Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder in which red blood cells break apart prematurely. PNH is caused by 2 factors: an acquired somatic mutation of the gene phosphatidylinositol glycan class A (PIGA) and a process that leads to these mutated stem cells multiplying and expanding. In individuals with PNH, some hematopoietic stem cells are defective, leading to the production of defective blood cells. These defective red blood cells are susceptible to premature destruction by the complement system, which is part of the immune system.1
The worldwide incidence and prevalence of PNH are detailed in Figure 1.2
Clinical Manifestations and Disease Course
The complement system’s destruction of red blood cells results in episodes of hemoglobin in the urine, known as hemoglobinuria. PNH manifests with hemolytic anemia, bone marrow failure, and thrombosis. The most common sign of PNH is the discoloration of concentrated urine in the morning, resulting from the excretion of hemoglobin and hemosiderin from lysed red blood cells. However, hemoglobin in urine may not always be visible.1,3 Table 1 lists the clinical manifestations of PNH, as well as the subjective and objective symptoms.1,3,4
The symptoms of PNH vary greatly between individuals, and most affected people do not exhibit all the associated symptoms. Patients with PNH are susceptible to developing blood clots, which are potentially life-threatening and may repeatedly occur. Additionally, there may be some degree of underlying bone marrow dysfunction.1
Delays in Diagnosis
Due to the multifactorial symptoms of PNH, the path to diagnosis is often lengthy and complex. If a patient is assessed for hemolysis and PNH is suspected, a flow cytometry test is conducted to determine the presence of glycosylphosphatidylinositol (GPI)-linked antigens on blood cells. The test calculates the percentage of red blood cells or white blood cells that entirely or partially lack GPI-linked antigens compared with normal cells. This percentage is called the PNH clone size. It is recommended to determine both the red blood cell and white blood cell clone sizes for a diagnosis due to limitations that arise when testing for only 1 or the other.5
A survey of 163 patients with PNH found that it takes almost 2 years on average to receive a diagnosis. Less than 40% of individuals are diagnosed within 12 months of symptom onset; in 24% of reported cases, it can take 5 years or longer to be diagnosed. Additionally, 79% of patients consult multiple providers before receiving a diagnosis. Individuals with PNH are at risk for complications of the disease prior to diagnosis, with an estimated 40% of patients having experienced a thromboembolic event before receiving a diagnosis.6
Differential Diagnoses
Several disorders present similar symptoms to those of PNH, making a differential diagnosis possible through comparisons.
PNH and acquired aplastic anemia are closely related. Research indicates that PNH may result from autoimmune bone marrow failure, which is the cause of the majority of acquired aplastic anemia cases and several cases of myelodysplasia. Acquired aplastic anemia is a rare disorder caused by almost complete bone marrow failure. In this disorder, the nearly complete absence of hematopoietic stem cells causes low levels of red and white blood cells and platelets. While the symptoms vary, they may include fatigue, dizziness, weakness, headaches, recurrent infections, and episodes of excessive bleeding.1
Paroxysmal cold hemoglobinuria is a rare autoimmune hemolytic disorder in which premature destruction of healthy red blood cells occurs within minutes to hours following exposure to cold. While red blood cells typically have a life span of about 120 days, in an individual with paroxysmal cold hemoglobinuria, red blood cells are destroyed suddenly and prematurely upon exposure to temperatures of 50 to 59 degrees Fahrenheit.1
PNH Diagnoses and Challenges
In an effort to improve PNH diagnoses, a study was conducted where 12 physicians with clinical expertise in PNH were recruited to develop consensus-based guidance on PNH screening and diagnosis. The participants were presented with several cases, with consensus being attained if more than 80% of the experts agreed on an approach during a second-round questionnaire.3
In the first case, the group reached a consensus that PNH should be considered as a possible diagnosis for patients with a history of aplastic anemia with or without worsening symptoms, such as fatigue and shortness of breath. In the second case, the panelists agreed that a PNH diagnosis should be considered for patients with unprovoked thrombosis associated with cytopenia. The experts also agreed, on another case, to consider PNH in patients with abdominal pain, cytopenia, and nonspecific symptoms. The study’s results indicated that PNH should also be considered as a possible diagnosis in patients presenting with portal vein thrombosis, thrombocytopenia or anemia, and nonspecific symptoms. The panelists determined that PNH should be considered for all patients with cytopenia and recurrent hematuria.3
Burden of Disease With Late Diagnosis
Although treatment options are available, the complexities involved in diagnosing PNH result in many individuals living with the condition for long periods without being aware of it. PNH has been characterized as “the most vicious acquired thrombophilic state known in medicine,” illustrating the serious risk of thrombosis and its associated morbidity and mortality in untreated patients.7
Thrombosis affects 13.3% of patients with PNH before treatment is started and 40% of overall patients; it accounts for up to 50% of mortality in untreated patients. About 42.8% of untreated patients have renal dysfunction, which may contribute to 8% to 18% of deaths. The 10-year mortality rate for PNH that is left untreated is 29%. A timely diagnosis and initiation of treatment may improve one’s quality of life and offer a near-normal life expectancy.8,9
Conclusion
PNH diagnosis remains challenging due to its multifactorial symptoms and the similarity of presentation to other disorders. However, correctly diagnosing PNH can significantly improve outcomes and extend the longevity of patients. Notable advancements have been made to enable earlier diagnoses of PNH while researchers work to further the diagnostic methodologies for this rare disorder.
References
1. Parker CJ. National Organization for Rare Disorders. Paroxysmal nocturnal hemoglobinuria. Updated January 5, 2023. Accessed July 18, 2023. https://rarediseases.org/rare-diseases/paroxysmal-nocturnal-hemoglobinuria/
2. Farooq Q, Saleem MW, Khan ZU, Hadi N. Paroxysmal nocturnal hemoglobinuria: a diagnostic “zero-sum-game.” Cureus. 2020;12(12):e11956. doi:10.7759/cureus.11956
3. Röth A, Maciejewski J, Nishimura JI, Jain D, Weitz JI. Screening and diagnostic clinical algorithm for paroxysmal nocturnal hemoglobinuria: expert consensus. Eur J Haematol. 2018;101(1):3-11. doi:10.1111/ejh.13059
4. Parker CJ. Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program. 2016;2016(1):208-216. doi:10.1182/asheducation-2016.1.208
5. Agarwal AM. ARUP Laboratories. Paroxysmal nocturnal hemoglobinuria – PNH. July 2020. Updated May 2023. Accessed July 18, 2023. https://arupconsult.com/content/paroxysmal-nocturnal-hemoglobinuria
6. Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: patient journey and burden of disease. J Manag Care Spec Pharm. 2020;26(suppl 12-b):S8-S14. doi:10.18553/jmcp.2020.26.12-b.s8
7. Chatzileontiadou S, Hatjiharissi E, Angelopoulou M, et al. Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): real world data of a Greek nationwide multicenter retrospective study. Front Oncol. 2023;13:e1128994. doi:10.3389/fonc.2023.1128994
8. Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: role of the complement system, pathogenesis, and pathophysiology. J Manag Care Spec Pharm. 2020;26(suppl 12-b):S3-S8. doi:10.18553/jmcp.2020.26.12-b.s3
9. Kulasekararaj AG, Lazana I. Paroxysmal nocturnal hemoglobinuria: where are we going. Am J Hematol. 2023;98(suppl 4):S33-S43. doi:10.1002/ajh.26882
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Reviewed August 2023
