Paroxysmal Nocturnal Hemoglobinuria (PNH)


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare genetic disorder that has a varied clinical presentation, mainly causing hemolytic anemia, hemoglobinuria, and somatic symptoms such as fatigue and dyspnea. Additional signs of PNH include thrombosis, renal insufficiency, and, in the later stages of the illness, bone marrow failure.1 PNH occurs due to an acquired mutation in the PIGA (phosphatidylinositol glycan anchor biosynthesis, class A) gene in self-renewing hematopoietic stem cells, which is then followed by clonal expansion.2 

PNH can affect people at any age, but the majority are diagnosed in their 30s.3

Three primary categories of PNH are included in the classification method suggested by the International PNH Interest Group4:

  • Classic or classical PNH: This disease is defined by the presence of a large granulocyte clone and intravascular hemolysis, as confirmed by laboratory and clinical findings, with no evidence of bone marrow deficiency. The majority of red blood cells are type III PNH cells, which leads to complete glycosylphosphatidylinositol-anchored protein [GPI-AP] deficiency.5
  • PNH with a primary bone marrow disorder: Patients with aplastic anemia (AA), myelodysplastic syndrome (MDS), and rarely, idiopathic myelofibrosis may have comorbid PNH, which is characterized by intravascular hemolysis as evidenced by clinical and/or laboratory findings and the detection of a cell clone with a PNH phenotype in peripheral blood.5
  • Subclinical PNH: The subclinical form of the disease is often present in patients with other bone marrow conditions (AA/serum PNH [sPNH], MDS/sPNH, idiopathic myelofibrosis/sPNH) who lack clinical or laboratory hemolysis but who have a minor cell clone with a PNH phenotype (typically <1%).5

Read about PNH guidelines

Classical Paroxysmal Nocturnal Hemoglobinuria

In classical PNH, disease is present with the absence of bone marrow disease.3 Patients with classical PNH typically have severe intravascular hemolysis along with an elevated reticulocyte count, a rise in lactate dehydrogenase (LDH) levels, and decreased haptoglobin levels. There are generally no karyotype defects or morphologic indicators of any other bone marrow pathology in this form of PNH.5 

Treatment of these patients with a complement inhibitor therapy addresses the severe constitutional symptoms linked to chronic complement-mediated intravascular hemolysis. It decreases transfusion requirements, improves PNH-related anemia, and enhances quality of life. One-half to two-thirds of patients achieve freedom from transfusion after treatment, and serum LDH concentration is restored to normal or nearly normal. However, mild to moderate anemia, hyperbilirubinemia, and reticulocytosis continue in almost all treated patients.6 

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PNH With a Primary Bone Marrow Disorder

In patients with AA/PNH and MDS/PNH, manifestations of intravascular hemolysis or bone marrow failure may show predominance in varying disease stages and frequently in combination. Due to the potential of clone expansion with the development of severe hemolysis and a high risk of thrombotic consequences, twice-yearly monitoring is required in patients with small PNH clones despite typically minor symptoms and laboratory evidence of only intravascular hemolysis.5

Patients with PNH who have a primary bone marrow disorder, such as AA or MDS, may develop acute myeloid leukemia as well.3 Most patients with AA/PNH and MDS/PNH have relatively small PNH clones and do not need any specific PNH treatment; instead, treatment should be given to address the underlying bone marrow failure syndrome in these individuals. It is necessary to treat the consequences of PNH (a complement inhibitor for hemolysis and anticoagulant therapy for thrombosis) in about 50% of patients who present with clinical PNH in the presence of bone marrow failure. There is no evidence that immunosuppressive therapy has an impact on clonal proliferation.6

Read about PNH diagnosis

Subclinical Paroxysmal Nocturnal Hemoglobinuria

Subclinical PNH has no symptoms, but the condition may still be detected by blood tests that are performed for other purposes.3 Patients with subclinical PNH do not exhibit any laboratory signs or clinical manifestations of hemolysis, and flow cytometry is currently the only method able to detect these minimal GPI-AP-deficient cells. Underlying illnesses that are defined by bone marrow dysfunction, especially AA and MDS, can be used to diagnose the subclinical form of PNH. Given that 15% to 17% of individuals with AA/sPNH eventually acquire the hemolytic form of AA/PNH, it is crucial to carefully evaluate these patients twice a year for hemolysis and symptoms of rapid clone proliferation.5 No specific therapy is available for the treatment of subclinical PNH, and treatment is focused on the underlying bone marrow failure syndrome.6 

Read about PNH testing

References

  1. Shah N, Bhatt H. Paroxysmal nocturnal hemoglobinuria. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated August 1, 2022. Accessed November 22, 2022.
  2. Devos T, Meers S, Boeckx N, et al. Diagnosis and management of PNH: review and recommendations from a Belgian expert panel. Eur J Haematol. 2018;101(6):737-749. doi:10.1111/ejh.13166
  3. Kugler M. What is paroxysmal nocturnal hemoglobinuria? Verywell Health. Updated August 24, 2022. Accessed November 22, 2022.
  4. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811. doi:10.1182/blood-2014-02-522128
  5. Almomen AK, Al Bakistani AG, Alsaeed A, et al. Paroxysmal nocturnal hemoglobinuria: diagnosis and management protocol. Journal of Applied Hematology. 2014;5(2):37-44. doi:10.4103/1658-5127.137081
  6. 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

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

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