Hemophilia medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Medical Therapy
Blood Clotting factor
Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII Troy.
If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be overcome with recombinant human factor VII (NovoSeven®), which is registered for this indication in many countries.
- The two main types of clotting factor concentrates available are:
- Plasma-Derived Factor ConcentratesPlasma is the liquid part of blood. It is pale yellow or straw colored and contains proteins such as antibodies, albumin and clotting factors. Several factor concentrates that are made from human plasma proteins are available. All blood and parts of blood, such as plasma, are routinely tested for the viruses. The clotting proteins are separated from other parts of the plasma, purified, and made into a freeze-dried product. This product is tested and treated to kill any potential viruses before it is packaged for use.
- Recombinant Factor ConcentratesUntil 1992, all factor replacement products were made from human plasma. In 1992, the U.S. Food and Drug Administration (FDA) approved recombinant factor VIII (8) concentrate, which does not come from human plasma. The concentrate is genetically engineered using DNA technology. Commercially prepared factor concentrates are treated to remove or inactivate bloodborne viruses. In addition, recombinant factors VIII (8) and IX (9) are available that do not contain any plasma or albumin and, therefore, cannot transmit any bloodborne viruses.
The products can be used as needed when a person is bleeding or they can be used on a regular basis to prevent bleeds from occurring. Today, people with hemophilia and their families can learn how to give their own clotting factor at home. Giving factor at home means that bleeds can be treated quicker, resulting in less serious bleeding and fewer side effects.
- Other treatment products:
- DDAVP® (Desmopressin Acetate)DDAVP® is a chemical that is similar to a hormone that occurs naturally in the body. It releases factor VIII (8) from where it is stored in the body tissues. For people with mild, and some cases of moderate hemophilia, this can work to increase their own factor VIII (8) levels so that they do not have to use clotting factor. This medicine can be given through a vein (DDAVP®) or through nasal spray (Stimate®).
- Amicar® (Epsilon Amino Caproic Acid)Amicar® is a chemical that can be given in a vein or by mouth (as a pill or a liquid). It prevents clots from breaking down, resulting in a firmer clot. It is often used for bleeding in the mouth or after a tooth has been removed because it blocks an enzyme in the saliva that breaks down clots.
- CryoprecipitateCryoprecipitate is a substance that comes from thawing fresh frozen plasma. It is rich in factor VIII (8) and was commonly used to control serious bleeding in the past. However, because there is no method to kill viruses, such as HIV and hepatitis, in cryoprecipitate it is no longer used as the current standard of treatment in the U.S. It is, however, still used in most developing countries.
In western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with Haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. [1] Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the New England Journal of Medicine demands more clinical studies addressing the cost-effectiveness of prophylactic treatment. [2]
As a direct result of the contamination of the blood supply in the late 1970s and early/mid 1980s with viruses such as Hepatitis and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurize) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay Tribunal in Ireland investigated, among other things, the slow adoption of the new methods.
Since 1993 (Dr. Mary Nugent), recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have become available and are widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.
It was claimed that Rasputin was successful at treating the Tsarevich Alexei of Russia's haemophilia: however, to this day it is unclear how he accomplished this.
Gene Therapy
Researchers are trying to find ways to correct the faulty genes that cause hemophilia. Gene therapy hasn't yet developed to the point that it's an accepted treatment for hemophilia. However, researchers continue to test gene therapy in clinical trials.For more information, go to the "Clinical Trials" section of this article. On 10 December 2011, a team of British and American investigators reported the successful treatment of haemophilia B using gene therapy. The investigators inserted the F9gene into an adeno-associated virus-8 vector, which has a propensity for the liver, where factor 9 is produced, and remains outside the chromosomes so as not to disrupt other genes. The transduced virus was infused intravenously. To prevent rejection, the people were primed with steroids to suppress their immune response.[18] In October 2013, theRoyal Free London NHS Foundation Trust in London reported that after treating six people with haemophilia in early 2011 with the genetically modified adeno-associated virus, over two years later all were still producing blood plasma clotting factor.
References
- ↑ Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med. 2007 Aug 9;357(6):535-44. PMID 17687129
- ↑ Roosendaal G, Lafeber F. Prophylactic treatment for prevention of joint disease in haemophilia--cost versus benefit. N Engl J Med. 2007 Aug 9;357(6):603-5. PMID 17687136