Hemophilia

In 1828, Dr. Schonlein, a professor at the University of Zurich, and his student, Friedrich Hopff, originally coined the term haemorrhaphilia, later shortened to haemophilia. However, historical documents contained references of hemophilia well before 1828.¹ 

In the 2nd century AD, the first recordings of excessive or abnormal bleeding were first described in the Talmud, Jewish rabbinical writings detailing religious laws and traditions. These laws allowed male infants to avoid circumcision if 2 of their brothers had previously died due to hemorrhage following the procedure. Abu Khasim, an Arabian physician in the 10th century, mentioned how male members within certain families died after traumatic events due to uncontrolled bleeding.¹ 

Hemophilia is frequently recognized as an inherited disorder running throughout the royal families in England, Russia, Spain, and Germany in the 19th and 20th centuries. There is a belief that Queen Victoria of England was a female carrier of what was termed “the Royal Disease” – in truth, hemophilia B, or factor IX deficiency. Three of her 9 children inherited the disorder with her son, Leopold, dying at age 30 after a fall that caused uncontrollable bleeding. Victoria’s daughter, Alice, passed the gene to her daughter Alix, who married Tsar Nicholas of Russia. Their son, Alexei, inherited hemophilia, which prompted Nicholas to hire a Siberian monk, Grigori Rasputin, as a healer for his son. This decision eventually led to the cascade of events that sparked the Russian Revolution in 1917.² Queen Victoria’s daughter, Beatrice, also passed the gene to several of her children. For 3 generations following Victoria, hemophilia appeared throughout various European royal families into which her children married, but eventually the disease disappeared.¹    

John Conrad Otto, a physician from Philadelphia, published an article in 1803 detailing a hemorrhagic bleeding disorder running in certain families that mostly affected men. He successfully traced the disease back to 1720 to a female ancestor living in Plymouth, New Hampshire. In a 1813 paper in the New England Journal of Medicine, John Hay suggested that men affected by the bleeding disorder might pass the trait to their unaffected daughters.¹

Prior to the 20th century, physicians suspected that individuals with hemophilia were prone to bleeding because they had more fragile blood vessels. Most of these individuals died in childhood or early adulthood due to hemorrhaging in vital organs, particularly the brain. Those who survived childhood eventually became crippled after repeated internal joint and muscle bleeding, placing hemophilia in the category of one of the most painful diseases of the period.²

Around the mid-1800s, Gregor Mendel made his groundbreaking scientific discovery of the principles of genetic inheritance in pea plants. While not directly connected with hemophilia, Mendel’s discovery sparked an influx of research studying genetic transmission of diseases that eventually promoted later understanding of the rare X-linked inheritance pattern of hemophilia types A and B.^3,4 

In 1926, Erik von Willebrand, a Finnish physician, detailed a disorder that he termed “pseudohemophilia” which affected men and women equally. This disorder later became known as von Willebrand disease (vWD).¹ 

Researchers started to identify clotting factor deficiencies caused by gene mutations beginning with factor I deficiency in 1920, factor II and V deficiencies in the 1940s, rare factor VII, X, XI, and XII deficiencies in the 1950s, and factor XIII deficiency in 1960.¹ 

Patek and Taylor identified factor VIII in 1937 after isolating what they called “antihemophilic factor” from the blood.⁵ This became the factor deficiency that later identified hemophilia type A. 

In 1957, Inga Marie Nilsson and a team of researchers at Malmo University in Sweden discovered that vWD resulted from deficiencies in von Willebrand factor (vWF), a protein responsible for blood clotting.¹ Nilsson and her colleagues also researched the close relationship between factor VIII and vWF, recognizing that decreased levels of factor VIII protein were found in individuals who also had vWF deficiency.⁵          

A decade prior to Nilsson’s discovery, Alfredo Pavlovsky, a doctor in Buenos Aires, Argentina, discovered hemophilia types A and B in his lab in 1947.¹ He differentiated hemophilia type A from type B after he observed that mixing plasma from a patient with hemophilia type A with plasma from a patient with hemophilia type B corrected the clotting time.^5,6

Hemophilia B was first described in 1952 after Stephen Christmas, a young boy prone to frequent bleeding episodes, was admitted to a hospital in London where Rosemary Biggs and R.G. MacFarlane led a pioneering group of researchers studying coagulation. Interestingly, they did not discover a factor VIII deficiency even though the boy had already been diagnosed at age 2 with hemophilia. They did, however, discover a factor IX deficiency. This finding confirmed Pavlovsky’s theory that there were indeed 2 separate types of hemophilia, proving the existence of hemophilia type B.⁷ 

History of Treatment Development

Due to a lack of understanding of the causes of hemophilia, early treatment consisted of magic spells, ice, bed rest, splinting, hydrogen peroxide, gelatin, and even snake venom with known blood clotting effects. Preventive bed rest decreased the risk of injury and reduced bleeding.² 

In the 1950s and early 1960s, the primary method of treating hemophilia as well as other bleeding problems involved whole blood or fresh frozen plasma (FFP), which required significant volumes to reach appropriate levels of factor VIII or IX in cases of severe bleeding.⁶ 

A significant breakthrough in hemophilia treatment occurred in 1965 when Dr. Judith Graham Pool identified that the precipitate left after thawing the frozen plasma contained plentiful amounts of factor VIII, which she coined as “cryoprecipitate”. This enabled patients with hemophilia type A to receive treatment that no longer required high-volume whole plasma blood transfusions. Blood banks could more easily store and produce cryoprecipitate. Patients with hemophilia type B still required FFP treatments until the 1970s, when clotting factor concentrates containing factor IX were developed.⁶

Read more about hemophilia therapies

By 1980, physicians became aware of the potential to spread blood-borne viruses like hepatitis C or human immunodeficiency virus (HIV) through blood transfusions or concentrates of clotting factors made from human blood donations. Unfortunately, approximately half of the individuals with hemophilia who received transfusions or clotting factor concentrate treatments in the 1980s eventually acquired hepatitis or HIV infections.⁶

This iatrogenic transmission outbreak mandated strict donor blood screening methods developed in the 1980s and 1990s to protect those receiving treatments. Additionally, researchers explored recombinant technologies using factor VIII and factor IX genes to produce factor proteins. This allowed for the manufacturing of synthetic clotting factor treatments, entirely circumventing the need for human blood donations, thereby eliminating the risk of transmitting blood-borne infections. These synthetic clotting factor products gained US Food and Drug Administration (FDA) approval- the first factor VIII product in 1992 and the first factor IX product in 1997.⁶

Research for hemophilia treatments continues to advance, including possibilities of gene therapy which may provide an alternative to intravenous factor replacement therapy.⁶ 

References

1. History of hemophilia. National Hemophilia Foundation. Accessed July 29, 2021.

2. History of hemophilia: the royal disease. ARJ Infusion Services. Accessed July 29, 2021.

3. Hemophilia throughout history. Encyclopedia.com. Accessed July 29, 2021.

4. Hemophilia: inheritance. MedlinePlus. Updated August 18, 2020. Accessed July 29, 2021.

5. Drelich DA. Hemophilia A. Medscape. Updated June 5, 2020. Accessed July 29, 2021.

6. Congenital hemophilia. Hemophilia & Rare Bleeding Disorders. Accessed July 29, 2021.Christmas disease. Medical History Tour. December 24, 2017. Accessed July 29, 2021.

Reviewed by Debjyoti Talukdar, MD, on 8/10/2021.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.