Hemophilia historical perspective
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]
Overview
Hemophilia was first described by Dr. John Conrad Otto, a physician practicing in Philadelphia in 1803 who wrote an account about "a hemorrhagic disposition existing in certain families." He recognized that the disorder was hereditary and that it affected mostly males and rarely affected females.
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Xyz Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Hemophilia historical perspective On the Web |
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American Roentgen Ray Society Images of Hemophilia historical perspective |
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Risk calculators and risk factors for Hemophilia historical perspective |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[4]
Overview
Historical Perspective
Discovery
- Hemophilia was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event].
- Hippocrates was the first one who observed the blood of wounded soldier was coagulated as cooled which is traced back to 400 B.C.
- Aristotle observed similar finding.
- According to many European historians, the earliest written references which could be implictaed as haemophilia are described in Jewish writings of the 2nd century AD.
- A ruling of Rabbi Judah the Patriarch exempts a woman's third son from being circumcised if his two elder brothers had died of bleeding after circumcision. Additionally,he had history of his three sons being died after circumcision
- Hemophilia was first discovered by Al-Zahrawi-Albucaisi, a physcian, in 936-1013 AD.
- His description corresponds with haemophilia.He described following points:
- His terminology was indicative of the real cause of the disease.
- He described inherited pattern of disease as it was in only one village.
- He tried to find a former description of the disease in some ancient physicians, but we found nothing.
- He noticed the limitation of the disease to males and their boys.
- He characterized the disease with easy bleeding after minor traumas which is nowadays considered the primal symptom of the disease.
- He admitted that he didn't know the cause of the disease which was impossible to be discovered in his time.
- He recommended using the cauterization of the bleeding place until the vessels stop bleeding.
- In 1803, an American physicain,Dr. John Conrad Otto, published an account about "a hemorrhagic disposition existing in certain families" in the "New York Medical Repository".
- He recognized that the disorder was hereditary and it affected only males.
- The disorder was transmitted by unaffected females to a proportion of their sons.
- He was able to trace the disease back to a woman who settled near Plymouth, New Hampshire in 1720 AD. These accounts
began to define a clinical syndrome on which the 19th century developed an extensive literature.
- The recent rather strange name 'haemophilia' which means 'love of blood' appeared in the title of Hopff's treatise of 1828 published at the University of Zurich.
- In 1886, Sir Frederick Treves described the case haemophilia in the female from a first-cousin marriage.
- In 1890, Konig describes the involvement of joints as the most characteristic symptom of
haemophilia.
- The association between [important risk factor/cause] and [disease name] was made in/during [year/event].
- In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].
- In [year], [gene] mutations were first implicated in the pathogenesis of [disease name].
Outbreaks
There have been several outbreaks of [disease name], which are summarized below:
Landmark Events in the Development of Treatment Strategies
In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name].
Impact on Cultural History
Famous Cases
The following are a few famous cases of hemophilia:
The Royal Hemophilia:
- In 19th and 20th centuries, Queen Victoria,passed the mutation to various royal houses through two of her five daughters (Princess Alice and Princess Beatrice), across the continent, including:
- The royal families of Spain
- Germany
- Russia
- Victoria's son Leopold suffered from the disease.
- The spread of hemophilia in the royal families of Europe played a crucial role in the development of medical knowledge about the disease.
- The condition was not reported among any of the Queen's antecedents, so that it was supposed that a mutation occurred at spermatogenesis in her father, Edward, Duke of Kent, a mischance perhaps made more likely by the fact that he was in his fifties when she was conceived.
Hemophilia in the British Royalty:
- William Hewson Leopold was severely affected and suffered numerous bleeding episodes.
- In 1868 the British Medical Journal noted a 'severe accidental haemorrhage' leading to 'extreme and dangerous exhaustion by the loss of blood' at the age of 15.
- In 1884, at the age of 30, he died of a cerebral hemorrhage after hitting his head.
- In 1907, his daughter, Alice, had a hemophilic son, Rupert, Viscount Trematon, who died at 21, also of a cerebral hemorrhage.
Haemophilia in the German and Russian Royalty:
- Alice, Victoria's third child, passed it on to at least three of her children:
- Prince Friedrich
- Princess Irene
- Princess Alix
- Princess Victoria
- Prince Friedrich Died before his third birthday of cerebral bleeding resulting from a fall.
- Princess Irene of Hesse and by Rhine (later Princess Heinrich of Prussia), who passed it on to two of her three sons: ** Prince Waldemar of Prussia. Survived to age 56;had no issue.
- Prince Heinrich of Prussia who died at age 4.
- Princess Alix of Hesse and by Rhine.
- Alix married Tsar Nicholas II of Russia and passed it on to her only son, Tsarevitch Alexei who was murdered by the
Bolsheviks at the age of 13.
- Alexei's haemophilia was one of the factors contributing to the collapse of Imperial Russia during the Russian Revolution of 1917.
- The illness of the Tsarevich cast its shadow over the whole of the concluding period of Tsar Nicholas II's reign and alone can explain it.
- Without appearing to be, it was one of the main causes of his fall, for it made possible the phenomenon of Rasputin (1869-1016) and resulted in the fatal isolation of the sovereigns who lived in a world apart and wholly absorbed in a tragic anxiety which had to be concealed from all eyes.
- Rasputin used hypnosis to relieve pain and/or slow hemorrhages, and sent away
- It is not known whether any of Alexei's sisters were carriers, as all four were executed with him before any of them had issue.
- One, Grand Duchess Maria, is thought by some to have been a symptomatic carrier, because she hemorrhaged during a
tonsillectomy.
- Princess Victoria of Hesse and by Rhine, Alice's oldest child and maternal grandmother to Prince Philip, Duke of Edinburgh, might have inherited the mutation, though the gene remained hidden for several generations before reappearing in the descendants of her eldest granddaughter, Princess Margarita of Greece and Denmark.
Hemophilia in the Spanish Royalty:
- Princess Beatrice, Victoria's ninth and last child, passed it on to at least two, if not three, of her children:
- Princess Victoria Eugenie
- Prince Leopold
- Prince Maurice
- Princess Victoria Eugenie of Battenberg (later Queen Victoria Eugenia of Spain), who passed it on to Infante Alfonso and Infante Gonzalo.
- Infante Alfonso of Spain, Prince of Asturiaswho died at age 31, bleeding to death after a car accident whereas Infante Gonzalo who died at age 19, bleeding to death after a car accident.
- Prince Leopold of Battenberg. Later Lord Leopold Mountbatten. Died at age 32 during a knee operation.
- Prince Maurice of Battenberg who killed in action in World War I in 1914 at the age of 23.
- Maurice's hemophilia is disputed by various sources. It seems unlikely that a known hemophiliac would be allowed to serve in combat.
Hemophilia in the Last Century:
- In 1905, Paul Oskar Morawitz (1879-1936) assembled coagulation factors into the scheme of coagulation.
- He demonstrated the role of calcium (Factor IV) and tissue thromboplastin (Factor III), prothrombin (Factor II)
in conversion to thrombin, which in turn converted fibrinogen (Factor I) into a fibrin clot.
- He introduced his landmark theory in Ergebn Physiol magazine.
- This theory persisted for 40 years.
- In 1944until Paul Owren, , discovered a bleeding patient who defied the four- factor concept of clotting.
- Owren observed a cofactor that was involved in the conversion of prothrombin to thrombin. Thus factor V was discovered.
- Many reputable scientists claimed early success in treating with unusual substances.
- In 1936 A report in The Lancet extolled the virtues of a bromide extract of egg white.
- As recently as 1966, a report in the esteemed scientific journal Nature claimed that peanut flour was also effective for the treatment of hemophilia.
- The first hint of success came with the report from R.G. Macfarlane in 1934 that snake venoms could accelerate the clotting of haemophilic blood, and he reported success in controlling superficial bleeds in people with hemophilia after topical application.
- Factor VIII was discovered in 1937 by American researchers A.J. Patek and F.H.L. Taylor.
- They found that intravenous administration of plasma precipitates shortens blood clotting time.
- Taylor later calls the precipitates anti- hemophilic globulin.
- In 1939, American pathologist Kenneth Brinkhous showed that people with hemophilia have a deficiency in the plasma factor he later called anti- hemophilic factor.
In 1952, Loeliger named this factor VII.
- Buenos Aires physician Pavlovsky reported that the blood from some hemophiliac patients corrected the abnormal clotting time in others.
- In 1952, Rosemary Biggs from Oxford U.K. calls it Christmas disease, named for the first patient, Stephen Christmas. The clotting factor was called Christmas factor or factor IX.
- Factor XI deficiency was described in 1953 as a milder bleeding tendency.
- In 1955, Ratnoff and Colopy identified a patient, John Hageman, with a factor XII deficiency who died from a thrombotic stroke, not a bleeding disease.
- Factor X deficiency was described in 1957 in a woman named Prower and a man named Stuart.
- In 1960, Duckert described patients who had a bleeding disorder and characteristic delayed wound healing. This fibrin stabilizing factor was called factor XIII.
- In the early days, treatment of hemophilia A patients consisted of giving whole blood units to relieve symptoms.
- Not until 1957 was it realized that the deficient coagulation protein was a component of the plasma portion of blood.
- In 1958, Inga Marie Nilsson, a Swedish physician, begins prophylaxis in treatment of boys with severe hemophilia A.
- Regular prophylactic treatment does not begin until the early 1970s.
- The World Federation of Haemophilia was established in 1963.
- Cryoprecipitate, a plasma derivative, was discovered by Dr. Judith Pool in
1964.
- This product is produced as an insoluble precipitate that results when a unit of fresh frozen plasma is thawed in a standard blood bank refrigerator.
- Cryoprecipitate contains fibrinogen, factor VIII, and vWF.
- This product is extracted from plasma and usually pooled before it is given to the patient according to weight and level of factor
VIII.
- This product presented a major breakthrough for the hemophilia population because it was an easily transfusable product affording the maximum level of factor to the individual.
- Next in the chronology of treatment products for hemophilia was clotting factor products. These freeze-dried products were developed in the early 1970s.
- The products were lyophilized and freeze dried and could be reconstituted and infused at
home.
- This treatment offered the hemophilia population an independence that they had never previously experienced. Finally they were in control because they could self- infuse when necessary and provide themselves with prompt care when a bleeding episode developed.
- Another landmark was the recognition by Italian Prof. Pier Mannucci in 1977 that desmopressin (DDAVP) could boost levels of both factor VIII and von Willebrand factor, and this remains a useful option in mild forms of these conditions.
- But a dark cloud loomed over the bleeding community.
- Approximately 80% to 90% of hemophilia A patients treated with factor concentrates in the period 1979- 1985 became infected with the HIV virus.
- Factor concentrates were made from pooled plasma from a donor pool that was less than adequately screened.
- Additionally, manufacturing companies were less than stringent with sterilization methods and screening for HIV virus did not occur in blood banks until 1985.
- When each of these factors is brought to bear, the tragedy to the bleeding community is easily understood.
- According to the National Hemophilia Foundation, there are 17,000 to 18,000 hemophilia patients (hemophilia A and B) in the United States.
- Of those, 4200 in the United States and about 1200 in the UK are infected with HIV/AIDS. There are no numbers available for wives or children who could have been secondarily infected.
- The hepatitis C virus (HCV) was first identified in 1989, and it soon became clear that an even higher proportion of people with hemophilia had been exposed to this virus.
- Fortunately, the introduction of physical treatments of concentrates such as exposure to heat or the addition of a solvent-detergent mixture has effectively eliminated the risk of the transmission of these viruses.
- The structure of the factor VIII gene was characterized and cloned in 1984.
- This led to the availability of recombinant factor VIII Recombinant products became available in 1989 and represent the highest purity product because they are not human derived.
- Recombinant technology uses genetic engineering to insert a clone of the factor VIII gene into mammalian cells, which express the gene characteristic.
- Production expenses for this product are unfortunately the most costly, and these costs are passed on to potential users. Most individuals with hemophilia in the United States use factor concentrates prophylactically.
10 Life expectancy of a child growing up with haemophilia today is comparable to that of someone without a bleeding disorder.
- In 1998, Gene therapy trials on humans began. In the future, gene therapy is considered a realistic goal.
References
Historical Perspective
Scientific Discovery[1]
- The first evidence of hemophilia is in the Talmud, Jewish holy text, which states that males did not have to be circumcised if two brothers had already died from the procedure.
- In the 12th century, the Arab physician Albucasis wrote of a family whose males died of bleeding after minor injuries.
- In 1803, Dr. John Conrad Otto, a Philadelphia physician, wrote an account about "a hemorrhagic disposition existing in certain families." He recognised that the disorder was hereditary and that it affected males and rarely females. He was able to trace the disease back to a woman who settled near Plymouth in 1720. 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).
- 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.
- The first usage of the term "hemophilia" appears in a description of the condition written by Hopff at the University of Zurich in 1828.[2]
- In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-hemophilic globulin.
- Pavlosky, a doctor from Buenos Aires, found Hemophilia A and Hemophilia B to be separate diseases by doing a lab test.
- This test was done by transferring the blood of one hemophiliac to another hemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of hemophilia.
- In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to hemophilia localised in the "Åland Islands", southwest of Finland. This bleeding disorder is called "Von Willebrand Disease".
European Royalty
Queen Victoria passed hemophilia on to many of her descendants.
- Hemophilia has featured prominently in European royalty and thus is sometimes known as 'the royal disease'. Queen Victoria passed the mutation for hemophilia B to her son Leopold and, through some of her daughters, to various royals across the continent, including the royal families of Spain, Germany and Russia. In Russia, Tsarevich Alexei Nikolaevich son of Nicholas II, was a descendant of Queen Victoria through his mother Empress Alexandra and suffered from hemophilia.[3][4]
- It was claimed that Rasputin was successful at treating Tsarevich Alexei's hemophilia. 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 hemophiliacs 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 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
- Ryan White was an American hemophiliac who became infected with HIV/AIDS through contaminated blood products.
- Prior to 1985, there were no laws enacted within the U.S. to screen blood. As a result, many people with hemophilia who received untested and unscreened clotting factor prior to 1992 were at an extreme risk for contracting HIV and hepatitis C via these blood products. It is estimated that more than 50% of the haemophilia population, i.e. 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 and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurized) 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 in Ireland investigated, among other things, the slow adoption of the new methods.
References
- ↑ "Hemophilia wikipedia".
- ↑ "The History of haemophilia". Retrieved 2007-06-27.
- ↑ Michael Price (8 October 2009). "Case Closed: Famous Royals Suffered From Hemophilia". ScienceNOW Daily News. AAAS. Retrieved 9 October 2009.
- ↑ Evgeny I. Rogaev; et al. (8 October 2009). "Genotype Analysis Identifies the Cause of the "Royal Disease"". Science. Retrieved 9 October 2009.