Six Characters in Search of An Author: The History of the Nomenclature of Coagulation Factors

'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 was a registrar at UCH who was a at at the time and did the work We and at it was difficult to the for of and He left for a post at I with subsequent on the of and X, in patients anticoagulant with and of factor X, and of to the Blood Research in Audrey her on and became Audrey She subsequently this to which made it even more difficult to her after I with her in about and she had She is still and in a of about the same and colleagues in described a similar patient et al, 1957). In this work was based on previous work and in Oxford A year before in laboratory to study for a on thromboplastin was on work on plasma taken from Miss and he an similar previous case from of what had been described as a case or factor deficiency et al, 1953). As was about to for suggested that he and this He that patient appeared to have the same defect. Stuart (Fig was a and a member of a large and in the of the of and His had been and significant However, he had also in December he had had a of the which had in for which he been with one of fresh blood. He was by these and had been to out of at the because of his and made his in the of by work he could The family was studied in with on family parents were and were to other as and was the of his and a detailed study of the pattern indicated an pattern of this bleeding disorder et al, 1957). Among his it was noted that one of his was with and that of his often showed after A brother had died of some years On a for many years, Stuart derived a modest but from the of his plasma to who used it to a Later in life, Stuart developed of the in the as well as A his he developed a of the for which he of the but from which he died on at the age of years. One of his Dr as a and whom I the of the of the I have Stuart with to and in By of Foundation for Medical and The results of in of these patients were The one stage prothrombin time was prolonged with and with thromboplastin. The prothrombin time using the the possibility of factor and prothrombin deficiency was by using a the serum from these patients was defective in the thromboplastin generation test, but normal of Christmas factor (factor The was that the bleeding tendency was the of deficiency of another coagulation factor, which was named the showed the new serum factor to be relatively adsorbed by such as barium sulphate and the level was reduced in the blood of patients on anticoagulant (dicoumarin) of Christmas factor and factor were associated with a bleeding The case of Hageman described in 1955 by of University in to be a in that a grossly clotting time was not associated with bleeding tendency at all & Hageman was old when he was admitted to hospital in for to to which he had had coagulation were although there was no history of a bleeding disorder and he had tonsillectomy at the age of years and had had dental extraction at the age of years. In the and were subsequently carried out after the transfusion of of fresh whole blood during and after the The surgeon was who later became a noted surgeon and a of Blood during was not and postoperative was also laboratory that the in vitro clotting defect could be corrected by the addition of normal plasma as well as serum adsorbed with barium sulphate. The factor, which was also stable when to for was called Hageman The of Hageman at the age of years He worked as on the and from the of the of a on his left He was on in hospital for a before being to on and out Shortly thereafter, on his in was found for he had an and was and the blood was and he died in a of et al, that he had died of and were found the and left of the 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 of harmonizing the nomenclature came from Irving Professor of with a special in at University who made the during a of the of Thrombosis and held in in 1954 and by Dr The for the of Blood factors was established in that same year the of Professor (Fig with the of a scientific in the and which was with a from the Institute of the As Irving subsequently that the was with most of the factors being to in the literature by often different terms were used for one of The was initially of from different all of whom were for significant in the discovery or application of knowledge these The of the for the of Blood were as (in Alexander Paul Koller Macfarlane Paul Owren Alfredo Pavlovsky Armand Quick and Irving Professor Irving of the for the of Blood photograph from et al & The first of the was a rather held in Oxford in and this was by a second in the following year, which was chosen to with a of the However, it was only after years of that the of factors I to IX was by the at a in in same as for the that factor, evidence as to its and had to be presented by a and this required the presence of not only the but also of colleagues who had taken part in the There had been about letters or or Roman numerals be A precedent of using a Roman to identify a coagulation factor had been by Paul Owren when he described factor V in In the of this helped to the and the of the subsequently recalled that to and in in the system of using Roman numerals was Paul noted that I that the Roman system has made very for workers who do not read or other (De not Dr with Dr for and the We at the present at I to this system for some Dr of wrote some years later that the adoption of a system of also another of the numerals in the fact that the names the of of the as well as all for Factor X to as was so at a of the committee in in was described as a of haemophilia or haemophilia was reported in and attributed to

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