Clinical
Presentation

Haemophilia B (HB; 2017 ICD-10-CM: D67) is an inherited bleeding disorder caused by the lack of coagulation factor (F) IX. The F9 gene encodes for FIX, which mediates the enzymatic conversion of FX to the activated form FXa. As a result of this congenital deficiency, patients with HB have a defective clotting process and an increased tendency to bleed spontaneously and in response to traumatic injury. Replacement of the missing clotting factor is the standard treatment to prevent and control bleeding.

HB accounts for approximately 10% of all bleeding disorders and has a prevalence of approximately 3 in 100,000 males in high-income countries.^1,2 The reported prevalence of HB differs depending on the economic status of a country.³ Globally, approximately 70% of patients with haemophilia are misdiagnosed and untreated; the majority of these patients live in developing countries.³

The clinical manifestations of HB are similar to those of haemophilia A, and include prolonged and repeated bleeding episodes. Unless properly treated, haemorrhage into joints and muscles causes painful, progressive arthropathy and muscular atrophy,⁴ and can result in severe disability with vocational and psychological sequelae. While joints and muscles are the most common spontaneous bleeding sites,⁵ central nervous system bleeds are the leading causes of death in patients with haemophilia, who are not infected with human immunodeficiency virus (HIV), accounting for approximately one-third of all deaths.⁶

HB is classified as 'mild', 'moderate' or 'severe' according to the residual activity of FIX.⁵ Patients with mild HB have severe bleeding during major trauma or surgery, but rarely have spontaneous bleeding. Patients with moderate HB experience occasional bleeding and prolonged bleeding with minor trauma or surgery. Severe HB is characterised by spontaneous bleeding into joints or muscles, predominantly in the absence of identifiable haemostatic challenge. Residual FIX activity is generally expressed as a percentage of ‘normal’, which is variable between individuals and may range from 50–150%.⁷

Classification of haemophilia B according to clotting factor levels⁵

HB is characterised by different underlying molecular defects affecting the F9 gene. Congenital haemophilia is inherited in an X-linked recessive manner. In approximately one-third of patients, however, there is no family history and haemophilia results from spontaneous mutation.⁵ This balance between gene loss caused by low reproductive fitness and spontaneous mutation has sustained haemophilia within the general population.

A large number of gene mutations are known to affect clotting factor expression, including missense or nonsense mutations, defects in mRNA splicing, insertions and deletions.⁸ The CDC Hemophilia B Mutation Project (CHBMP) F9 Mutation List provides an overview of more than 1000 unique mutations identified to date for the F9 gene encoding FIX.⁹

1. Stonebraker JS, Bolton-Maggs PH, Michael Soucie J, Walker I, Brooker M. A study of variations in the reported haemophilia B prevalence around the world. Haemophilia 2012;18:e91-4.
2. World Federaton of Hemophilia (WFH): Report on the Annual Global Survey 2015; 2016.
3. O'Mahony B, Black C. Expanding hemophilia care in developing countries. Semin Thromb Hemost 2005;31:561-8.
4. Luck JV, Jr., Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg 2004;12:234-45.
5. World Federation of Hemophilia (WFH): Guidelines for the Management of Hemophilia; 2012.
6. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110:815-25.
7. Moser KA, Adcock Funk DM. Chromogenic factor VIII activity assay. Am J Hematol 2014;89:781-4.
8. Goodeve AC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost 2015;13:1184-95.
9. Li T, Miller CH, Payne AB, Craig Hooper W. The CDC Hemophilia B mutation project mutation list: a new online resource. Mol Genet Genomic Med 2013;1:238-45.