Introduction

Hemophilia is a rare genetic disorder where blood does not clot normally. The term hemophilia has Greek roots; the two parts are hemo, meaning blood and philia, meaning a tendency towards. Thus, people with hemophilia have a tendency to bleed. The blood disorder manifests itself in three forms, Hemophilia A, Hemophilia B, and Hemophilia C.

In the United States about 400 boys are born with hemophilia every year. Hemophilia is almost exclusively seen in the male population because the trait for hemophilia is only expressed on the X chromosome. Since males only inherit one X chromosome (from their mother) there is not another copy of the X chromosome that can mask the hemophilia trait. Females can inherit the gene from their mother or their father and be carriers of the hemophilia gene. However, hemophilia will not be expressed in a female unless she inherits both X chromosomes that have the hemophilia trait. Hemophilia is a recessive trait similar to blue eyes and blond hair.

A person who has hemophilia is lacking a sufficient amount of a certain protein, also known as clotting factor. In order for proper blood coagulation to occur, the body’s clotting factors work to form a blood clot. When a blood vessel is injured a blood clot is needed to stop the vessel from bleeding. Blood platelets form the clot and the clotting factors help the platelets clump and stick together to cover the injury and stop the bleeding. When the clotting protein is not present, clotting occurs at a much slower rate and sometimes will not happen at all.

A seemingly minor or small injury to a person with hemophilia can take much more time to heal because of the slower rate of coagulation. Fortunately, there are injections that people with hemophilia can take to normalize the clotting process.

History

Hemophilia has been indirectly known about since the second century AD. There are accounts of hemophilia like symptoms in the Jewish Rabbinical writings. During those times families did not have to get their baby boys circumcised if they already had two sons die after the procedure.

A Philadelphia doctor, Dr. John Otto, wrote about a “hemorrhagic disposition in certain families.” Dr. Otto saw that the bleeding disorder was genetic and that males were significantly more likely to have the condition. After some research, he determined that a woman who settled in Plymouth in 1720 was the likely source of the disorder. In 1828, Hopff was the first to use the term hemophilia when he was describing its symptoms and the conditions.

In England, hemophilia plagued the royal family because Queen Victoria (1837-1901) was a carrier of the disorder. She passed hemophilia on to one of her sons, and two of her daughters became carriers. When her daughters married royalty from other countries, hemophilia was then passed into the ruling families of Russia, Spain and Germany.

Dr. Pavlosky, a doctor from Argentina, determined that there were two types of hemophilia while testing the effects of blood transfusions between two people with hemophilia. He was testing two people with different factor deficiencies, VIII and IX. He saw that after he gave one patient blood from the other that clotting occurred normally, and vice-versa.

Genetics

Hemophilia is a sex-linked, recessive disorder that is passed from mother to child on the X-chromosome. Females have two X-chromosomes so they might have one with the hemophilia trait and one chromosome without it; she will not have hemophilia because the hemophilia trait is masked by the other normal blood clotting gene. Males have one X-chromosome and one Y-chromosome so if they inherit an X-chromosome that has the hemophilia trait they will have hemophilia because it is impossible for the Y-chromosome to mask the symptoms. Y-chromosomes do not have the blood clotting trait on it, so males rely completely on the clotting factor trait that is on their X-chromosome.

A seemingly healthy female who is a carrier of hemophilia has a 50% chance of passing on the chromosome with hemophilia on it to her children. If she has a son and he receives the chromosome with normal clotting factor, he will not have hemophilia. If he receives the chromosome with hemophilia he will be a person with hemophilia. Notice that his condition was not dependent on the genetics of his father. A daughter of the mother of a carrier has a 50% chance of being a carrier of hemophilia and 50% chance of not carrying the disease. The only way that hemophilia will be expressed is if the daughter received the hemophilia chromosome from her mother and her father is a person with hemophilia. However, this outcome is extraordinarily rare. Genetic testing can he done to screen for hemophilia when a woman is pregnant.

People with hemophilia may not always have the condition due to the genetics of their parents. About 30% occur from a random genetic mutation. The cause of the mutation is unknown.

Occurrence
The incidence of hemophilia A in the United States one in 5,000 births. For hemophilia B the incidence is one in 50,000 births. Since hemophilia rarely effects females, these figures are for the male population. In the United States, about 400 new people with hemophilia are born each year. The total number of people living with hemophilia in this country is around 18,000.

Treatment

Hemophilia is treated with Factor Replacement Therapy. This involves giving the patient the necessary amount of clotting factor through an injection so that their blood clots at a normal rate. This treatment does not cure hemophilia, nor is there a cure for hemophilia. Factor replacement comes in two forms—human plasma or genetically engineered formula also known as recombinant. After the factor is injected it boosts the body’s ability to clot, however the effect only lasts about two or three days.

People with hemophilia can receive factor on different schedules, either prophylaxis or demand. Prophylaxis treatment involves patients receiving factor infusions on a regular basis in order to keep the clotting factor at a normal level. This is a preventive method. The demand method treats a bleed when it occurs. Bleeds can be painful if they go untreated. The ultimate goal of both treatments is prevention of joint and muscle damage. Research has shown that prophylaxis treatment is the most effective in preventing joint damage. The most at risk joints are knees, elbows and ankles. Exercises to increase joint flexibility and muscle strength are usually recommended for people with hemophilia.

Hemophilia A is the most prevalent type of all clotting disorders. One in every 5,000 boys born have hemophilia and the number is evenly spread across different races. People with hemophilia A lack clotting factor VIII. Recombinant or plasma infusions can be used to treat hemophilia A.

Hemophilia B is sometimes called Christmas disease, after the first person who was diagnosed with it. Hemophilia B occurs about one in every 25,000 male births and can be found equally in all races. Factor IX is the clotting factor that people with hemophilia B are missing. Either recombinant or plasma infusions can be used to treat hemophilia B.

Hemophilia C is much different than A and B. The genetics are such that both men and women can have hemophilia C because it is a dominant—not recessive—trait. The incidence is about one in 100,000 and is often found in people of Ashkenazi Jewish ancestry. The clotting factor that is missing is Factor XI. Fresh frozen plasma is the only treatment for hemophilia C that is approved for use in the United States.

Levels of Hemophilia

Mild hemophilia is defined as 6%-49% of normal factor levels and is generally not noticeable until a serious injury, surgery or tooth extraction. Clotting problems usually occur only after such events.

Moderate hemophilia occurs in about 15% of the hemophilia population. Bleeding occurs after an injury and also spontaneously, for which there is no cause.

Severe hemophilia affects about 60% of people with hemophilia. A bleed usually happens after injury and spontaneous bleeds happen more often, affecting joints and muscles.

Types of Hemophilia

Hemophilia A is the most prevalent types all clotting disorders. One in every 5,000 boys born have hemophilia and the number is evenly spread across different races. People with hemophilia A lack clotting factor VIII. Recombinant or plasma infusions can be used to treat hemophilia A.

Hemophilia B is sometimes called Christmas disease, after the first person who was diagnosed with it. Hemophilia B occurs about one in every 25,000 males births and can be found equally in all races. Factor IX is the clotting factor that people with hemophilia B are missing. Either recombinant or plasma infusions can be used to treat hemophilia B.

Hemophilia C is much different than A and B. The genetics are such that both men and women can have hemophilia C because it is a dominant—not recessive—trait. The incidence is about one in 100,000 and is often found in people of Ashkenazi Jewish ancestry. The clotting factor that is missing is Factor XI. Frozen plasma is the only treatment for hemophilia C that permitted in the United States.

Levels of Hemophilia

Mild hemophilia is defined as 6%-49% of normal factor levels and people generally not noticeable until a serious injury, surgery or tooth extraction. Clotting problems usually only after occur after such events.

Moderate hemophilia occurs in about 15% of the hemophilia population. Bleeding occurs after an injury and also spontaneously, for which there is no cause.
Severe hemophilia affects about 60% of people with hemophilia. A bleed usually happens after injury and spontaneous bleeds happen more often, effecting joints and muscles.

Hemostasis: How does bleeding stop?

Damage to small blood vessels and capillaries frequently occurs. When these vessels are damaged, there are three basic mechanisms that promote hemostasis or the stoppage of bleeding.

Following damage, there is an immediate reflex that promotes vasoconstriction, thus diminishing blood loss. Exposed collagen from the damaged site will promote the platelets to adhere.

When platelets adhere to the damaged vessel, they undergo degranulation and release cytoplasmic granules, which contain serotonin, a vasoconstrictor, and ADP and Thromboxane A₂.

The ADP attracts more platelets to the area, and the Thromboxane A₂ promotes platelet aggregation, degranulation, and vasoconstriction. Thus ADP and Thromboxane A₂ promote more platelet adhesion and therefore more ADP and thromboxane. The positive feedback promotes the formation of a platelet plug.

The final hemostatic mechanism is coagulation.

Damaged tissue releases factor III, which with the aid of Ca²⁺ will activate factor VII, thus initiating the extrinsic mechanism. Factor XII from active platelets will activate factor XI, thus initiating the intrinsic mechanism.

Both active factor VII and active factor XI will promote cascade reactions, eventually activating factor X.

Active factor X, along with factor III, factor V, Ca²⁺, and platelet thromboplastic factor (PF3), will activate prothrombin activator.

Prothrombin activator converts prothrombin to thrombin.
Thrombin converts fibrinogen to fibrin.

Fibrin initially forms a loose mesh, but then factor XIII causes the formation of covalent cross links, which convert fibrin to a dense aggregation of fibers. Platelets and red blood cells become caught in this mesh of fiber, thus the formation of a blood clot.



Reproduced with permission. © 2009 The McGraw-Hill Companies, Inc.