Paroxysmal Nocturnal Hemoglobinuria (PNH)

Posted onAuthorVirtual Medical Academy

What is PNH?

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, progressive, and potentially life-threatening blood disorder. PNH is characterized by red blood cell (RBC) destruction within blood vessels (also known as intravascular hemolysis, or IVH) and white blood cell and platelet activation, which may lead to blood clots (thrombosis).

PNH is caused by an acquired genetic mutation (not inherited) that may happen any time after birth and results in the production of abnormal blood cells that are missing important protective blood cell surface proteins.

These missing proteins enable the complement system to ‘attack’ and destroy or activate these abnormal blood cells.

PNH can occur in children and adults at any age; the average age of diagnosis is in the early 30s. It affects both men and women and people of every racial and ethnic group.

PNH is estimated to affect approximately 16-20 people per million worldwide.

Signs & Symptoms

How is PNH Diagnosed and Monitored?

PNH can be diagnosed from a simple blood test (high-sensitivity flow cytometry), which can detect and count PNH blood cells.

Another type of blood test is used to monitor ongoing PNH disease activity. This test measures lactate dehydrogenase (LDH), an enzyme that is released from red blood cells during IVH.

Monitoring LDH regularly is a very important part of managing PNH. If high levels of LDH are present, it means that many red blood cells have been destroyed within blood vessels. This has been shown to correlate with complications, such as thrombosis and early mortality.

Diverse symptoms and varied clinical presentation can delay diagnosis by up to 10 years.

The Complement System

What Role Does Complement Inhibition Play in Treating PNH?

In PNH, immediate, complete and sustained terminal complement inhibition (by blocking the C5 protein) is the proven standard of care to prevent the destruction of PNH red cells and activation of PNH white cells and platelets. This helps reduce symptoms and complications and improve survival, transforming the lives of those impacted by PNH.

References

  1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood. 2014;124(18):2804-2811.
  2. Holguin MH, et al. Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest. 1989;84(1):7 17.
  3. Jang, J. H., et al. (2016). Predictive Factors of Mortality in Population of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Results from a Korean PNH Registry. Journal of Korean medical science, 31(2), 214–221.
  4. Anita Hill, et al. The Incidence and Prevalence of Paroxysmal Nocturnal Hemoglobinuria (PNH) and Survival of Patients in Yorkshire. Blood2006; 108 (11): 985.
  5. Hill, A., Richards, S. J., & Hillmen, P. (2007). Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. British journal of haematology, 137(3), 181–192.)
  6. Hillmen, P., et al. (2007). Effect of the complement inhibitor eculizumab on thromboembolism on patients with paroxysmal nocturnal hemoglobinuria. Blood, 110(12), 4123-4128.
  7. Kulasekararaj, A. G., et al. (2019). Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood, 133(6), 540–549.
  8. Hillmen, P., et al. (1995). Natural history of paroxysmal nocturnal hemoglobinuria. The New England journal of medicine, 333(19), 1253–1258.
  9. O’Connell, T., et al. (2020). Cost-Utility Analysis of Ravulizumab Compared with Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria. PharmacoEconomics, 38(9), 981–994
  10. Fletcher M, et al. Current international flow cytometric practices for the detection and monitoring of paroxysmal nocturnal haemoglobinuria clones: A UK NEQAS survey. Cytometry B Clin Cytom. 2017;92(4):266-274.
  11. Jang JH, Kim JS, Yoon SS, et al. Predictive factors of mortality in population of patients with paroxysmal nocturnal hemoglobinuria (PNH): results from a Korean PNH registry. J Korean Med Sci. 2016;31(2):214-221.
  12. Lee, J. W., et al. (2019). Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood, 133(6), 530–539.
  13. Merle, N. S., et al. (2015). Complement System Part II: Role in immunity. Frontiers of Immunology, 6:257.
  14. Garred, P., Tenner, A. J., & Mollnes, T. E. (2021). Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics. Pharmacological Reviews, 73(2) 792-827.

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