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COAGULATION CORNER: MAY 2011

It is with great sadness that the coagulation community has lost a dear friend Diane Shafer.  Diane was a well respected professional who taught so many people coagulation through her lectures.  She was a friend and a mentor and will be missed by so many people.  Our lives were richer because of her, but will not be the same without her.  I dedicate this to her and thank her for the endless hours that we spent together and all that I learned from her- she was truly royalty-

Royal Coagulation

I admit - I was up at 4 am to watch Kate and William get married, just as I watched Diana and Charles many years ago.  Bloodlines are very important to royalty- as we are reminded of Kate being from a common background. Well, if you look at the background of “royal coagulation” adding a little common blood may be a good thing!

Hemophilia has been present in many royal families including Great Britain’s Queen Victoria(1819 -1901) who was married to Albert, and it appears passed this disease to Spanish royalty and Russian royalty.

Background:

A deficiency in FVIII clotting activity leads to a common bleeding disorder, hemophilia A. This is an X linked disorder which affects 1 in 5000 males due to mutations in the FVIII gene. This heterogeneous disorder results in variable severity and can be due to gene deletions, exon inversions, translocations, nonsense shifts, premature stops as well as missense point mutations. These all can cause defects in the expression, secretion and the half-life of FVIII in circulation. Some mutations can generate stable but dysfunctional FVIII molecules resulting in various severity of the disease. The different degrees of hemophilia are classified into three categories dependent of the circulating FVIII levels: (1) severe hemophilia A when the level of FVIII in the plasma of the patient is less than 2% of the FVIII found in normal plasma; (2) moderate hemophilia A (2%-5%) and (3) mild hemophilia A (6%-40%). Some patients who lack functional FVIII may demonstrate trace to normal levels of circulating nonfunctional FVIII antigen.

Now back to those families:

Queen Victoria felt that since their children presented with fair hair and blue eyes, their blood was lymphatic, and what they really needed was some more black eyed Princes and Princesses to marry so they could have some strong blood- Really?  Ever hear of consanguinity? Besides she was the carrier!  Her eighth child Prince Leopold, presented with severe hemorrhages, and died at the age of 31 due to a minor fall- so my guess is he had moderate hemophilia. He was married and had 2 children a daughter and a son. Monarchs arranged marriages to consolidate political alliances and this effort did a good job of spreading this disorder to Spain, Russian and Prussia.  So Leopold’s daughter Alice had to have hemophilia- X linked recessive- gets the X from Mom and Dad- had a hemophilic son- Rupert and a boy and girl whose status was unknown.

Victoria’s youngest daughter Beatrice had 1 daughter and 3 sons, 2 of which were hemophilic, so Beatrice was clearly a carrier.  Beatrice’s daughter Eugenie married King Alfonso XIII of Spain and had 6 children, 2 of whom were hemophilics- she was also a carrier.  One of her children was the father of Juan Carlos the current King of Spain. So explains the Spanish connection-

Now on to Russia. Alice, Victoria’s third child, had 6 children and 3 were hemophilic.  Her daughter Irene married her first cousin (not good) Prince Henry of Prussia and gave birth to 2 hemophilic children- so now Prussia royalty is included. Her sister Alix another carrier married Tsar Nikolas and carried the disease into the Russian imperial family. She had four girls, but alas finally had a son, and yes of course he was a hemophilic.  But sadly all were murdered in the Russian revolution. DNA testing of the Romanov family remains in 2009 showed that one of the four daughters, thought to be Maria by American researchers and Anastasia by Russian researchers, was a carrier. Grand Duchess Maria was thought by some to have been a symptomatic carrier because she hemorrhaged during a tonsillectomy.

So how did all of this start?  Queen Victoria’a father, Prince Edward, Duke of Kent was not a hemophiliac-her mother Victoria, was not known to have a family history of the disease, although it is possible that the mutation began at her conception and was passed down only to Victoria and not to her other children. In the same way, had Queen Victoria herself only had seven children, the mutation would likely be assumed today to have occurred at the conception of Princess Alice, as she was the only known carrier among Victoria and Albert's first seven children.

At least one modern descendant of Queen Victoria has been diagnosed with haemophilia: Ferdinand Soltmann, the son of Princess Xenia of Hohenlohe-Langenberg, born 2005. Xenia is a male-line descendant of Victoria, but the disease did not come from Xenia's maternal family, the Croÿs. If the disease came from Xenia, there are two possibilities. The first possibility is that it would have had to be inherited from her father, Kraft, Prince of Hohenlohe-Langenberg, a descendant of Victoria through the female line. Kraft had some clotting issues, which led the family to believe he may have been a mild haemophiliac. If Kraft was a haemophiliac, then his daughters Xenia and Cécile were definitely carriers. The second possibility is that Xenia or Ferdinand had a spontaneous mutation, as Victoria herself apparently had. Because the last known descendent with haemophilia of Queen Victoria's family tree died in the 1940s, the exact type of haemophilia found in this family remained unknown until 2009. Using genetic analysis of the remains of the assassinated Romanov dynasty, and specifically Tsarevich Alexei, Rogaev et el were able to determine that the "Royal Disease" is actually haemophilia B.

Hemophilia B is an inherited, X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well. Severe disease, defined as less than 1% factor IX activity, accounts for 50% of those with hemophilia B.Moderate disease, defined as 1-5% factor IX activity, typically presents in children aged 1-2 years and accounts for 30% of those with hemophilia B. Mild disease is defined as levels greater than 5% factor IX activity and accounts for 20% of those with hemophilia B.

Hemophilia is suggested by a history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, or familial hemorrhage. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases, hematologic malignancies (acquired form), and allergic drug reactions

So what does this mean for today’s Royal family?   Since the present royal family of England descended from Edward VII, Victoria’s  first son, that lineage is free from hemophilia.

Good news, unless of course Kate is a carrier……

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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