haemophilia haemophilia haemophilia, or hemophilia (from ancient greek αἷμα (haîma) 'blood', and φιλία (philía) 'love of'), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. this results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. those with a mild case of the disease may have symptoms only after an accident or during surgery. bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness. not to be confused with hematolagnia. haemophiliaother nameshemophiliaa drawing of clotting factor viiipronunciation/hiːməˈfɪliə/ specialtyhaematologysymptomseasy and prolonged bleedingusual onsetat birthcausesusually geneticdiagnostic methodblood testpreventionpreimplantation screeningtreatmentreplace missing blood clotting factorsfrequency1 in 7,500 males (haemophilia a), 1 in 40,000 males (haemophilia b) there are two main types of haemophilia: haemophilia a, which occurs due to low amounts of clotting factor viii, and haemophilia b, which occurs due to low levels of clotting factor ix. they are typically inherited from one's parents through an x chromosome carrying a nonfunctional gene. rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. other types include haemophilia c, which occurs due to low levels of factor xi, von willebrand disease, which occurs due to low levels of a substance called von willebrand factor, and parahaemophilia, which occurs due to low levels of factor v. haemophilia a, b, and c prevent the intrinsic pathway from functioning properly; this clotting pathway is necessary when there is damage to the endothelium of a blood vessel. acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. diagnosis is by testing the blood for its ability to clot and its levels of clotting factors. prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. human embryos in research can be regarded as the technical object/process. missing blood clotting factors are replaced to treat haemophilia. this may be done on a regular basis or during bleeding episodes. replacement may take place at home or in hospital. the clotting factors are made either from human blood or by recombinant methods. up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. the medication desmopressin may be used in those with mild haemophilia a. studies of gene therapy are in early human trials. haemophilia a affects about 1 in 5,000–10,000, while haemophilia b affects about 1 in 40,000 males at birth. as haemophilia a and b are both x-linked recessive disorders, females are rarely severely affected. some females with a nonfunctional gene on one of the x chromosomes may be mildly symptomatic. haemophilia c occurs equally in both sexes and is mostly found in ashkenazi jews. in the 1800s haemophilia b was common within the royal families of europe. the difference between haemophilia a and b was determined in 1952. signs and symptoms an illustration of a woman with hemophilia characteristic symptoms vary with severity. in general symptoms are internal or external bleeding episodes, which are called "bleeds". people with more severe haemophilia experience more severe and more frequent bleeds, while people with mild haemophilia usually experience 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. 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. 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. 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 cases of severe and moderate haemophilia. complications may arise from the disease itself 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 (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. 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. genetics x-linked recessive inheritance typically, females possess two x-chromosomes, and males have one x and one y-chromosome. since the mutations causing the disease are x-linked recessive, a female carrying the defect on one of her x-chromosomes may not be affected by it, as the equivalent dominant allele on her other chromosome should express itself to produce the necessary clotting factors, due to x inactivation. therefore, heterozygous females are just carriers of this genetic disposition. however, the y-chromosome in the male 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 the disorder will develop. 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 expressed far more commonly among males than females, while females, who must have two deficient x-chromosomes in order to have haemophilia, are far more likely to be silent carriers, survive childhood and to submit each of her genetic children to an at least 50% risk of receiving the deficient gene. 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. 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 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. if a male has the disease and has children with a female who is not 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% and 40% of normal levels of active clotting factor. diagnosis haemophilia can be diagnosed before, during or after birth if there is a family history of the condition. several options are available to parents. if there is no family history of haemophilia, it is usually only diagnosed when a child begins to walk or crawl. they may experience joint bleeds or easy bruising. mild haemophilia may only be discovered later, usually after an injury or a dental or surgical procedure. before pregnancy genetic testing and counselling are available to help determine the risk of passing the condition onto a child. this may involve testing a sample of tissue or blood to look for signs of the genetic mutation that causes haemophilia. during pregnancy a pregnant woman with a history of haemophilia in her family can test for the haemophilia gene. such tests include: chorionic villus sampling (cvs): a small sample of the placenta is removed from the womb and tested for the haemophilia gene, usually during weeks 11–14 of pregnancy amniocentesis: a sample of amniotic fluid is taken for testing, usually during weeks 15–20 of pregnancy there is a small risk of these procedures causing problems such as miscarriage or premature labour, so the woman may discuss this with the doctor in charge of her care. after birth if haemophilia is suspected after a child has been born, a blood test can usually confirm the diagnosis. blood from the umbilical cord can be tested at birth if there's a family history of haemophilia. a blood test will also be able to identify whether a child has haemophilia a or b, and how severe it is. classification there are several types of haemophilia: haemophilia a, haemophilia b, haemophilia c, parahaemophilia, acquired haemophilia a, and acquired haemophilia b. haemophilia a is a recessive x-linked genetic disorder resulting in a deficiency of functional clotting factor viii. haemophilia b is also a recessive x-linked genetic disorder involving a lack of functional clotting factor ix. haemophilia c is an autosomal genetic disorder involving a lack of functional clotting factor xi. haemophilia c is not completely recessive, as heterozygous individuals also show increased bleeding. the type of haemophilia known