Haemophilia
Overview
Haemophilia is a group of hereditary
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...

 genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

s that impair the body's ability to control blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 clotting or coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

, which is used to stop bleeding when a blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 is broken. Haemophilia A
Haemophilia A
Haemophilia A is a deficiency in clotting factor VIII.Haemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild haemophilia A has been described in heterozygous females, presumably due to extremely unfavourable lyonization...

 (clotting factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...

 deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births. Haemophilia B
Haemophilia B
Haemophilia B is a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX. It is the second most common form of haemophilia, rarer than haemophilia A. It is sometimes called Christmas disease after Stephen Christmas, the first patient described...

 (factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...

 deficiency) occurs in around 1 in about 20,000–34,000 male births.

Like most recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...

 sex-linked, X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...

 disorders, haemophilia is more likely to occur in males than females.
Encyclopedia
Haemophilia is a group of hereditary
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...

 genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

s that impair the body's ability to control blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 clotting or coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...

, which is used to stop bleeding when a blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 is broken. Haemophilia A
Haemophilia A
Haemophilia A is a deficiency in clotting factor VIII.Haemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild haemophilia A has been described in heterozygous females, presumably due to extremely unfavourable lyonization...

 (clotting factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...

 deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births. Haemophilia B
Haemophilia B
Haemophilia B is a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX. It is the second most common form of haemophilia, rarer than haemophilia A. It is sometimes called Christmas disease after Stephen Christmas, the first patient described...

 (factor IX
Factor IX
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to...

 deficiency) occurs in around 1 in about 20,000–34,000 male births.

Like most recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...

 sex-linked, X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...

 disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very low, so females are almost exclusively asymptomatic carrier
Asymptomatic carrier
An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others...

s of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Although it is not impossible for a female to have haemophilia, it is unusual: a female with Haemophilia A or B would have to be the daughter of both a male haemophiliac and a female carrier, while the non-sex-linked Haemophilia C, which can affect either sex, is extremely rare.

Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

 formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a person without it, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.

Signs and symptoms

Characteristic symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

s vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds". Patients with more severe haemophilia suffer more severe and more frequent bleeds, while patients with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.

Prolonged bleeding and re-bleeding are the diagnostic symptoms of haemophilia. Internal bleeding
Internal bleeding
Internal bleeding is bleeding occurring inside the body. It can be a serious medical emergency depending on where it occurs , and can potentially cause death and cardiac arrest if proper medical treatment is not received quickly....

 is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...

. This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.

Children with mild to moderate haemophilia may not have any signs or symptoms at birth especially if they do not undergo circumcision
Circumcision
Male circumcision is the surgical removal of some or all of the foreskin from the penis. The word "circumcision" comes from Latin and ....

. Their first symptoms are often frequent and large bruise
Bruise
A bruise, also called a contusion, is a type of relatively minor hematoma of tissue in which capillaries and sometimes venules are damaged by trauma, allowing blood to seep into the surrounding interstitial tissues. Bruises can involve capillaries at the level of skin, subcutaneous tissue, muscle,...

s and haematoma
Hematoma
A hematoma, or haematoma, is a localized collection of blood outside the blood vessels, usually in liquid form within the tissue. This distinguishes it from an ecchymosis, which is the spread of blood under the skin in a thin layer, commonly called a bruise...

s from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue
Soft tissue
In anatomy, the term soft tissue refers to tissues that connect, support, or surround other structures and organs of the body, not being bone. Soft tissue includes tendons, ligaments, fascia, skin, fibrous tissues, fat, and synovial membranes , and muscles, nerves and blood vessels .It is sometimes...

, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure
Dentistry
Dentistry is the branch of medicine that is involved in the study, diagnosis, prevention, and treatment of diseases, disorders and conditions of the oral cavity, maxillofacial area and the adjacent and associated structures and their impact on the human body. Dentistry is widely considered...

, an accident, or surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.

Complications

Severe complications are much more common in severe and moderate haemophiliacs. Complications may be both directly from the disease or from its treatment:
  • Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
  • Joint damage from haemarthrosis
    Hemarthrosis
    Hemarthrosis is a bleeding into joint spaces.-Causes:It usually follows injury but occurs mainly in patients with a predisposition to hemorrhage such as those being treated with warfarin and patients with hemophilia.It can be associated with knee joint arthroplasty.-Treatment:In hemophilia it may...

    , potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis
    Arthritis
    Arthritis is a form of joint disorder that involves inflammation of one or more joints....

    .
  • Transfusion transmitted infection
    Transfusion transmitted infection
    A Transfusion transmitted infection is a virus, parasite, or other potential pathogen that can be transmitted in donated blood through a transfusion to a recipient...

    from blood transfusions that are given as treatment.
  • Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
  • Intracranial haemorrhage
    Intracranial hemorrhage
    An intracranial hemorrhage is a hemorrhage, or bleeding, within the skull.-Causes:Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks. It can result from physical trauma or nontraumatic causes such as a ruptured aneurysm...

    is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea
    Nausea
    Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

    , loss of consciousness, brain damage
    Brain damage
    "Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...

    , and death
    Death
    Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....

    .

Life expectancy

Like most aspects of the disorder, life expectancy
Life expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...

 varies with severity and adequate treatment. People with severe haemophilia who don't receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years. By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years. Today with appropriate treatment, males with haemophilia typically have a near normal quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...

 with an average lifespan approximately 10 years shorter than an unaffected male.

Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...

 to HIV/AIDS acquired through treatment with contaminated blood products. The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of patients with haemophilia. Two other major causes of death include: hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...

 infections causing cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

 and, obstruction of air or blood flow due to soft tissue haemorrhage.

Causes

  • Haemophilia A
    Haemophilia A
    Haemophilia A is a deficiency in clotting factor VIII.Haemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild haemophilia A has been described in heterozygous females, presumably due to extremely unfavourable lyonization...

    is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 80% of haemophilia cases.
  • Haemophilia B
    Haemophilia B
    Haemophilia B is a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX. It is the second most common form of haemophilia, rarer than haemophilia A. It is sometimes called Christmas disease after Stephen Christmas, the first patient described...

    is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.
  • Haemophilia C
    Haemophilia C
    Haemophilia C is a mild form of haemophilia affecting both sexes. However, it predominantly occurs in Jews of Ashkenazi descent. It is the fourth most common coagulation disorder after von Willebrand's disease and haemophilia A and B...

    is an autosomal
    Autosome
    An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...

     genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI
    Factor XI
    Factor XI or plasma thromboplastin antecedent is the zymogen form of factor XIa, one of the enzymes of the coagulation cascade. Like many other coagulation factors, it is a serine protease. In humans, Factor XI is encoded by the F11 gene....

    . Haemophilia C is not completely recessive: heterozygous individuals also show increased bleeding.

Genetics

Females possess two X-chromosomes, males have one X and one Y-chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...

. Since the mutations causing the disease are X-linked, a woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...

 on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and he will develop the illness.

Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence haemophilia is far more common among males than females. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia
Menorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...

 (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.

A mother who is a carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...

 has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father.

Genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...

 and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...

, is available to pregnant women who may be carriers of the condition.

As with all genetic disorders, it is of course also possible for a human to acquire it spontaneously through mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

, rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.

If a female gives birth to a haemophiliac child, either the female is a carrier for the disease or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing
Genetic fingerprinting
DNA profiling is a technique employed by forensic scientists to assist in the identification of individuals by their respective DNA profiles. DNA profiles are encrypted sets of numbers that reflect a person's DNA makeup, which can also be used as the person's identifier...

, however, it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.

If a male is afflicted with the disease and has children with a female who is not even a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).

Severity

There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, patients with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1-5% active factor have moderate haemophilia, and those with mild haemophilia have between 5-40% of normal levels of active clotting factor.

Diagnosis

Haemophilia A can be mimicked by von Willebrand disease
Von Willebrand disease
von Willebrand disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor , a multimeric protein that is required for...

.
  • von Willebrand Disease could significantly affect as many as 1 in 10,000 people.
  • von Willebrand Disease type 2A, where decreased levels of von Willebrand Factor can lead to premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 2A is inherited in an autosomal dominant fashion.
  • von Willebrand Disease type 2N, where von Willebrand Factor cannot bind Factor VIII, autosomal recessive inheritance. (i.e.; both parents need to give the child a copy of the gene).
  • von Willebrand Disease type 3, where lack of von Willebrand Factor causes premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 3 is inherited in an autosomal recessive fashion.


Additionally, severe cases of vitamin K deficiency
Vitamin K deficiency
Vitamin K deficiency is a form of avitaminosis resulting from insufficient vitamin K.-Causes:Vitamin K-deficiency may occur by disturbed intestinal uptake , by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K deficiency...

 can present similar symptoms to haemophilia. This is because vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...

 is necessary for the human body to produce several protein clotting factors. This vitamin deficiency is rare in adults and older children but is common in newborns. Infants are born with naturally low levels of vitamin K and do not yet have the symbiotic gut flora
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....

 to properly synthesise their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as "haemorrhagic disease of the newborn
Haemorrhagic disease of the newborn
Haemorrhagic disease of the newborn is a coagulation disturbance in newborns due to vitamin K deficiency. As a consequence of vitamin K deficiency there is an impaired production of coagulation factors II, VII, IX, X, C and S by the liver.-Causes:...

", to avoid this complication newborns are routinely injected with vitamin K supplements.

Management

Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

, recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...

, or a combination of the two. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.

If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII
Factor VII
Factor VII is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients...

 (NovoSeven), which is registered for this indication in many countries.

In early 2008, the US Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) approved Xyntha (Wyeth
Wyeth
Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

) anti-haemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 (Dr. Mary Nugent) recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO
Chinese Hamster Ovary cell
Chinese hamster ovary cells are a cell line derived from the ovary of the Chinese hamster. They are often used in biological and medical research and commercially in the production of therapeutic proteins. They were introduced in the 1960s and grow as a cultured monolayer...

) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.

In Western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...

comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI. Prophylactic treatment, however, resulted in average costs of $
United States dollar
The United States dollar , also referred to as the American dollar, is the official currency of the United States of America. It is divided into 100 smaller units called cents or pennies....

300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin. This study resulted in the first (October 2008) FDA approval to label any Factor VIII product to be used prophylactically. As a result, the factor product used in the study (Bayer's Kognate) is now labelled for use to prevent bleeds, making it more likely that insurance carriers in the US will reimburse consumers who are prescribed and use this product prophylactically. Despite Kognate only recently being "approved" for this use in the US, it and other factor products have been well studied and are often prescribed to treat Haemophilia prophylactically to prevent bleeds, especially joint bleeds.

Preventive exercises

It is recommended that people affected with haemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles. Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems. Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.

Alternative medicine

While not a replacement for traditional treatments, preliminary scientific studies indicate that hypnosis
Hypnosis
Hypnosis is "a trance state characterized by extreme suggestibility, relaxation and heightened imagination."It is a mental state or imaginative role-enactment . It is usually induced by a procedure known as a hypnotic induction, which is commonly composed of a long series of preliminary...

 and self-hypnosis may be effective at reducing bleeds and the severity of bleeds and thus the frequency of factor treatment. Herbs which strengthen blood vessels and act as astringents may benefit patients with haemophilia, however there are no peer reviewed scientific studies to support these claims.

Contraindications

Anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

s such as Heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...

 and Warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects
Side Effects
Side Effects is an anthology of 17 comical short stories written by Woody Allen between 1975 and 1980, all but one of which were previously published in, variously, The New Republic, The New York Times, The New Yorker, and The Kenyon Review. It includes Allen's 1978 O...

. For instance, medications which contain aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

, ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

, or naproxen sodium should not be taken because they are well known to have the side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...

 of prolonged bleeding.

Also contraindicated are activities with a high likelihood of trauma, such as motorcycling
Motorcycling
Motorcycling is the act of riding a motorcycle. A variety of subcultures and lifestyles have been built up around motorcycling.-Benefits:Robert M. Pirsig's book Zen and the Art of Motorcycle Maintenance was a paean celebrating motorcycling...

 and skateboarding
Skateboarding
Skateboarding is an action sport which involves riding and performing tricks using a skateboard.Skateboarding can be a recreational activity, an art form, a job, or a method of transportation. Skateboarding has been shaped and influenced by many skateboarders throughout the years. A 2002 report...

. Popular sports with very high rates of physical contact and injuries such as American football
American football
American football is a sport played between two teams of eleven with the objective of scoring points by advancing the ball into the opposing team's end zone. Known in the United States simply as football, it may also be referred to informally as gridiron football. The ball can be advanced by...

, hockey
Hockey
Hockey is a family of sports in which two teams play against each other by trying to maneuver a ball or a puck into the opponent's goal using a hockey stick.-Etymology:...

, boxing
Boxing
Boxing, also called pugilism, is a combat sport in which two people fight each other using their fists. Boxing is supervised by a referee over a series of between one to three minute intervals called rounds...

, wrestling
Wrestling
Wrestling is a form of grappling type techniques such as clinch fighting, throws and takedowns, joint locks, pins and other grappling holds. A wrestling bout is a physical competition, between two competitors or sparring partners, who attempt to gain and maintain a superior position...

, and rugby
Rugby football
Rugby football is a style of football named after Rugby School in the United Kingdom. It is seen most prominently in two current sports, rugby league and rugby union.-History:...

 should be avoided by people with haemophilia. Other active sports like soccer, baseball
Baseball
Baseball is a bat-and-ball sport played between two teams of nine players each. The aim is to score runs by hitting a thrown ball with a bat and touching a series of four bases arranged at the corners of a ninety-foot diamond...

, and basketball
Basketball
Basketball is a team sport in which two teams of five players try to score points by throwing or "shooting" a ball through the top of a basketball hoop while following a set of rules...

 also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.

Epidemiology

Haemophilia is rare, with only about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B. About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females. It is estimated that about 2500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.

History

Scientific discovery

The first medical professional to describe a disease was Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas. While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.

In 1803, Dr. John Conrad Otto
John Conrad Otto
John Conrad Otto was a United States physician.-Biography:...

, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders." He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness
Color blindness
Color blindness or color vision deficiency is the inability or decreased ability to see color, or perceive color differences, under lighting conditions when color vision is not normally impaired...

 by John Dalton
John Dalton
John Dalton FRS was an English chemist, meteorologist and physicist. He is best known for his pioneering work in the development of modern atomic theory, and his research into colour blindness .-Early life:John Dalton was born into a Quaker family at Eaglesfield, near Cockermouth, Cumberland,...

 who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John Hay published an account in The New England Journal of Medicine.

A Finnish Doctor in 1924 discovered a heredity bleeding disorder similar to Haemophilia localised in a group of islands (called the "Aland Islands") which are located to the southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".

The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich
University of Zurich
The University of Zurich , located in the city of Zurich, is the largest university in Switzerland, with over 25,000 students. It was founded in 1833 from the existing colleges of theology, law, medicine and a new faculty of philosophy....

. In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin. In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.

European royalty

Haemophilia has featured prominently in European royalty
Haemophilia in European royalty
Haemophilia figured prominently in the history of European royalty in the 19th and 20th centuries. Britain's Queen Victoria, through two of her five daughters , passed the mutation to various royal houses across the continent, including the royal families of Spain, Germany and Russia. Victoria's...

 and thus is sometimes known as "the royal disease". Queen Victoria passed the mutation for Haemophilia B to her son Leopold and, through some of her daughters, to various royals across the continent, including the royal families of Spain
House of Bourbon
The House of Bourbon is a European royal house, a branch of the Capetian dynasty . Bourbon kings first ruled Navarre and France in the 16th century. By the 18th century, members of the Bourbon dynasty also held thrones in Spain, Naples, Sicily, and Parma...

, Germany, and Russia
Romanov
The House of Romanov was the second and last imperial dynasty to rule over Russia, reigning from 1613 until the February Revolution abolished the crown in 1917...

. In Russia, Tsarevich Alexei Nikolaevich
Tsarevich Alexei Nikolaevich of Russia
Alexei Nikolaevich of the House of Romanov, was the Tsesarevich and heir apparent to the throne of the Russian Empire. In English, his title is usually given as Tsarevich, a title that has a separate meaning in Russia. Alexei was the youngest child and only son of Emperor Nicholas II and Empress...

, son of Nicholas II, was a descendant of Queen Victoria through his mother Empress Alexandra and suffered from haemophilia.

It was claimed that Rasputin was successful at treating the Tsarevich's haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Alexei.

In Spain, Queen Victoria's youngest daughter, Princess Beatrice
Princess Beatrice of the United Kingdom
The Princess Beatrice was a member of the British Royal Family. She was the fifth daughter and youngest child of Queen Victoria and Prince Albert. Juan Carlos, King of Spain, is her great-grandson...

, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain. Two of her sons were haemophiliacs and both died from minor car accidents: Her eldest son, Prince Alfonso of Spain, Prince of Asturias, died at the age of 31 from internal bleeding after his car hit a telephone booth. Her youngest son, Infante Gonzalo
Infante Gonzalo of Spain
Infante Gonzalo of Spain was the fourth surviving son and youngest child of King Alfonso XIII of Spain and his wife Princess Victoria Eugenie of Battenberg....

, died at age 19 from abdominal bleeding following a minor car accident where he and his sister hit a wall while avoiding a cyclist. Neither appeared injured or sought immediate medical care and Gonzalo died two days later from internal bleeding.

Blood contamination issues

Prior to 1985, there were no laws enacted within the U.S. to screen blood. As a result, many haemophilia patients who received untested and unscreened clotting factor prior to 1992 were at an extreme risk for contracting HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

 and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

 via these blood products. It is estimated that more than 50% of the haemophilia population, over 10,000 people, contracted HIV from the tainted blood supply in the United States alone.

As a direct result of the contamination of the blood supply in the late 1970s and early/mid 1980s with viruses such as hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...

 and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurise) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay Tribunal
Lindsay Tribunal
The Lindsay Tribunal was set up in Ireland in 1999 to investigate the infection of haemophiliacs with HIV and Hepatitis C from contaminated blood products supplied by the Blood Transfusion Service Board.There are about 400 haemophiliacs in Ireland...

 in Ireland investigated, among other things, the slow adoption of the new methods.

See also

  • Coagulopathy
    Coagulopathy
    Coagulopathy is a condition in which the blood’s ability to clot is impaired. This condition can cause prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.The normal clotting process depends on the interplay of various proteins in...

  • Contaminated haemophilia blood products
    Contaminated haemophilia blood products
    Contaminated hemophilia blood products were a serious public health problem in the late 1970s through 1985. These products caused large numbers of haemophiliacs to become infected with HIV and hepatitis C...

  • List of haemophilia organisations
  • Purpura secondary to clotting disorders
    Purpura secondary to clotting disorders
    Purpura secondary to clotting disorders are purpura which occur due to hereditary disorders of blood coagulation in which there is a deficiency or qualitative abnormality of a single coagulation factor, as in hemophilia or von Willebrand's disease....


External links

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