Haemophilia

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.

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 related von Willebrand disease (vWD) is much milder than any of the three haemophilias; only von Willebrand disease type 3 comes close in severity to the haemophilias. vWD is due to mutations in the coagulation protein von Willebrand factor. It is the most common coagulation disorder.

Genetics

Haemophilia A and B are inherited in an X-linked recessive pattern. It is caused by a mutation 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 considered to be types of haemophilia because they are passed on through autosomes rather than through the X chromosome.

Women have two X-chromosomes, whereas men 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 will not be affected by it, as the equivalent allele on her other chromosome would express itself to produce the necessary clotting factors. However the Y-chromosome in men has no gene for factors VIII or IX. If the gene responsible for blood clotting on a man'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 man receives his single X-chromosome from his mother, the son of a healthy woman silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease. In contrast, for a woman 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 men than women. However, haemophiliac daughters are more common than they once were, as improved treatment for haemophilia means that more men survive to adulthood and become parents. Adult women with haemophilia menstruate periodically, so they must take clotting factor to survive.

As with all genetic disorders, it is of course also possible for a person to acquire it fresh (de novo), rather than inheriting it, because of a new mutation in one of his or her parents' gametes. Spontaneous mutations account for about 1/5 of all hemophilia A and 1/3 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.

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.

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 and Russia. For this reason it was once popularly called "the royal disease." No other royal families inherited the illness.

The diseases were passed on to:

• Princess Alice, who passed it onto:
  • Irene, who passed it onto two of her three sons: Waldemar and Henry
  • Friedrich
  • Alexandra, who passed onto her only son, Alexei. Alexei's hemophilia was a major factor leading to the collapse of Imperial Russia during the Russian Revolution of 1917.
  • 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.
• Prince Leopold, who passed it onto Alice, who in turn passed it onto one of her two sons, Rupert.
• Princess Beatrice, who passed it onto two of her four children:
  • Victoria Eugenie, who passed it onto Alfonso (Prince of the Asturias) and Infante Gonzalo.
  • Leopold