Six Characters in Search of An Author: The History of the Nomenclature of Coagulation Factors
2003; Wiley; Volume: 121; Issue: 5 Linguagem: Inglês
10.1046/j.1365-2141.2003.04333.x
ISSN1365-2141
Autores Tópico(s)Hemophilia Treatment and Research
Resumo'Quando i personaggi sono vivi, vivi veramente davanti al loro autore, questo non fa altro che seguirli nelle parole, nei gesti.…'. Luigi Pirandello: Sei personaggi in cerca d'autore (Nobel Laureate for Literature, 1934) Our knowledge of the blood coagulation system has expanded tremendously in the last 60 years. Many of the coagulation factors were identified through the detailed study of individual patients with a clear hereditary bleeding tendency. However, it became apparent by the mid-1950s that a unified nomenclature was desirable because many of the coagulation factors had been named independently by several groups of workers who studied different properties and who initially thought that they had discovered different factors. An international committee was, therefore, established in 1954 with the aim of harmonizing the nomenclature of the various factors. Roman numerals were assigned at various meetings of this committee held between 1955 and 1963. The current nomenclature is not entirely satisfactory, and perhaps the time has now come for a complete revision in the light of recent insights into the complex mechanism of blood coagulation. This is primarily an account of how the current nomenclature of the blood coagulation factors came into being, but it is also the more personal story of six patients whose names are still associated with several important haemostatic proteins: Christmas (factor IX), Stuart and Prower (factor X), Hageman (factor XII), Fletcher (prekallikrein) and Fitzgerald (high-molecular-weight kininogen). In the modern era of evidence-based medicine, only the results of large randomized and controlled trials and meta-analyses seem to command respect and credibility. It can be difficult in this intellectual climate to appreciate that humble case reports, usually banished to the last pages of modern journals, have often been the source of great advances in the past. In particular, many of the advances in coagulation medicine have come from case reports from physicians who have written about patients encountered in their busy everyday practice, patients in whom they recognized something special or unusual, and from whom they have learnt important clinical and scientific lessons. By the middle of the 19th century, a simple theory of blood clotting had evolved which was based upon the work of, among others, Andrew Buchanan (1798–1882), Olaf Hammersten (1841–1912), Alexander Schmidt (1831–1894) and Paul Morawitz (1879–1930). The theory envisaged the involvement of just four factors: thrombokinase (or thromboplastin) derived from damaged tissues or cells, prothrombin, fibrinogen and calcium. Thromboplastin was released into the circulation at the site of tissue damage and reacted with prothrombin in the presence of calcium to form thrombin, which in turn reacted with fibrinogen to form fibrin. By the 1940s, it became clear that other proteins were involved. One of the first relevant observations was made by Armand Quick (1894–1977) who had developed the one-stage prothrombin time. He noted that the prothrombin time of plasma lengthened on storage but was corrected by the addition of fresh plasma derived from a patient being treated with a coumarin anticoagulant (dicoumarin) (Quick, 1943). This observation led Quick to infer that there was a labile factor in plasma that was destroyed on storage, as well as a stable factor, the level of which was reduced by coumarins. In 1947, Paul Owren (1905–1990) published the details of work carried out carried out at the University of Oslo for his doctoral thesis (Owren, 1947). He observed a prolonged prothrombin time in a woman with a lifelong bleeding tendency, which was corrected by adding normal plasma from which all the prothrombin had been removed by adsorption with aluminium hydroxide. He postulated that the patient lacked a factor normally present in plasma and which is necessary for the normal interaction between prothrombin and thromboplastin. He was subsequently able to show that this new factor was relatively labile, unlike prothrombin, and it was not present in normal serum. He initially called it factor V, setting a precedent for Roman numerals to identify coagulation factors. However, he later renamed it proaccelerin on the basis of subsequent work because of the evidence that the factor is a precursor of a substance (accelerin) that accelerates the reaction of prothrombin and thromboplastin. Owren also subsequently assigned the name factor VI to accelerin, which is now known to be the activated form of factor V (Va) rather than an entirely separate entity. Shortly thereafter, it was shown that a small proportion of serum would shorten the prothrombin time of plasma diluted with plasma which had been adsorbed with barium sulphate. This suggested that adsorption had removed not only prothrombin but another necessary factor which was replaced by adding serum, which was called 'serum prothrombin conversion accelerator' (SPCA) (De Vries et al, 1949). The same group also described a bleeding disorder in a young girl which they attributed to congenital deficiency of this newly identified coagulation factor (Alexander et al, 1951). In Switzerland, Koller et al (1951) independently identified the same factor, which they termed factor VII. Although haemophilia was recognized by 1850 as a well-defined clinical entity with a clear pattern of X-linked inheritance, the aetiology remained elusive for many years. While the coagulation time of haemophilic blood, as measured in glass tubes by the Lee and White method, was typically grossly prolonged, the one stage prothrombin time was normal and furthermore the defect could be corrected in vitro by the addition of plasma from patients taking coumarin anticoagulants. The possibility that tissue thromboplastin in people with haemophilia was somehow defective was ruled out by showing that haemophilic tissue extract showed normal activity. Similarly, platelet function was also shown to be normal in haemophilia by several groups. The term 'antihaemophilic globulin' (AHG) was first used in 1937 to describe a concentrated globulin derived from normal plasma which reduced the coagulation time of haemophilic blood (Patek & Taylor, 1937). With the development of Cohn fractionation, it was subsequently shown that the active factor was present in fractions I and III of normal plasma, but not in similar fractions of haemophilic plasma. Unlike factor V and VII, this 'antihaemophilic globulin' (AHG) could not be wedged into the existing classical theory of coagulation as it seemed to play no part in either the thromboplastin–prothrombin reaction or subsequent steps. The development of a new test, the thromboplastin generation test, was an important advance as it enabled a more detailed analysis and localization of clotting defects (Biggs & Douglas, 1953). By using either the absorbed plasma or the serum or the platelet component from the patient and completing the system with the two remaining components from normal blood, it was possible to ascribe the cause to a clotting defect of one or more of these components. As anticipated, the results of the thromboplastin generation test in classical haemophilia were indicative of a defect in the plasma component. A further complication arose when it also soon became apparent that haemophilia was not a homogeneous disorder in terms of the clotting defect. Alfredo Pavlovsky (1907–1984) in Buenos Aires reported that 'occasionally (in vitro) the blood of some of the haemophilic patients with a greatly prolonged clotting time…when added to other haemophilic blood possessed a coagulant action nearly as effective as normal blood' (Pavlovsky, 1947). We now know that this was due to the normal level of factor VIII in the plasma of patients with haemophilia B correcting the defect in patients with the much commoner form, haemophilia A. Christmas factor (later to be labelled factor IX) was the first coagulation protein to be named after a patient, a precedent established by Biggs (1912–2001, Fig 1) and Macfarlane (1907–1987, Fig 2) in Oxford in 1952. In December of that year, they published the clinical and laboratory findings of seven patients with what appeared to be classical haemophilia, but in whom the thromboplastin generation test indicated a defect in the serum component. The authors named the disease after their first patient, Stephen Christmas: 'The naming of clinical disorders after patients was introduced by Sir Jonathan Hutchinson [British surgeon 1828–1913] and is now familiar from serological research; it has the advantage that no hypothetical implication is attached to such a name' (Biggs et al, 1952). The Christmas edition of the British Medical Journal (BMJ) typically publishes light-hearted and even frivolous papers. The timing of the publication was perfect and the BMJ agreed to accept the paper at very short notice but the response to this important publication was not all entirely positive. As Rosemary Biggs recalled many years later, 'everybody read the article because they thought it was something to do with overeating' (Lee & Rizza, 1998). Some thought it was a student's prank or that the story had been made up. Two letters appeared in the BMJ the following month, from a Dr Kemp of Birmingham and Douglas Collins, Professor of Pathology in Leeds, protesting at the frivolity of using a Christian festival for the name of a disease and suggesting that some sort of an apology would be appropriate. Collins concluded: 'Some parents live to regret the names they have thoughtlessly bestowed upon their innocent children. Would it not be possible …in your capacity as registrar of its birth, to substitute some less ridiculous name?' Macfarlane, Biggs and Douglas replied that they were too modest to suggest a seven name eponym. The only alternative name they could think of was 'hereditary hypocoprothrombinaemia'. However, they did promise that if they found the precursor protein, they would resist the urge to call it 'Christmas Eve factor'. The distinguished serologist Alexander Wiener also wrote to the journal to protest at the name and urged the adoption of the alternative name of haemophilia B (Wiener, 1953). Dr Rosemary Biggs (1912–2001). Reproduced from the collection of the Oxford Haemophilia Centre, with permission. Professor R.G. Macfarlane (1907–1987). Photograph taken on his 60th birthday. Reproduced from the collection of the Oxford Haemophilia Centre, with permission. Stephen Christmas (Fig 3) was born on 12 February 1947 and was just 5 years old when his case history was published. Stephen and his older brother, Robin, were born in London to British parents, their names deliberately chosen with an evident sense of humour because of their associations with the Christmas season. Their father, Eric, was an actor who spent part of the war on tour to entertain troops. Shortly after the end of the war, the family later emigrated to settle in Toronto in Canada, and it was there at the age of 2 years that haemophilia was diagnosed at the Hospital for Sick Children. There was no family history of haemophilia and his bleeding tendency had first been noted when he was 20 months old. The family returned to Britain in 1952 to visit their relatives, and during the trip Stephen was admitted to hospital in London and a sample of his blood was sent to Biggs and Macfarlane in Oxford. Stephen never relinquished his ties with Britain and was the only member of his family not to renounce British citizenship to become a Canadian. Stephen had a passion for photography and studied the subject at the Ryerson Institute of Technology (now Ryerson University) in Toronto. He was employed for some years as a medical photographer at the Hospital for Sick Children in Toronto, although he mainly worked as a cab driver which he found easier because of his disability. Later in life, Stephen became an active worker for the Canadian Haemophilia Society (CHS) and an outspoken critic of the Canadian regulatory authorities. He campaigned tirelessly for the cause of blood safety and helped to secure financial compensation for patients infected with human immunodeficiency virus. His name reappeared in the medical literature again in 1992 when his genotype was studied, which turned out to be a hitherto unreported mutation (cysteine 206 serine) (Taylor et al, 1992). Sadly, he died the following year at the age of 46 years from acquired immunodeficiency syndrome, contracted through treatment with blood products. Ironically, he died just before Christmas on 20 December 1993. In reporting his death, the Toronto Globe and Mail noted that 'Christmas was not only an inspirational symbol for haemophiliacs, but he was also an activist who was critical in bringing the tainted-blood issue to national attention'. A photograph of Stephen Christmas, taken in 1957 when he was 10 years old, during an admission to Toronto General Hospital to receive a plasma transfusion for a haemarthrosis. The physician on his left is Dr J. Lawrence Naiman. Photograph kindly provided by the patient's brother, Robin Christmas. Although the discovery of Christmas factor (factor IX) is usually associated with the names of Biggs and Macfarlane, it must be acknowledged that others described identical conditions some months beforehand. In April 1952, Paul Aggeler (1911–1969) and colleagues in San Francisco described the case of a 16-year-old boy with the classical symptoms of haemophilia but in whom the prolonged coagulation time was not corrected in vitro by the addition of antihaemophilic globulin (Cohn fraction I) or plasma adsorbed with barium sulphate (BaSO4) (Aggeler et al, 1952). The authors of the paper called the new factor 'plasma thromboplastin component' (PTC). Irving Schulman independently reported another similar case in August 1952, involving an 11-month-old boy of Italian extraction (Schulman & Smith, 1952). Among the extensive laboratory investigations carried out, it was noted that the patient's plasma normalized the recalcification time of plasma from a patient known to have haemophilia and that, in reverse, plasma from a patient with haemophilia also normalized the recalcification time of the new patient's plasma. Schulman noted that there was no family history in this case and thus considered that it must be different from the usual hereditary form of haemophilia and proposed the alternative names of 'parahaemophilia' and 'pseudohaemophilia'. However, it is a fact that only the term 'Christmas disease' stood the test of time and still remains in widespread use in the English-speaking world, although the associated term 'Christmas factor' has largely been superseded. Factor X was discovered by the study of two patients with a congenital bleeding tendency. Miss Audrey Prower (Fig 4) was 22-year-old when she was admitted to University College Hospital in London in 1956 for investigation of a bleeding tendency prior to a dental extraction (Telfer et al, 1956; Denson, 1957). She had a significant past medical history, including significant bleeding after two previous dental extractions in 1939 and 1945. She had also bled profusely after tonsillectomy at the age of 8 years, requiring a blood transfusion. Furthermore, her brother had died of postoperative bleeding after tonsillectomy when he was 5 years old. Miss Prower reported that she had heavy periods but said that she did not feel that she bruised easily or bleed unduly from cuts or scratches. Both her parents were already dead and there was no definite history in other relatives who were questioned. On this occasion, there was intermittent bleeding for 8 d after the dental extraction which was treated with local application of fibrin foam, thrombin and Stypven. Blood transfusion did not prove necessary. Miss Audrey Prower (photograph taken in 1956). Photograph kindly provided by Dr Kenneth Denson. I am grateful to Dr Kenneth Denson of the Thame Thrombosis and Haemostasis Research Foundation (UK) for sharing his recollections of his work on this interesting patient with me (personal communication, 2002). 'Audrey Prower was a delightful and co-operative young lady who presented with bleeding after dental extraction, and a history of bleeding following tonsillectomy which required blood transfusion, and menorrhagia. She subsequently delivered two male infants following normal pregnancies in 1959 and 1962. She was given whole blood transfusions post partum after the first because concentrates were not available, and suffered no untoward bleeding. After the second infant she bled seven days post partum and I dashed up to University College Hospital (UCH) in London from Oxford with a newly developed concentrate of factors II, VII, IX and X, kindly provided by Dr Ethel Bidwell. This miraculously stemmed all bleeding and the obstetricians were very impressed. I bled her on numerous occasions. Every new paper necessitated visits to Audrey and she cheerfully donated her rare blood. In the 1954/1960 era, freeze-drying was unheard of, most laboratories had a 4°C fridge but very few boasted a freezer. I managed to persuade the hospital chef to let me keep her plasma samples in the kitchen freezer. They didn't like me using the meat freezer and would only allow me to use the fish freezer, and so all tubes of Prower plasma, some of which were despatched to London, Oxford and the Continent, were deposited among the haddock, cod and plaice, and smelled faintly of fish. Whilst there was an element of serendipity in discovering factor X, Audrey Prower had been seen at two other London teaching hospitals and UCH despatched her to the cottage hospital (St Pancras) for dental extraction without investigating her. Trevor Telfer was a registrar pathologist at UCH who was a visiting pathologist at St. Pancras at the time and we did the work jointly. We both smoked pipes and at times it was difficult to see the water bath for clouds of St. Bruno and Bulwark cut plug tobacco smoke! He left shortly afterwards for a consultant post at Rochester. I got good mileage, with subsequent papers on the assay of VII and X, electrophoretic studies, levels in patients receiving anticoagulant therapy with Dindevan and genetic variants of factor X, and of course moving to the Blood Coagulation Research Unit in Oxford! Audrey lost her unusual surname on marriage and became Audrey Smith. She subsequently changed this to Conway-Smith, which made it even more difficult to finally trace her after I lost touch with her in about 1970 and she had moved house.' She is still alive and lives in a south-western suburb of London. At about the same time, Cecil Hougie (1922–present) and colleagues in Chapel Hill (North Carolina, USA) described a similar patient (Hougie et al, 1957). In fact, this work was partly based on Hougie's previous work and contacts in Oxford (Robb-Smith, 1993). A year before Hougie arrived in Oxford, Danny Bergsagel joined Macfarlane's laboratory to study for a D Phil on thromboplastin formation. Bergsagel was involved on work on plasma taken from Miss Prower, and he remembered an apparently similar previous case report from North Carolina of what had been described as a case 'congenital hypoproconvertinaemia' or atypical factor VII deficiency (Lewis et al, 1953). As Hougie was about to leave for Chapel Hill, Bergsagel suggested that he should try and track down this patient. He succeeded and, sure enough, that patient appeared to have exactly the same defect. Rufus Stuart (Fig 5) was a 36-year-old farmer and lay-Baptist preacher, a member of a large and interrelated kindred living in the Blue Ridge mountains of the north-western corner of North Carolina and neighbouring Virginia. His principal problems had been recurrent epistaxis and significant bruising. However, he had also experienced occasional haemarthroses and, in December 1955, he had had a particularly severe haemarthrosis of the right hip which had resulted in anaemia for which he been transfused with one unit of fresh blood. He was partially crippled by these repeated bleeds and had been forced to drop out of school at the eighth grade because of his condition and made his living in the hamlet of Lansing by finding whatever casual manual work he could (Graham, 1988). The family was studied in detail, with information collected on 164 family members. Mr Stuart's parents were consanguineous and were related to each other as aunt and nephew (his father was the son of his mother's oldest sister) and a detailed study of the inheritance pattern clearly indicated an autosomal recessive pattern of this bleeding disorder (Graham et al, 1957). Among his five children, it was noted that one of his sons was troubled with recurrent epistaxis and that 'the buttocks of his daughter often showed persistent bruising after disciplinary spanking.' A brother had died of haemorrhage some years earlier. On a positive note, for many years, Mr Stuart derived a modest but welcome regular income from the sale of his plasma to commercial companies who used it to produce a diagnostic reagent. Later in life, Mr Stuart developed salmonella osteomyelitis of the pelvis in the 1960s, as well as bilateral cataracts. A life-long chain smoker since his youth, he eventually developed a squamous cell carcinoma of the lung for which he underwent wedge resection of the lung but from which he ultimately died on 16 January 1989 at the age of 70 years. One of his physicians, Dr John Graham, remembered him as a 'noble and unassuming man whom I place near the top of the list of the greatest persons I have ever known' (Graham, 1988). Rufus Stuart (front), with (left to right) Drs Hougie, Barrow and Graham in 1957. Taken from: Owen (2001). By permission of Mayo Foundation for Medical Education and Research. The results of tests in both of these patients were identical. The one stage prothrombin time was prolonged both with Russell's viper venom (Stypven) and with brain thromboplastin. The abnormal prothrombin time using the snake venom excluded the possibility of factor VII deficiency, and prothrombin deficiency was excluded by using a two-stage assay. Moreover, the serum from these patients was defective in the thromboplastin generation test, but contained normal amounts of Christmas factor (factor IX). The inescapable conclusion was that the bleeding tendency was the consequence of deficiency of yet another coagulation factor, which was named the Stuart–Prower factor. Further tests showed the new serum factor to be relatively stable, adsorbed by inorganic precipitates such as barium sulphate and the level was reduced in the blood of patients on anticoagulant (dicoumarin) therapy. Deficiencies of Christmas factor and Stuart–Prower factor were undoubtedly associated with a bleeding disorder. The case of John Hageman described in 1955 by Oscar Ratnoff (1916–present) of Case Western Reserve University in Cleveland (USA) proved to be a real conundrum, in that a grossly abnormal clotting time was apparently not associated with any bleeding tendency at all (Ratnoff & Colopy, 1955; Ratnoff, 1980). Mr Hageman was 37-years old when he was admitted to hospital in July 1953 for surgery to correct pyloric obstruction secondary to duodenal ulceration, which he had had since 1943. Routine coagulation tests were performed, although there was absolutely no history of a bleeding disorder and indeed he had undergone tonsillectomy at the age of 6 years and had had dental extraction at the age of 36 years. In the event, partial gastrectomy and gastrojejunostomy were subsequently carried out after the transfusion of 3500 ml of fresh whole blood during and after the procedure. The surgeon was Norman Shumway, who later became a noted cardiothoracic surgeon and a pioneer of cardiac transplantation. Blood loss during surgery was not excessive and postoperative recovery was also uneventful. Further laboratory studies demonstrated that the in vitro clotting defect could be corrected by the addition of normal plasma as well as serum adsorbed with barium sulphate. The presumed missing factor, which was also stable when heated to 50°C for 30 min, was called Hageman factor. The eventual death of John Hageman at the age of 52 years occurred unexpectedly. He worked as brakeman (guard) on the railways and fell from the ladder of the carriage of a moving train on 11 March 1968, fracturing his left hemi-pelvis. He was kept on bed rest in hospital for a week before being allowed to walk on crutches and carry out physiotherapy exercises. Shortly thereafter, on his twelfth day in hospital, 'he was found gasping for breath; he had an ashen colour and was pulseless, and the blood pressure was unobtainable. Despite oxygen and cardiac massage, he died in a matter of minutes' (Ratnoff et al, 1968). Somewhat paradoxically, post-mortem examination revealed that he had died of massive pulmonary embolism, and five emboli were found blocking the main right and left branches of the pulmonary artery. It became apparent by the mid-1950s that a unified nomenclature was desirable because many of the coagulation factors were named independently by several groups of workers who studied different properties and who initially thought that they had discovered different factors. The idea of harmonizing the nomenclature came from Irving Wright (1901–1997), Professor of Internal Medicine with a special interest in cardiology at Cornell University (New York), who made the suggestion during a meeting of the International Conference of Thrombosis and Embolism held in Basel (Switzerland) in 1954 and chaired by Dr Fritz Koller. The International Committee for the Nomenclature of Blood Clotting factors was duly established in that same year under the Chairmanship of Professor Wright (Fig 6) with the primary objective of developing a common scientific terminology in the field, and which was funded with a grant from the National Heart Institute of the United States Public Health Service. As Irving Wright subsequently recalled: 'At that time, the situation was chaotic, with most of the factors being referred to in the literature by multiple, often totally unrelated names: 14 different terms were used for one of them' (Wright, 1962). The Committee was initially composed of 23 members from 15 different countries, all of whom were selected for having 'played significant roles in the discovery or application of knowledge regarding these factors'. The founding members of the International Committee for the Nomenclature of Blood Clotting Factors were as follows (in alphabetical order): Takeshi Abe (Tokyo, Japan), Benjamin Alexander (Boston, USA), Tage Astrup (Washington DC, USA), Ken(neth) Brinkhous (Chapel Hill, USA), Pietro De Nicola (Pavia, Italy), Erwin Deutsch (Vienna, Austria), Paul Fantl (Melbourne, Australia), Robert Hunter (Dundee, UK), L. Jacques (Saskatoon, Canada), Erik Jorpes (Stockholm, Sweden), Fritz Koller (Vice Chairman) (Zurich, Switzerland), K. Lenggenhager (Bern, Switzerland), R. Macfarlane (Oxford, UK), Willy Merz (Lausanne, Switzerland), Paul Owren (Oslo, Norway), Alfredo Pavlovsky (Buenos Aires, Argentina), Armand Quick (Milwaukee, USA), Oscar Ratnoff (Cleveland, USA), Laszlo Róka (Frankfurt, Germany), Walter Seegers (Detroit, USA), Jean-Pierre Soulier (Paris, France), Marc M. Verstraete (Leuven, Belgium) and Irving S. Wright (Chairman) (New York, USA). Professor Irving Wright (1901–1997). Chairman of the International Committee for the Nomenclature of Blood Clotting Factors, 1954–1962. Original photograph from Owen et al (1975). Copyright, Lippincott Williams & Wilkins, Baltimore. The first meeting of the Committee was a rather informal gathering held in Oxford in 1955, and this was followed by a second meeting in Boston the following year, which was chosen to coincide with a meeting of the International Haematological Conference (IHC). However, it was only after 3 years of deliberation that the designation of factors I to IX was officially approved by the Committee, at a meeting in Rome in 1958 (the same venue as for the IHC meeting that year). For each factor, evidence as to its existence and character had to be presented by a proposer and this required the physical presence of not only the proposer but also of colleagues who had taken part in the research. There had been considerable debate about whether letters or Arabic or Roman numerals should be used. A precedent of using a Roman numeral to identify a coagulation factor had been set by Paul Owren when he described factor V in 1947. In fact, the location of this meeting probably helped to sway the eventual outcome and the Chairman of the Committee himself subsequently recalled that 'finally ideas began to crystallize and appropriately, in Rome in 1958, the system of using Roman numerals was adopted' (Wright, 1963) (Table I). Paul Fantl (Melbourne, Australia) noted that 'through correspondence, I find that the Roman numeral system has made life very easy for workers who do not read English or any other western language' (De Nicola, 1961). Perhaps not surprisingly, Dr Taki Abe (Tokyo, Japan) concurred: 'I agree with Dr Fantl's idea, particularly for India, China and the South-east Asian countries. We prefer numbers, at the present moment at least. Therefore, I want to continue this system for some time'. Dr John Graham of Chapel Hill wrote some years later that the adoption of a system of impersonal numbers also served another purpose: 'the political subtlety of the Latin numerals lay in the fact that replacing the names bypassed the ego investment of each of the discoverers as well as foiling all claims for priority' (Graham, 1988). Factor X (previously commonly referred to as Stuart–Prower factor) was so designated at a meeting of the committee in Montreux in 1959. What was originally described as a third type of haemophilia or haemophilia C was reported in 1953 and attributed to def
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