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• W1569003946 abstract "Every year the Dutch scientific community involved in hemostasis and thrombosis research meets for 2 days in Houthalen, a little village in the north of Belgium, close to the Dutch border. These meetings, organized by the Dutch Society for Thrombosis and Hemostsis (NVTH) and sponsored by the Dutch Thrombosis Foundation (TSN), are attended by PhD students, technicians and senior scientists. The program includes familiar themes such as platelet biology, thrombophilia, vascular biology and a variety of clinical topics and changes every year. The meetings also provide ample opportunity for the participants to exchange views and thoughts on an informal basis during the dinner party and the many happy hours. This year the NVTH symposium celebrated its 31st birthday. During the past 15 years, a number of interactive, thematic courses for graduate and PhD students and other interested scientists have also been given as satellite activities. Altogether it is a successful formula which every year attracts more than 250 people involved in hemostasis and thrombosis research and adequately reflects the scientific efforts and advances in this field in the Netherlands. As of 1984, the program of the symposium further includes a special event, the ‘Van Creveld lecture’. Every year a prominent scientist or scholar, usually Dutch, is invited to give a seminar on a topic which is generally of broad scientific interest, although highlights and breakthroughs in hemostasis and thrombosis research are fairly popular themes. Over the past years many prominent scientists and authorities in the field have given this lecture, including Jan Sixma, Coen Hemker, Jan Wouter ten Cate, Desire Collen, Leo Vroman (well known in the Netherlands for his poetry and perhaps a little less so in the USA for his studies of factor (F)XII, coagulation and surface chemistry), Cees Smit (a former coordinator of the Dutch Society of Hemophilic Patients), Bonno Bouma and Pier Mannucci, the editor‐in‐chief of this journal. These lectures are always received with enthusiasm and respect. One may raise the question: who was Van Creveld, and why an annual tribute to him? Why are these lectures in his honor? The answer is simple: he is considered to be the godfather of Dutch hemophilia care and was the founder of a school of talented thrombosis and hemostasis researchers. Much of the past and current basic and clinical research on hemostasis and thrombosis in the Netherlands stems directly or indirectly from his work initiated in the early 1930s. The board of the NVTH therefore felt it appropriate to dedicate a special lecture to him, a member of the generation of clinicians and scientists who launched ‘the renaissance period of blood coagulation’[1De Nicola P. Thirty Years of Studies on Blood Coagulation: 1935–1965. Lischi Pisa: 1979.Google Scholar]. As a former (and last) PhD student of Van Creveld, I had the opportunity to become acquainted with him at close hand and to appreciate his personality, perceptive abilities, scholastic views and pioneering work on the identification and preparation of the procoagulant substances lacking in the blood of hemophilia patients. This knowledge, together with my involvement in factor FVIII and von Willebrand factor (VWF) research during the past 35 years, prompted me to write an account of the research activities of Van Creveld in the field, describing his contribution to the discovery of FVIII and the significance of his scientific career as a catalyst for future thrombosis and hemostasis research in the Netherlands. Simon Van Creveld (1894–1971), pediatrician and director of the pediatric clinic of the University of Amsterdam from 1938 to1964, was an outstanding and distinguished clinician and a coagulation researcher ‘avant la lettre’. Most of his achievements accomplished during the early years of his career are somewhat outside the scope of this journal and will not be discussed here. (For instance, he first described Ellis–Van Creveld syndrome or congenital chondroectodermal dysplasia, recognized a clinical entity which later turned out to be glycogen storage disease, first described an enteral disorder subsequently identified as pancreas fibrosis and discovered platelet factor 3.) His scientific interests are reflected in his activities in the later stages of his career when he focused his research on hemorrhagic diatheses in childhood. These were the most productive years of his life as a scientist and he wrote numerous publications. In particular, his contributions to unravelling the clotting defect of hemophilia and to putting the acquired scientific knowledge into clinical practice are renowned, at least in the Netherlands. This was the era which saw the birth of coagulation research in the Netherlands and set the stage for ongoing, successful work. During the decade preceding World War II, Van Creveld and his coworkers started their work on the identification and purification of a substance contained in normal blood and thought to be responsible for the clotting defect of hemophilia. At that time it was already well recognized that blood transfusions could help to control the hemorrhagic crises of hemophilia. This knowledge, together with growing evidence that the underlying problem was essentially plasmatic or a serum‐related phenomenon [2Weil P.E. L'hémophilie, pathogénie et sérothérapie.Presse Méd. 1905; 13: 673Google Scholar, 3Addis T. The pathogenesis of hereditary haemophilia.J Path Bact. 1911; 15: 427Crossref Google Scholar, 4Feissly R. Etudes sur l'hémophilie.Bull Mém Soc Méd Hôp Paris. 1923; 47: 1778Google Scholar, 5Govaerts P. Gratia A. Contribution à l'étude de l'hémophilie.Rev Belge Sc Méd. 1931; 3: 689-95Google Scholar], led Van Creveld to identify the substance thought to be responsible for the apparent hemostatic defect. He was probably one of the first (possibly preceded by Patek in 1911) to demonstrate that a ‘dispersed protein’ fraction obtained from serum reduced the clotting time of hemophilic blood. This observation was first published in 1934 in a Dutch pediatric journal, written in Dutch, which for obvious reasons was not readily accessible to the international reader [6Van Creveld S. Zeldzame haemorrhagische diathesen. (Acuut haemorrhagisch oedeem‐sporadische haemophilie).Maandschrift voor Kindergeneeskunde. 1934; 3: 351-66Google Scholar]. The studies were confirmed and extended and 1 year later appeared in English in Acta Brevia Neerlandica, another Dutch journal publishing papers on physiological, pharmacological and biochemical topics [7Bendien W.M. Van Creveld S. Investigations on haemophilia.Acta Brevia Neerlandica. 1935; 5: 135-8Google Scholar]. Although edited in English, this journal was likewise not easily accessible to a broader public. Perhaps this is the reason why Van Creveld's work is somewhat overlooked in the international literature. The latter publication also refers to clinical experiments in which he injected procoagulant protein fractions, obtained by salting out or ultrafiltration, into hemophilic patients. Details are lacking, but these clinical experiments were apparently successful, since he stated: ‘Sometimes we injected our solutions into hemophilia patients, intramuscularly as well as intravenously, and determined the coagulation time at 37 °C, before and a half an hour after the injection. The provisional results justify a continuation of the research in this direction’[7Bendien W.M. Van Creveld S. Investigations on haemophilia.Acta Brevia Neerlandica. 1935; 5: 135-8Google Scholar]. In a subsequent series of papers published at relatively short intervals, again in Acta Brevia Neerlandica, Van Creveld and his coworker Bendien and later Mastenbroek and Paulssen documented more clearly the fact that from both biochemical and clinical points of view their ‘coagulation‐globulin’, later known as antihemophilic factor (AHF), indeed contained the active principle lacking in hemophilia [8Bendien W.M. Van Creveld S. Investigations on haemophilia II.Acta Brevia Neerlandica. 1937; 7: 1-3Google Scholar, 9Bendien W.M. Van Creveld S. Investigations on haemophilia III.Acta Brevia Neerlandica. 1937; 7: 1-4Google Scholar, 10Bendien W.M. Van Creveld S. Investigations on haemophilia IV. Further experiments with extracts from the human placenta.Acta Brevia Neerlandica. 1938; 8: 136-9Google Scholar, 11Van Creveld S. Investigations on haemophilia V. The coagulation promoting activity of preserved blood and plasma.Acta Brevia Neerlandica. 1940; 10: 191-5Google Scholar, 12Van Creveld S. Mastenbroek G.G.A. Investigations on haemophilia VI. Clotting promoting activity of dialysis products of normal plasma.Acta Brevia Neerlandica. 1941; 11: 207-10Google Scholar, 13Van Creveld S. Mastenbroek G.G.A. Investigations on haemophilia VII. Human plasma fractions in haemophilia.Acta Brevia Neerlandica. 1946; 14: 51-5Google Scholar, 14Van Creveld S. Paulssen M.M.P. Investigations on haemophilia VIII. Plasma transfusions in haemophilia.Acta Brevia Neerlandica. 1949; 17: 1-9Google Scholar, 15Van Creveld S. Paulssen M.M.P. Investigations on haemophilia IX. Further study on the effect of transfusions of heparin plasma and citrated plasma in haemophilia.Acta Brevia Neerlandica. 1950; 17: 55-63Google Scholar]. The interpretation of their data was somewhat clouded, because at the beginning of their studies it was not entirely clear whether they used serum or plasma as the starting material for their experiments. Initially (1934) they concluded that serum contained the antihemophilic substance [6Van Creveld S. Zeldzame haemorrhagische diathesen. (Acuut haemorrhagisch oedeem‐sporadische haemophilie).Maandschrift voor Kindergeneeskunde. 1934; 3: 351-66Google Scholar], whereas about 5 years later they supported the view that plasma contained the clot‐promoting entity. In retrospect, an understandable switch of thoughts. FIX deficiency had not yet been discovered and as hemophilia A and B are clinically indistinguishable, it is obvious that this may have obscured the interpretation of their observations. However, in view of the relative prevalence of hemophilia A and B, it would seem likely that most of their clinical studies concerned FVIII and hemophilia A patients. Van Creveld later became aware of this, since he stated [16Van Creveld S. Transfusions in hemophilia. The hemophiliac and his world. Proceedings of the 5th Congress of the World Federation of Hemophilia, Montreal 1968.Bibl Haemat. Karger, 1970: 1-8Google Scholar]: ‘At present the question might be put forward in how far Weil's patients who reacted favorably to serum transfusions (described in [2Weil P.E. L'hémophilie, pathogénie et sérothérapie.Presse Méd. 1905; 13: 673Google Scholar]) were not suffering from classic hemophilia, but from Christmas disease’. Secondly, as also noted by Patek and colleagues (see below), they could have encountered stability problems with their protein fractions isolated from serum. This was probably the reason that further studies were focused on plasma fractionation. Our current knowledge indeed predicts that fresh serum may certainly contain active FVIII (FVIIIa), but because of dissociation of the A domains readily loses its activity. Van Creveld was not the only one active in the field. In the mid 1930s Patek and Taylor of the Boston City Hospital and Harvard Medical School and Pohle and Taylor also observed, probably independently of Van Creveld, that protein fractions isolated from plasma were able to correct the clotting time of hemophilic blood, both in vitro and in vivo[17Patek A.J. Stetson R.P. Hemophilia. I. The abnormal coagulation of the blood and its relation to the blood platelets.J Clin Invest. 1936; 15: 531-42Crossref PubMed Google Scholar, 18Patek A.J. Taylor F.H.L. Hemophilia. II. Some properties of a substance obtained from normal human plasma effective in accelerating the coagulation of hemophilic blood.J Clin Invest. 1937; 16: 113-24Crossref PubMed Google Scholar, 19Pohle F.J. Taylor F.H.L. The coagulation defect in haemophilia. The effect in haemophilia of intramuscular administration of a globulin substance derived from normal human plasma.J Clin Invest. 1937; 16: 741-7Crossref PubMed Google Scholar]. Similar fractions from hemophilic blood were ineffective. These studies are notable for their systematic approach and lucidity (although the question of hemophilia A or B was still not an issue) and were published in high‐quality journals. It is not surprising, therefore, that their impact was greater than that of Van Creveld's papers. Nevertheless, it seems justifiable to conclude that Van Creveld and his coworkers were among the first to discover AHF. According to Van Creveld this was not a matter of debate: ‘With pleasure we mention the fact that this part of our research work, as well as our results obtained by application in vivo, has since then been fully confirmed by the investigations of Patek and Taylor’[9Bendien W.M. Van Creveld S. Investigations on haemophilia III.Acta Brevia Neerlandica. 1937; 7: 1-4Google Scholar]. And: ‘These results (described in [6Van Creveld S. Zeldzame haemorrhagische diathesen. (Acuut haemorrhagisch oedeem‐sporadische haemophilie).Maandschrift voor Kindergeneeskunde. 1934; 3: 351-66Google Scholar, 7Bendien W.M. Van Creveld S. Investigations on haemophilia.Acta Brevia Neerlandica. 1935; 5: 135-8Google Scholar]) were confirmed by the work of Patek and Taylor and of Patek and Stetson. I think that we may say that our work was the starting point for the preparation of the concentrates of the antihemophilic factor, which in recent year revolutionized the treatment of hemophiliacs’[16Van Creveld S. Transfusions in hemophilia. The hemophiliac and his world. Proceedings of the 5th Congress of the World Federation of Hemophilia, Montreal 1968.Bibl Haemat. Karger, 1970: 1-8Google Scholar]. The work was extended and followed by a number of other publications, mainly Dutch, in which he described his experience with procoagulant materials isolated from plasma and other tissues such as placenta. Then the topic became silent in the literature. The World War II had interrupted the progress of his investigations. When the occupation of Holland came to an end, Van Creveld resumed his work on the problem of hemophilia. The technology of plasma fractionation evolved rapidly and significant world‐wide progress was made in the preparation of therapeutically effective AHF concentrates. Van Creveld welcomed these advances with enthusiasm and they inspired him to continue his research with even more energy. In the 1950s several studies of the preparation, characterization and clinical efficacy of FVIII concentrates were performed under his supervision [16Van Creveld S. Transfusions in hemophilia. The hemophiliac and his world. Proceedings of the 5th Congress of the World Federation of Hemophilia, Montreal 1968.Bibl Haemat. Karger, 1970: 1-8Google Scholar]. In addition, he published more than 100 papers (again most of them in Dutch medical journals) on clinical aspects of hemophilia A and related disorders and also initiated research on other features of the hemostatic system such as FV, FIX and the fibrinolytic system. In 1964 Van Creveld resigned as director of the Pediatric Clinic. He left behind a well‐equipped laboratory and proper facilities for advanced biochemical studies. When I joined the Department of Pediatrics in 1969, I came across instruments which one does not expect to find in a pediatric clinic, including an original Tiselius free electrophoresis apparatus with Schlieren optics, light scattering equipment, and a complete liquid and high‐voltage paper chromatography set‐up. I still consider these tools as remarkable souvenirs of his passion to obtain insight into the biochemical backgrounds of hemophilic diseases. In fact, using his light scattering device, P. Bolhuis and I showed for the first time that in solution the FVIII–VWF complex is globular in nature (unpublished observations). We also played with the Tiselius apparatus (a beautiful instrument) and demonstrated the anomalous electrophoretic behavior of the complex in solution. As we now know, this is a consequence of the mixed oligomeric structure of the FVIII–VWF complex. Van Creveld's affinity for basic research is also illustrated by his constant efforts to interest prominent biochemists in his work. He frequently visited Professor E. C. Slater, director of the Department of Biochemistry of the University of Amsterdam, and discussed biochemical issues with him. In 1949 he also became one of the first members of the Netherlands Organization for the Advancement of Pure Scientific Research (ZWO) and was able to obtain sympathy for his work through other members primarily involved in basic science. He further received substantial support from this organization to intensify his research program on the hemophilias. Van Creveld was also a frequent visitor at the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (the CLB, my current employer), where he was able to benefit more directly from the plasma fractionation technology developed by this institution and to explore possibilities for new treatment strategies. Interestingly, in its first years the CLB (founded in 1943) shared laboratory space with Van Creveld's laboratory. Although Van Creveld resigned in 1964 and left the University of Amsterdam, this was not the end of his professional career. On the contrary. He continued his work at the ‘Hemophilia Clinic’, a comprehensive hemophilia care facility located in the woods of Oud Bussum, a village about 32 km east of Amsterdam. The clinic was founded by him and officially opened in 1964 by Queen Juliana of the Netherlands [20A de Knecht‐van Eekelen. Hemofilie, een Ziekte in Beweging. De Geschiedenis van de Van Creveld Kliniek. Utrecht: Van Creveld Kliniek, 1998.Google Scholar]. ‘With the opening of the Hemophilia Clinic at Huizen, in 1964, the Netherlands became the first country in the world where hemophilic children could receive comprehensive treatment and be educated to take their place in the outside world’, he declared proudly [21Van Creveld S. The Dutch Haemophilia Clinic. Amsterdam: Abbott Universal Ltd., 1967: 18-21Google Scholar]. The clinic not only accommodated hemophilia patients. It also had a research unit which was designed to realize one of Van Creveld's ultimate wishes, a hemophilia center with its own research facilities. In 1968 I was engaged by Van Creveld as a PhD student to further characterize FVIII. I was recommended for this position by the late Professor Victor Koningsberger, who was my tutor of biophysical chemistry when I was a graduate student at the University of Utrecht. It is interesting to note that in the mid 1950s Victor Koningsberger shared a project with Earl Davie as a postdoctoral fellow in Professor Fritz Lipmann's laboratory in Boston and published with him a paper on the purification of tryptophanyl‐tRNA synthetase [22Davie E.W. Koningsberger V.V. Lipmann F. The isolation of a tryptophan‐activating enzyme from pancreas.Arch Biochem Biophys. 1956; 56: 21-38Crossref Scopus (55) Google Scholar]. Indeed a small world! I stayed for about 1 year in the Hemophilia Clinic, and this was one of the most remarkable periods of my scientific career. Van Creveld entertained great hopes of my mission to further characterize FVIII. He was an impatient man and could hardly wait for breakthroughs (which I failed to produce). In fact, with time the late Dr De (I.A.) Mochtar, pediatrician and Van Creveld's advisor and right‐hand man, persuaded him to bring the research activities back to Amsterdam. So that is what happened. I moved to the Department of Pediatrics and under the supervision of Mochtar, initiated studies on the purification and characterization of FVIII, the subject of my thesis. The laboratory in Oud Bussum gradually lost its function as a research facility. Personally, I believe that in terms of basic science, the academic infrastructure and critical mass of the research unit were not sufficient to guarantee a successful future. The clinic still exists and is flourishing, although now affiliated with the Academic Hospital of the University of Utrecht. It bears its founder's name: the Van Creveld Kliniek. Van Creveld's name still has a magic sound in the Dutch hemophiliac community. What of the impact of his work and achievements on the development of hemostasis and thrombosis research in the Netherlands in general? His influence was probably significant. Pertinent to this point is the fact that some of Van Creveld's pupils and trainees still remained active in hemostasis and thrombosis research after they left the Department of Pediatrics. Thus, Clemens Haanen, now emeritus Professor of Hematology, obtained his PhD in 1955 with a thesis on FV. He moved to the University of Nijmegen, where he established his own coagulation laboratory. There he supervised in the mid 1960s the work of the late Schoenmakers, who published a series of excellent papers on the characterization of FXII. He edited a hemostasis and thrombosis manual, a popular handbook which was on the shelf of many laboratories for years. Haanen also founded in 1959 the group ‘Bloedstolling en Hemostase’ (Blood Coagulation and Hemostasis), one of the working parties of the Foundation for Medical Research (FUNGO), and was a cofounder of the working party ‘Trombose‐ en Hemostase‐Onderzoek Nederland’ (Thrombosis and Hemostasis Research in the Netherlands, the predecessor of the NVTH). I would also like to mention Pieter Brakman, another of Van Creveld's pupils. Van Creveld stimulated Brakman to initiate studies on the fibrinolytic system, a line of research which was intended to provide insight into the variations in the clinical bleeding of patients with hemophilia. He allowed him to continue his work in Astrup's laboratory in Copenhagen. Brakman returned to Holland and became director of the Gaubius Laboratory, an institute now known to have contributed significantly to our present knowledge of the fibrinolytic system and the biology of the vascular system. I should further mention Jeanne Stibbe who, under the shared supervision of Van Creveld and Coen Hemker, performed a study on the stability of FVIII. After defending her thesis in 1967, she went to the University of Rotterdam. She was one of the first to introduce home treatment successfully, an advanced and nowadays established regimen of hemophilia care. Dr Stibbe was also one of the founders of the present NVTH in 1984. I also recall Dr Mochtar, who together with Van Creveld performed clinical studies on ‘deuteronhemophilia’ (hemophilia B). After the retirement of Van Creveld, he remained at the Pediatric Clinic and became responsible for hemophilia care. He consolidated research lines on hemophilia initiated by Van Creveld and was also one of his advisors at the Hemophilia Clinic in Oud Bussum. He was my personal and favorite tutor who, in the footsteps of Van Creveld, did his utmost to promote my PhD work and to provide me with ample opportunities to complete my thesis. Unfortunately, Mochtar died prematurely of heart disease in 1980. Perhaps I should finally mention Coen Hemker, although Hemker spent only a ‘blue Monday’ at the Pediatric Clinic and then in the early 1960s did his PhD in Slater's department, before moving to the University of Leiden and later Maastricht. Altogether an interesting family who have in common not only their more or less tight connections with Van Creveld during their academic training and the planning of their careers, but also the fact that like myself, they maintained their interest in the physiology of the hemostatic system and successfully initiated and extended their own research programs in the field. Van Creveld was a pioneer indeed, a proud and ambitious man with an intuition for the right direction. Of this the NVTH symposium is the living testimony. I thank E. Sputnesset for her help in tracing old literature and H. Veder for his archive material and the sketch drawn by Van Creveld. I would also like to thank E. W. Davie, J. J. M. de Vijlder, H. C. Hemker and P. Brakman for their valuable information about historical issues and W. G. van Aken, J. N. Mulvilhill for critically reading the manuscript and M. H. Hollestelle for reproduction of figures." @default.
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• W1569003946 title "Van Creveld, pioneer of hemophilia care and coagulation research in the Netherlands: a personal account" @default.
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