Christmas Disease and Hemostasis

Happy holidays everyone! In keeping with the holiday theme, I thought this would be a great time to talk about Christmas Disease. Christmas disease is when, after kissing a stranger under the mistletoe, you develop a fever and sore throat. Okay, I’m kidding, that’s not Christmas disease. That’s probably mono. Patients with Christmas disease, now known as Hemophilia B, can’t stop bleeding, which can be lethal. Using Christmas disease as our guide, we’ll delve into the intricacies of blood clotting, unravel the pathophysiology of bleeding disorders, and explore the genetics of European royalty. We’ll also learn about the world’s most expensive medication and examine the fascinating historical impact of Christmas disease.

Oops, you’ve accidentally cut yourself while making food for the holiday party! Not to worry though – soon the bleeding will stop on its own through a process called hemostasis. Let’s zoom in to the injury to learn how this happens on a microscopic level.

Our blood vessels are lined with endothelial cells. When these cells are damaged, they spring into action by releasing substances that squeeze and narrow the blood vessel. This is called vasoconstriction and reduces blood flow and bleeding.

To fully seal the leak, a clot needs to form through a process called coagulation1. First, platelets, which are little sticky cellular chunks floating in our blood, rush to the injury site and cluster to form a preliminary platelet plug. These platelets adhere to underlying collagen fibres, which are exposed after damage to the endothelial cells. An important protein involved in this step is von Willebrand factor, which links platelet receptors to collagen to secure platelets in place.

This platelet plug is then reinforced by fibrin, a stretchy protein that weaves into a sturdy mesh to stabilize the clot and provide a scaffold for more platelets to stick to. Fibrin is the final product of a series of reactions called the coagulation cascade, which is composed of several enzymes in the blood called “factors” that activate each other in a domino effect. Those who have studied this in class before with all its Roman numeral glory are probably already triggered by just seeing this diagram. I would like to present a different diagram that I think is a simpler and more accurate representation of the coagulation cascade2.

Smooth muscle cells underneath the endothelial cell layer have a protein called tissue factor on their surface. After tissue damage, smooth muscle cells and their tissue factor become exposed to coagulation factors in the blood. Tissue factor forms a complex with activated factor 7 in the blood that activates factor 10. Activated factor 10 combines with activated Factor 5 to convert a little bit of prothrombin into thrombin. Thrombin is the central factor of the coagulation cascade because it converts fibrinogen into fibrin, as well as activates factor 13 which cross-links the fibrin to make the mesh.

Thrombin also activates factors 5, 8, and 11. Factor 11 activates factor 9. Factor 8 and 9 combine to activate factor 10, which combines with factor 5 to make more thrombin. Thrombin makes more fibrin and activates more factors, perpetuating the cycle. In addition, each activated factor will activate several copies of the next factor, which amplifies the reaction with every loop. The amplification and the circular feedback of the coagulation cascade allows a small initial quantity of thrombin to kickstart the formation of a massive amount of fibrin and form a sturdy clot1,2.

If a person lacks any of these coagulation factors or cannot properly form the platelet plug, they will have a bleeding disorder3. These patients frequently bleed from their nose and gums. They can bruise easily, bleed heavily from minor injuries, and bleed painfully into their joints. Female patients can have very heavy period bleeding. Without proper management, dental procedures and surgeries can lead to extensive blood loss. Internal bleeding, particularly within the brain, can be life-threatening. In fact, before effective therapies were developed in the 1970s, patients with severe bleeding disorders rarely lived past 20 years old4.

Let’s dive into the world of bleeding disorders, starting with Christmas disease5,6, now more well known as hemophilia B. This is a genetic deficiency in factor 9, which can range from a reduced amount of working factor 9 to a complete absence. Christmas disease predominantly affects men because the factor 9 gene is located on the X chromosome, making it an X-linked recessive disease. In males, who only have one X chromosome, a mutated factor 9 gene will cause Christmas disease. Conversely, in females, who have two X chromosomes, they have a backup functional factor 9 gene and generally have no symptoms. However, they are carriers have a 50% chance of passing on the mutated gene to their children. The most famous example of a carrier is Queen Victoria of the United Kingdom, whose genetic legacy profoundly affected European royalty and history7,8. Though unaffected herself, one of her sons was affected and two of her daughters were also carriers, who then introduced the disease into royal families across Europe. Several royal princes of Spain, Germany, and Russia were affected and many died young from bleeding, giving it the name “royal disease”7. Notably, the Queen’s great-grandson Alexei, son and heir of the Russian Emperor Nicholas II, suffered several life-threatening bleeding episodes in his childhood. Desperately, his parents eventually turned to Grigori Rasputin, a mysterious Russian self-proclaimed holy man, who miraculously stopped several bleeding episodes just by prayer and magic9. He was appointed as Alexei’s faith healer and soon became an influential and controversial figure in the Russian court. The success of Rasputin’s unconventional treatments has long been a subject of historical debate. One theory points out that Rasputin prevented royal doctors from treating Alexei. At that time, aspirin was commonly used for pain relief in bleeding disorders, but its blood thinning properties, through inhibiting production of the platelet activator thromboxane A2, was still unknown. Thus, Rasputin could have inadvertently reduced the severity of Alexei’s bleeding episodes by preventing doctors from giving Alexei aspirin9. In the end, this was all for nothing, as Alexei was eventually executed along with the rest of the royal family in 1918 after the Russian monarchy was overthrown. The revolution was fueled by discontent over the monarchy’s unchecked power and worsened by Rasputin’s sexual scandals, debauchery, and perceived influence over the Empress herself. If Alexei did not have a bleeding disorder, who knows how differently history might have unfolded?

Treatment for Christmas disease has drastically changed since Rasputin’s time5,6. To prevent bleeding, patients receive infusions of donor or synthetic factor 9 to replenish their deficiency. This can be every day for the most severe cases, or only before surgery in mild cases. Unfortunately, in some patients, frequent injections can cause the immune system to produce antibodies that neutralize the factor, making it less effective. A ground-breaking development occurred in 2022 when the FDA approved a gene therapy for Christmas Disease. Modified viruses introduce the factor 9 gene into a patient’s liver cells, which then begin producing factor 9 after a single dose. While gene therapy is an incredibly exciting new advancement in hemophilia treatment, that single dose costs $3.5 million, making it the most expensive medication in the world10. Most patients will probably stick to Factor 9 infusions for now. Other than medications, patients should exercise but avoid contact sports. Patients should also avoid blood thinners such as anticoagulants and NSAIDs such as aspirin, which can worsen bleeding. Proper planning and precautions should be done before dental procedures or surgery. Overall, with proper treatment, patients with Christmas disease can lead relatively healthy lives5,6.

Understanding Christmas disease lays the groundwork for understanding several other bleeding disorders like von Willebrand disease and hemophilia A, which are discussed in more detail in the video description. Basically, anything that goes wrong with the platelet plug or the coagulation cascade can cause a bleeding disorder, and treatment usually involves replenishing the missing component and taking precautions discussed previously.

I’d like to end the video with the story behind the name Christmas disease. In 1952, a paper describing a new bleeding disorder was published in the British Medical Journal11. The authors named it Christmas disease after the first patient they studied, a young boy named Stephen Christmas in Toronto, Canada. It was a happy coincidence that this was also published in the Christmas edition of the journal. Stephen’s condition resulted in several hospitalizations in his childhood and teenage years12. In 1965, treatment for bleeding disorders changed dramatically when Dr. Judith Pool discovered a highly efficient way of extracting coagulation factors from plasma to use for factor infusion 4,13. Life expectancy and quality of life of patients with Christmas disease and other bleeding disorders vastly improved, and Stephen was able to go to university and later worked as a photographer and cab driver12,14. Unfortunately, the 1980s marked the start of the HIV pandemic. In Canada, coagulation factor concentrates were made from pooling thousands of donors, and all it took was one donor with HIV to contaminate the entire batch. At least 2000 Canadians contracted HIV and an additional 30,000 contracted hepatitis C from contaminated blood product transfusions, resulting in over 8000 deaths as the aftermath of the “tainted blood disaster”, one of the worst public health failures in Canada15-17. Infuriatingly, a later investigation uncovered that to cut costs, blood banks sourced their blood from high-risk patients such as prisoners and continued to distribute contaminated blood, while attempting several cover-ups17. Tragically, Stephen also contracted HIV from blood transfusions. He joined the Canadian Hemophilia Society and dedicated himself to tirelessly advocating for blood safety. He helped secure financial compensation for those impacted by contaminated blood, improving the lives of many victims of this disaster12,14,18. Stephen Christmas passed away in 1993 from complications of AIDS, 4 days before Christmas, and is remembered as an inspirational advocate for people with bleeding disorders12,14.

Today, advances in treatment have vastly improved the lives of patients with bleeding disorders, with life expectancy nearing that of the general population. Blood products are meticulously screened and the risk of getting a blood-borne disease from a transfusion is incredibly low19. Advances in understanding coagulation have not only improved treatments for bleeding disorders but have also led to the development of blood thinners that help prevent heart attacks and strokes, which I’ll discuss in a future video. I hope you enjoyed learning about Christmas disease, and perhaps you now have some interesting trivia to share at your holiday celebrations. I wish you and your loved ones a safe and wonderful holiday season! See you next time on Medicurio.

Additional Info:

Understanding Christmas disease lays the groundwork for understanding several other bleeding disorders, most of them extremely rare20. We’ll discuss the two most common ones: hemophilia A and von Willebrand Factor disease. Hemophilia A is similar to Christmas disease except this time the deficiency is in factor 8. In fact, the only way to tell the difference is by measuring levels of factor 8 or 9 in the blood. The Factor 8 gene is also on the X chromosome, so hemophilia A also predominantly affects men. It is more common than Christmas disease and patients usually experience more severe bleeding. Hemophilia A is also treated with Factor 8 infusion, and a similar expensive gene therapy was just approved in 2023. Hemophilia A has two additional treatments that we’ll discuss: desmopressin and emicizumab.

Endothelial cells in the lung have cellular compartments called Weibel-Palade bodies that contain factor 8 complexed with von Willebrand factor and several other molecules involved in clotting and inflammation21. The medication desmopressin stimulates release of these Weibel-Palade bodies into the blood to increase levels of factor 8 and von Willebrand factor22. This is useful for treating mild Hemophilia A.

To understand how the other treatment emicizumab works, let’s look at the step in the coagulation cascade where Factor 8 and 9 combine to activate factor 10. Factor 8’s job is to hold factor 9 and 10 together, allowing factor 9 to cut off part of factor 10 to activate it. In hemophilia A, factor 9 cannot activate factor 10 without factor 8. So, scientists developed emicizumab, an antibody that essentially does factor 8’s job by holding Factor 9 and 10 together. In addition to these various treatments, patients with hemophilia A should have the same precautions as those with Christmas disease.

Von Willebrand disease (VWD) is the most common hereditary bleeding disorder, caused by a deficiency or dysfunction of von Willebrand factor (VWF). It affects both sexes, unlike Christmas disease and Hemophilia A. Treatment varies based on the type and severity of VWD but often includes desmopressin, which stimulates the release of VWF stored in the body as described above. VWF replacement therapies are also used for more severe cases.

References:

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  3. Goodman DM, Burke AE, Livingston EH. Bleeding Disorders. JAMA 2012;308(14):1492.
  4. Bleeding disorders history: from 2AD to the present. National Bleeding Disorders Foundation. https://www.hemophilia.org/bleeding-disorders-a-z/overview/history
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  9. Hemophilia in the Romanov family. National Bleeding Disorders Foundation. https://www.hemophilia.org/news/hemophilia-in-the-romanov-family
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  14. Kopplin P. From eponym to advocate: The story of Stephen Christmas. Hektoen International, 2020;12(2).
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  16. Norris S, Nixon A, Murray A. AIDS: Medical and scientific aspects. Government of Canada, 2001.
  17. Picard A, Poulin J. Krever Inquiry. The Canadian Encyclopedia, 2021. https://www.thecanadianencyclopedia.ca/en/article/krever-inquiry
  18. Picard A. Tatinted-blood compensation incomplete as deadline nears. The Globe and Mail, 2010. https://www.theglobeandmail.com/life/health-and-fitness/tainted-blood-compensation-incomplete-as-deadline-nears/article1212056/
  19. O’Brien, S. Surveillance Report 2022. Canadian Blood Services, 2023. https://professionaleducation.blood.ca/en/transfusion/publications/surveillance-report
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