Hemophilia

Table of Contents

Haemophilia or hemophilia is the name of any of several hereditary genetic illnesses that impair the body's ability to control bleeding. Genetic deficiencies (or, very rarely, an autoimmune disorder) cause lowered plasma clotting factor activity so as to compromise blood-clotting; when a blood vessel is injured, a scab will not form and the vessel can continue to bleed excessively for a very long period of time. The bleeding can be external, if the skin is broken by a scrape, cut or abrasion, or it can be internal, into muscles, joints or hollow organs. It might therefore present visibly as skin bruises, or subtly as melena, hematuria, or bleeding in the brain.

Forms

• Haemophilia A - factor VIII deficiency, "classic haemophilia" (X-linked)
• Haemophilia B - factor IX deficiency, "Christmas disease" (X-linked)
• Haemophilia C - factor XI deficiency (Ashkenazi Jews, autosomal recessive)

The unrelated type 1 and type 2 von Willebrand disease (vWD) are milder than any of the three haemophilias; only type 3 von Willebrand disease expresses a severity similar to the haemophilias. vWD is caused by mutations in the coagulation protein von Willebrand factor. It is the most common coagulation disorder present in 1% of the population.

Genetics

Haemophilia A and B are inherited in an X-linked recessive pattern. They are caused by mutations affecting the genes encoding one of the clotting factors. The genes for both Haemophilia A and Haemophilia B are located on the X chromosome; other clotting factor deficiencies exist, but are not X linked resulting in different clinical symptoms. Females possess two X-chromosomes, whereas males have one X and one Y chromosome. Since the mutations causing the disease are recessive, a woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors. However the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome is deficient there is no equivalent on the Y-chromosome, so the deficient gene is not masked by the dominant allele and he will develop the illness. Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence haemophilia is far more common among males than females. However it is possible for female carriers to become mild Haemophiliacs due to lyonisation of the X chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Haemophilia is particularly dangerous in adult females because of the recurring bloodflows involved in menstruation. As with all genetic disorders, it is of course also possible for a human to acquire it spontaneously (de novo), rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 1/3 of all hemophilia A and 1/5 of all hemophilia B cases. Genetic testing and genetic counseling is recommended for families with hemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.

Probability

If a female gives birth to a haemophiliac child, she is possibly a carrier for the disease. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier, specifically It is estimated that about 0.006% percent of the United States population suffers from Haemophilia.

Treatment

Though there is no cure for haemophilia, it can be controlled with regular injections 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. The increasing availability of human recombinant replacement blood products means the incidence of inhibitor formation is decreasing. 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. 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. As a direct result of the contamination of the blood supply in the late 1970's and early 1980's with virologic agents such as HIV and Hepatitis, 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. More recently, recombinant factor products (which are typically cultured in Chinese hamster ovaries and involve little, if any contact with 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 also 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. Haemophilia figured prominently in the history of European royalty. Queen Victoria passed the mutation to her son Leopold and, through several of her daughters, to various royals across the continent, including the royal families of Spain, Germany and Russia. For this reason it was once popularly called "the royal disease".

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