Hemophilia – “The Royal Disease”

Called “the royal disease”, hemophilia is widely documented in the courts of European countries in the 19th and early 20th centuries. And, if you follow some conspiracy theories, is even linked to the Bolshevik Revolution in Russia. The story goes as follows: Queen Victoria herself was a carrier of the disease, caused by genetic mutation and carried through the female chromosome, and she passed her faulty genes to one of her sons and two of her daughters, who then went on to marry into other European courts. With World Hemophilia Day upon us, we at FindMeCure want to take a brief look at history before defining the challenges we face today in the fight against the disease.

Hemophilia in the past

The queen herself was probably a carrier of hemophilia B, caused by the insufficiency of clotting factor IX in the blood. This type of hemophilia rarely affects women severely but is life threatening for males and so, her son Leopold died at the age of 30 after an accident in which he injured his knee and hit his head.

Victoria’s daughters, however, though unaffected themselves, passed on the recessive genes. Princess Alice’s son died due to hemophilia-related complication, while her daughter Irene married the Prussian prince and spread the mutation in the German court.

Alice had another daughter who was a carrier of the disease – princess Alix. And here’s where the story gets interesting if you’re into royal drama. Alix went on to marry Prince Nicholas II of Russia. Their youngest child and only son – Alexei Nikolaevich suffered from hemophilia B throughout his short life. There are numerous accounts of his lonely childhood and his parents’ overprotective efforts to cocoon him away from any danger. Afraid he might injure himself, they never let him engage in ordinary child play and even time with his sisters were limited. According to historians, due to his disease, he was in a wheelchair when the royal family was assassinated by the Bolsheviks.

Victoria’s second daughter Beatrice, on the other hand, spread the disease to the Spanish royal family. Fortunately, none of her children carried this grim “tradition”, as her sons who inherited hemophilia didn’t have children of their own and her daughter’s children didn’t have the recessive gene.

But it’s not just royalty that were affected by the disease. Among the rumored to have carried this genetic mutation were also American president Abraham Lincoln, Mother Teresa and even Genghis Khan – which would make the disease centuries old and presents a few curious questions for evolution biologists.

Haemophilia Nowadays

It was in the middle of the 20th century that scientist were finally able to differentiate between hemophilia A, which is caused by not enough clotting factor VIII, and hemophilia B. this allowed for the development of treatments replacing the insufficient clotting factors – VIII or IX respectively.

The clotting factors needed can be derived from human plasma or recombinant (DNA molecules formed by genetic recombination of two or more sources done in a lab), but a few problems arise. One, some people develop antibodies so they either require higher “doses” or a non-human replacement. However, the non-human alternatives developed in the 90s (which are factor products that used Chinese hamster ovary tissue as their main source) are so expensive, they’re nearly inaccessible in developing countries.

This is all made even trickier to solve when we consider that preventative use is highly preferable in moderate-to-severe cases of hemophilia. What this means is that in order to prevent spontaneous bleeding or joint damage (as hemophilia patients are prone to in-joint bleeding), the replacement therapy should be taken a few times a week, instead of on-demand.

What are we doing about it?

A 2017 report on recent clinical trials in hemophilia shows that medical research is beginning to address this exact issues. The prophylactic treatment, which is now the standard method of treatment in almost all but mild hemophilia cases, presents some financial as well as logistic challenges for patients. New research seeks to overcome them by:

• extending the life of the replacement factors (meaning less frequent procedures for patients),
• replacing the gene responsible for the production of the necessary factor (which would be a long-term solution)
• developing a sort of artificial proteins to mimic the function of factor VIII in haemophilia A

 Emerging treatment options may reduce the frequency of (extended half-life products) or eliminate (gene therapy) the need for scheduled factor concentrate infusions, or provide a subcutaneous administration option (bispecific antibody, AT3, and TFPI targeting therapies). In addition, the nonfactor replacement strategies provide a promising treatment option for patients with inhibitors, presently the greatest unmet medical need in hemophilia.^[1]

All of this sounds promising and it gives us hope for the future of hemophilia treatment. However, a study published in 2015 on the NCBI website, suggests there is an information barrier that prevents hemophilia patients from entering clinical trials. Although 71% of the respondents said the development of new treatment was necessary and 87% agreed it was “desirable”, almost half of them (48%) felt they were insufficiently informed about clinical trials.

These numbers matter, because when it comes to willingness to participate in a clinical trial being informed about the process was a major factor, the study found^[2], and we at FindMeCure already know that knowledge and awareness can make all the difference.

Article by Nelly Katsarova

^[1] https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.24543

^[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385080/