities

The course of PNH can be insidious and chronic, especially when accompanied by comorbid conditions. The presence of comorbid aplastic anemia is a crucial prognostic factor; accompanying pancytopenia and venous (hepatic, abdominal, and cerebral) thrombosis can be fatal.4 

The prognosis for patients with PNH varies according to the severity of symptoms and the development of complications, including hemolysis, bone marrow failure, and thrombophilia.5 The risk for thromboembolism, the main cause of death, is significantly increased in patients with PNH hemolysis.8 In some cases, even anticoagulation therapy cannot stop thromboembolic events. Pulmonary hypertension or impaired renal function may also be associated with PNH.9

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Studies on Life Expectancy

In a study performed between 1940 and 1970 of 80 consecutive patients treated with supportive measures (oral anticoagulant medication after an established thrombosis and transfusions) at the Hammersmith Hospital in London, the median survival following a diagnosis was 10 years. Of these patients, 22 (28%) lived for another 25 years, and 12 of the 35 patients (34%) who lived for 10 years or longer experienced a spontaneous clinical recovery.6 

A large retrospective study that included 460 patients with PNH revealed a time-dependent increase in survival. The median survival time was found to be 22 years. This increased survival time was accredited to modern supportive interventions, improvements in the treatment of thrombosis, and immunosuppressant treatment for patients with AA-PNH syndrome.7 

In the era before complement inhibitor treatment, the survival of patients with PNH was reported to be much lower than that of matched controls, with approximately 50% of patients dying as a result of their disease.6 A study done in 2011, after the approval of Soliris, showed improved survival in the patients treated with the complement inhibitor therapy. No mortalities were noted in the patients who started Soliris before 50 years of age.10 

Even with the best supportive treatments, the 10-year survival rate of patients with PNH ranged from 50% for those in whom the disease was diagnosed between 1940 and 1970 to 75% for those in a more recent series, according to retrospective data analysis. Thromboembolism accounts for between 40% and 67% of fatalities with a known cause, making it the most common cause of death among patients with PNH.2 

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References

  1. ​​What to know about paroxysmal nocturnal hemoglobinuria (PNH). Medical News Today. Updated October 21, 2021. Accessed November 30, 2022.
  2. Schrezenmeier H, Muus P, Socié G, et al. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica. 2014;99(5):922-929. doi:10.3324/haematol.2013.093161
  3. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. StatPearls [Internet]. August 1, 2022. Accessed November 30, 2022.
  4. Besa EC. Paroxysmal nocturnal hemoglobinuria follow-up: prognosis. Medscape. Updated May 20, 2021. Accessed November 30, 2022.
  5. Besa EC. Paroxysmal nocturnal hemoglobinuria overview. Medscape. Updated May 20, 2021. Accessed November 30, 2022.
  6. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;333(19):1253-1258. doi:10.1056/NEJM199511093331904
  7. de Latour RP, Mary JY, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood. 2008;112(8):3099-3106. doi:10.1182/blood-2008-01-133918
  1. Socié G, Schrezenmeier H, Muus P, et al. Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories: an analysis of the International PNH Registry. Intern Med J. 2016;46(9):1044-1053. doi:10.1111/imj.13160
  2. Füreder W, Sperr WR, Heibl S, et al. Prognostic factors and follow-up parameters in patients with paroxysmal nocturnal hemoglobinuria (PNH): experience of the Austrian PNH network. Ann Hematol. 2020;99(10):2303-2313. doi:10.1007/s00277-020-04214-z

Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood. 2011;117(25):6786-6792. doi:10.1182/blood-2011-02-333997

Reviewed by Kyle Habet, MD, on 11/30/2022.

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