Haemophilia swept through the royal families of Europe in the 19th and early 20th centuries. Mutations in blood-clotting factors and the genetic basis of the inheritance of haemophilia were unknown at that time. Moreover, effective treatments to stem uncontrolled bleeding were not available. We now know haemophilia is a recessive X chromosome-linked disease that predominantly affects males who have inherited a deficiency of blood-clotting factors VIII or IX. The royal families of Europe in the 19th and early 20th centuries would have been utterly amazed to learn about gene therapy for haemophilia and that injections of blood-clotting factors can substantially reduce bleeding episodes.
Mutations in blood-clotting factors VIII or IX cause haemophilia
Haemophilia is an inherited genetic disease resulting from mutations in the genes for blood-clotting protein factor VIII (haemophilia A) and factor IX (haemophilia B) that lead to much reduced clotting activity. Consequently, excessive bleeding occurs either spontaneously or following injury or surgery. In the most serious cases, bleeding in the joints and various organs is painful and difficult to control.
Haemophilia is an X chromosome-linked genetic disease that affects predominantly males. If the mother (XX) has one faulty X-h chromosome and one normal X-H chromosome, she will not develop the disease, but her sons (X-hY or X-HY) will have a 50% chance of receiving the faulty chromosome (X-hY) and developing the disease.
Aleksei Nikolaevich heir to the Russian throne was born with the “bleeding disease”
In 1904, Alexandra Feodorovna of Hesse, the German wife of Tsar Nicholas II, gave birth to a baby boy named Aleksei Nikolaevich. They immediately wrapped him tightly in swaddling clothes as was the custom at that time. Not long after, blood started to ooze from his navel, which petrified Alexandra as, she recognised it as a sign of the Hesse bleeding disease – now known as haemophilia.
Over the next few years, Aleksei’s family attempted to shield him from injuries that might cause life-threatening bleeds. They went out of their way to keep Aleksei’s haemophilia secret from the public. Because he was heir to the Romanov throne, he could not be seen to have any physical defects. But in 1912, Aleksei nearly died after a severe bout of bleeding which, the public heard about – and the secret was out.
Except for ice packs, there was no treatment in the early years of the 20th century, as the molecular and genetic basis of haemophilia was unknown. In desperation, Alexandra turned to her friend – the mystic ‘mad monk’ Rasputin, for companionship, solace, and guidance. She was extremely unpopular owing to the control the loathsome, promiscuous Rasputin had over her. Alexandra tried aspirin to control Aleksei’s pain which Rasputin strongly advised against. Did Rasputin know that aspirin thins the blood and prolongs bleeding episodes?
Aleksei Nikolaevich was only 14 years old when he and the rest of his family were murdered on 18 July 1918 by the Bolsheviks during the Russian Revolution. His remains were found in 2007, and DNA analysis confirmed he had been suffering from haemophilia B (Factor IX deficiency).
Haemophilia in European royal families in the 19th and early 20th centuries
In England, Queen Victoria unknowingly passed the haemophilia gene to her son Prince Leopold, who died age 30 after a minor fall. She also passed the haemophilia gene to her daughter Princess Alice, who married Count Louis IV of Hesse. Alice and Louis had two healthy daughters – Alexandra Foedorovna (Aleksei Nikolaevich’s mother) and Irene who married Prince Henry of Prussia. Irene gave birth to three sons, two of whom had haemophilia. Her youngest son, who was a haemophiliac, died age four after falling over and banging his head.
Beatrice, another of Queen Victoria’s daughters, only had one daughter – Victoria Eugenie who, married Alfonso XIII of Spain. She bore two sons with haemophilia – one died of a bleed after a car accident at the age of 31. How different the course of history might have been had so many European royal males not inherited haemophilia in the 19th and early 20th centuries!
Current treatments for haemophilia
There is no cure for haemophilia A or B, but desmopressin (DDAVP) can be used for mild to moderate haemophilia. DDAVP is slowly infused into a vein, which releases additional clotting factors VIII or IX. For moderate to severe haemophilia, the patient may be given an intravenous (IV) infusion of clotting factors from donated human blood or from genetically engineered clotting factors. Frequent IV infusions may have to be given if the bleeding is internal and persistent. If severe bleeding damages the joints, physiotherapy may help. Occasionally, surgery to insert an artificial joint may be considered, but surgery itself carries the risk of further bleeds.
Recent advances in gene therapy for haemophilia
Gene therapy for haemophilia A, called Roctavian, was approved by the American Food and Drug Administration (FDA) in 2022. The gene for factor VIII was cloned in a disabled adeno-associated virus (AAV) vector and infused into the liver where the exogenous factor VIII is expressed. A once-only treatment is sufficient to continuously generate enough factor VIII in the blood to suppress bleeding in severe cases of haemophilia A.
Hemgenix is a gene therapy for severe haemophilia B, which was approved by the FDA in 2022 and by the NHS in 2024. It employs a similar approach in which the gene for factor IX is expressed in the liver in a single once-only infusion. Blood levels of factor IX, which persist for many months, are high enough to control bleeding that is spontaneous or caused by injury. It also eliminates the need for frequent injections. The main drawbacks are the complexity of the procedure and the cost – $2.5mn per treatment. Also, pharmaceutical companies are reluctant to invest long-term in drugs and procedures that involve once-only treatments that are too expensive for general use.
A cautionary tale
In the 1970s and early 1980s in the UK, about 6,000 people with haemophilia and other bleeding disorders were infused with clotting factors derived from pooled human blood plasma contaminated with HIV and hepatitis viruses. Because of the shortage of blood products in the UK at that time, clinics and hospitals used pooled blood plasma from American drug addicts and prisoners that was contaminated with these viruses. Some of those who were infected unknowingly transmitted the viruses to their partners before their symptoms became apparent. Over 3,000 haemophiliacs have died and more than 1,250 have developed HIV, including 380 children. Fewer than 250 are still alive. By the mid-1980s, there was better vetting of donors and donated blood was routinely heat-treated to eliminate viruses. Moreover, the risk of receiving contaminated human blood plasma was further reduced with the increasing use of genetically engineered clotting factors.
With the availability of desmopressin, gene therapy, genetically engineered factors VIII/IX, and much safer donated blood, most males born with haemophilia in the UK in the 21st century can look forward to a normal lifespan.
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