Haemophilia B

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Haemophilia B
Other namesHemophilia B, Christmas disease
X-linked recessive (2).svg
This condition is inherited in an X-linked recessive manner.
Specialty Haematology
Symptoms Easy bruising [1]
CausesFactor IX deficiency [1]
Diagnostic method Bleeding scores, Coagulation factor assays [2]
TreatmentFactor 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]

Contents

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]

Most individuals who have Hemophilia B and experience symptoms are men. [6] The prevalence of Hemophilia B in the population is about one in 40,000; Hemophilia B represents about 15% of patients with hemophilia. [6] Many women carriers of the disease have no symptoms. [6] However, an estimated 10-25% of women carriers have mild symptoms; in rare cases, women may have moderate or severe symptoms. [6]

Signs and symptoms

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

Complications

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. [7]

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. [8]

Genetics

X chromosome Human male karyotpe high resolution - X chromosome cropped.png
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. [9] [10]

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 patients experience episodes of excessive bleeding in childhood but have few bleeding problems after puberty. [10]

This lack of protein attachment to the DNA was thereby turning off the gene that produces clotting factor IX, which prevents excessive bleeding. [10]

Pathophysiology

Coagulation (FIX is on left) Coagulation full.svg
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. [11]

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. [11]

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

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

Differential diagnosis

The differential diagnosis for this inherited condition is the following: haemophilia A, factor XI deficiency, von Willebrand disease, fibrinogen disorders and Bernard–Soulier syndrome [10]

Treatment

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]

Etranacogene dezaparvovec (Hemgenix) was approved for medical use in the United States in November 2022. [6] It is the first gene therapy approved by the US Food and Drug Administration (FDA) to treat Hemophilia B. [6]

Dental considerations

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]

Research

In July 2022 results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses. [14] [15] [16]

History

Factor IX PDB 1pfx EBI.jpg
Factor IX

Stephen Christmas (12 February 1947 – 20 December 1993) was the first patient described to have Christmas disease (or Haemophilia B) in 1952 by a group of British doctors. Christmas was born to a British family in London. He was the son of film and television actor Eric Christmas. [17] He emigrated to Toronto, Ontario, Canada, with his family, and was there at the age of two years that hemophilia was diagnosed at the Hospital for Sick Children. The family returned to London in 1952 to visit their relatives, and during the trip Stephen was admitted to hospital. A sample of his blood was sent to the Oxford Haemophilia Centre in Oxford, where Rosemary Biggs and Robert Gwyn Macfarlane discovered that he was not deficient in Factor VIII, which is normally decreased in classic hemophilia, but a different protein, which received the name Christmas factor in his honour (and later Factor IX). [17] Stephen was dependent on blood and plasma transfusions, and was infected with HIV in the period during which blood was not routinely screened for this virus. He became an active worker for the Canadian Hemophilia Society and campaigned for transfusion safety ever since getting infected, but developed AIDS and died from it in 1993. [17]

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. [18] 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 was not available for haemophilia B patients until 1997.[ citation needed ]

Society and culture

In 2009, an analysis of genetic markers revealed that haemophilia B was the blood disease affecting many European royal families of the United Kingdom, Germany, Russia and Spain: so-called "Royal Disease". [19] [20]

See also

Related Research Articles

<span class="mw-page-title-main">Haemophilia</span> Genetic disease involving blood clotting

Haemophilia, or hemophilia, is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or an altered level of consciousness.

<span class="mw-page-title-main">Haemophilia A</span> Medical condition

Haemophilia A is a blood clotting disorder caused by a genetic deficiency in clotting factor VIII, thereby resulting in significant susceptibility to bleeding, both internally and externally. This condition occurs almost exclusively in males born to carrier mothers due to X-linked recessive inheritance. Nevertheless, rare isolated cases do emerge from de novo (spontaneous) mutations.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

von Willebrand disease Medical condition

Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition.

<span class="mw-page-title-main">Haemophilia C</span> Medical condition

Haemophilia C (also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome) is a mild form of haemophilia affecting both sexes, due to factor XI deficiency. It predominantly occurs in Ashkenazi Jews. It is the fourth most common coagulation disorder after von Willebrand's disease and haemophilia A and B. In the United States, it is thought to affect 1 in 100,000 of the adult population, making it 10% as common as haemophilia A.

<span class="mw-page-title-main">Bleeding diathesis</span> High tendency to bleed due to a blood clotting disorder

In medicine (hematology), bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability, in turn caused by a coagulopathy. Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin, such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation.

<span class="mw-page-title-main">Factor VII</span> Mammalian protein found in humans

Coagulation factor VII is a protein involved in coagulation and, in humans, is encoded by gene F7. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, it is converted to factor VIIa, which in turn activates factor IX and factor X.

<span class="mw-page-title-main">Factor IX</span> Protein involved in coagulation

Factor IX, also known as Christmas factor, is one of the serine proteases involved in coagulation; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B.

<span class="mw-page-title-main">Coagulopathy</span> Condition involving impaired blood clotting ability

Coagulopathy is a condition in which the blood's ability to coagulate is impaired. This condition can cause a tendency toward prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.

<span class="mw-page-title-main">Fresh frozen plasma</span> Liquid portion of whole blood

Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors or low levels of other blood proteins. It may also be used as the replacement fluid in plasma exchange. Using ABO compatible plasma, while not required, may be recommended. Use as a volume expander is not recommended. It is administered by slow injection into a vein.

Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding.

<span class="mw-page-title-main">Hypoprothrombinemia</span> Medical condition

Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.

<span class="mw-page-title-main">Factor X deficiency</span> Medical condition

Factor X deficiency is a bleeding disorder characterized by a lack in the production of factor X (FX), an enzyme protein that causes blood to clot in the coagulation cascade. Produced in the liver FX when activated cleaves prothrombin to generate thrombin in the intrinsic pathway of coagulation. This process is vitamin K dependent and enhanced by activated factor V.

<span class="mw-page-title-main">Factor VII deficiency</span> Medical condition

Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor in the extrinsic pathway.

Prothrombin complex concentrate (PCC), also known as factor IX complex, sold under the brand name Kcentra among others, is a combination medication made up of blood clotting factors II, IX, and X(3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein. Another product, activated prothrombin complex concentrate or FEIBA, may be used for acquired hemophilia.

<span class="mw-page-title-main">Factor VIII (medication)</span> Pharmaceutical drug

Factor VIII is a medication used to treat and prevent bleeding in people with hemophilia A and other causes of low factor VIII. Certain preparations may also be used in those with von Willebrand's disease. It is given by slow injection into a vein.

Recombinant factor VIIa (rfVIIa) is a form of blood factor VII that has been manufactured via recombinant technology. It is administered via an injection into a vein. It is used to treat bleeding episodes in people who have acquired haemophilia, among other indications. There are several disimilar forms, and biosimilars for each. All forms are activated.

<span class="mw-page-title-main">Jeanne Lusher</span> American physician

Jeanne Marie Lusher, M.D. was an American physician, pediatric hematologist/oncologist, and a researcher in the field of bleeding disorders of childhood, and has served as the director of Hemostasis Program at the Children's Hospital of Michigan until her retirement on June 28, 2013.

Acquired haemophilia A (AHA) is a rare but potentially life-threatening bleeding disorder characterized by autoantibodies directed against coagulation factor VIII. These autoantibodies constitute the most common spontaneous inhibitor to any coagulation factor and may induce spontaneous bleeding in patients with no previous history of a bleeding disorder.

Etranacogene dezaparvovec, sold under the brand name Hemgenix is a gene therapy used for the treatment of hemophilia B. Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy which consists of a viral vector carrying a gene for clotting Factor IX. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Hemophilia B is a genetic bleeding disorder resulting from missing or insufficient levels of blood clotting Factor IX, a protein needed to produce blood clots to stop bleeding.

References

  1. 1 2 3 4 5 MedlinePlus Encyclopedia : Hemophilia B
  2. 1 2 Konkle, Barbara A.; Nakaya Fletcher, Shelley (1993). "Hemophilia B". GeneReviews®. University of Washington, Seattle. PMID   20301668.
  3. ↑ Kliegman, Robert (2011). Nelson textbook of pediatrics (19th ed.). Philadelphia: Saunders. pp. 1700–1. ISBN   978-1-4377-0755-7.
  4. 1 2 3 "Haemophilia B (Factor IX Deficiency) information | Patient". Patient. 3 July 2014. Archived from the original on 2024-02-26. Retrieved 2016-04-21.
  5. ↑ Biggs, R.; Douglas, A. S.; Macfarlane, R. G.; Dacie, J. V.; Pitney, W. R.; Merskey, C.; O'Brien, J. R. (27 December 1952). "Christmas Disease". BMJ. 2 (4799): 1378–1382. doi:10.1136/bmj.2.4799.1378. PMC   2022306 . PMID   12997790.
  6. 1 2 3 4 5 6 "FDA Approves First Gene Therapy to Treat Adults with Hemophilia B". U.S. Food and Drug Administration (FDA). 22 November 2022. Retrieved 22 November 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. ↑ "Hemophilia A". College of Dental Hygienists of Ontario.
  8. ↑ Glick, Michael (2015). Burket's Oral Medicine (12th ed.). PMPH USA. pp. 473, 475, 481, 482. ISBN   978-1-60795-188-9.
  9. ↑ "OMIM Entry - # 306900 - HEMOPHILIA B; HEMB". omim.org. Retrieved 2016-10-07.
  10. 1 2 3 4 "Hemophilia".
  11. 1 2 3 Hemophilia B (Factor IX Deficiency) at eMedicine
  12. ↑ Beck, Norman (2009). "Transfusion-Related Problems". Diagnostic Hematology. pp. 407–423. doi:10.1007/978-1-84800-295-1_19. ISBN   978-1-84800-282-1.
  13. ↑ Brewer, Andrew; Correa, Maria Elvira (May 2006). Guildelines for Dental Treatment of Patients with Inherited Bleeding Disorders (PDF). Treatment of Hemophilia. Vol. 40. World Federation of Hemophilia. p. 9.
  14. ↑ Chowdary, Pratima; Shapiro, Susan; Makris, Mike; Evans, Gillian; Boyce, Sara; Talks, Kate; Dolan, Gerard; Reiss, Ulrike; Phillips, Mark; Riddell, Anne; Peralta, Maria R.; Quaye, Michelle; Patch, David W.; Tuddenham, Edward; Dane, Allison; Watissée, Marie; Long, Alison; Nathwani, Amit (21 July 2022). "Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B". New England Journal of Medicine. 387 (3): 237–247. doi: 10.1056/NEJMoa2119913 . PMID   35857660.
  15. ↑ "Novel gene therapy could reduce bleeding risk for haemophilia patients". ScienceDaily (Press release). University College London. 20 July 2022.
  16. ↑ Gallagher, James (20 July 2022). "Transformational therapy cures haemophilia B". BBC News.
  17. 1 2 3 Giangrande, Paul L. F. (June 2003). "Six Characters in Search of An Author: The History of the Nomenclature of Coagulation Factors". British Journal of Haematology. 121 (5): 703–712. doi:10.1046/j.1365-2141.2003.04333.x. PMID   12780784.
  18. ↑ Schramm, Wolfgang (November 2014). "The history of haemophilia – a short review". Thrombosis Research. 134: S4–S9. doi:10.1016/j.thromres.2013.10.020. PMID   24513149.
  19. ↑ "Case Closed: Famous Royals Suffered From Hemophilia". ScienceAdviser. 18 October 2021. doi: 10.1126/article.31560 .
  20. ↑ Rogaev, Evgeny I.; Grigorenko, Anastasia P.; Faskhutdinova, Gulnaz; Kittler, Ellen L. W.; Moliaka, Yuri K. (6 November 2009). "Genotype Analysis Identifies the Cause of the 'Royal Disease'". Science. 326 (5954): 817. doi: 10.1126/science.1180660 . PMID   19815722.

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