Chapter 2
Hemophilia Throughout History

Although the science of genetics was centuries away, early writers and scientists suspected a family connection to serious bleeding problems. Despite this and other ancient references to the disease dating back almost two thousand years, it has taken many centuries for full understanding to occur. While the hereditary component was recognized, the cause of the problem was thought to be weak blood vessels, not missing clotting factors, as is known today. Understanding of how blood clots did not occur until the 1960s, and the disorder was not called hemophilia until 1828, when a physician named Frederick Hopff, studying at the University of Zurich, gave the disease its current name.

An early reference to the bleeding disorder occurred in the second century A. D. when Jewish writings in the Talmud advised parents to refrain from having a male child circumcised if two previous males in the family had died from bleeding following the procedure. One thousand years later, a Jewish physician recognized the bleeding condition to be hereditary from the mother's side of the family. He advised against circumcising any male children of the same mother when previous male infants had died from bleeding, even if the children had different fathers.

An Arabian physician who lived in Spain, named Albucasis (935–1013), is considered by historians of hemophilia to be one of the key people in the history of the disease. Albucasis was a surgeon who also contributed to the entire field of medicine. His written description of the disease was considered thorough and was the first account of hemophilia by a physician. He, like others, described a family where males died from bleeding problems.

In America, an early reference to hemophilia came in 1803, when Dr. John Conrad Otto of Philadelphia traced a hemorrhagic condition through three generations of a family to a woman who lived near Plymouth, New Hampshire, in 1720. Conrad also recognized that the disease was passed from generation to generation by the mother. His published account of the disease in one family was the first description of hemophilia in America. His observations were recorded in the Medical Repository, America's first scientific journal. He wrote:

About seventy or eighty years ago a woman by the name of Smith… transmitted the following idiosyncrasy to her descendants.… If the least scratch is made on the skin of some of them, as mortal a hemorrhage will eventually ensue as if the largest wound is inflicted.… It is a surprising circumstance that the males only are subject to this strange affection, and that all of them are not liable to it.… Although the females are exempt, they are still capable of transmitting it to their male children.¹⁰

Gregor Mendel and His Peas

In the mid-1800s, Gregor Mendel (1822–1884) made a discovery seemingly unconnected to hemophilia, but which became important in the later understanding of the disease. Mendel, an Austrian monk trained in physics, discovered the basic principles of genetics through his work with plants. He was not a well-known scientist of his day, and he worked alone to discover patterns of inheritance.

As a young boy, Mendel was an excellent student and loved nature, but his parents were poor farmers unable to pay for a university education. So, as a way to continue his education, he entered an Augustinian monastery, where he taught natural science to high school students and bred plants and animals.

At the time of Mendel's work, a common theory was that plants obtained their characteristics through the influence of the environment. On one of his daily walks, Mendel discovered a plant that looked different from others of that variety. He transplanted it next to a more typical plant to see what would happen and found that instead of the plant's characteristics being influenced by the environment, the offspring retained the traits of the parent plants. This gave him the idea of heredity.

Mendel began growing sweet peas, and over a period of seven years observed how characteristics of mature plants, like color patterns, passed from generation to generation. He counted the actual ratio of colors in each new plant as a way to predict what future plants would look like. Mendel referred to the parts responsible for inheritance as "factors"; today we call them genes. He recognized that the new plants were receiving half of their characteristics from each parent plant, and he also discovered the concept of dominant (stronger) characteristics. Although other scientists noticed that certain traits pass from animals and plants to their offspring, Mendel was the first to document his results using statistics, and to publish his findings. Unfortunately, his work was published in a local, little-read scientific journal, so it was not until 1900, sixteen years after his death, that scientists discovered his publication. This rediscovery of his principles laid the foundation for modern genetics and its application to humans as well as to plants. Without Gregor Mendel's scientific writings on patterns of inheritance, much of the progress made concerning hemophilia, which occurred in the twentieth century, would have been impossible. Unfortunately, the human application of his principles came too late to explain the appearance of hemophilia in the royal families of Europe.

The Disease of Royalty

The family connection seen in hemophilia received the most publicity during the reign of Queen Victoria of England (1837–1901). Her eighth child, Leopold, had hemophilia and suffered hemorrhages that occurred as often as once a month. Queen Victoria was very protective of Leopold, allowing him few normal activities during his childhood for fear of causing a hemorrhage. Despite the protection given him, he died at the age of thirty-one from a brain hemorrhage after a minor fall. Prior to Leopold's hemophilia, there was no known history of the disease in Queen Victoria's family, leading many historians to believe that Queen Victoria passed the disease because of spontaneous gene mutation. At the time, it was commonly believed the hemophilia in Queen Victoria's family was the result of a curse. Leopold's condition received much attention when it was reported in the British Medical Journal in 1868. Queen Victoria herself left a written account of her son's battle with hemophilia in correspondence with her prime minister, Benjamin Disraeli.

Of Queen Victoria's nine children, only three inherited the gene for hemophilia—Leopold, who had the disease, and Alice and Beatrice, who were carriers. Alice and Beatrice passed the defective gene to some of their daughters, who became carriers, who then passed the gene to their sons who had the disease. Beatrice married into the royal family in Spain, and brought the disease of hemophilia to that monarchy. Beatrice's daughter was a carrier and passed the disease of hemophilia to two of her three sons, who both died in young adulthood. Queen Victoria wrote about the family illness, "Our whole family seems persecuted by this awful disease, the worst I know."¹¹

One of Alice's daughters, Alexandra, married Nicholas II, a Russian czar of the Romanov family, thus introducing the gene for hemophilia into another royal line. Empress Alexandra gave birth to four girls, and a son, Prince Alexis, who had severe hemophilia. Alexis bruised easily, and one of his knees was permanently damaged from episodes of joint bleeding. A Russian Siberian monk named Rasputin gained great favor in the royal court by treating Alexis with hypnosis to relieve his pain from joint bleeds and also to control some of his bleeding episodes. It is thought that the amount of attention paid to Alexis's illness by his parents, particularly his mother, drew attention away from political problems in Russia in the early 1900s. This may have contributed to the Russian Revolution and the overthrowing of the czar's government in 1917 by the Bolsheviks, who set up a Communist regime. The Bolsheviks murdered the Russian royal family, including fourteen-year-old Alexis and his four sisters, who ranged in age from seventeen to twenty-five.

The current royal family in England descended from Queen Victoria's son, Edward VIII, who did not have hemophilia. The daughter of Beatrice also carried the gene for hemophilia, but gave birth to male children only. Two of her three sons had hemophilia, but only one lived past twenty and he died while a young adult. Irene, one of the daughters of Alice, was also a carrier. She produced two sons, both with hemophilia. One died as a small child, and the other lived into adulthood but did not inherit a throne. Alexandra of Russia, the final carrier of hemophilia and also a daughter of Alice, was murdered in 1918 along with her husband, Nicholas, Alexis, the son who had hemophilia, and their four young daughters who had not married. Thus, the European royal line of hemophilia no longer exists. The disappearance of hemophilia in the European royal families demonstrates the deadliness of hemophilia before modern treatment, since many of the royals died from hemorrhages, which are treatable today.

Christmas Disease

The knowledge of hemophilia advanced in the mid-1900s with the discovery of another form of hemophilia called Christmas disease. Christmas disease is an alternate name for hemophilia B, named for a ten-year-old British boy, Stephen Christmas, who was the first recognized with this type of hemophilia. In 1952, R.A. Biggs, A.S. Douglas of Oxford University and Dr. Mcfarlane, a hematologist, published a paper describing Stephen Christmas's disease as different from hemophilia A, which before that time was thought to be the only type of hemophilia. They based their finding on previous work by a doctor in Argentina.

In 1944, Dr. Pavlosky, the doctor in Argentina, performed a lab test in which he mixed the blood of two hemophiliacs. To his surprise, the blood of each hemophiliac, when mixed with the other blood, caused clotting. At the time, there was no explanation for the phenomenon. Biggs, Douglas, and Mcfarlane used Dr. Pavlosky's discovery eight years later when they were trying to solve the mystery of Stephen Christmas's bleeding disorder. Their work identified two types of hemophilia and recognized that the cause of each was different. Those patients with hemophilia A still had factor IX, the clotting factor for hemophilia B, and hemophilia B patients, while missing the clotting factor for their disease, still had the clotting factor for A. This explains why Dr. Pavlosky achieved clotting when he mixed the two types of blood together. They called the new hemophilia Christmas disease (after their patient), or hemophilia B. It was not until the 1960s that the clotting factors were identified and named, including factor VIII, responsible for hemophilia A, and factor IX, responsible for hemophilia B.

The History of Hemophilia Treatments

While scientists throughout history were attempting to understand hemophilia, many treatments were tried in desperation. Patients were subjected to everything from magic spells to superstitious incantations.

An early treatment for bleeding in the Middle East involved applying ashes to external wounds to stop bleeding. This treatment went along with the culture's reliance on plants, herbs, and nature to cure or relieve conditions.

The use of ice, rest, and splints was also an early treatment and continued to be used until around 1940 for any type of bleeding episode. Kathy Bosma, nurse coordinator at the Comprehensive Center for Bleeding Disorders at Michigan State University, says,

When I talk to my adult patients, they remember when they were kids spending weeks or months in bed. The idea was that keeping them in bed would decrease their activity, and this would minimize the bleeding. They spent a great deal of childhood in bed packed in ice. The ice helped manage the pain and constrict blood vessels, which slows bleeding. Without factor [either factor VIII or factor IX], many of these patients now have terrible joints due to chronic bleeding.¹²

Actually, ice, rest, and splints are still used today, but only for external bleeding or, in the case of splints, for rest of a joint damaged by internal bleeding, not as a way to stop bleeding. Since the most dangerous bleeding is internal, this offered limited help.

Blood transfusions were the first treatment for internal bleeding that actually contained some of the missing clotting factors that are an essential part of modern treatment. Blood transfusions involve removing a pint of blood from a donor and giving it to a patient through a needle placed in a vein. The first blood transfusion given to treat hemophilia was performed in 1840 by a surgeon in London, who administered it to a young man who bled profusely following surgery. The physician reported the case in the British medical journal, Lancet. However, at the time, most doctors knew nothing about clotting factors in blood, the different blood types, or even the technique for administering blood, so were unwilling to try the treatment.

It was not until the 1930s that blood transfusions as a method of treatment became popular. The discovery just before 1920 that the cause of hemophilia was a problem of blood clotting and not weak blood vessels encouraged doctors to use whole blood to treat hemophiliacs after they had suffered a serious bleed. Whole blood contains red blood cells, white blood cells, platelets, and plasma plus some of the clotting factors and must be matched to a patient's blood type to prevent an adverse reaction. While this saved some lives by replacing lost blood, it was not totally effective in improving clotting because a pint of blood, the usual amount administered in a transfusion, does not contain enough clotting factors to replace all the factors missing in a hemophiliac. Byard Foraker, a patient with hemophilia, described his early treatment. "By the time I was 24, I had been in the hospital 125 to 130 times. When I was young, the only thing they had to treat me with was whole blood. I always had to go to the hospital because they didn't have anything like the treatments they have today."¹³

Also in the 1930s, physicians tried fasting as a treatment. This required patients to go without food for forty-eight hours. One hemophiliac, named Ben Lederman, was a teenager during the 1930s, and remembers that era as a time of "witches' brews."¹⁴ After he listed everything from cod liver oil to brewer's yeast used as treatments in those days, he said with humor, "Fasting for 48 hours was naturally the final prescription for getting a good clot."¹⁵

Another treatment, which sounded little better than witches' brews, actually showed some promise in helping blood clot. In 1934, R.G. Mcfarlane, a British hematologist (a specialist in diseases of the blood), reported using a topical solution of snake venom to treat bleeding episodes in hemophiliacs. He discovered that snake venom applied to the wound actually hastened blood clotting, but its use was limited to external bleeding.

The 1950s saw the use of fresh plasma from pigs and cows as a treatment. Plasma is the almost clear, liquid part of blood minus the cells, and is the part of blood containing the clotting factors. It does not need to be matched to the patient's blood type as whole blood does. While the treatment sometimes helped, an unfortunate side effect for a few was allergic reactions to the animal products. As with whole blood, plasma did not contain sufficient amounts of clotting factors to be a totally successful treatment. It was not until later that blood products containing concentrated amounts of clotting factors became the treatment of choice.

The Modern Era of Treatment

While some earlier treatments offered limited help, Dr. Judith Pool is credited with making the first major breakthrough in treating hemophilia A with concentrated amounts of factor VIII. Dr. Pool and her associates made the discovery in 1964 and 1965 that when frozen plasma is slowly thawed, it separates into layers. The bottom layer is rich in clotting factor VIII, the factor missing in type A hemophilia. This discovery was important because for the first time, sufficient amounts of the missing clotting factor could be administered without adding a large volume of fluid to the person's circulatory system and putting unnecessary strain on the heart. The new substance was named cryoprecipitate. Unlike giving whole blood transfusions, cryoprecipitate did not need to match a person's specific blood type. Administration required mixing the thawed plasma with a saline solution and giving it to the patient through a needle into a vein. Several of these small bags of cryoprecipitate were sometimes needed to stop the bleeding. George McCoy used this treatment before other methods were developed. "Before clotting concentrates were available, I used cryoprecipitate, which I kept at home in eight individual plastic bags. I would warm them in pans of water, hang them on an IV pole, self-infuse, and keep changing the bags. It was a long, slow, tedious process that took a few hours each time I needed to infuse."¹⁶ The problem with the new treatment was that it sometimes contained viruses from the human donors, which could cause disease in the person receiving it. Despite this risk, the discovery of cryoprecipitate revolutionized the treatment of hemophilia and was considered a miraculous discovery.

The next advancement in treatment was the introduction of freeze-dried factor concentrates. This discovery made it easier for patients to administer clotting factors at home, thus dramatically decreasing the need for frequent trips to the emergency room. The new innovation in treatment was also made from the plasma of blood donors, but was supplied as a freeze-dried powder. This product was more stable than cryoprecipitate, which had to be administered within four hours of thawing, and was available for both types of hemophilia. It came in small glass bottles, and the patient only needed to add sterile water to the powder, mix it, and then administer it using a sterile needle. With the use of freeze-dried factor concentrates, hemophiliacs were able to travel, attend school regularly, hold down jobs, and lead more normal lives. However, like cryoprecipitate, the factor sometimes contained dangerous viruses from the donors.

The New Treatments Become Dangerous

In the 1980s, the treatment, which had offered so much hope to hemophiliacs, suddenly became their worst enemy. The advent of AIDS, a noncurable disease that destroys the body's immune system, had a profound effect on the hemophiliac community. Because AIDS was a new, previously unknown disease, no one suspected that the nation's blood supply would become the vehicle for transmission of a deadly disease to patients requiring blood transfusions or blood products. Unfortunately, the AIDS virus was present in some of the blood used to make cryoprecipitate and the freeze-dried factor concentrates. These products were manufactured from human plasma, and the concentration of clotting factors necessary to stop the bleeding of a hemophiliac came from pooling the blood of multiple donors. Thus, every time a patient received a treatment, he was exposed to the blood of many people. At the time, there was no way to kill the virus in the donated blood. As a result, more than four thousand hemophiliacs contracted AIDS and subsequently died from the very treatment designed to save their lives.

The advent of AIDS caused a frantic search for a safe blood supply for hemophiliacs as well as others. Various methods to kill viruses in blood products were invented. Factors were treated using steam under pressure or dry heat, and very fine filtering devices removed viruses from products. Even pasteurization, first used to purify milk, was used. This method involved heating liquid clotting factor to 140 degrees for ten hours. Another method mixed chemicals with the factors to dissolve the virus's protective coating, thus killing it.

While these methods worked, scientists believed that the safest solution centered on finding a source of treatment not involving the use of human blood. The first step was the discovery in 1984 of the genes that code the human body for the production of factors VIII and IX. Once the genes were isolated, they were placed in living animals, such as baby hamsters, which became factories for producing the clotting proteins, thus bypassing the need for human blood as a source of clotting factors. Since the resulting factor did not involve human blood, there were no viruses and it was considered a safe alternative to factors derived from plasma. This method is known as recombinant DNA technology and was introduced in 1992 as a new treatment for hemophilia. The term recombinant simply means the genes are rearranged (recombined) experimentally from a molecule of DNA (the carrier of genetic information inside cells) and placed in a desired order. Before recombinant DNA technology was offered to the general population, it was tested in volunteers for safety. George McCoy, a thirty-nine-year-old hemophiliac, volunteered to be the first patient to receive the new recombinant DNA clotting factor, which did not involve the use of blood. He says, "I felt that genetic engineering and recombinant technology were the best hope for the future because we knew there was contamination possibility in other products."¹⁷ In the years it took to develop this product, the national blood supply became safe, but so many in the hemophilia community had died from AIDS contracted from using human blood that hemophiliacs embraced the new DNA treatment as a safe method for stopping bleeding without the necessity of using products derived from plasma.

Living and Dying with Hemophilia

While many deaths occurred in the 1980s from AIDS, there were also many deaths prior to the middle of the twentieth century because of inadequate treatment methods. Before 1970, people with severe hemophilia often died in childhood or early adulthood from uncontrollable bleeding episodes. Speaking about what life was like for a hemophilia one hundred years ago, Kathy Bosma, a nurse who works with hemophilia patients, says, "Life was so different for people with hemophilia. People weren't expected to live past 30. Today, we expect people with hemophilia to grow old."¹⁸ Common causes of death before 1970 were uncontrolled bleeding after accidents or surgery, or bleeding into vital parts of the body, like the brain. For those who survived childhood, crippling from repeated hemorrhages into joints was common. Today, the lifespan of people with hemophilia, if the AIDS virus has not affected them, is near average. Deaths in the hemophilic population in the modern era are mostly unrelated to their bleeding disorder.

The history of hemophilia has progressed from a time of little understanding and no effective treatment to great strides in understanding everything from genetics to how to prevent bleeds by administering concentrated forms of clotting factors. These discoveries greatly improve the quality of life for those with hemophilia.