hemophilia

Definition

Hemophilia is a genetic disorder—usually inherited—of the mechanism of blood clotting. Depending on the degree of the disorder present in an individual, excess bleeding may occur only after specific, predictable events (such as surgery, dental procedures, or injury), or occur spontaneously, with no known initiating event.

Description

The normal mechanism for blood clotting is a complex series of events involving the interaction of the injured blood vessel, blood cells (called platelets), and over 20 different proteins which also circulate in the blood.

When a blood vessel is injured in a way that causes bleeding, platelets collect over the injured area, and form a temporary plug to prevent further bleeding. This temporary plug, however, is too disorganized to serve as a long-term solution, so a series of chemical events occur, resulting in the formation of a more reliable plug. The final plug involves tightly woven fibers of a material called fibrin. The production of fibrin requires the interaction of several chemicals, in particular a series of proteins called clotting factors. At least thirteen different clotting factors have been identified.

The clotting cascade, as it is usually called, is the series of events required to form the final fibrin clot. The cascade uses a technique called amplification to rapidly produce the proper sized fibrin clot from the small number of molecules initially activated by the injury.

In hemophilia, certain clotting factors are either decreased in quantity, absent, or improperly formed. Because the clotting cascade uses amplification to rapidly plug up a bleeding area, absence or inactivity of just one clotting factor can greatly increase bleeding time.

Hemophilia A is the most common type of bleeding disorder and involves decreased activity of factor VIII. There are three levels of factor VIII deficiency: severe, moderate, and mild. This classification is based on the percentage of normal factor VIII activity present:

• Individuals with less than 1% of normal factor VIII activity level have severe hemophilia. Half of all people with hemophilia A fall into this category. Such individuals frequently experience spontaneous bleeding, most frequently into their joints, skin, and muscles. Surgery or trauma can result in life-threatening hemorrhage, and must be carefully managed.
• Individuals with 1–5% of normal factor VIII activity level have moderate hemophilia, and are at risk for heavy bleeding after seemingly minor traumatic injury.
• Individuals with 5–40% of normal factor VIII activity level have mild hemophilia, and must prepare carefully for any surgery or dental procedures.

Individuals with hemophilia B have symptoms very similar to those of hemophilia A, but the deficient factor is factor IX. This type of hemophilia is also known as Christmas disease.

Hemophilia C is very rare, and much more mild than hemophilia A or B; it involves factor XI.

Hemophilia A affects between one in 5,000 to one in 10,000 males in most populations.

One recent study estimated the prevalence of hemophilia was 13.4 cases per 100,000 U.S. males (10.5 hemophilia A and 2.9 hemophilia B). By race/ethnicity, the prevalence was 13.2 cases/100,000 among white, 11.0 among African-American, and 11.5 among Hispanic males.

— Jennifer F. Wilson, MS

For more information on hemophilia, visit Britannica.com.

A rare, hereditary blood disorder marked by a tendency toward excessive bleeding. It is almost entirely restricted to males, and is transmitted as a sex-linked mendelian recessive trait passing from an affected male through an unaffected or very mildly affected daughter to appear again in a grandson. Queen Victoria was a carrier, and several of her male descendants were affected. See also Human genetics; Sex-linked inheritance.

Classical hemophilia (hemophilia A) is due to a deficiency of the antihemophilic factor or factor VIII, a clotting factor which is normally present in the blood in trace amounts and is essential for normal fibrin formation. Hemophilia B is a similar sex-linked bleeding disorder affecting males but characterized by a deficiency of another blood clotting factor, factor IX. It can only be distinguished from hemophilia A, which it closely resembles, by laboratory tests. Hereditary deficiencies of other clotting factors may give rise to bleeding disorders similar to hemophilia, but they are inherited as autosomal dominant or recessive characteristics.

Treatment consists in the intravenous administration of potent concentrates of factor VIII or IX prepared from human plasma and they are very effective in the management of hemophilia A and B, respectively. See also Blood; Hemorrhage.

A sex-linked genetic disease manifested in males and ^^| characterized by severe hemorrhage.

Definition

Hemophilia is a coagulation disorder arising from a genetic defect of the X chromosome; the defect can either be inherited or result from spontaneous gene mutation. In each type of hemophilia (hemophilias A, B, and C), a critical coagulation protein is missing, causing individuals to bleed for long periods of time before clotting occurs. Depending on the degree of the disorder in the affected individual, uncontrolled bleeding may occur spontaneously with no known initiating event, or occur after specific events such as surgery, dental procedures, immunizations, or injury.

Description

The body's normal mechanism for blood clotting is a complex series of events (coagulation cascade) involving interaction between the injured blood vessel, blood cells called platelets, 13 specific coagulation factors (designated by Roman numerals I through XIII), and other substances that circulate in the blood.

When blood vessels are injured in a way that causes bleeding, platelets collect over the injured area, forming a temporary plug to prevent further bleeding. This temporary plug, however, is too disorganized to serve as a long-term solution, so a series of chemical events occurs that results in the formation of a more reliable plug. The final plug or clot involves tightly woven fibers of a material called fibrin. The production of fibrin requires the interaction of a series of proteins, clotting factors I through XIII, in a process called amplification to rapidly produce the proper-sized fibrin clot from the small number of molecules initially activated by the injury. In the complex coagulation process, the absence or inactivity of just one clotting factor can greatly increase bleeding time. In hemophilia, certain clotting factors are either decreased in quantity, absent altogether, or improperly formed, preventing the formation of a clot and resulting in uncontrolled bleeding.

Hemophilia A is the most common type of coagulation disorder and involves decreased activity of factor VIII. There are three levels of factor VIII deficiency: severe, moderate, and mild. This classification is based on the percentage of normal factor VIII activity present:

• Individuals with less than 1 percent of normal factor VIII activity level have severe hemophilia. Half of all people with hemophilia A fall into this category. Such individuals frequently experience spontaneous musculoskeletal bleeding into their joints, skin, and muscles. Surgery or trauma can result in life-threatening hemorrhage and must be carefully managed.
• Individuals with 1–5 percent of normal factor VIII activity level have moderate hemophilia and are at risk for heavy bleeding after seemingly minor traumatic injuries.
• Individuals with 5–40 percent of normal factor VIII activity level have mild hemophilia and must prepare carefully for any surgery or dental procedures.

In hemophilia B, or Christmas disease, the deficient clotting factor is factor IX, but the symptoms are very similar to those of hemophilia A. Factor IX is produced in the liver and is dependent on interaction with vitamin K in order to function properly. A deficiency in vitamin K can affect the clotting factor's performance as well as a deficiency in the factor itself.

Hemophilia C is rare and much milder than hemophilia A or B. It involves reduced activity of factor XI and is characterized by mild bleeding such as nosebleeds (epistaxis) or prolonged menstrual bleeding, or mild bleeding after tonsillectomies or dental extractions.

Demographics

Hemophilia A affects between one in 5,000 to one in 10,000 males in most populations. Hemophilia B occurs in one in 40,000 to 50,000. The prevalence of hemophilia is estimated to be 13.4 cases per 100,000 U.S. males (10.5 hemophilia A and 2.9 hemophilia B). By race/ethnicity, the prevalence is 13.2 cases in 100,000 among white males, 11.0 among African-American males, and 11.5 among Hispanic males. Hemophilia C occurs primarily among individuals of Jewish descent.

Causes and Symptoms

Hemophilia A and B are both caused by a genetic defect present on the X chromosome. (Hemophilia C is inherited in a different fashion.) About 70 percent of all people with hemophilia A or B inherited the disease. The other 30 percent develop from a spontaneous genetic mutation.

Both factors VIII and IX are produced by a genetic defect of the X chromosome, so hemophilia A and B are both sex-linked diseases passed on from a female to male offspring. (All humans have two chromosomes determining their gender: females have XX, males have XY. Because the trait is carried only on the X chromosome, it is called sex-linked.) Because a female child always receives two X chromosomes, she will nearly always receive at least one normal X chromosome. Therefore, even if she receives one flawed X chromosome, she will still be capable of producing a sufficient quantity of factors VIII and IX to avoid the symptoms of hemophilia. Such a person who has one flawed chromosome but does not actually suffer from the disease is called a carrier. She carries the flaw that causes hemophilia and can pass it on to her offspring. If, however, she has a son who receives her flawed X chromosome, he will be unable to produce the right quantity of factors VIII or IX, and he will suffer some degree of hemophilia. (Males inherit one X and one Y chromosome and, therefore, have only one X chromosome.)

In rare cases, a hemophiliac father and a carrier mother can pass on the right combination of parental chromosomes to result in a hemophiliac female child. However, the vast majority of people with either hemophilia A or B are male.

About 30 percent of all people with hemophilia A or B are the first member of their family to ever have the disease. These individuals have had the unfortunate occurrence of a spontaneous mutation, meaning that in their early development, some random genetic accident affected their X chromosome, resulting in the defect that causes hemophilia A or B. Once such a spontaneous genetic mutation takes place, offspring of the affected person can inherit the newly created, flawed chromosome.

In the case of severe hemophilia, the first bleeding event usually occurs prior to 18 months of age. In some babies, hemophilia is suspected immediately when a routine circumcision (removal of the foreskin of the penis) results in unusually heavy bleeding. Toddlers are at particular risk because they fall frequently and may bleed into the soft tissue of their arms and legs. These small bleeds result in bruising and noticeable lumps but do not usually require treatment. As a child becomes more active, bleeding may occur into the muscles, a much more painful and debilitating situation. These muscle bleeds result in pain and pressure on the nerves in the area of the bleed. Damage to nerves can cause numbness and decreased ability to use the injured limb.

Christmas disease varies from mild to severe, but mild cases are more common. The severity depends on the degree of deficiency of factor IX. Hemophilia B symptoms are similar to those of hemophilia A, including numerous large and deep bruises and prolonged bleeding.

Some of the most problematic and frequent bleeds occur into the joints, particularly the knees and elbows. Repeated bleeding into joints can result in scarring within the joints and permanent deformities. Individuals may develop arthritis in joints that have suffered continued irritation from the presence of blood. Mouth injuries can result in compression of the airway, which interrupts breathing and can be life-threatening. A blow to the head, which might be totally insignificant in a normal child, can result in bleeding into the skull and brain. Because the skull has no room for expansion, the hemophiliac is at risk for brain damage due to blood taking up space and exerting pressure on the delicate brain tissue.

People with hemophilia are at very high risk of severe, heavy, uncontrollable bleeding (hemorrhage) from injuries such as motor vehicle accidents and also from surgery.

Some other rare clotting disorders such as von Willebrand's disease present similar symptoms but are not usually called hemophilia.

When to Call the Doctor

Hemophilia is usually discovered when an injury initiates bleeding and the bleeding will not stop. In very young children, spontaneous musculoskeletal bleeding may occur around the time the child begins to walk; these episodes may be the first sign of hemophilia. In some children, a simple surgical procedure, such as a tooth extraction or injection, may present with uncontrolled bleeding. Any signs of deep bruises or the presence of prolonged bleeding after a bump or an injury that breaks the skin should be reported to a physician or emergency service immediately. Bleeding under the skin (hematoma), which looks like a severe bruise, should also be reported and medical care sought immediately.

Diagnosis

Various diagnostic tests are available to measure, under carefully controlled conditions, the length of time it takes to produce certain components of the final fibrin clot. The activated partial thromboplastin time (APTT) is performed and will typically be prolonged while a prothrombin time (PT) will likely be normal. Factor assays, measurement methods performed by the clinical laboratory, can determine the percentage of factors VIII and IX present compared to normal percentages. This information helps to confirm a diagnosis of hemophilia and identifies the type and severity of hemophilia present.

Families with a history of hemophilia can also have tests done during a pregnancy to determine whether the fetus will have hemophilia. Chorionic villous sampling is a test that examines proteins for deficiencies or defects that are characteristic of hemophilia. The test can be performed at 10 to 14 weeks; test performance is associated with a 1 percent risk of miscarriage. Amniocentesis is a method of withdrawing amniotic fluid from the placenta to allow examination of fetal cell DNA shed into the amniotic fluid, helping to identify genetic mutations. Amniocentesis can be performed at 15 to 18 weeks gestation and is associated with a one in 200 risk of miscarriage.

Treatment

The treatment of hemophilia involves replacing or supplementing the deficient coagulation factors. Various preparations of factors VIII and IX are available to replace missing factors as needed. Cryoprecipitate, for example, is a single- or multiple-donor human plasma preparation rich in coagulation factors; it is made available as a frozen concentrate. Fresh frozen plasma is a single-donor preparation of factor-rich plasma; it is used primarily for replacing factor XI in individuals with hemophilia C. Concentrated factor preparations may be obtained from a single donor, by pooling the donations of as many as thousands of donors, or by laboratory creation through highly advanced genetic techniques. These preparations are administered directly into the individual's veins (intravenous administration).

The frequency of treatment with coagulation factors depends on the severity of the individual's disease. Relatively mild disease will only require treatment in the event of injury, or to prepare for scheduled surgical or dental procedures. More severe disease will require regular treatment to avoid spontaneous bleeding.

Appropriate treatment of hemophilia can decrease suffering and be lifesaving in the presence of hemorrhage. Complications associated with treatment, however, can also be quite serious. About 20 percent of all individuals with hemophilia A begin to produce antibodies in their blood against the specific factor protein; the presence of antibodies may then rapidly destroy infused factor VIII. The presence of such antibodies may greatly hamper efforts to prevent or stop a major hemorrhage.

Individuals who receive coagulation factors prepared from pooled donor blood were once at risk for serious infections that could be passed through the infusion of human blood products, such as the hepatitis virus and HIV. Concern has also been raised about the possibility of hemophiliacs contracting a fatal slow virus infection of the brain (Creutzfeldt-Jakob disease) from blood products. However, more sensitive testing techniques have been developed and as of 2004 were employed by the companies producing pooled precipitates from human plasma. These improved methods of donor testing, as well as methods of inactivating viruses present in donated blood, have greatly lowered the risk of infection.

Molecular biological techniques have introduced gene therapies as new treatment possibilities for hemophilia. Gene therapy involves sophisticated methods of transferring new genes to hemophiliacs, correcting deficiencies or defects in the clotting mechanism. These methods are being researched in the early 2000s.

Prognosis

Variations in the type and severity of hemophilia makes it difficult to generalize a prognosis, however, for individuals with mild hemophilia, the prognosis is quite good. Those with more severe hemophilia can also live relatively normal lives with careful management and avoidance of injury. Many individuals achieve normal life expectancy. Without treatment of bleeding episodes, severe muscle and joint pain and eventually permanent damage can occur. Much depends upon the physical activity level of the individual and the possibility of accidental injuries or surgeries required for other conditions, which cannot be predicted.

Prevention

Because of its genetic origins, hemophilia cannot be prevented in those born with the inherited defects or factor deficiencies. However, individuals who have a family history of hemophilia may benefit from genetic testing and counseling before deciding to have a baby.

The most important way for individuals with hemophilia to prevent complications of the disease is to avoid activities that may lead to injury. Those individuals who require dental work or any type of surgery may need to be pre-treated with an infusion of factor VIII to avoid hemorrhage. Hemophiliacs should also avoid medications or drugs that promote bleeding; aspirin is one such medication and many prescription drugs have anticoagulant properties.

Parental Concerns

When a child has an inherited coagulation disorder such as hemophilia, parents will be concerned about the possibility of trauma or injury that may lead to potentially dangerous bleeding episodes. The watchfulness of parents along with effective management of hemophilia by physicians can help the child to lead a relatively normal life. Careful avoidance of injury is essential. Counseling is available to help children handle the psychosocial aspects of living with hemophilia. Education is available from public health organizations to help parents be informed about their child's condition.

See also Coagulation disorders.

Resources

Books

Britton, Beverly. Diseases and Disorders: Hemophilia. Farmington Hills, MI: Gale, 2003.

Khoury, Muin J., Wylie Burke, and Elizabeth J. Thomson, eds. Genetics and Public Health in the 21st Century: Using Genetic Information to Improve Health and Prevent Disease. New York: Oxford University Press, 2000.

McDougald, Monroe. Hemophilia Care in the New Millennium. Lancaster, UK: Kluwar Academic Publishers, 2001.

Rodriguez-Merchan, E. C., et al. Inhibitors in Patients with Hemophilia. Oxford, UK: Blackwell Publishing, 2002.

Organizations

National Hemophilia Foundation. 116 West 32nd St., 11th Floor, New York, NY 10001. Web site: www.hemophilia.org.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812–8923. Web site: www.rarediseases.org.

Web Sites

"Hemostatis and Coagulation." The Merck Manual Online, 2003. Available online at www.merckcom/pubs/mmanual/section11/chapter131.131c.htm (accessed October, 22, 2004).

March of Dimes. Available online at www.modimes.org (accessed October 22, 2004).

[Article by: L. Lee Culvert Jennifer F. Wilson, MS]

Hemophilia A and hemophilia B are genetic disorders in the blood-clotting system, characterized by bleeding into joints and soft tissues, and by excessive bleeding into any site experiencing trauma or undergoing surgery. Hemophilia A and B are clinically indistinguishable. Both have the same type of bleeding manifestations, and both affect males almost exclusively. The two conditions can be distinguished by detecting the responsible defective proteins.

Contrary to popular belief, individuals with hemophilia rarely bleed excessively from minor cuts or scratches. Hemophilia A and B are both worldwide in distribution, affecting all racial and ethnic groups. The prevalence of hemophilia A is approximately 1 in 10,000 males, and that of hemophilia B is 1 in 30,000 males.

The disorder was recognized (although not named) in Babylonian times. A second-century Jewish rabbi gave permission for a woman not to have her third son circumcised after her first two sons died from the procedure. No doubt the most famous carrier of hemophilia was the nineteenth-century Queen Victoria, whose son, Prince Leopold, had the disorder, and whose two daughters inherited and passed on the gene. Ultimately several of the European royal families were affected by Queen Victoria's gene.

There are a number of clotting factors that interact to form a stable blood clot following injury or surgery. Each factor has a name and is produced in certain cells (usually in the liver), encoded by a certain gene. Hemophilia is caused by a defect in one of these genes. In the case of hemophilia A, factor VIII (FVIII) is deficient or absent. In hemophilia B, FIX is deficient in amount or absent, or it does not function properly.

The genes encoding FVIII and FIX are on the long arm of the X chromosome. Because males have only one X chromosome, hemophilia A and hemophilia B affect males almost exclusively. If a boy's X chromosome has the defective gene that causes hemophilia A or B, the boy will have hemophilia.

Since boys with hemophilia have only an X chromosome carrying the defective gene that causes hemophilia A or B, and no gene for the production of normal FVIII (or FIX), and since fathers pass an X chromosome on to their daughters, all of their daughters will be "obligate carriers" for hemophilia. Obligate carriers—individuals who are definitely carriers—include daughters of men with hemophilia and women who have a maternal family history of hemophilia and one or more affected sons or grandsons.

In general, such carrier females do not bleed excessively, as their other X chromosome, with a gene for normal FVIII (or FIX) production, results in intermediate levels of FVIII (or FIX). However, carrier females have a fifty-fifty chance of passing their X chromosome that bears the hemophilia gene to each child they might have. A son would have an equal chance of being normal or having hemophilia. A girl would have an equal chance of being normal or being a carrier, like her mother.

Gene Defects Causing Hemophilia

Hundreds of defects in the FVIII gene have been shown to cause hemophilia A. These include deletions of varying sizes in the gene, stop codons, frameshift mutations, and point mutations. Inversion of the gene is the most common mutation. The same types of defects are found in the FIX gene. This makes population screening for hemophilia impractical: There are too many possible mutations to screen for. However, affected members of a given family will all have the same defect.

It is useful to determine (by gene analysis) which defect is present in the FVIII or FIX gene of a particular family with hemophilia, so that one can look for this defect in possible carrier females. Identification of carrier females permits genetic counseling and decision making, on the part of parents, regarding childbearing.

Detection of Fviii or Fix Gene Defect in Family: Carrier Detection

A number of different techniques are available for carrier detection. Linkage analysis using DNA polymorphisms to track defective FVIII or FIX genes is possible in large families. Use of intragenic polymorphisms in both the FVIII and FIX genes allows precise detection of carrier females in most families studied. In persons with hemophilia A, the FVIII gene inversion can be tested for by Southern blotting.

If the gene defect in the family is not known, the inversion mutation in an affected male is generally sought first, as this mutation accounts for at least 20 percent of all cases of hemophilia A, and the test is relatively simple to perform. Although more time-consuming, point-mutation screening also can be done, using a variety of methods. For researchers working on the FVIII or FIX genes, there are sites on the Internet that are valuable resources, as they contain regularly updated listings of all reported mutations in each of these genes, and other useful information.

Because of a high mutation rate, approximately one-third of infants found to have hemophilia A or B have no family history of the disorder, the condition having occurred spontaneously. However, hemophilia is genetically transmitted to future generations.

Differences in Severity of Hemophilia

There are different degrees of severity of hemophilia A and B. Clinical severity usually correlates with the individual's circulating FVIII or FIX level (determined by doing an FVIII or FIX assay on a venous blood sample). The severity is generally the same in all affected members of a family.

Normal values for FVIII and FIX can range between 50 and 150 percent of the mean value, while severely affected individuals generally have levels of less than or equal to 1 percent, moderately affected persons 1 to 5 percent, and mildly affected persons 5 to 35 percent. Severely affected individuals often have spontaneous joint and muscle hemorrhages, whereas mildly affected persons bleed only with trauma or surgery.

Treatment

Treatment for bleeding episodes consists of replacing the missing clotting factor by intravenous infusion of FVIII (or FIX). There are both human plasma-derived FVIII and FIX concentrates and recombinant DNA-derived FVIII and FIX concentrates. The useful life for both proteins (FVIII and FIX) once infused is relatively short (on average, half is degraded within twelve hours for FVIII and within eighteen hours for FIX). Thus for serious bleeding episodes or surgery, frequent repeat dosing (or continuous infusion) is often necessary.

Prophylaxis is also used, particularly in persons with severe hemophilia A or B. This consists of giving FVIII three times weekly, and FIX twice weekly (in view of its longer half-life, once infused). The aim of prophylaxis (which is often begun between age one and three) is to prevent joint bleeding (and the resulting increase in joint destruction and disability).

Persons with mild hemophilia A can often be treated with the synthetic agent DDAVP (1-deamino-8-D-arginine vasopressin). This analogue of the naturally occurring antidiuretic hormone vasopressin results in a rapid release of whatever FVIII (and another large plasma glycoprotein, von Willebrand factor) is in the individual's body storage sites. Thus, following intravenously administered DDAVP, FVIII (and von Willebrand factor) increase (two-to tenfold), but then fall back to baseline within approximately twelve to fifteen hours. This drug comes in several formulations, for intravenous, subcutaneous, and intranasal use.

It is hoped that gene therapy for persons with severe hemophilia may eventually become a realistic option. In early 2002 there were several ongoing phase-one trials (very early research studies) in human subjects with severe hemophilia, using different vectors and different techniques. However, formidable challenges remain.

Bibliography

Lakich, Delis, et al. "Inversions Disrupting the Factor VIII Gene as a Common Cause of Severe Haemophilia A." Nature Genetics 5 (1993): 236-241.

Lillicrap, David. "The Molecular Basis of Haemophilia B." Haemophilia 4 (1998): 350-357.

Potts, D. M., and W. T. W. Potts. Queen Victoria's Gene: Haemophilia and the Royal Family. Gloucestershire, U.K.: Sutton Publishing, 1995.

Internet Resources

Haemophilia B Mutation Database. King's College London. http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html.

Hemophilia: The Royal Disease. University at Buffalo, SUNY. http://ublib.buffalo.edu/libraries/projects/cases/hemo.htm.

National Hemophilia Foundation. http://www.hemophilia.org.

—Jeanne M. Lusher

A hereditary disease caused by a deficiency of a substance in the blood that aids in clotting. Hemophiliacs can bleed to death even from small cuts and bruises, because their blood has largely lost the ability to clot.

A condition characterized by impaired coagulability of the blood, and a strong tendency to bleed. See also deficiency of the following clotting factors, afibrinogenemia and hypoprothrombinemia, and proconvertin, stuart factor, plasma thromboplastin antecedent, hageman factor and fibrin stabilizing factor.

• h. A — classical hemophilia, due to deficiency of clotting factor VIII-C; occurs in dogs, horses and cats and is transmitted by the female to the male as a sex-linked recessive abnormality.
• h. B — a form similar to classical hemophilia but due to a deficiency of clotting factor IX; called also christmas disease and factor IX deficiency. Occurs in dogs and cats.
• h. C — in dogs an autosomal dominant form due to deficiency of clotting factor XI (plasma thromboplastin antecedent). Called also factor XI deficiency. The disease also occurs in cattle but the clinical disease is minor and it is inherited as a recessive character.
• double h. — dogs with both hemophilia A and hemophilia B have been produced experimentally.
• vascular h. — deficiency of clotting factor VIII and factor VIII-related antigen occurs in many breeds of dogs, particularly Doberman Pinschers, and in rabbits and pigs. See also von willebrand's disease.

Dansk (Danish)
n. - bløder, blødersygdom, hæmofil, hæmofili

Français (French)
n. - hémophilie

Deutsch (German)
n. - Bluterkrankheit, Hämophilie

Ελληνική (Greek)
n. - (παθολ.) αιμοφιλία

Italiano (Italian)
emofilia

Português (Portuguese)
n. - hemofilia (f) (Med.)

Русский (Russian)
гемофилия

Español (Spanish)
n. - hemofilia

Svenska (Swedish)
n. - hemofili (blödarsjuka)

中文（简体）(Chinese (Simplified))
血友病

中文（繁體）(Chinese (Traditional))
n. - 血友病

한국어 (Korean)
n. - 혈우병

日本語 (Japanese)
n. - 血友病

עברית (Hebrew)
n. - ‮דממת, המופיליה‬

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