Haemophilia is a pair of disorders (Haemophilia A and B) in which an essential component of blood clotting is completely or partially missing. Haemophilia A is deficiency of factor VIII and haemophilia B (synonym Christmas disease) is deficiency of factor IX
It is a sex-linked disease in that the relevant chromosomal locus is on the X-chromosome. Females can be carriers of the disease but only their male offspring are affected.
Bleeding problems in association with a family history of the disease. Typically bleeding into the joints is the most serious complication leading to joint destruction and contractures.
Treatment is classically by replacement of the missing clotting factors. Until the development of recombinant factors these were derived from donated blood. This has led to a large number of people with haemophilia contracting HIV and hepatitis C before the routes of transmission of these disease were recognised. However there is emerging evidence that recombinant factor VIII is more likely to promote the formation of anti-factor VIII alloantibodies (inhibitors) due to the plasma product having epitopes protected so it is possible that the plasma product will stage a come back. However emicizumab mimics the cofactor function of factor VIII and if initial human trial results are reproduced will prove much more convenient treatment than factor VIII. These new treatments are likely to remain competitive for some time with viral vector therapy if they have excellent response rates.
Viral Vector Therapy
Haemophilia B was the first to be successfully treated with an adenovirus-associated virus (AAV) vector that expressed a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) with response and no major complications. It took another 5 years to develop a similar treatment for the commoner Haemophilia A as the viral vectors established as reasonably safe could not transfect with sufficient genetic material to carry the whole factor VIII gene. However B-domain depleted human factor VIII (AAV5-hFVIII-SQ) does work. Viral vector therapy will not be possible for many patients with contraindications such as previous exposure to close relatives of the vector virus, active hepatitis, immunosupression and that are inhibitor antibody negative.
- ↑ BIGGS R, DOUGLAS AS, MACFARLANE RG, DACIE JV, PITNEY WR, MERSKEY. Christmas disease: a condition previously mistaken for haemophilia. British medical journal. 1952 Dec 27; 2(4799):1378-82.
- ↑ Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, Manglani MV, Ross C, Young G, Seth T, Apte S, Nayak DM, Santagostino E, Mancuso ME, Sandoval Gonzalez AC, Mahlangu JN, Bonanad Boix S, Cerqueira M, Ewing NP, Male C, Owaidah T, Soto Arellano V, Kobrinsky NL, Majumdar S, Perez Garrido R, Sachdeva A, Simpson M, Thomas M, Zanon E, Antmen B, Kavakli K, Manco-Johnson MJ, Martinez M, Marzouka E, Mazzucconi MG, Neme D, Palomo Bravo A, Paredes Aguilera R, Prezotti A, Schmitt K, Wicklund BM, Zulfikar B, Rosendaal FR. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. The New England journal of medicine. 2016 May 26; 374(21):2054-64.(Link to article – subscription may be required.)
- ↑ Shima M, Hanabusa H, Taki M, Matsushita T, Sato T, Fukutake K, Fukazawa N, Yoneyama K, Yoshida H, Nogami K. Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. The New England journal of medicine. 2016 May 26; 374(21):2044-53.(Link to article – subscription may be required.)
- ↑ Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011. DOI: 10.1056/NEJMoa1108046
- ↑ Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. The New England journal of medicine. 2017 Dec; 377(26):2519-2530.(Print-Electronic) (Link to article – subscription may be required.)
- ↑ van den Berg HM. A Cure for Hemophilia within Reach. The New England journal of medicine. 2017 Dec; 377(26):2592-2593.(Print-Electronic) (Link to article – subscription may be required.)