Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, life-threatening condition affecting hematopoietic stem cells. It is characterized by the premature destruction of erythrocytes, which results in the deposition of hemoglobin in the blood and eventual excretion in the urine.1  

Patients diagnosed with PNH have a PIG-A gene deletion. This mutation decreases their production of glycosylphosphatidylinositol (GPI) proteins, which play a key role in enabling additional protective proteins to stick to the surface of erythrocytes. The lack of GPI anchor proteins on the surface of erythrocytes leads to premature hemolysis.1

Factors Influencing Prognosis

Many factors influence the prognosis of PNH, including disease severity and the development of complications.2 Variations in disease expression, such as different degrees of hemolysis, thrombophilia, and bone marrow failure can affect patient morbidity and disease progression.3 

Effects of Complications on PNH Prognosis

A global observational study published in 2014 analyzed data from 1610 patients with PNH listed in the International PNH Registry. Thrombotic events occurred in approximately 16% of patients, while 14% of patients reported a history of impaired renal function. Around 17% of patients with PNH stopped working or worked less due to their condition, reporting a decreased quality of life.3,4

The leading cause of death among patients with PNH is thrombotic events,3,5 followed by complications related to bone marrow failure.3 Venous or arterial thrombosis may occur in the liver, abdomen, and/or brain. Venous thromboembolism is more common than arterial thrombosis.5 

Other documented complications of PNH that influence morbidity and mortality include pulmonary hypertension, dysphagia, acute or chronic renal disease, and erectile dysfunction. PNH patients with acute renal disease are best treated with continuous renal replacement therapy (CRRT).5

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Effects of Disease Progression on PNH Prognosis

A critical prognostic factor is the presence of an aplastic phase, which can influence the progression to pancytopenia and/or thrombosis, causing life-threatening complications.2 Another factor that may influence prognosis is the leukemic transformation of PNH clones, which results in PNH transforming into acute (or possibly even chronic) leukemia.6

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Longitudinal Study on PNH Prognosis

In 1996, the French Society of Haematology published results from a longitudinal study of 220 patients with PNH in France over a period of 46 years (1950 to 1995). The researchers discovered various factors that predicted a better or worse prognosis in patients with PNH.7

The 10-year survival rate after initial PNH diagnosis was estimated at around 65%, while the 15-year survival rate was around 48%. The predominant complications of PNH included pancytopenia (15%), thrombosis (28%), and myelodysplastic syndrome (5%).7 

Poorer survival prognosis correlated with the incidence of thrombosis (relative risk [RR]: 10.2; 95% CI, 6-17; P <.0001), PNH evolution to pancytopenia (RR: 5.5; 95% CI, 2.8-11; P <.0001), and myelodysplastic syndrome or acute leukemia (RR: 19.1; 95% CI, 7.3-50; P <.001).7

Other factors correlated with poorer PNH prognosis included age over 55 years at PNH diagnosis (RR: 4; 95% CI, 2.4-6.9; P <.0001), thrombocytopenia at PNH diagnosis (RR: 2.2; 95% CI, 1.3-3.8; P <.003), and the need for additional treatment (RR: 2.1; 95% CI, 1.3-3.6; P <.003).7

Patients with PNH had a higher risk of future thrombosis if they were over the age of 54 years at diagnosis (RR: 2.6; 95% CI, 1.5-4.6; P =.0014), had an infection at diagnosis (RR: 2.6; 95% CI, 1.3-5.2; P =.0099), or had a previous history of thrombosis at diagnosis (RR: 5.1; 95% CI, 2.5-10.6; P =.0002).7

Patients with PNH were more likely to progress to pancytopenia if they did not have concurrent anemia (RR: 4.03; 95% CI, 1.3-12.2; P =.03) or neutropenia (RR: 2.45; 95% CI, 1.1-5.7; P =.03) at the time of diagnosis.7

Risk factors for the progression of PNH to myelodysplastic syndrome or acute leukemia included abdominal pain crisis at presentation (RR: 10.5; 95% CI, 2.5-44.0; P =.004) and diagnosis after 1983 (RR: 8.45; 95% CI, 1.8-40.7; P =.004).7

A history of aplastic anemia prior to PNH diagnosis predicted an improved prognosis for patients with PNH (RR: 0.32; 95% CI, 0.14-0.72; P <.02).7

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The Advent of Complement Inhibitors: Changing Prognosis

A study published in 2022 indicated that between 29% and 44% of patients with PNH experience thrombotic events. Prior to the advent of complement inhibitors such as Soliris® (eculizumab) and Ultomiris® (ravulizumab), approximately 22% to 67% of deaths in patients with PNH occurred secondary to these thrombotic events. The risk of thromboembolism increases with increased hemolysis and concentrations of PNH clone GPI-negative granulocytes above 50% to 60%.8 

The early detection of PNH is the most important factor influencing prognosis and disease progression. The development of complement inhibitor treatments has critically improved patient prognosis. Both Soliris and Ultomiris reduce PNH complications, including renal damage, pulmonary hypertension, and thromboembolism risk, all of which greatly influence the disease course and survival outcomes.8 

Following the development of these therapies, PNH patient survival changed from a previous 10 to 22 years to a current normal life span when compared to data reported in the general population.4

A recent analysis published in 2016 reviewed prognostic data from 2356 patients with PNH enrolled in the International PNH Registry. Compared to previous studies in which patients with hemolytic PNH demonstrated the worst prognosis, current patients with hemolytic PNH in the era of complement inhibitors do not have the worst prognosis. The analysis revealed that older age and decreased performance status affected survival rates, but treatment with complement inhibitors improved survival.9

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References

  1. Paroxysmal nocturnal hemoglobinuria (PNH). MedlinePlus. Accessed November 21, 2022.
  2. Besa EC. Paroxysmal nocturnal hemoglobinuria follow-up: prognosis. Medscape. Updated May 20, 2021. Accessed November 21, 2022.
  3. Besa EC. Paroxysmal nocturnal hemoglobinuria: epidemiology. Medscape. Updated May 20, 2021. Accessed November 21, 2022.
  4. 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
  5. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated August 1, 2022. Accessed November 21, 2022.
  6. Chen Y, Tao S, Deng Y, Song L, Yu L. Chronic myeloid leukemia transformation in a patient with paroxysmal nocturnal hemoglobinuria: a rare case report with literature review. Int J Clin Exp Med. 2015;8(5):8226-8229. 
  7. Socié G, Mary JY, de Gramont A, et al; French Society of Haematology. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet. 1996;348(9027):573-577. doi:10.1016/s0140-6736(95)12360-1
  8. Szlendak U, Budziszewska B, Spychalska J, Drozd-Sokołowska J, Patkowska E, Nowak J. Paroxysmal nocturnal hemoglobinuria: advances in the understanding of pathophysiology, diagnosis, and treatment. Pol Arch Intern Med. 2022;132(6):16271. doi:10.20452/pamw.16271
  9. 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

Reviewed by Debjyoti Talukdar, MD, on 11/25/2022.

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