queen Hemophilia A

Queen Victoria reigned as British sovereign from 1837 until 1901. Britian enjoyed prosperity and growth under her monarchy, but her genetic legacy was another story.

Hemophilia A, a bleeding disorder caused by a mutation in the factor VIII gene, is the most common coagulation factor deficiency. It is transmitted in an X-linked recessive fashion in most cases, but in 30% of patients, the mutation is spontaneous. Patients have a decrease in – or total absence of – factor VIII, one of the factors in the intrinsic pathway of coagulation. Because of their diminished ability to make fibrin, patients with hemophilia A are prone to bleeding episodes, which typically present as recurrent, painful bleeding into joints, prolonged bleeding after dental extraction, or severe bleeding episodes following a traumatic injury.

Diagnosis of hemophilia A is made using laboratory testing. The INR, TT, platelet count and bleeding time are normal (because none of these tests measures the intrinsic pathway of coagulation!).  The PTT, which does measure this pathway, is prolonged. Also, when you do a mixing study (in which you mix the patient’s sample with blood from a “normal” patient who has factor VIII, and run the PTT again), the PTT will “correct”. This is because in the mixing study, you’ve added enough factor VIII (from the “normal” patient’s blood) to make the PTT run normally. You can also order quantitative and qualitative factor VIII assays, as well as DNA testing.

Patients with mild hemophilia are treated with DDAVP (desmopressin), which raises the serum level of factor VIII. Patients with severe hemophilia (who can’t make factor VIII at all) must receive factor VIII replacement.

Back to Queen Victoria. There was no known history of a bleeding tendency in any of Queen Victoria’s ancestors; she is thought to be one of the smaller number of patients who develop a spontaneous mutation. Interestingly, DNA evidence from her descendants indicates that the mutation was in the factor IX gene – which is the gene involved in hemophilia B (a less common type of hemophilia with an inheritance pattern and clinical symptoms virtually identical to hemophilia A).

Because the factor VIII gene is on the X chromosome, women with one mutated factor VIII gene still have another, normal factor VIII gene on their other X chromosome. They carry the disease, but do not manifest the symptoms. Men who inherit the mutated factor VIII gene, however, do not have another normal X chromosome, so they have full-blown hemophilia.

Queen Victoria, therefore, had no symptoms of hemophilia. However, she did pass the gene on to three of her children: Alice and Beatrice, who were carriers, and Leopold, who died of the disease at 31 years as a result of a cerebral hemorrhage following a fall. Through marriages into other royal families, the disease spread to many of the monarchies in Europe, often with disastrous consequences.

One royal family, headed by Victoria’s granddaughter Alix (who was a carrier) and her husband Nicholas II (the Czar of Russia at the time), suffered a particularly tragic end. Alix’s son, Alexis, suffered from severe hemophilia. When traditional medical treatments did not work, Alix sought help from unconventional sources, most notably the Mad Monk Rasputin. Rasputin’s influence over Alix contributed to the family’s decreasing popularity and their eventual mass murder in 1917.

 

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