When you bleed, your body normally pools blood cells together to form a clot to stop the bleeding. The clotting process is encouraged by certain blood particles (platelets and plasma proteins). Hemophilia occurs when you have a deficiency in one of these clotting factors.

Hemophilia is inherited. However, about 30 percent of people with hemophilia have no family history of the disorder. In these people hemophilia is caused by a genetic change (spontaneous mutation).

There are several types of hemophilia. They are classified according to which clotting factor is deficient:

• Hemophilia A, the most common type, is caused by insufficient clotting factor VIII.
• Hemophilia B, the second most common type, is caused by insufficient clotting factor IX.
• Hemophilia C, in which signs and symptoms are often mild, is caused by insufficient clotting factor XI.

Hemophilia inheritance

Everyone has two sex chromosomes, one from each parent. A female inherits an X chromosome from her mother and an X chromosome from her father. A male inherits an X chromosome from his mother and a Y chromosome from his father.

Hemophilia inheritance depends on your type of hemophilia:

• Hemophilia A or B. The gene that causes them is located on the X chromosome, so it can't be passed from father to son. Hemophilia A or B almost always occurs in boys and is passed from mother to son through one of the mother's genes. Most women with the defective gene are simply carriers and experience no signs or symptoms of hemophilia. Women can experience bleeding symptoms if their factor VIII or IX is moderately decreased.
• Hemophilia C. This disorder can be passed on to children by either parent. Hemophilia C can occur in girls and boys.

Another mild and rare form of haemophilia is known as parahaemophilia and is due to a deficiency in factor V.^[4]A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as acquired haemophilia A.^[5]Acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth.^[6]

Like other recessive sex-linked, X chromosome disorders, haemophilia A and B are 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 remote, so females are almost exclusivelyasymptomatic carriers 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: daughters which are the product of both a male with haemophilia A or B and a female carrier will possess a 50% chance of having haemophilia.

People with haemophilia have lower clotting factor level of blood plasma or impaired activity 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 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 cases 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. The word is from the Greek haima ???? 'blood' and philia ????? 'love'.^[7]

Signs and symptoms

Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds".^[8][9] People with more severe haemophilia suffer more severe and more frequent bleeds, while people with mild haemophilia usually suffer more minor symptoms except after surgery or serious trauma. In cases of moderate haemophilia symptoms are variable which manifest along a spectrum between severe and mild forms.^{[citation needed]}

In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding 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.^[10] 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.^[10] Bleeding into soft tissues such as muscles andsubcutaneous 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. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, 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, an accident, or surgery. 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:^[11]

• Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
• Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
• Transfusion transmitted infection 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 is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.

Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction.^[12] If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis. In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in cartilage and bone destruction.^[13]

Genetics

Females possess two X-chromosomes, males have one X and one Y-chromosome. 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 alleleon 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.

X-linked recessive inheritance

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 (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 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. This is a recessive trait and can be passed on if cases are more severe with carrier.Genetic testing and genetic counselling is recommended for families with haemophilia.Prenatal testing, such as amniocentesis, 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, 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 son, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, 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, people 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.^[10]

Diagnosis

could significantly affect as many as 1 in 10,000 people.Haemophilia A can be mimicked by 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.
• 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 can present similar symptoms to haemophilia. This is because vitamin K 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 to properly synthesise their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as "haemorrhagic disease of the newborn". To avoid this complication, newborns are routinely injected with vitamin K supplements.

Classification

There are several types of haemophilia, such as:

• Haemophilia A is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII ^[16]
• Haemophilia B is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. ^[17]
• Haemophilia C is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, asheterozygous individuals also show increased bleeding.^[15]
•