Apr 28, 2011 - FIGURE 2 George Washington Crile. (Photo courtesy ... in the United States practiced by Crile, .... [11] J. R. Green, Note on the action of sodium.
RETROSPECTROSCOPE
Anticoagulants: An Essential Transfusion Component How They Came About Max E. Valentinuzzi
Since the life of a living body is in its blood, I have made you put it in the altar, so that atonement may thereby be made for your own lives, because it is the blood, as the seat of life, that makes atonement. —Leviticus 17:11
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omeone may question the subject matter of this note as being inserted within the overall bioengineering frame. Well, he/she may have a point; however, think of the rheological, mechanical, electrical, thermic, and magnetic properties of blood, the technology surrounding it, the mathematical attempts to model some hematological behavior … ain’t all that bioengineering or biomedical engineering. In 1970, being at Baylor College of Medicine, in Houston, Texas, the then chair of the Department of Physiology, Dr. Hebbel E. Hoff (my mentor, scientist, and true science historian too), and I became interested in the history of anticoagulants. Probably, to the dismay of many disbelieving young students of today, e-mails and Internet were unknown, as well as personal computers and laptops. Thus, the traditional letter sent via snail mail to get in touch with someone and the interlibrary loan system, all time-consuming tasks, were the only means to search for information. I still have several thick folders keeping that correspondence and materials collected in those days. Most of the latter obviously coincides with the contributing names given by Mollison [1] in
Digital Object Identifier 10.1109/MPUL.2011.940394 Date of publication: 28 April 2011
from dog to man, in Paris (15 June 1667), actually 345 and 344 years, respectively. Richard Lower, in Oxford, reported to Robert Boyle on the method of transfusing the blood out of one animal into another, and this account was written on 6 July 1665 and imparted by Boyle to the Royal Society, leading to the transfusion on 19 November 1666 at that society. Apparently, the idea started with the proposal by Cristopher Wren to Robert a nice and detailed historical paper on the Boyle and others that he could inject same subject (which I recommend for the liquids into the blood stream in dogs by interested reader). means of syringes improvised from quills and bladders. From an account given by Dr. Timothy Clarck, one of his Majesties’ Blood: Elixir of Life physicians, these took place in 1656–1657 The biblical quotation heading this note is as materializing, perhaps, the first intracertainly not the oldest reference to this venous injection, and the latter was probsubject matter, for there are previous acably the hint leading the Royal Society to counts dealing with blood as an overall propose a trial of transfusion during the cure that delve deeper in time and are public meeting of 17 May 1665. Lower apfull of fascinating and daring stories [2], pears to have been directly in charge, and [3]. Medieval alchemists, indeed, kept all these events were reported in Philosearching for the mythical elixir of life, a sophical Transactions [4], [5]. universal medicine containing the recipe To the then recently for eternal youth, promfounded Academie des ising and appealing, and Sciences de Paris, there blood was the first and Medieval alchemists came in the last days of easiest candidate to think kept searching for 1666 news of the English about and try (http:// the mythical elixir of experiments; much noise www.answers.com/topic/ life, and blood was rose, involving the cure elixir-of-life-2). the first and easiest of all diseases and an alThis note does not most complete transforintend to be a transfucandidate to think mation of medicine. Ideas sion review, for there about and try. went as far astray as to are many authoritative declare that the transfuones filling the history sion might change vicious trends, and the of medicine literature. Thus, I will only lion’s blood would turn cowardice into refer to it tangentially, as the main lifedaring courage, but more appealing was saving procedure requires an indisthe hope of rejuvenation. However, many pensable coadjutant to reach success: experiments on animals ended in their an anticoagulant. Hence, let us start at deaths, seemingly because blood clotted closer times when the elixir of life was in the veins of the recipient, and the word considered to be blood, and, honoring “success” used in the English reports the truth, they were not too mistaken. should be taken with a grain of salt. The early French trajectory of transfusion, Transfusion: Early Trials in the with seven documented experiments and Nascent Modern World meteoric rise and equally quick decline Not too far ahead in time is the 350th annibecause of the opposition of the Faculty versary of the first transfusion from dog to of Medicine and further prohibition by dog, in London (19 November 1666), and MARCH/APRIL 2011
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problem in his doctoral disthe Parliament of Paris in April sertation: 1668, gives a picture of the T “Le sang doit donc concept of circulation only a I s’introduire dans la partie ABK few years after Harvey’s De (Figure 1) de nôtre tube or, s’il Motu Cordis and before Lower From B the Artery se coagulait, on ne pourrait pointed out its respiratory nullement observer la hauteur function. Reports from both A de la colonne de mercure, non countries are rather inexact plus que les modifications que and somewhat confusing; one K cette colonne éprouve, ainsi document, for example, says K que nous le verrons bientôt.” that a “cannula placed in the (The blood must then get into carotid of a large dog was conpart ABK of our tube but, if it nected to the vein of a smaller ABK: Tubing Filled with Blood at Arterial Pressure (in Red) clots, one cannot observe at one, and blood passed with IK: Mercury Column Measuring Blood Pressure all the height of the mercury impetuosity into the little aniIT: Upper Terminal Tubing Part Filled with Air (in Blue) column, not more than the mal.” Louis Gayen, an original changes intended by this colmember of the Academie and FIGURE 1 Redrawn and simplified after Poiseuille's thesis. umn so that we could well see a surgeon of Paris and of the Coagulation occurred in the ABK portion of the tubing, that is, them) [18]. And he proceeded Armies, must perhaps have after blood came out of the animal's artery. Poiseuille, as Hales to say “La première chose à been a central figure in the ex- before him, was able to get the blood pressure value early in the experiments, before clotting was established. faire avant d’aller plus loin, periments [4], [5]. était donc de trouver un corps In 1688, that is, 20 years success (to a 15-year boy and a 45-year liquide qui, introduit dans la partie ABK, after the early transfusion attempts, man), a third to the young Swedish et recevant le sang au sortir de l’artère, Claude Perrault, a controverted physiCount Eric Bonde (died soon thereafpùt transmettre sur la surface de mercian turned into architect, produced a ter), a fourth to a mentally disturbed cure la force dont est animé le sang dans four-volume compendium of his works, figure of the Paris streets (apparently l’artère, et cela en empechant sa coagulaincluding in it the observations on the twice restored to good senses but falltion ou plutôt en conservant sa liquidité.” transfusion of blood from one animal ing back to his former state), and a fifth (The first thing to do before any further to another. He mentioned disputes that that ended in the criminal case menstep is taken is to find a liquid substance broke out on the subject and even that tioned above. No further transfusions that, introduced in that portion ABK, on led to a criminal trial because of a were performed in man, neither in Parreceiving the blood coming out of artery, man’s death after transfusion. is nor in England. The net result was hinders its coagulation or conserves its In the years immediately following that for about two and a half centuries liquid state.) [8, p. 24]. Poiseuille carried its discovery in 1635, the Academie the procedure resulted out experiments in vitro with potassium received much critiin oblivion after the procarbonate (K2CO3), commonly called potcism in France. Henrihibition Paris Edict of Louis Habert de Montash (potasse in French), and with sodium Common knowledge 1668 [5]. mor (1600?–1679) was carbonate (Na2CO3) and sodium bicaris the crust or scab a leader among these bonate (NaHCO3). Results with the two quickly formed after a dissidents, and, around former were poor, but the latter produced The Clotting Problem small bleeding wound 1654, Montmor opened the expected anticoagulant effect at least Common knowledge is is inflicted on the skin. his home to academic for two hours. Thus, this must very likethe crust or scab that meetings that led to the ly have been the first attempt to prevent quickly forms after a creation of the Montmor blood clotting. small bleeding wound is Academy in 1657 (Brown, [6]. Withinflicted on the skin. It is the result of a in its frame, the news of transfusion protective mechanism—coagulation— The Anticoagulant Saga aroused an equal interest as they did in preventing further loss of the precious Salts, in general, do show some anticothe Academie Française, and, accordred fluid. The early direct measurements agulant effects, and this fact had been ing to one account, the services of Jean of arterial blood pressure carried out by apparently known for quite a time, alBaptiste Denís, with a doctorate probHales [7 ] and Jean Marie Poiseuille [8] though we could not exactly trace back ably in medicine from Montpellier, and in the horse, the former using a simple how such information came about. Paul Emmerez, a surgeon, were envertical open small glass pipe, and in Adolph Fick, a famous German physiolgaged to carry out experiments of their other mammals, the latter by means of ogist known for his basic principle of deown. After several trials in dogs, they an open U-tube mercury manometer, termining average cardiac output, used felt ready to perform the experiment were all marred by coagulation ending sodium bicarbonate as anticoagulant from sheep or calf onto man. At least always hopelessly in a long static blood when testing his C-spring blood presfive were done, two apparently with sausage. Poiseuille clearly addressed the sure recorder [9]. He clearly describes, 46 IEEE PULSE
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FIGURE 2 George Washington Crile. (Photo courtesy of http://www.facebook. com/pages/George-Washington-Crile/ 112738482074934.)
“Bei meinem neuen Blutwellenzeichner ist die Federe mit Alkohol gefüllt, und ihr Inneres wird durch geeignete Schläuche mit dem Blutgefässe in Verbindung gesetzt. Die Schläuche sind natürlich mit Kohlensäurer Natronlösung gefllt.” [In my blood pressure recorder, the pen is filled with alcohol, and its inside gets connected to the blood vessel via suitable tubing. The tubes, of course, are filled with sodium bicarbonate] ([9, p. 543]. Fick used the word natürlich (of course) as a well-understood need, which makes us guess that by the mid-19th century the anticoagulant requirement was well established even though its full solution was still awaited. In 1887, Green [10], from the Physiological Laboratory, Cambridge, started a long paper by saying: The influence of the different inorganic salts present in blood plasma in the process of coagulation has been to a large extent overlooked. Schmidt has pointed out that a solution of fibrinogen and paraglobulin in dilute alkalies will not clot unless a certain proportion of NaCl was added, and it has long been known that, on the other hand, MgSO4 and NaSO4 exercise a restraining influence on coagulation. The salts, however, have not been regarded as playing a leading part in the process. After a long series of tests, he reported that MgSO4 and Na2SO4 prevented clotting while CaSO4 favored it. Green [11] also
Claude Bernard’s philosophical standexperimented with leech extract finding a ings, as he was particularly critical of clear clotting delay, already anticipating a theories that could not be tested, and demonstration that came later on. In it, he underlined the differences from hyGreen concludes that fibrin is decomposed potheses that could endure laboratory by the action of neutral salts. testing. Soon thereafter, Pekelharing, Green mentions Alexander Schmidt, said, “Ich habe in Beziehung hierauf a professor of physiology at der Kaidas Blut des Hundes, des Kaninchens serliche Universität zu Dorpat (Dorpat, und des Pferdes untersucht, und jedesEstonia’s capital city, which was later mal gefunden, dass mit Natriumcitrat renamed Tartu). This investigator, afgemischtes Blut ebenso so leicht wie ter years of dedicated research, pubmittelst Kaliumoxalat flüssig gehaltenes lished an impressive book about blood gebracht wird …” (I have investigated [12], of which a previous edition had the blood of dogs, rabbits, and horses, appeared in 1892. Obviously, Green and I have always found that blood must have been aware of the works by mixed with sodium citrate remains liqthis author, who took good care in reuid as when it is mixed with potassium viewing the other reports and reviews. oxalate) ([15, p. 14]. Griesbach [16] reSchmidt devotes Chapter 3 of his book ported that ammonium citrate interferes to the “supposed specific action of with clotting, while Pekelharing [17] in calcium salts in the coagulation of fia second shorter paper realized that such brinogen” (Über die angebliche specclotting prevention was due to the afifische Bedeutung der Kalksalze für finity of calcium for citric die Fasserstoffgerinnung) acid. Within the same pe[12]. In this chapter, riod, Wright [18] underBrücke is referred too, The history bitterly took the transfusion exwho was also heavily teaches that violence periments in three dogs concerned with blood has many times with decalcified blood uscoagulation in 1857 [40]. pushed ahead ing oxalate, based on the The studies of Arthe frontiers of previous discoveries by thus and Pagés [13] on Arthus and Pagès [13]. In the coagulation of milk knowledge. 1899, Arthus [19] pubshowed that the converlished another book resion of caseinogen to caviewing the subject. All the other most sein required calcium, as had already important contributors to the subject of been shown for blood coagulation by coagulation were recognized and disHammarsten [14]. (The book by Hamcussed, and a new one named Lilienfeld marsten was digitalized in December [20]–[22] also joined, who wrote sev2008 and can be obtained from the Unieral papers. versity of Virginia. In 1899, this author The 20th century wrote “Weitere Bewas dawning while iträge zur Kenntniss Sabbatani [23] said at der Fibrinbildung (in the very beginning of German, Other cona long paper: “È noto tributions to knowlda tempo che i citrate edge of fibrinogen alcalini, aggiunti al formation),” which sangue, ne impedisappeared in Hoppecono la coagulazione” Seyler’s Zeitschrift fr (It has been noted for physiologische Chemie , some time ago that alvol. 28, nos. 1–2, pp. kaline citrates mixed 98–114, 1875). The with blood hinder (its) former investigator, coagulation …) [23], Arthus, introduced and he proceeded with the use of sodium FIGURE 3 Luis Agote (1868–1954). a detailed descripoxalate as an antico(Photo courtesy of http://www. tion of the many exagulant for blood and educar-argentina.com.ar/ periments to confirm milk. He followed HISTORIA/BIO/a1.htm.) MARCH/APRIL 2011
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FIGURE 4 Autographed photo taken in Buenos Aires on 9 November 1914, during the transfusion procedure, at the Rawson Hospital. (Photo courtesy of http://www.cruzadadelrosario.org.ar/revista/0410/agote.htm.)
by 1908–1910, both salts no doubt had the need of ionic calcium in the clotting been in use for about two decades, and process. Trisodic citrate immobilizes caltheir use in clinical transfusion was not to cium, and thus, it prevents clotting. Essurprise anybody. sentially, the same report was repeated The First World War (WWI; 1914– by the same author in 1901. 1918) was approaching, and its sad conseIn 1906, Nolf [24], from the Institute quences served as undesired but needed to of Physiology of Liege, Belgium, tried booster transfusion. Yes, indeed, the histo develop a general theory of blood tory bitterly teaches that coagulation, mainly disviolence has many times cussing such mechanism pushed ahead the fronin fish. This author went Sodium citrate had tiers of knowledge [27]. apparently deeper into the Several authors added subject, because later on, been known for more practical experience, he published a long series its anticoagulant and, not unexpectedly as of papers [25]. Unfortuproperties for quite a in other scientific disclonately, I only got shorttime before 1914. sures, even some controprinted and incomplete versies showed up. Let us pieces so that I cannot asquickly review them folsess the significance of his lowing as much as possible the chronolreports. The current access via Internet is ogy of the different reports and sticking highly restricted even though the papers exclusively to papers in mainstream jourcan be confusedly located in small bits. It nals. They precisely cover the war years. seems obvious to underline that the search Hustin (1872–1967) has been credof an adequate anticoagulant required ited as having performed on 27 March knowledge of the mechanisms of coagu1914, in Bruxelles, Belgium, the first lation, which clearly explains why the transfusion using citrated blood [28]. papers so far referred to mostly deal with It was reported to the Societé Royale, the latter aspect. Practically coincident where he described the procedure, as with these contributions, Gengou [26], in carried out with human blood to dogs a long detailed paper, devoted a full secand humans. Hustin mentions in the first tion (Chapter 2) to the action of sodium paragraph of his report the American citrate on molecular adhesion. Besides, he surgeon George W. Crile (1864–1943) compared this salt with oxalates, which but without offering any reference; showed anticoagulant effects too. Hence, 48 IEEE PULSE
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however, Kazi [29] says that in August 1906, at St. Alexis Hospital in Cleveland, the first successful transfusion of blood from one human to another took place in the United States practiced by Crile, a well-known and active physician; he published a book in 1909 that perhaps should be considered the first hematology treatise. Crile probably used an anticoagulant, but I could not find a specific description, because I could not get hold of the book. Thereafter, the scientific literature shows eight reports, with the first six being packed between 1914 and 1915. Raulston and Woodyatt [30], from Rush Medical College in Chicago, reported on blood transfusion in diabetes mellitus, but they concentrated on the metabolic aspects derived from the procedure without even mentioning the use of anticoagulants. A short paragraph in page 997, written in a smaller case, makes a brief historical review referring only to diabetes or depancreatized animals. Agote [31], at the Instituto Modelo de Clínica Médica, of the Rawson Hospital in Buenos Aires City, carefully explained the procedure he used with his collaborators after previous tests in dogs. The concentrations of sodium citrate ranged between 0.75 g and 1.25 g in 300 cm3 of blood (that is, 0.25% and 0.42%). The transfusion was performed on 9 November 1914. A second patient, a woman, who had suffered severe hemorrhages, was also transfused on 15 November. Soon thereafter, Lewisohn [32], [33] reported a similar medical act using exactly the concentrations of sodium citrate as Agote had done before. Lewinsohn said in page 142 of his first paper: “As this is only a preliminary report I shall refrain from giving detailed data about all my experiments and only state the most important results in the briefest terms.” Thus, the information from it is scarce. In his second paper, he stated to have transfused 30 patients applying the same method. There is also a short note by Richard Weil [34], where there is nothing relevant to comment about. And the controversy broke out [35], even with articles published in American and Argentine newspapers (which do not need to be referred to herein, because
they tend to unnecessaror so. However, accepting The question of ily dramatize the scene), Hedon’s more-refined and has been carried on definition given above determining the right for too many years [36], (dosage and the clinical doses, designing an [37]. The interested readsetting), Hustin should adequate technique, er may find details in the only be considered as an and trying one of Web. Sometimes, human antecessor on the right these substances responses are excessively track, and Agote would in the clinical driven by the ego, eastake the first place. Howily leaving out the generever, that saga was not environment were ous side. However, two devoid of human constill open. other papers [38], [39] flict driven, perhaps by briefly reviewed the subselfishness and personal ject closely in time to the ambitions of academic described transfusion events. In the secglory. The history of science and techond one, Hedon [39] specifically states: nology shows several examples that, in “Si donc nous désignons sous le nom de many respects, appear definitely more transfusion de sang citraté la transfusion impressive and salient than the anticodu sang simplement additionné de la proagulant saga, and in a sense, blurring portion de citrate convenable pour le renthe actual contributions of their actors: dre incoagulable, nous devons dire que la anesthesia, in the mid-1800s, the birth première transfusion de cette sorte a été of microbiology in the second half of practiquée chez l’ homme par Agote” (If that century (even stained with dishonthen we call transfusion of citrated blood est acts), the development of computers that transfusion of blood simply added to in the 1940s–1950s, and the discovery the convenient proportion of citrate for and elaboration of the polio vaccine in making it non coagulable, we must say the 1950s. All the participants in the anthat the first transfusion of this kind was ticoagulant saga were motivated wellpracticed by Agote) [39]. meant physicians who, especially durThe contributions that follow thereing the stressing WWI years, wanted to after better belong to the overall field of offer a truly, desperately needed new hematology, which encompasses submedical tool to the emergency surgery jects such as blood groups, transfusion faced in the battlefields. techniques and technology, blood banks, blood preservation, prevention of diseases Acknowledgments transmitted via transfusion, and the like. The following persons and institutions Thus, 1918 appears as a good time limit to gave me kind and generous assistance stop this historical note. during the 1970–1971 period when I collected most of the material used for this note. Prof. Paul Bordet, from the Discussion and Conclusions Institut Pasteur du Brabant and Faculté Sodium citrate had been known for its de Médicine et de Pharmacie, Université anticoagulant properties for quite a time Libre de Bruxelle, Belgium; Mademoibefore 1914, as it was also established that selle M. Lavoye, adjunct director of the oxalate and hirudin had similar properBibliothéque Générale de l’Université ties, the latter substance found in the de Liege, Belgium; Prof. Marcel Florkin, salivary glands of leeches. Thus, no one de l’Institut Lion Fredericq, Belgium; during the period of WWI could seriously Dr. Roberto Beretervide, from the Insticlaim originality for its use. tuto Modelo de Clínica Médica, Buenos At that moment, the question of Aires; Mr. Leonardo Valentinuzzi, who determining the right doses, designing performed several searches in some an adequate technique, and trying one Buenos Aires newspapers; la Biblioof these substances in the clinical enthèque Nationale de Paris; and the New vironment were still open. The articles York Public Library. referred to above seem to indicate the Hustin-Agote-Lewinsohn-Weil chronoMax E. Valentinuzzi (maxvalentinuzzi@ logical sequence, all four using sodium arnet.com.ar) is with the Instituto de Ingeniera citrate, and the latter three within a year
Biomdica (IIBM), University of Buenos Aires (UBA), Argentina.
References [1] P. L. Mollison, “The introduction of citrate as an anticoagulant,” Br. J. Haematol., vol. 108, no. 1, pp. 13–18, 2000. [2] P. Learoyd. (2006, Jan.). A short history of blood transfusion. Leeds Blood Centre, stt-042, 18 pp [Online]. Available: http://hospital.blood.co.uk/library/pdf/ trainingeducation/historyoftransfusion.pdf [3] A. N. Kaadan and M. Angrini. (2009). Blood transfusion in history. History of Medicine Department, Aleppo University, Syria, 46 pp [Online]. Available: http://www.ishim. net/Articles/Blood%20 Transfusion%20 in%20History.pdf [4] H. E. Hoff and R. Guillemin, “The first experiments on transfusion in France,” J. Hist. Med. Allied Sci., vol. 18, no. 2, pp. 103–124, 1963. [5] H. E. Hoff and R. Guillemin, The tercentena r y of tra nsf usion i n ma n, Cardiovasc. Res. Center Bul., vol. 6, no. 2, pp. 47–57, 1967. [6] H. Brown, Scientific Organizations in Seventeenth Century France (1620–1680) . New York: Russell & Russell, 1934 (reissued 1967), xxii. [7] S. Hales, Statical Essays. London, 1733. See F. A. Willius and T. E. Keys, Classics of Cardiology (2 vols.). New York: Dover, 1941. [8] J. M. Poiseuille, “Récherches sur la force du coeur aortique,” Thése doctorale No. 166, Faculté de Médicine de Paris, Imprimerie Didot Le Jeune, 45 pp, 1828. [9] A. Fick, “Ein neuer blutwellenzeichner [in German, A new blood wave recorder],” Reicherts und du Bois Reymond’s Archives fr Anatomie und Physiologie, S583, pp. 543–548, 1864. [10] J. R. Green, “On certain points connected with the coagulation of the blood,” J. Physiol., vol. 8, pp. 354–371, 1887. [11] J. R. Green, Note on the action of sodium chloride in dissolving fibrin, J. Physiol., vol. 8, pp. 372–377, 1887. [12]A. Schmidt, Beitrage zur Blutlehre [in German, Contributions to Knowledge of Blood ]. Wiesbaden: Verlag von J. F. Beergman, 1895, 5 chapters, 250 pp. MARCH/APRIL 2011
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[13] M. Arthus and C. Pagés, “Nouvelle theorie chimique de la coagulation du sang [in French, New chemical theorie for blood coagulation],” Archives de Physiologie Normale et Pathologique, 5th series, vol. 22, pp. 739–746, 1890. [14] O. Hammarsten, Untersuchungen über die Faserstoffgerinnung [in German, Investigations on the Clotting Fibrous Stuff ], Series III. Uppsala: Nova Acta Regiae Societatis Scientiarum, vol. 10, pp. 1–130. [15] C. A. Pekelharing, Untersuchungen über das Fibrinferment [in German, Investigations on Fibrinogen]. J. Müller: Amsterdam, 1892, 51 pp. [16] H. Griesbach, “Beiträge zur Kenntniss des Blutes (in German, Contribution to blood knowledge),” Archiv für die Gesammte Physiologie, vol. 15, pp. 473–550, 1891. [17] C. A. Pekelharing, “Über die gerinnung des blutes [in German, On blood’s coagulation],” Deutsches Medizinisches Wochenschrift, vol. 18, pp. 1133–1136, 1892. [18] A. E. Wright, “A new method of blood transfusion,” Br. Med. J., vol. 2, p. 1203, Dec. 5, 1891. [19] M. Arthus, La Coagulation du Sang (Series Scientia, Biologie no. 5). Paris: Carré et Naud, 1899, 9 chapters, 93 pp. [20] L. Lilienfeld, “Haematologische untersuchungen [in German, Hematological investigations],” Arch. Physiol., pp. 115– 154, 1892. [21] L. Lilienfeld, “Über leukocyten und blutgerinnung [in German, On leukocytes and blood coagulation],” Arch. Physiol., pp. 167–174, 1892. [22] L. Lilienfeld, ‘Über den flssigen zustand des blutes und die blutgerinnung [in German, On the liquid state of blood and its coagulation],” Arch. Physiol., pp. 550–556, 1892. [23] L. Sabbatani, “Calcio e citrato trisodico nella coagulazione del sangue, della linfa e del latte [in Italian, Calcium and sodium citrate in blood, lymph and milk coagulation],” Atti della Reale Accademia delle Scienze di Torino, vol. 36, pp. 27–53, 1900.
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[24]P. Nolf, “La coagulation du sang du poisson [in French, Coagulation of fish’s blood],” Arch. Int. Physiol., vol. 4, pp. 216–259, 1906. [25] P. Nolf, “Contribution à l’étude de la coagulation du sang [in French, Contribution to the study of blood coagulation],” Arch. Int. Physiol., vol. 6, pp. 1–72, 115–191, 306–359, vol. 7, pp. 280–312, 379–410, 411–461, 1908. [26] O. Gengou, “Contribution a l’étude de l’adhésion moléculaire et de son intervention dans divers phénoménes biologiques [in French, Contribution to the study of molecular adhesion and of its intervention in different biological phenomena],” Arch. Int. Physiol., vol. 7, pp. 1–87, pt. I, vol. 7, pp. 115–210, pt. II, 1908. [27]W. H. Schneider, “Blood transfusion in peace and war, 1900–1918,” Soc. Hist. Med., vol. 10, no. 1, pp. 105–126, 1997. [28]A. Hustin, “Note sur une nouvelle méthode de transfusion [in French, Note about a new method of transfusion], Ann. Soc. Roy. Sci. Méd. Bruxelles, vol. 72, no. 4, pp. 104–111, 1914. Also in J. Méd. Bruxelles, vol. 12, pp. 436–439, 1914. [29] R. A. Kazi. (2003). The life and times of George Washington Crile: An outstanding surgeon. Internet J. Otorhinolaryngol. [Online]. 2(2) Available: http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijorl/ vol2n2/crile.xml [30]B. O. Raulston and R. T. Woodyatt, “Blood transfusion in diabetes mellitus,” J. Amer. Med. Assoc., vol. 62, pp. 996–999, Mar. 28, 1914. [31]L. Agote, “Nuevo procedimiento para la transfusión de sangre [in Spanish, New procedure for blood transfusin],” Anales del Instituto Modelo de Clínica Médica, vol. 1, no. 2, pp. 24–30, Jan. 1915. [32] R. Lewisohn, “A new and greatly simplified method of blood transfusion. A preliminary report,” Med. Rec., vol. 87, pp. 141–142, Jan. 23, 1915. [33]R. Lewisohn, “The citrate method of blood transfusion in children,” Amer. J. Med. Sci., vol. 150, pp. 886–889, 1915.
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