as parahaemophilia is a mild and rare form and is due to a deficiency in factor v. this type can be inherited or acquired. a non-genetic form of haemophilia is caused by autoantibodies against factor viii and so is known as acquired haemophilia a. it is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors. acquired haemophilia can be associated with cancers, autoimmune disorders and following childbirth. management there is no long-term cure. treatment and prevention of bleeding episodes is done primarily by replacing the missing blood clotting factors. clotting factors commercially produced factor concentrates such as "advate", a recombinant factor viii, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection. clotting factors are usually not needed in mild haemophilia. in moderate haemophilia clotting factors are typically only needed when bleeding occurs or to prevent bleeding with certain events. in severe haemophilia preventive use is often recommended two or three times a week and may continue for life. rapid treatment of bleeding episodes decreases damage to the body. factor viii is used in haemophilia a and factor ix in haemophilia b. factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. some people 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 person becomes refractory to replacement coagulation factor as a result of high levels of circulating inhibitors, this may be partially overcome with recombinant human factor viii. in early 2008, the us food and drug administration (fda) approved an anti-haemophilic drug completely free of albumin, which made it the first anti-haemophilic drug in the us to use an entirely synthetic purification process. since 1993 recombinant factor products (which are typically cultured in chinese hamster ovary (cho) 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. clotting factors are either given preventively or on-demand. preventive use 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 (or episodic) treatment involves treating bleeding episodes once they arise. in 2007, a trial 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. preventative treatment, however, resulted in average costs of $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. most haemophiliacs in third world countries have limited or no access to commercial blood clotting factor products. other desmopressin (ddavp) may be used in those with mild haemophilia a. tranexamic acid or epsilon aminocaproic acid may be given along with clotting factors to prevent breakdown of clots. pain medicines, steroids, and physical therapy may be used to reduce pain and swelling in an affected joint. in those with severe hemophilia a already receiving fviii, emicizumab may provide some benefit. different treatments are used to help those with an acquired form of hemophilia in addition to the normal clotting factors. often the most effective treatment is corticosteroids which remove the auto-antibodies in half of people. as a secondary route of treatment, cyclophosphamide and cyclosporine are used and are proven effective for those who did not respond to the steroid treatments. in rare cases a third route or treatment is used, high doses of intravenous immunoglobulin or immunosorbent that works to help control bleeding instead of battling the auto-antibodies. contraindications anticoagulants such as heparin and warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. also contraindicated are those drugs which have "blood thinning" side effects. for instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding. also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. popular sports with very high rates of physical contact and injuries such as american football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia. other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor. prognosis like most aspects of the disorder, life expectancy varies with severity and adequate treatment. people with severe haemophilia who do not 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 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 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 people with haemophilia. two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage. epidemiology haemophilia frequency is 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 2,500 canadians have haemophilia a, and about 500 canadians have haemophilia b. history "about seventy or eighty years ago, a woman by name of smith, settled in the vicinity of plymouth, new hampshire, and transmitted the following idiosyncrasy to her descendants. it is one, she observed, to which her family is unfortunately subject, and had been the source not only of great solicitude, but frequently the cause of death. if the least scratch is made on the skin of some of them, as mortal a hemorrhagy will eventually ensue as if the largest wound is inflicted. (…) so assured are the members of this family of the terrible consequences of the least wound, that they will not suffer themselves to be bled on any consideration, having lost a relation by not being able to stop the discharge occasioned by this operation." john c. otto, 1803 scientific discovery the excessive bleeding was known to ancient people. the talmud instructs that a boy must not be circumcised if he had two brothers who died due to complications arising from their circumcisions, and maimonides says that this excluded paternal half-brothers. this may have been due to a concern about hemophilia. the first medical professional to describe the disease was arab surgeon al-zahrawi, also known as 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, john conrad otto, 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 by john dalton who studied his own family). otto was able to trace the disease back to a woman who settled near plymouth, new hampshire, in 1720. the idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when john f. hay, published an account in the new england journal of medicine. in 1924, a finnish doctor discovered a hereditary bleeding disorder similar to haemophilia localised in åland, 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. 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 in european royalty haemophilia has featured prominently in european royalty and thus is sometimes known as 'the royal disease'. queen victoria passed the mutation for haemophilia b to her son leopold and, through two of her daughters, alice and beatrice, to various royals across the continent, including the royal families of spain, germany, and russia. in russia, tsarevich alexei, the son and heir of tsar nicholas ii, famously had haemophilia, which he had inherited from his mother, empress alexandra, one of queen victoria's granddaughters. the haemophilia of alexei would result in the rise to prominence of the russian mystic grigori rasputin, at the imperial court. it was claimed that rasputin was successful at treating tsarevich alexei's haemophilia. at the time, a common treatment administered by professional doctors was to use aspirin, 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 tsarevich alexei. in spain, queen victoria's youngest daughter, princess beatrice, 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, died at age 19 from abdominal bleeding following a minor car accident in which 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. treatment the method for the production of an antihaemophilic factor was discovered by judith graham pool from stanford university in 1964, and approved for commercial use in 1971 in the united states under the name cryoprecipitated ahf. together with the development of a system for transportation and storage of human plasma in 1965, this was the first time an efficient treatment for haemophilia became available. blood contamination main article: contaminated haemophilia blood products ryan white was an american haemophiliac who became infected with hiv/aids through contaminated blood products. up until late 1985 many people with haemophilia received clotting factor products that posed a risk of hiv and hepatitis c infection. the plasma used to create the products was not screened or tested, nor had most of the products been subject to any form of viral inactivation. tens of thousands worldwide were infected as a result of contaminated factor products including more than 10,000 people in the united states, 3,500