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 of and of in at the of using a for the name of a disease and that some of an would be to the names they have upon their it not be possible as of to some Biggs and that they were to a seven name The only name they could of was However, they that they the precursor they would the to it The Alexander also to the to at the name and the of the name of haemophilia B 1953). Rosemary Biggs from the of the Oxford with Macfarlane on his from the of the Oxford with Stephen Christmas was on and was just years when his case was Stephen and his were in to British their names with an of because of their with the Christmas was an who part of the on to Shortly after the of the the later to in in and it was there at the of years that haemophilia was at the for was no of haemophilia and his bleeding had first been noted when he was The to in to their and the Stephen was to in and a of his blood was to Biggs and Macfarlane in Stephen his with and was the only of his not to British to a Stephen had a for and studied the at the of in He was for some years as a at the for in he as a which he because of his in Stephen became an active for the and an of the He for the cause of blood and to for patients with name in the in when his was which out to be a et al, he the following at the of years from through with blood he just Christmas on December In his the and noted that was not only an for but he was also an who was in the to A of Stephen in when he was years an to to a plasma for a The on his is by the Although the of Christmas factor (factor IX) is usually associated with the names of Biggs and it be that described some In Paul and in described the case of a with the classical of haemophilia but in whom the prolonged coagulation time was not corrected in vitro by the addition of globulin or plasma adsorbed with barium et al, 1952). The authors of the paper called the new factor thromboplastin independently reported another similar case in an of & 1952). the laboratory carried it was noted that the plasma the time of plasma from a patient known to have haemophilia and in plasma from a patient with haemophilia also the time of the new plasma. noted that there was no in this case and that it be different from the hereditary form of haemophilia and the names of and However, it is a that only the term the test of time and still in in the the associated term has been was discovered by the study of two patients with a congenital bleeding tendency. Prower was when was to University in in for of a bleeding to a et al, had a bleeding after two in and had also after at the of a blood had of bleeding after when he was years Prower reported that had but that not that or from or were and there was no in other who were this there was bleeding for after the which was treated with of and not Prower in by I to of the and for his of his work on this patient with Prower was a and young who with bleeding after and a of bleeding following which blood and subsequently two following normal in and was blood after the first because were not and no the seven and I to University in from Oxford with a newly developed of factors VII, and by This all bleeding and the were very I on new paper to and In the was of, had a but very a I to the to plasma in the using the and would only to the and all tubes of Prower plasma, some of which were to Oxford and the were among the and and of there was an of in factor Prower had been at two other and to the for was a at who was a at at the time and the work We and at it was difficult to the for of and He for a at I with subsequent on the of and in patients anticoagulant with and of factor and of to the in on and became subsequently this to which made it even more difficult to after I with in about and had is still and in a of about the same and in described a similar patient et al, In this work was based on work and in Oxford A in laboratory to study for a on thromboplastin was on work on plasma from and he an similar 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 was a and a of a large and in the of the of and had been and However, he had also in December he had had a of the which had in for which he been with one of fresh 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 was studied in with on 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, his it was noted that one of his was with and that of his often showed after A had of some years a for many Stuart derived a but from the of his plasma to who used it to a in 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 on at the of years. One of his as a and whom I the of the of the I have Stuart with to and in By of 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 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 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 at all & Hageman was when he was to in for to to which he had had coagulation were there was no of a bleeding disorder and he had at the of years and had had at the of years. In the and were subsequently carried out after the of of fresh blood and after the The surgeon was who later became a noted surgeon and a of was not and 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 of years He as on the and from the of the of a on his He was on in for a being to on and out Shortly thereafter, on his in was for he had an and was and the blood was and he in a of et al, that he had of and were the and 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 of with a special in at University who made the a of the of and held in in 1954 and by The for the of factors was established in that same the of with the of a scientific in the and which was with a from the of the As subsequently that the was with of the factors being to in the by often different terms were used for one of The was initially of from different all of whom were for in the or of knowledge these The of the for the of were as (in Alexander Paul Koller Macfarlane Paul Owren Alfredo Pavlovsky Armand Quick and of the for the of from et al & The first of the was a rather held in Oxford in and this was by a in the following year, which was to with a of the However, it was only after years of that the of factors I to was by the at a in in same as for the that factor, evidence as to and had to be by a and this the presence of not only the but also of who had part in the 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 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 with for and the We at the present at I to this system for some of some years later that the of a system of also another of the numerals in the that the names the of of the as well as all for to as was at a of the committee in in was described as a of haemophilia or haemophilia was reported in and attributed to deficiency of a plasma thromboplastin which was present in serum as well as plasma et al, The clinical described in a paper from the in and the in was bleeding after or than but in to classical haemophilia, was and and were The in vitro in the clotting was corrected by addition of plasma from patients with classical The at a in in that thromboplastin and Hageman factor be assigned the Roman numerals and based on the of A congenital bleeding disorder associated with and was described in and to deficiency of a factor et al, The of this new factor was at a of the in in and it was factor However, a of the that the was more than with other factors and the was not it is shown that the factor is not a fibrinogen or to that he would be a to this factor a rather than a because there is in much about the function therefore, about the By what had termed of had been and the of the were to into The following the publication of a article by Macfarlane in which he out for the very first time the of blood coagulation as a of which in the of and which of as well as and to the In this he also used for the first time the as a to activated clotting but a at the in for this to of a The and initially rather meetings of the evolved to more and international could present new to the who still the became the on and in and this in turn the of the current on and The to a As of the he had to the when it was with on the nomenclature of blood clotting factors. The first of the in was Macfarlane of Oxford of his in the of blood Although no more clotting factors were with Roman numerals after factor in other important proteins in the coagulation were soon In the of the of a named Fletcher in was destroyed by of the were to because of to and this of an girl of the was to coagulation were carried out but the results were and was to the University of for et al, other were also to have similar there was no personal or of a bleeding A of normal plasma was which appeared to a coagulation factor that corrected the in vitro clotting defect of the to which the name of Fletcher factor was The Fletcher by In a was to the in with The activated thromboplastin time was greatly prolonged at with a of but the prothrombin time was the story Fitzgerald was an with no known of bleeding or of or a small a plasma from the patient to the University of I was in We the coagulation of and the presence of a We thought initially that this patient have Fletcher factor deficiency but one the of all known clotting factors in the Fletcher factor were to be to that his plasma was a new clotting As and I were not only in but also in other activated which out to be and I also a study on the in reaction using with a at I to to blood from Fitzgerald a of He was a as I by The authors that factor after of Hageman factor but the of in response to such as The authors of this named the factor as Fitzgerald factor et al, at the same similar patients with coagulation but no apparent bleeding were identified and described as and first the of these factors was but further showed that Fletcher factor was to plasma and that Fitzgerald factor was the same as The in these two were not associated with a bleeding the in the coagulation Hageman factor, Fletcher factor and Fitzgerald factor were all as However, a study of these patients has also light on the of and the important between the of and coagulation can be activated by with and to which in turn on to is a of of tissue and of is no that of the nomenclature of coagulation factors has and clinical in the The work of the an of international to a scientific This of is now but was not in this However, the nomenclature have not with the in of the clotting The of in current is based on the in which the coagulation factors were discovered and no account of the of the involvement of coagulation factors. the of of which was in but which in to this have a nomenclature for coagulation factors which was established a but which is now recognized to be not at in some I and are now more usually to by their of fibrinogen and prothrombin, and factors and VI are the international nomenclature was of the of of and the for new evidence is still no as to the of factor and the even it in 1963. In the in that year, Macfarlane to it by that just III and it just it is This is not it is We do in I and this is not that that factor III be for a factor which the of is a very because it in at the In coagulation medicine, have the names of some coagulation factors to be replaced by an of Roman By the names of many patients who have to advances in medicine in the to this the names of such as and are to be introduced into system of nomenclature of coagulation some could be to some of the more and personal names from the past. I to Christmas of for his of his of the and and about Prower and the work on factor of the the of Fitzgerald as well as about his work on this

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