The Royal Case of Haemophilia

 

If you read last week's article, you might have remembered me mentioning a name of a genetic disorder called Haemophilia. This horrific condition once played absolute havoc with several European royal families and can be judged as partially response for the downfall of the Russian Empire. 

So, bit of a background about Haemophilia. This disorder affects the body's ability to make blood clots- or scabs. Without blood clots, bleeding will continue. Bleeding inside joints or inside the brain can result in seizures and death. 

The two main types of haemophilia are haemophilia A, caused by low amounts of clotting factor VIII, and haemophilia B, which is caused by low levels of clotting factor IX.  Both of these clotting factors are essential for stopping bleeding and are proteins coded for by genes located on the X-chromosome. Haemophilia arises when these genes are non-functional. As the genes are located on the X-chromosome, this means both forms of Haemophilia are X-linked. For those who didn't read my article this week, this is a form of inheritance that involves the sex chromosomes. 

So going off on a bit of a tangent, the sex chromosomes are the X chromosomes and the Y chromosomes. Every person inherits one sex chromosome from each parent. If someone inherits one X chromosome from one parent and an X chromosome from another parent, they are female. If they inherit an X chromosome from one parent and a Y chromosome from another parent, they are male. As such, a person can either get an X or a Y chromosome from their father, but only an X from their mother. 

 

As women have two X chromosomes, this means that they would have two copies of the Factor VIII and Factor IX genes. But men would only have one copy.  That means that if a man has a non-functional factor VIII or factor IX gene, they would not be producing any factor VIII or factor IX, giving them haemophilia. In females, they would need both copies of the factor VIII or Factor IX to be non-functional to give them haemophilia. If only one of their copies was mutated and non-functional, they would have another copy producing the clotting factors. This means that they would be a carrier of the mutations and can pass this on to their children. 

So, these days, haemophilia is reasonably well managed. Clotting factors can now be injected to replace the missing clotting factor in the blood and prophylaxis to prevent bleeding can also be given.  People with the disease often live to a near- normal life expectancy.

But let’s cast our mind back to the late 1800's and early 1900's where haemophilia wasn't well managed. There was next to nothing that doctors could do other than give pain relief and advise rest. Aspirin could be offered- but doctors, due to lack of understanding of haemophilia, did not know this was one of the worst things you could actually do. Aspirin thins the blood making the bleeding much worse.

 In 1904, Tsarevich Alexi Nikolaevich, the heir to the Russian Empire was born in St Petersburg. At this time, Russia was a very powerful empire that spanned from the Arctic Ocean to the Black Sea in the south, Central Asia and some parts of Northeast Asia. The Russians were ruled by an absolute monarch - the Tsar. By 1897, the population had reached 125.6 million. 38% of this would have been serfs- a kind of slave with limited rights until their emancipation in 1861.

Alexei, 1916

 

After the birth of four girls who couldn't inherit (yes, I know but it's the 1900's), Tsar Nicholas and his wife Alexandra were beyond desperate for an heir. So, when Alexei was born, there was widespread joy around St Petersburg.  

Initially, the child seemed healthy, weighing 11 pounds at birth. But after they cut his umbilical cord, his navel continued to bleed and did not clot. Tsar Nicholas reflected that in 48 hours Alexei had lost '1/8 to 1/9 of the total quantity' of his blood.  This child has been so longed for and desired that it was devastating when the child was found to have haemophilia B to such a severe extent that trivial injuries such as a bruise or a cut were life-threatening. From the age of five, Alexei had two navy sailors accompanying him at all times to prevent any injuries. The nature of his illness was kept secret, leading to mass speculation.  

Now, this is when a certain person called 'Rasputin' (Ra Ra Rasputin, Lover of the Russian Queen... Thank you Boney M!) enters the scene. So those who are unfamiliar with the lyrics of Boney M and the general history, Rasputin was an apparent holy man and mystic. He gets quite a bit of a following in St Petersburg and many of his followers are rather influential. Ultimately, he gets popular amongst the aristocracy who are apparently curious about the occult and the supernatural.  

Grigori Rasputin, c.1910s

  So, Alexandra is desperate to help her son, and this leads to her crossing paths with Rasputin. She and Nicholas first meet Rasputin in 1905 and meet him again in July and October 1906. It's unclear when the Tsar and Tsarina first became convinced that Rasputin could heal the Tsarevich but there are two records about Rasputin healing Alexei successfully.

In 1907, Alexei fell over, damaging his leg and triggering an internal haemorrhage. There was nothing doctors could do and the child was left racked in pain, feverish and his leg swollen. Rasputin was asked by Alexandra to pray over Alexei. Rasputin did so and soon after he left, the swelling in Alexei's leg went down, and the next day, Alexei's fever had broken. 

In 1912, Alexei jumped into a rowboat and hit his groin. A large bruise appeared in minutes but started to reduce in size. It's believed that the bruise was a hematoma- a large collection of blood outside of a blood vessel. This is different to a bruise- which is a smaller amount of blood leaking from smaller capillaries. A few weeks later, Alexei and his mother were riding in a carriage. The juddering of the carriage is believed to have caused the hematoma to rupture. This caused haemorrhages in his thigh and abdomen. For 11 days, Alexei screamed in pain, had a dangerously high fever and received the last sacrament on the 8th of October. Alexandra asked Rasputin for help, and received a telegram from him, reassuring her that the 'little one' would not die and telling her not to let the doctors 'bother him'.  Amazingly, Alexei started to recover. His temperature dropped and the hematoma disappeared. 

Rasputin's apparent heeling has been the subject of a lot of a speculation. One theory is that he used hypnosis or administered certain herbs. One theory is that the doctors were giving Alexei aspirin, and Rasputin praying over the boy and stopping the doctors from 'bothering' him was preventing the doctors from administrating it.  Rasputin was assassinated in 1916 by a group of noblemen who wished to end his influence (in the words of the iconic Boney M.... Ra-Ra-Rasputin, Russia's greatest love machine. And so, they shot him 'til he was dead.). 

Eventually, the Russian revolution breaks out and sadly, Alexei is killed alongside his father, mother and his four sisters. He was 13 years old. In the months leading up to his death, Alexei was reliant on a wheelchair after several haemorrhages. Now, I'm not trying to downplay the actions of his murderers but it is possible that Alexei might not have made it to adulthood and even if he had, he may have died young and would have been left immobile for the rest of his life.

Now, how exactly did Alexei actually inherit the mutated gene for Haemophilia?

Well, the answer is, if you are unfamiliar with royal lineages, somewhat surprising.  The source of the haemophilia mutation can be traced back, though Alexei's ancestors, to a certain British ruler.... Queen Victoria. How is the Russian royal family remotely linked to the British Royal family? Again, that comes back to Queen Victoria and the number of children and descendants she produced. Queen Victoria was known as the 'grandmother of Europe' as so many of her children and grandchildren married into various royal families around Europe.

Queen Victoria, 1882

 

Now we can work out that the mutation did not come from Alexei's father. He did not have Haemophilia himself and because he would have had only one X chromosome, he could have passed it on. This means that Alexei could only have got the mutation from his mother - Alexandra Feodorovna.  

Born Alix of Hesse, Alexandra was born to Louis IV Grand Duke of Hesse and Princess Alice of the United Kingdom- the second daughter of Queen Victoria. As Louis did not have haemophilia, the mutation could not have possibly come from his side of the family. This meant it had to come from Alice and her mother Queen Victoria. 

Alexandra Feodorovna, 1908

 

It's believed that it was a random mutation, where the DNA coding for a gene is spontaneously changed. In this case, a random change must have altered the DNA coding for the Factor IX gene stopping the protein being produced.  

But how were we able to conclude that Queen Victoria was the source of the mutation and not her own ancestors?  Well, there was no record of the disorder appearing in her family tree at all before her. As the disorder is X-linked dominant, if Queen Victoria was not the source, there would have been records of her male ancestors having the illness. Also making it likely that Queen Victoria was the source is the age of her father when she was born. Paternal age is known to increase the chance of random and spontaneous mutation, and Prince Edward was 51 years old.  

So, was Alexei seriously unlucky being the only descendent of Queen Victoria with Haemophilia? 

After all, Alexandra had two X chromosomes with only one being mutated. That meant that her child could have inherited the unmutated version, meaning there would have only been a 50% chance that her male children would have had Haemophilia. The same odds would have been in place for any other female child or grandchild of Queen Victoria who had inherited the mutated gene from her. 

But as it happens, no. Alexei may have been the most high profile case of haemophilia- maybe due to the Russian Revolution and Rasputin, but he was not by far the only case. In fact, haemophilia tore through several royal families, making its way into the Spanish, German and French royal families as well as the English royal dynasty. It was actually known as the 'Royal Disease'. 

Queen Victoria's own son Prince Leopold had haemophilia. He suffered from recurrent joint pain and died from a cerebral haemorrhage after slipping in Cannes. He was 30 years old. He fathered a son who inherited his Y chromosome and as such escaped the disorder. His daughter Alice however was a carrier. For a male and female whose father has haemophilia and mother is not a carrier, these are the only possible outcomes. Her son Rupert also inherited the disorder and died at the age of 20 from an intracerebral haemorrhage. He had no children. 

Queen Victoria's daughters Princess Alice and Princess Beatrice were carriers and gave the gene to their children - Princes Freidrich and Leopold respectively.  Prince Freidrich- the older brother of Alexandra Feodorovna. died after a bad fall.  He was two. Prince Leopold died at the age of 32 during a hip operation. He had no children. Princess Alice also passed on the gene to her grandson Henry though her daughter Irene; he died at four years old after a head injury.  Irene also had a child called Waldemar. He died at the age of 56 due to a lack of blood transfusion facilities at a clinic. Of all the descendants of Queen Victoria suffering from haemophilia, he lived the longest number of years. He died in 1945, compared to his brother who died in 1904. This goes to show how the management of haemophilia was starting to improve.  Princess Beatrice also had two grandchildren with the disorder Alfonso and Gonzalo, sons of her daughter Victoria Eugenie. Alfonso died at the age of 31 of internal bleeding after a car crash, whilst Gonzalo died at 19, also in a car crash.  He was the last descendent to be born with the disorder, although the last descendent to die was Waldemar. 

 

Alexei's sisters Olga, Tatiana, Maria and Anastasia may also have been carriers of the haemophilia gene. Maria was believed to have haemorrhaged in 1914 during a tonsillectomy and the doctor performing the operation had to be ordered to continue by Olga's mother. Carriers of the gene can have similar symptoms to haemophilia including a lower blood clotting factor, causing heavy bleeding. DNA testing on the remains of the imperial family in 2009 proved that Alexei, his mother and one of his sisters were carriers. 

                                                   From left to right, Maria, Tatiana, 

                                                        Anastasia and Olga in 1914

 

It is interesting to ask 'What if?' questions about haemophilia and its impact on the Romanovs. 

Tsarina Alexandra arguably only fell in with Rasputin and his 'spiritism'  in a desperate attempt to cure and save her son (She believed he was a holy healer, who would heal her son... Ra-Ra-Rasputin... okay I'm done now :D) 

Rasputin can also be judged to play quite a role in the eventual fall of the Romanov dynasty. His close relationship with the imperial family resulted in quite a bit of damage to their reputations and public image. This may have contributed to the anger of the population and the outbreak of the Russian Revolution.

So, is it possible that without Alexei's haemophilia, there would have been no Russian Revolution? As the Bolsheviks and eventually the Communist Party of the Soviet Union took control, is it also possible that there would have been no Soviet Union, and the major events that Russia has begun would never have happened? How different would the political landscape potentially be?

But perhaps nothing would have been different without haemophilia. With or without Rasputin, Tsarina Alexandra was viewed with suspicion by the people during WW1, as she was German-born. Her reputation certainly wasn't helped by her relationship with Rasputin, but it was never particularly good in the first place. The people were already facing hardship such as shortages of bread and grain and the Bolsheviks became popular promising an end to the war, land for the lower classes and food for all. Prior to WW1, the events of Bloody Sunday in 1905, when the Imperial Guard shot and killed at least 100 demonstrators, had already caused anger and mistrust towards the Tsar.  It is entirely possible that the 1917 revolution and subsequent events may have happened anyway. 

It's stirring and rather poignant to think about and it ultimately highlights how much impact a simple, random mutation can ultimately have on you and the people around you. For me, this is part of the reason why I think genetics is so fascinating. Something so small and seemingly insignificant can have such wide reaching consequences. 

Tomb of Tsar Nicholas II, Alexandra, Olga, Tatiana and Anastasia. 

 

 

Very long article this week and thank you very much for getting though it! Hope it was somewhat interesting for you, and I'll try to do a shorter one next week!

Jess x