Paroxysmal Nocturnal Hemoglobinuria (PNH)
What is PNH?
PNH is a rare, acquired, clonal disorder of hematopoietic stem cells that is characterized by hemolysis, bone marrow failure, and thrombosis1,2
- PNH develops due to a mutation in PIGA, which is necessary for the creation of GPI anchors on the cell surface that attach proteins, including CD55 and CD591,3,4
- CD55 and CD59 normally prevent the complement system from destroying normal cells, and in PNH, loss of the GPI anchor results in the lack of CD55 and CD59 on cells1,4-6
- This leads to complement-mediated hemolysis1,4
The complement system features 3 pathways made up of a large number of distinct plasma proteins that react with one another to help fight infection. Each pathway is triggered differently but ultimately leads to cell destruction4
US incidence rate of PNH8
≈ 6 cases per 1 million person-years
US prevalence of PNH8
12 to 13 per 1 million individuals
PNH affects adults irrespective of age or sex2,8
- Median age at onset is ~36 years
- PNH rarely occurs in children
The Burden of PNH2
Key signs and symptoms
- Anemia (median hemoglobin level, 9.8 g/dL)
- Thrombotic events are the leading cause of mortality in PNH, accounting for ≤67% of deaths with a known cause
- 13% of patients have a history of thrombotic events
- Hemoglobinuria (45%)
- Fatigue (81%)
- Abdominal Pain (35%)
These symptoms can have a substantial impact on quality of life, hospitalization and employment.
Unmet Medical Needs in PNH
Flow cytometry is the gold-standard test to diagnose PNH; however, late diagnosis and delayed treatment remain barriers due to the rarity of PNH and numerous symptoms that overlap with other disorders
Due to the multifactorial symptoms of PNH, diagnosis can be challenging, often characterized by a lengthy and complex patient experience9
Approximately one-third of patients on standard of care fail to achieve hemoglobin stabilization (defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion)10
Twenty-six percent to 34% of patients on standard of care require chronic RBC transfusions which can lead to transfusion dependence and complications such as iron overload10-12
Mechanism of Disease Video
In paroxysmal nocturnal hemoglobinuria, dysregulation of the complement system leads to complement-mediated hemolysis.13-15
Acronyms: Ab = antibody; Ag = antigen; CD = cluster of differentiation; GPI = glycosylphosphatidylinositol; GlcNAc = N Acetylglucosamine; Man = mannose; MASP = mannose-binding lectin associated protein; MBL = mannose-binding lectin; MOD = mechanism of disease; PNH = paroxysmal nocturnal hemoglobinuria; RBC = red blood cell.
References: 1. Brodsky RA. Blood. 2014;124(18):2804-2811. 2. Schrezenmeier H, Röth A, Araten DJ, et al. Ann Hematol. 2020;99(7):1505-1514. 3. Hillmen P, Lewis SM, Bessler M, et al. N Engl J Med. 1995;333(19):1253-1258. 4. Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology. 5th ed. Garland Science. 2001. Accessed April 27, 2022. https://www.ncbi.nlm.nih.gov/books/NBK10757. 5. Farkas I, Baranyi L, Ishikawa Y, et al. J Physiol. 2002;539(Pt2):537-545. 6. Fujita T, Inoue T, Ogawa K, et al. J Exp Med. 1987;166(5):1221-1228. 7. Taylor BES, Appelboom G, Zilinyi R, et al. Neuroimmunol Neuroinflamm. 2015;2(2):93-101. 8. Jalbert JJ, Chaudhari U, Haixin Zhang, et al. Blood. 2019;134(suppl1) [abstract 3407]. 9. Bektas M, Copley-Merriman C, Khan S, et al. J Manag Care Spec Pharm. 2020;26(12-b suppl):S8-S14. 10. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, et al. Blood. 2019;133(6):530-539. 11. Risitano AM, Imbriaco M, Marando L, et al. Br J Haematol. 2012;158(3):415-418. 12. Höchsmann B, Leichtle R, von Zabern I, et al. Vox Sang. 2012;102(2):159-166. 13. Risitano AM. In: Lambris JD, Holers V, Ricklin D, eds. Complement Therapeutics: Advances in Experimental Medicine and Biology. New York City, NY: Springer; 2013:155-172. 14. Brodsky RA. In: Hoffman R, Benz EJ, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. 7th ed. Philadephia, PA: Elsevier,Inc; 2018: 415-424. 15. Schubart A, Anderson K, Mainolfi N, et al. Proc Natl Acad Sci USA. 2019;116(16):7926-7931.