Chapter 1
Understanding Hemophilia

Hemophilia is caused by the body's inability to make a protein necessary for blood to clot. When a person with hemophilia is injured, the blood clots very slowly or sometimes does not clot at all. This can lead to excessive bruising and painful bleeding inside the body into muscles, joints, or body cavities. The word hemophilia literally describes the disease: "hemo" means blood and "philia" means having a tendency toward something. Therefore, a person with hemophilia has a tendency toward bleeding.

Hemophilia is a rare, genetic disease, which means it is inherited and is passed from one generation to the next. Hemophilia occurs almost exclusively in males and affects only one of every ten thousand. It is a chronic disease, meaning there is currently no cure and the problem lasts throughout the life of the affected person. At present, there is no way to prevent hemophilia, but it can be treated.

Unlike some other inherited diseases, such as sickle cell anemia or cystic fibrosis, hemophilia is not predominant in any particular race, nationality, or socioeconomic group. Hemophilia can be found in people of all races in populations throughout the world and occurs at similar rates among all ethnic and racial groups. Hemophilia is also known to exist in horses and in nine breeds of dogs.

The A and B of Hemophilia

The two most common types of hemophilia are hemophilia A and hemophilia B, also called Christmas disease, since it was named after a young boy, Stephen Christmas, who was the first person identified to have this type of hemophilia. A person with hemophilia will have either A or B, but not both types. These two types of hemophilia account for almost 100 percent of hemophilia cases, although there is a type C hemophilia, which affects both sexes and causes mild bleeding, like nosebleeds, unrelated to trauma (a bodily injury). Other diseases where blood clotting is not normal are not classified as hemophilia. Some of these bleeding diseases are so rare that there are only a few known cases in the world.

Of the two main types, hemophilia A is the most common. Eighty percent of all cases of hemophilia are classified as hemophilia A. Hemophilia A affects about 13,500 Americans. The disease is also called classic hemophilia.

Classic or hemophilia A is caused by a decreased or missing factor in the blood called factor VIII, which is one of the chemicals necessary for effective blood clotting. Factor VIII is manufactured in the liver and circulates in the liquid part of the blood known as the plasma. Varying amounts of factor VIII in the blood determine whether the disease is classified as mild, moderate, or severe. The usual amount of factor VIII in the blood is stated in lab books as 55 to 145 percent of normal. This measurement is based on testing the blood of a large group of people with supposedly normal amounts of the factor. One hundred percent is the average in the tested group, with a range of values from 55 to 145. The test does not directly measure the clotting factor, but measures its functional activity. In mild hemophilia A, the person may have 5 to 50 percent of the normal amount of factor VIII working to clot blood. If only 1 to 5 percent of factor VIII is active, the person's blood clots less well, and he has moderate hemophilia. In severe hemophilia the person has as little as 1 percent or less of factor VIII and is prone to more frequent and severe bleeds.

Hemophilia B, or Christmas disease, has similarities with A but affects fewer people and is caused by a lack of a different clotting factor. In contrast to hemophilia A, which affects one in ten thousand people, hemophilia B is rarer still, affecting only one in forty thousand people. Hemophilia B is responsible for 15 to 20 percent of hemophilia cases. In hemophilia B the missing or defective clotting factor is called factor IX, which, like the factor missing in hemophilia A, circulates in the plasma portion of the blood ready to help with blood clotting. Like hemophilia A, not everyone with hemophilia B bleeds with the same intensity, due to varying amounts of factor IX in their blood. Normal percentages for factor IX are 60 to 140, with 100 being the average amount. Mild hemophilia B patients possess 5 to 50 percent of clotting factor IX, moderate cases will have 1 to 5 percent of the clotting factor, and severe cases will have less than 1 percent available to help form a clot. All members of a family with hemophilia tend to have the same amount of clotting factor.

The Family Connection

Hemophilia is a genetic disorder, which means it is passed from one generation to the next. Genes, inside body cells, are responsible for each person's unique characteristics, and determine everything from a person's height and eye color to tendencies toward some illnesses. If a gene is defective or missing, then it can cause an illness such as hemophilia. "One hundred thousand genes carry the instructions to bring a baby to life. The only difference between a baby with hemophilia and a baby without hemophilia is that one gene does not work properly in the hemophilic child,"² says Peter Jones, M.D. In addition to hemophilia, there are about four thousand diseases caused by genetic defects.

In hemophilia, there is usually a family history of the disease. Family members carry a defective version of the gene that is necessary to complete a clot that will stop the bleeding until the body can repair the damaged area.

To comprehend how hemophilia is passed from one generation to the next, it is necessary to understand chromosomes. All humans have twenty-three pairs of chromosomes, which are threadlike chemical structures inside cells. Chromosomes carry genes, which contain the code for inherited traits. Half of each chromosome pair is inherited from a person's mother and half from the father.

One pair of chromosomes is responsible for determining a person's sex. If a person receives two X chromosomes, one from the mother and one from the father, to make a pair, a female results (XX). If an X and a Y chromosome are joined, the sex is male (XY). This is important in hemophilia, since the affected blood clotting genes in hemophilia are on the X chromosome. Because the blood clotting genes reside on the chromosome that determines sex, the disease is called X-linked or sex-linked.

Women can be carriers of hemophilia, meaning they can pass it on to sons without having symptoms themselves. This is true because the genes determining hemophilia are recessive. Genes are either dominant (stronger) or recessive (weaker). In the science of genetics, recessive diseases require two defective genes, one from the mother and one from the father, before the actual disease is present in their child. Hemophilia is carried on the X chromosome, and so if one of a woman's X chromosomes carried the defect, her other normal X chromosome would dominate, canceling out the defective one. Since it is unlikely that a woman would have defective genes on both X chromosomes, women rarely have hemophilia. Since men have only one X chromosome, if they receive a defective X chromosome from their mother, they do not have a second normal X chromosome, capable of producing the missing clotting factor, to counteract the defective one. Because of this, one defective gene is enough to cause hemophilia.

The chances of a son having hemophilia if the mother has a defective gene are 50 percent, or one chance out of two. La Donna Loehrke of North Dakota had the following reaction when informed that her son had hemophilia. "I was upset, mad, unbelieving, and feeling that it was my fault. Although it runs in our family, we thought it would not happen to us."³ The 50 percent chance is true for every pregnancy a woman has. This means if a carrier woman gives birth to one son who has hemophilia, the next time she gives birth to a son, there is still a 50 percent chance that he will also have hemophilia. An example of this is the family of Ricky Ray, a hemophilia patient from Florida, whose two brothers also have hemophilia.

In a similar way, daughters of carrier women have a 50 percent chance of receiving the faulty gene and becoming carriers. This means any future male children they have also have a 50 percent chance of having hemophilia.

There is only one way that a female could suffer from the disease of hemophilia. If her mother were a carrier and contributed the defective gene and her father had hemophilia, both her X chromosomes would carry the gene for hemophilia and she would have the disease. Not every female born to the family would necessarily have hemophilia, since some females might inherit the mother's normal X chromosome. Therefore, females born to that family would have a one in two chance of having hemophilia.

In one-third of all cases of hemophilia, no family history can be found. In these cases, the disease is caused by spontaneous gene mutation. A mutation is a permanent, unusual change in a gene, which prevents it from performing its task. Hemophilia is actually thought to have originated hundreds of generations ago through gene mutation. Gene mutations can occur at the very beginning of a pregnancy or much later in life in a parent, who can then pass the mutated gene to future offspring. Genes mutate due to aging or exposure to chemicals or radiation. In the case of hemophilia, the change affects the genes that code for factor VIII or factor IX, and becomes a permanent part of the genetic makeup of that person.

To Clot or Not

A person born with hemophilia has inherited a problem with blood clotting. The process of blood clotting is complex, but basically involves three steps. If any of these steps does not work, then the person will bleed longer than normal. In hemophilia, the first two steps occur normally, but the third step of blood clotting is impaired, which prevents the final clot from forming.

The first step occurs when a person receives an injury that allows blood to escape from an artery or a vein. The blood vessel immediately constricts (becomes smaller) to decrease the flow of blood.

The second event involves platelets, one of the three types of cells circulating in the blood. The other two types of cells are red blood cells and white blood cells, but only platelets contribute to clotting. Platelets migrate to the opening in the vessel and clump together in an attempt to plug the leaking blood. Their purpose is to form a soft clot until a more permanent one can be made. This step takes about one minute. Platelets also have a role in the final clot when protein factors are added to them to make a stronger, permanent clot.

Step three of the clotting process is the most complex because it involves twelve clotting factors, identified by roman numerals. These protein factors work together to form the final clot of fibrin, which is a tangle of threads forming a net over the platelets to hold them firmly against the open wound. This step of forming the final clot includes factor VIII and factor IX and a few clotting factors found in surrounding tissue. The process of forming a final clot is often referred to as a clotting cascade because each factor or chemical stimulates the next factor in a series of events that results in a clot. This can take from two to six minutes. The clotting cascade is similar to setting a row of dominos on end and pushing the first one in line, which topples the second one, and so on until all dominos react to that initial push. If any one domino fails to topple, all dominos after it remain standing. In blood clotting, the final clot depends on all the clotting factors being present and working. If any are missing, the process of forming a clot comes to a halt, which is what happens in hemophilia. The missing or defective factor VIII or IX stops the progression of the clotting cascade.

The Symptoms of Hemophilia

Since the clotting cascade is incomplete in a hemophiliac, bleeding can range from a minor to a very serious event. The main problem is that the person with hemophilia will bleed longer than normal and needs close attention to assure the bleeding is controlled.

Contrary to common belief, hemophiliacs will not bleed to death from a skin cut. Hemophiliacs take longer to form a clot than the average person, but their bleeding is not faster. It is slow, steady, and continuous, but it does not gush from the wound. Therefore, normal first aid measures will control most external bleeds.

Internal bleeding is far more serious than minor cuts on the skin's surface, since it is less obvious and may go unnoticed. Internal bleeding can be caused by injury or can occur spontaneously. Most hemophiliacs learn to recognize signs of an internal bleed. When the bleeding is in a joint, the first symptom may be a prickly or bubbly sensation. As the bleeding continues, it can cause severe pain, particularly if it is bleeding into a rigid space like a joint and is not controlled. Later symptoms are numbness, swelling, or tightness.

Bleeding into joints is the most common type of internal bleeding. Treatment needs to be started in the first four hours to prevent pain from the accumulation of blood. Over a period of time, joint bleeds can lead to arthritis and permanent joint damage. Peter Green, a lecturer in molecular genetics, described his experience with joint bleeds in a medical journal. "I had my first hemorrhage into an ankle joint before I could walk, and as childhood progressed, more of my joints succumbed to their first bleed. Every bleed into a joint was, at that time, untreatable and took its course, subsiding over 3 to 10 days. I missed a great deal of school because of my disease, and spent many days in hospital."⁴

Muscle bleeding can also happen spontaneously or following an injury. Bleeding into muscles, if not controlled, causes swelling, which has the potential for damaging nerves and blood vessels by pressing on them. This leads to paralysis or permanent muscle damage if the bleeding is not treated promptly.

Signs of Bleeding in Other Body Parts

Other signs of bleeding include bruises, blood in the urine or bowels, nosebleeds, bleeding inside the head, and neck and throat hemorrhages. Both children and adults with hemophilia bruise easily, but it is rarely a problem. Bleeding into the brain, however, is very serious and can result in death. Often symptoms are not apparent until several days after the injury. Signs of a brain hemorrhage include changes in level of consciousness, head-aches, or nausea and vomiting. David Dupuy of Massachusetts, says,

David [his son] fell and hit his head at the same time our daughter had the flu. The bump went down quickly and we thought he was OK. Alicia had experienced severe headaches with her flu, and soon David also had headaches. We thought he had the flu, too. After a week, he still had headaches and became very dizzy whenever he sat up. We had him tested, and cranial exams showed he had slight bleeding against the brain.⁵

When a person with hemophilia has a head injury, it is a serious event and treatment measures begin immediately to avoid a brain hemorrhage.

Neck and throat bleeding are also serious because the swelling that results from accumulation of blood can press on the trachea (airway) and interfere with breathing. Any swelling in the neck area of a hemophiliac is investigated as soon as possible for cause.

Signs of Hemophilia by Age

The ages at which symptoms first occur in a hemophiliac are a clue to the severity of the disease. When a child is born with severe hemophilia, defined as less than 1 percent of clotting factor, the symptoms most often occur during the first eighteen months of life. It is rare for a spontaneous bleed to occur in an infant who is not walking or crawling—most bleeds follow trauma (bodily injury) or invasive procedures. Following birth, events such as routine injections or circumcision, a common surgical procedure performed on males, can initiate bleeding episodes. Once a baby starts walking, bleeding may occur following a minor injury. Jill and Ric Lathrop of Wisconsin noticed bruising on their infant son, Sam. "Most photographs of Sam from 9 months to 14 months show him with bruises of various shades of yellow, green, and purple."⁶

Toddlers often fall, and bleeding from the lips and tongue is common since these areas contain many blood vessels and bleed easily. Nathan Lambing had this type of injury. His father, Eric, said, "When he was learning to walk, he fell and put his teeth through his upper lip, causing a bleed."⁷ About the age of two or three, painful bleeding into muscles or joints following trauma is seen. Those with severe hemophilia bleed into joints, muscles, and other tissues with slight injury or even no obvious injury. They also hemorrhage following surgery or dental extractions. They may have as many as one serious bleed per week.

Moderate hemophiliacs have lengthy bleeds after minor injuries as well as surgery or dental work. Moderate bleeders average a bleed every month.

In milder cases of hemophilia, the first serious bleed may not happen until the child has dental work, surgery, or a more serious accident. Sharon Whiddon of Pennsylvania relates this incident about her son's first bleed. "George's first bleed and subsequent diagnosis happened when he was 15, following wisdom tooth surgery. Before that we had no idea."⁸ In some cases of mild hemophilia, the disease is not diagnosed until adulthood. The average number of bleeds per year for mild cases is zero to one. Although the number of times the mild hemophiliac bleeds is no more than many other people experience, the difference remains in the difficulty of controlling the bleeding in a hemophiliac.

Knowledge about blood clotting, symptoms, and patterns of inheritance is essential to a full understanding of hemophilia. Patients are often the experts in the disease, since they live with the effects daily. Peter Green discovered at a young age that he was more knowledgeable than some in the medical field. "'So how long have you had this bad blood?' I was asked as I registered with a new family doctor at the age of 13. I patiently explained that since haemophilia was an inherited disease, I had, of course, had it since birth; my mother was a carrier and her father also had the disease. That many doctors have never heard of Christmas disease [hemophilia B] … is surprising but not uncommon."⁹

As Peter Green discovered, many medical professionals, in addition to nonmedical people, do not have full understanding of the disease of hemophilia. Because hemophilia is rare, and genetics and blood clotting are difficult topics for most people to comprehend, a commitment to understanding the disease is the only way for those involved with the care of hemophiliacs to cope. This same principle of commitment to understanding is important for medical personnel and for those interested in learning about the disease. Fortunately, today there is a lot of information available about hemophilia. This has not always been true, because the history of hemophilia leading to the discovery of its causes was long and difficult.