Hemophilia

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 and result 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

where x is the number of unaffected sons. (More complicated formulae could be used if healthy grandchildren and other relatives were to be taken into consideration.)

Table

Ignoring the possibility of de novo mutations, the following table shows how people's chances of inheriting haemophilia depend on their sex and their parents' haemophilia-gene status.

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, requiring the amount of the factor has to be increased or non-human replacement products to 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.

History

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".

Victoria appears to have been a de novo case, as her mother's family is not known to have had the disease, and it is improbable that Victoria's mother had had a hemophiliac-suffering man siring her child: her husband, the Duke of Kent, was not hemophiliac, and the probability of the Duchess to have had a lover suffering from hemophilia is minuscule (in those centuries male hemophiliacs tended not to sire children, as they died usually early).

The disease was passed on to:

• Princess Alice, who passed it onto at least three of her children:
  • Princess Irene, who passed it onto two of her three sons: Waldemar and Henry
  • Prince Friedrich
  • Princess Alix, who passed onto her only son, Alexei. Alexei's hemophilia was one of the factors contributing to the collapse of Imperial Russia during the Russian Revolution of 1917. One of Alexandra's daughters, Maria is thought to have been a symptomatic carrier, due to the fact that she haemorrhaged during a tonsilectomy.
  • It does not appear that Princess Alice's oldest daughter Victoria, maternal grandmother to Prince Philip, inherited the mutation, or if she did, that she passed it on to her descendants. One of Alice's daughters, Princess Elizabeth, remained childless, while another, Princess May, died in childhood, so it is unknown if either would have been a carrier.
• Prince Leopold, a sufferer (one of the rare male hemophiliacs of such early era who himself had children), who passed it onto his daughter, Alice, who in turn passed it onto her older son, Rupert. The younger son, Maurice, died in infancy, so it is not known if he was a sufferer.
• Princess Beatrice, who passed it on to at least two, if not three of her four children:
  • Princess Victoria Eugenie, who passed it onto Infante Alfonso, Prince of the Asturias) and Infante Gonzalo. Her two daughters, Infanta Beatrice and Infanta Maria Cristina, may be carriers, but none of their descendants have had the disease as of 2004.
  • Prince Leopold
  • Prince Maurice (Several sources have mentioned that Prince Maurice was a haemophiliac, while others dispute this. It is unknown whether he had the disease.)

Those who suffered from or carried haemophilia are enclosed in a box.