Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic condition in which persistent complement-mediated intravascular hemolysis of erythrocytes results in episodes of increased hemoglobin excretion in the urine, especially during periods of stress. PNH is caused by an acquired somatic mutation of the PIGA gene in hematopoietic stem cells, which undergo a process of replication and clonal expansion.1 

Risk Factor From Comorbidity

The only known risk factor for PNH is a medical history of aplastic anemia. PNH eventually develops in approximately 1 in every 10 people with a diagnosis of aplastic anemia.2 On the other hand, aplastic anemia also develops in some patients with PNH.2 Because of the bidirectional relationship between PNH and aplastic anemia, the 2 conditions are diagnosed concurrently in approximately 40% of cases.3 

Read more about PNH comorbidities

Risk Factors of Ethnicity/Race

The prevalence of aplastic anemia is higher in Asian countries than in Western Europe and the United States. Given the relationship between aplastic anemia and PNH, researchers have hypothesized that the prevalence of PNH-related bone marrow failure may be higher in Asia than the prevalence of PNH-related thrombosis.4

Risk Factors of Age

PNH occurs at any age. Age in itself is not a risk factor for PNH, but the disease is most commonly diagnosed in adults approximately 30 to 40 years old.2

Read more about PNH epidemiology

Risk Factors of Gender 

No relationship has been found between gender and risk for PNH. Some sources claim that PNH affects women and men equally, whereas others suggest a slight female predominance.1

Risk Factors of Genetics

PNH is predominantly caused by somatic mutations in the PIGA gene on the short arm of the X chromosome. The disease is nearly always acquired and not caused by inheritance of genetic risk factors.5,6

Although PIGA mutations are not inherited, current genetic research indicates that PNH hematopoietic stem cells may have an intrinsic clonal advantage that allows them to replicate and multiply faster than normal hematopoietic stem cells. This advantage may be due to interplay between PIGA mutations and secondary mutations similar to those that contribute to oncogenic transformations. Some proposed secondary mutations are found in the NRA, JAK2, and HMG2A genes; in addition, cytogenetic alterations may promote PNH pathogenesis.6

This being said, recent scientific literature has documented rare cases due to PIGT germline mutations.5,7-9 This type of PNH is autoinflammatory in nature. For the disease to manifest, a mutated PIGT allele must be inherited from one parent, and a somatic variant that deletes the corresponding allele on chromosome 20q must be acquired. In these rare cases, inheritance of a PIGT mutation from one parent is a risk factor for the development of inflammatory PNH.5,8 

A history of aplastic anemia is the predominant risk factor for PNH. In addition, several other risk factors correlate with decreased survival and a higher incidence of thrombosis in patients with PNH. 

A single-center study of 68 patients with PNH reported that the presence of urinary hemoglobin and infection at the time of presentation were risk factors for thrombosis, and that major hemorrhage, thrombosis, and an absolute neutrophil count (ANC) higher than 1000/µL of blood independently predicted inferior survival.10

Researchers at the Cleveland Clinic and 2 other research institutions reported that the absence of PNH clones, a suboptimal response to immunosuppressive therapies, older age at the onset of aplastic anemia/PNH, and the presence of certain secondary somatic mutations increased the risk that aplastic anemia/PNH would progress to malignancy.11

Read more about PNH clinical trials

References

  1. Paroxysmal nocturnal hemoglobinuria. NORD (National Organization for Rare Disorders). Accessed November 29, 2022.
  2. PNH – paroxysmal nocturnal hemoglobinuria. AA •MDS International Foundation. Accessed November 29, 2022.
  3. de Latour RP, Risitano A, Dufour C. Severe aplastic anemia and PNH. In: Carreras E, Dufour C, Mohty M, Kröger N, eds. The EBMT Handbook: Hematopoietic Stem Cell Transplantation and Cellular Therapies. 7th ed. Chapter 77. Springer; 2019. doi:10.1007/978-3-030-02278-5_77
  4. Hill A, DeZern AE, Kinoshita T, Brodsky RA. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers. 2017;3:17028. doi:10.1038/nrdp.2017.28
  5. Paroxysmal nocturnal hemoglobinuria: causes. Medline Plus. Accessed November 29, 2022.
  6. Lee SCW, Abdel-Wahab O. The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance. J Clin Invest. 2014;124(10):4227-4230. doi:10.1172/JCI77984
  7. Murakami Y, Kawamoto M, Inoue N, et al. Paroxysmal nocturnal hemoglobinuria caused by Pigt mutations; atypical PNH. Blood. 2016;128(22):2450. doi:10.1182/blood.V128.22.2450.2450
  8. Brodsky RA. Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiency. J Clin Invest. 129(12):5074-5076. doi:10.1172/JCI131647
  9. Osato M, Murakami Y, Murata S, et al. Elucidation of autoinflammatory mechanism in Pigt-PNH. Blood. 2017;130(Suppl 1):2201. doi:10.1182/blood.V130.Suppl_1.2201.2201
  10. Smith SB, Tefferi A, Hoyer JD, Wolanskyj AP. Risk factors for survival and thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH): a single institution study of 68 patients. Blood. 2005;106(11):1051. doi:10.1182/blood.V106.11.1051.1051
  11. Newly identified risk factors help predict how aplastic anemia can become malignant. Cleveland Clinic Consult QD. Accessed November 29, 2022.

Reviewed by Hasan Avcu, MD, on 12/2/2022.