Haemophilia B

Other names: Hemophilia B
This condition is inherited in an X-linked recessive manner.
Specialty| Haematology
Symptoms| Easy bruising[1]
Causes| Factor IX deficiency[1]
Diagnostic method| Bleeding scores, Coagulation factor assays[2]
Treatment| Factor IX concentrate[1]

Haemophilia B, also spelled Hemophilia B is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII deficiency (haemophilia A).[3]

Haemophilia B was first recognized as a distinct disease entity in 1952.[4] It is also known by the eponym Christmas disease,[1] named after Stephen Christmas, the first patient described with haemophilia B. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.[4][5]

## Contents

* 1 Signs and symptoms
* 1.1 Complications
* 2 Genetics
* 3 Pathophysiology
* 4 Diagnosis
* 4.1 Differential diagnosis
* 5 Treatment
* 5.1 Dental considerations
* 6 History
* 7 Society
* 8 See also
* 9 References
* 10 Further reading
* 11 External links

## Signs and symptoms[edit | edit source]

Symptoms include easy bruising, urinary tract bleeding (haematuria), nosebleeds (epistaxis), and bleeding into joints (haemarthrosis).[1]

### Complications[edit | edit source]

Patients with bleeding disorders show a higher incidence of periodontal disease as well as dental caries, concerning the fear of bleeding which leads to a lack of oral hygiene and oral health care. The most prominent oral manifestation of a mild haemophilia B would be gingival bleeding during exfoliation of primary dentition, or prolonged bleeding after an invasive procedure/tooth extraction; In severe haemophilia, there may be spontaneous bleeding from the oral tissues (e.g. soft palate, tongue, buccal mucosa), lips and gingiva, with ecchymoses. In rare cases, haemarthrosis (bleeding into joint space) of the temporomandibular joint (TMJ) may be observed.[6]

Patients with haemophilia will experience many episodes of oral bleeding over their lifetime. Average 29.1 bleeding events per year are serious enough to require factor replacement in F VIII-deficient patients which 9% involved oral structures. Children with severe haemophilia have significant lower prevalence of dental caries and lower plaque scores compared with matched, healthy controls.[7]

## Genetics[edit | edit source]

X chromosome

The factor IX gene is located on the X chromosome (Xq27.1-q27.2). It is an X-linked recessive trait, which explains why males are affected in greater numbers.[8][9]

In 1990, George Brownlee and Merlin Crossley showed that two sets of genetic mutations were preventing two key proteins from attaching to the DNA of people with a rare and unusual form of haemophilia B – haemophilia B Leyden – where sufferers experience episodes of excessive bleeding in childhood but have few bleeding problems after puberty.[9] This lack of protein attachment to the DNA was thereby turning off the gene that produces clotting factor IX, which prevents excessive bleeding.[9]

## Pathophysiology[edit | edit source]

Coagulation (FIX is on left)

Factor IX deficiency leads to an increased propensity for haemorrhage, which can be either spontaneously or in response to mild trauma.[10]

Factor IX deficiency can cause interference of the coagulation cascade, thereby causing spontaneous haemorrhage when there is trauma. Factor IX when activated activates factor X which helps fibrinogen to fibrin conversion.[10]

Factor IX becomes active eventually in coagulation by cofactor factor VIII (specifically IXa). Platelets provide a binding site for both cofactors. This complex (in the coagulation pathway) will eventually activate factor X.[11]

## Diagnosis[edit | edit source]

Accumulation of a large amount of blood in the trachea and bronchi.

The diagnosis for haemophilia B can be done via the following tests/methods:[2]

* Coagulation screening test
* Bleeding scores
* Coagulation factor assays

### Differential diagnosis[edit | edit source]

The differential diagnosis for this inherited condition is the following: haemophilia A, factor XI deficiency, von Willebrand disease, fibrinogen disorders and Bernard–Soulier syndrome[9]

## Treatment[edit | edit source]

Treatment is given intermittently, when there is significant bleeding. It includes intravenous infusion of factor IX and/or blood transfusions. NSAIDS should be avoided once the diagnosis is made since they can exacerbate a bleeding episode. Any surgical procedure should be done with concomitant tranexamic acid.[4][12]

### Dental considerations[edit | edit source]

Surgical treatment, including a simple dental extraction, must be planned to minimize the risk of bleeding, excessive bruising, or haematoma formation. Soft vacuum-formed splints can be used to provide local protection following a dental extraction or prolonged post-extraction bleed.[13]

## History[edit | edit source]

Factor IX

In the 1950s and 1960s, with newfound technology and gradual advances in medicine, pharmaceutical scientists found a way to take the factor IX from fresh frozen plasma (FFP) and give it to those with haemophilia B. Though they found a way to treat the disease, the FFP contained only a small amount of factor IX, requiring large amounts of FFP to treat an actual bleeding episode, which resulted in the person requiring hospitalization. By the mid-1960s scientists found a way to get a larger amount of factor IX from FFP. By the late 1960s, pharmaceutical scientists found methods to separate the factor IX from plasma, which allows for neatly packaged bottles of factor IX concentrates. With the rise of factor IX concentrates it became easier for people to get treatment at home.[14] Although these advances in medicine had a significant positive impact on the treatment of haemophilia, there were many complications that came with it. By the early 1980s, scientists discovered that the medicines they had created were transferring blood-borne viruses, such as hepatitis, and HIV, the virus that causes AIDS. With the rise of these deadly viruses, scientists had to find improved methods for screening the blood products they received from donors. In 1982, scientists made a breakthrough in medicine and were able to clone factor IX gene. With this new development it decreased the risk of the many viruses. Although the new factor was created, it wasn't available for haemophilia B patients until 1997.[citation needed]

## Society[edit | edit source]

Main article: Haemophilia in European royalty

In 2009, an analysis of genetic markers revealed that haemophilia B was the blood disease affecting many European royal families of Great Britain, Germany, Russia and Spain: so-called "Royal Disease".[15][16]

## See also[edit | edit source]

* Haemophilia C
* Haemophilia in European royalty

## References[edit | edit source]

1. ↑ 1.0 1.1 1.2 1.3 1.4 "Hemophilia B: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on 2016-07-05. Retrieved 2016-09-21.
2. ↑ 2.0 2.1 Konkle, Barbara A.; Josephson, Neil C.; Nakaya Fletcher, Shelley (1 January 1993). "Hemophilia B". GeneReviews. Archived from the original on 20 October 2019. Retrieved 7 October 2016.update 2014
3. ↑ Kliegman, Robert (2011). Nelson textbook of pediatrics (19th ed.). Philadelphia: Saunders. pp. 1700–1. ISBN 978-1-4377-0755-7.
4. ↑ 4.0 4.1 4.2 "Haemophilia B (Factor IX Deficiency) information | Patient". Patient. Archived from the original on 2016-04-08. Retrieved 2016-04-21.
5. ↑ Biggs R, Douglas AS, MacFarlane RG, Dacie JV, Pitney WR, Merskey C, O'Brien JR (1952). "Christmas disease: a condition previously mistaken for haemophilia". Br Med J. 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790.
6. ↑ "Hemophilia A" (PDF). College of Dental Hygienists of Ontario. September 2, 2015.
7. ↑ Glick, Michael (2015). Burket's Oral Medicine. USA: People's Medical Publishing House. pp. 473, 475, 481, 482. ISBN 978-1-60795-188-9.
8. ↑ "OMIM Entry - # 306900 - HEMOPHILIA B; HEMB". omim.org. Archived from the original on 2017-01-28. Retrieved 2016-10-07.
9. ↑ 9.0 9.1 9.2 9.3 "Hemophilia". Archived from the original on 2018-07-28. Retrieved 2021-09-28.
10. ↑ 10.0 10.1 "Hemophilia B: Practice Essentials, Background, Pathophysiology". eMedicine. Medscape. 24 August 2016. Archived from the original on 10 October 2016. Retrieved 7 October 2016.
11. ↑ "Factor IX Deficiency: Background, Pathophysiology, Epidemiology". eMedicine. Medscape. 24 August 2016. Archived from the original on 6 October 2016. Retrieved 7 October 2016.
12. ↑ Beck, Norman (2009). Diagnostic hematology. London: Springer. p. 416\. ISBN 9781848002951. Archived from the original on 14 October 2021. Retrieved 7 October 2016.
13. ↑ Andrew Brewer, Maria Elvira Correa (May 2006). "Guildelines for Dental Treatment of Patients with Inherited Bleeding Disorders" (PDF). Treatment of Hemophilia. 40: 9 – via World Federation of Hemophilia (WFH).
14. ↑ Schramm, Wolfgang (November 2014). "The history of haemophilia – a short review". Thrombosis Research. 134: S4–S9. doi:10.1016/j.thromres.2013.10.020. ISSN 1879-2472. PMID 24513149. – via ScienceDirect (Subscription may be required or content may be available in libraries.)
15. ↑ Michael Price (8 October 2009). "Case Closed: Famous Royals Suffered From Hemophilia". ScienceNOW Daily News. AAAS. Archived from the original on 20 October 2013. Retrieved 9 October 2009.
16. ↑ Evgeny I. Rogaev; et al. (8 October 2009). "Genotype Analysis Identifies the Cause of the "Royal Disease"". Science. 326 (5954): 817. Bibcode:2009Sci...326..817R. doi:10.1126/science.1180660. PMID 19815722. S2CID 206522975.subscription required

## Further reading[edit | edit source]

* Franchini, Massimo; Frattini, Francesco; Crestani, Silvia; Sissa, Cinzia; Bonfanti, Carlo (1 January 2013). "Treatment of hemophilia B: focus on recombinant factor IX". Biologics: Targets and Therapy. 7: 33–38. doi:10.2147/BTT.S31582. ISSN 1177-5475. PMC 3575125. PMID 23430394.
* Nathwani, Amit C.; Reiss, Ulreke M.; Tuddenham, Edward G.D.; Rosales, Cecilia; Chowdary, Pratima; McIntosh, Jenny; Della Peruta, Marco; Lheriteau, Elsa; Patel, Nishal; Raj, Deepak; Riddell, Anne; Pie, Jun; Rangarajan, Savita; Bevan, David; Recht, Michael; Shen, Yu-Min; Halka, Kathleen G.; Basner-Tschakarjan, Etiena; Mingozzi, Federico; High, Katherine A.; Allay, James; Kay, Mark A.; Ng, Catherine Y.C.; Zhou, Junfang; Cancio, Maria; Morton, Christopher L.; Gray, John T.; Srivastava, Deokumar; Nienhuis, Arthur W.; Davidoff, Andrew M. (20 November 2014). "Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B". New England Journal of Medicine. 371 (21): 1994–2004. doi:10.1056/NEJMoa1407309. ISSN 0028-4793. PMC 4278802. PMID 25409372.

## External links[edit | edit source]

Classification|

* ICD-10: D67
* ICD-9-CM: 286.1
* OMIM: 306900
* MeSH: D002836
* DiseasesDB: 5561

|

External resources|

* MedlinePlus: 000539
* eMedicine: emerg/240

* v
* t
* e

Disorders of bleeding and clotting

Coagulation * coagulopathy * Bleeding diathesis

Clotting|

| By cause|

* Clotting factors
* Antithrombin III deficiency
* Protein C deficiency
* Activated protein C resistance
* Protein S deficiency
* Factor V Leiden
* Prothrombin G20210A
* Platelets
* Sticky platelet syndrome
* Thrombocytosis
* Essential thrombocythaemia
* DIC
* Purpura fulminans
* Antiphospholipid syndrome

|

Clots|

* Thrombophilia
* Thrombus
* Thrombosis
* Virchow's triad
* Trousseau sign of malignancy

By site|

* Deep vein thrombosis
* Bancroft's sign
* Homans sign
* Lisker's sign
* Louvel's sign
* Lowenberg's sign
* Peabody's sign
* Pratt's sign
* Rose's sign
* Pulmonary embolism
* Renal vein thrombosis

Bleeding|

| By cause|

| Thrombocytopenia|

* Thrombocytopenic purpura: ITP
* Evans syndrome
* TM
* TTP
* Upshaw–Schulman syndrome

* Heparin-induced thrombocytopenia
* May–Hegglin anomaly

|

Platelet function|

* adhesion
* Bernard–Soulier syndrome
* aggregation
* Glanzmann's thrombasthenia
* platelet storage pool deficiency
* Hermansky–Pudlak syndrome
* Gray platelet syndrome

Clotting factor|

* Haemophilia
* A/VIII
* B/IX
* C/XI
* von Willebrand disease
* Hypoprothrombinemia/II
* Factor VII deficiency
* Factor X deficiency
* Factor XII deficiency
* Factor XIII deficiency
* Dysfibrinogenemia
* Congenital afibrinogenemia

Signs and symptoms|

* Bleeding
* Bruise
* Haematoma
* Petechia
* Purpura
* Nonthrombocytopenic purpura

By site|

* head
* Epistaxis
* Haemoptysis
* Intracranial haemorrhage
* Hyphaema
* Subconjunctival haemorrhage
* torso
* Haemothorax
* Haemopericardium
* Pulmonary haematoma
* abdomen
* Gastrointestinal bleeding
* Haemobilia
* Haemoperitoneum
* Haematocele
* Haematosalpinx
* joint
* Haemarthrosis

* v
* t
* e

X-linked disorders

X-linked recessive

Immune|

* Chronic granulomatous disease (CYBB)
* Wiskott–Aldrich syndrome
* X-linked severe combined immunodeficiency
* X-linked agammaglobulinemia
* Hyper-IgM syndrome type 1
* IPEX
* X-linked lymphoproliferative disease
* Properdin deficiency

Hematologic|

* Haemophilia A
* Haemophilia B
* X-linked sideroblastic anemia

Endocrine|

* Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy
* KAL1 Kallmann syndrome
* X-linked adrenal hypoplasia congenita

Metabolic|

* Amino acid: Ornithine transcarbamylase deficiency
* Oculocerebrorenal syndrome

* Dyslipidemia: Adrenoleukodystrophy

* Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency
* Pyruvate dehydrogenase deficiency
* Danon disease/glycogen storage disease Type IIb

* Lipid storage disorder: Fabry's disease

* Mucopolysaccharidosis: Hunter syndrome

* Purine–pyrimidine metabolism: Lesch–Nyhan syndrome

* Mineral: Menkes disease/Occipital horn syndrome

Nervous system|

* X-linked intellectual disability: Coffin–Lowry syndrome
* MASA syndrome
* Alpha-thalassemia mental retardation syndrome
* Siderius X-linked mental retardation syndrome

* Eye disorders: Color blindness (red and green, but not blue)
* Ocular albinism (1)
* Norrie disease
* Choroideremia

* Other: Charcot–Marie–Tooth disease (CMTX2-3)
* Pelizaeus–Merzbacher disease
* SMAX2

Skin and related tissue|

* Dyskeratosis congenita
* Hypohidrotic ectodermal dysplasia (EDA)
* X-linked ichthyosis
* X-linked endothelial corneal dystrophy

Neuromuscular|

* Becker's muscular dystrophy/Duchenne
* Centronuclear myopathy (MTM1)
* Conradi–Hünermann syndrome
* Emery–Dreifuss muscular dystrophy 1

Urologic|

* Alport syndrome
* Dent's disease
* X-linked nephrogenic diabetes insipidus

Bone/tooth|

* AMELX Amelogenesis imperfecta

No primary system|

* Barth syndrome
* McLeod syndrome
* Smith–Fineman–Myers syndrome
* Simpson–Golabi–Behmel syndrome
* Mohr–Tranebjærg syndrome
* Nasodigitoacoustic syndrome

X-linked dominant

* X-linked hypophosphatemia
* Focal dermal hypoplasia
* Fragile X syndrome
* Aicardi syndrome
* Incontinentia pigmenti
* Rett syndrome
* CHILD syndrome
* Lujan–Fryns syndrome
* Orofaciodigital syndrome 1
* Craniofrontonasal dysplasia

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