Hemophilia A (Classic Hemophilia) – Factor VIII Deficiency

Hemophilia A (HEMA), although rare, is one of the most common X-linked genetic diseases and the second most common disease of hemostasis after von Willebrand disease (vWD).1 It affects males more than females, with a worldwide incidence of 1 in 4000 to 1 in 5000 live male births. It is about 4 times more common than hemophilia B.2 HEMA is a heterogeneous condition whose manifestations depend on how severely factor VIII function is affected by F8 gene mutations. 

In general, the statistics for HEMA phenotypes are as follows3:

  • HEMA is severe in 50% to 60% of patients (factor VIII activity <1%);
  • HEMA is moderate in 25% to 30% (factor VIII activity 2%-5%);
  • HEMA is mild in 15% to 20% (low factor VII activity but not <5%).

The prevalence of HEMA also varies by region, with 43% of the entire population of affected persons living in India, Bangladesh, Indonesia, and China. In only 12% has the disease been diagnosed.4 In 2016, the number of people in the United States living with HEMA was approximately 20,000.1 In 2018, the World Federation of Hemophilia Annual Global Survey found that the number of people with HEMA is 210,454, up from 78,629 in 1999.5 One recent meta-analysis suggests that the number of men living with any type of hemophilia is more than 1.12 million worldwide. It is estimated that per every 100,000 males, there are 17.1 cases of HEMA, and of these, 6 cases are severe.6,7 

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Approximately 30% of females with heterozygous pathogenic variants in the F8 gene (carriers) will have mild HEMA, with factor VIII activity below 40% but not below 5%.8 It is estimated that for every male with HEMA, there are 2.7 to 5 female carriers.9 Severe hemophilia in women is extremely rare, and epidemiological data are scarce.  

Acquired HEMA results from the development of antibodies against factor VIII and is very rare, with an incidence of 1 case per 1 million per year.3 

Hemophilia B (Christmas Disease) – Factor IX Deficiency

Hemophilia B (HEMB) is an X-linked recessive disorder of coagulation that comprises approximately 20% of cases of hemophilia and has a prevalence of 1 in 15,00 to 1 in 30,000, or 5 per 100,000 male live births.7,10 HEMB is caused by a genetic mutation to the F9 gene; such mutations are more numerous than F8 gene mutations. However, a higher prevalence of less severe mutations of F9 may explain why HEMB is less prevalent than HEMA. Approximately one-third to one-half of affected persons have severe disease.10 

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Generalizing this information to the worldwide population, approximately 1.1 million males have HEMB; however, many mild forms of the disease may go undetected, and approximately 41,800 cases are severe. 

Hemophilia C – Factor XI Deficiency

Hemophilia C (HEMC) is a rare autosomal-dominant bleeding disorder that affects both women and men.11 It accounts for a quarter of rare bleeding disorders (bleeding disorders not explained by vWD, HEMA, or HEMB) and has a prevalence of 1 in 1 million in the global population; however, it is likely that this number is underestimated.11,12

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Disease is severe in 20% of patients with HEMC. The prevalence of HEMC in Ashkenazi Jews is much higher, at 1 in 450 individuals.11  

References

1. CDC. Data & Statistics | Hemophilia | NCBDDD | CDC. Centers for Disease Control and Prevention. Published September 14, 2020. Accessed August 10, 2021. https://www.cdc.gov/ncbddd/hemophilia/data.html

2. CDC. What is Hemophilia? | CDC. Centers for Disease Control and Prevention. Published May 12, 2020. Accessed August 10, 2021. https://www.cdc.gov/ncbddd/hemophilia/facts.html

3. Hemophilia A: Practice Essentials, Background, Pathophysiology. Published online July 19, 2021. Accessed August 10, 2021. https://emedicine.medscape.com/article/779322-overview#a5

4. Shetty S. Haemophilia – diagnosis and management challenges. Mol Cytogenet. 2014;7(Suppl 1):I44. doi:10.1186/1755-8166-7-S1-I44

5. Stonebraker JS, Bolton-Maggs PHB, Brooker M, et al. The World Federation of Hemophilia Annual Global Survey 1999-2018. Haemophilia. 2020;26(4):591-600. doi:10.1111/hae.14012

6. Prevalence of Hemophilia Worldwide Is Triple That of Previous Estimates, New Study Says. AJMC. Accessed August 10, 2021. https://www.ajmc.com/view/prevalence-of-hemophilia-worldwide-is-triple-that-of-previous-estimates-new-study-says-

7. Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica. 2019;104(9):1702-1709. doi:10.3324/haematol.2019.221093

8. Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia A. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed August 10, 2021. http://www.ncbi.nlm.nih.gov/books/NBK1404/

9. Hermans C, Kulkarni R. Women with bleeding disorders. Haemophilia. 2018;24(S6):29-36. doi:10.1111/hae.13502

10. Iorio A, Stonebraker JS, Chambost H, et al. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 2019;171(8):540-546. doi:10.7326/M19-1208

11. Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. Hematol Am Soc Hematol Educ Program. 2016;2016(1):663-669. doi:10.1182/asheducation-2016.1.663

12. Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. 2014;167(3):304-326. doi:10.1111/bjh.13058

Reviewed by Harshi Dhingra, MD, on 8/11/2021.

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