a short history of transfusion medicine

R E V I E W

A short history of transfusion medicine

T.J. Green W a l t

he association of blood with life and vitality was recorded in early history. This is indicated in the Old Testament by the following: “Because the life of the T flesh is in the blood and I have given it to you on the

altar to make an atonement for your souls: for it is the blood that maketh an atonement for the soul. Therefore, I said unto the children of Israel: No soul of you shall eat blood, neither shall any stranger that sojourneth among you eat blood” (LeviticusXVI1:ll). Denial of transfusions on religious grounds is based on this and other biblical admonitions. “Only flesh with the life thereof, which is the blood thereof, shall ye not eat” (Genesis E 4 ) and “Be steadfast in not eating the blood; for the blood is the life; and thou shalt not eat the life with the flesh. Thou shalt not eat it; thou shalt pour it out upon the earth as water” (DeuteronomyXI1:ll).

Claims of transfusions prior to the 17th centuryare either mythical or apocryphal. Ovid recounted that the witch, Medea, rejuvenated Jason’s father, Aeson, by slitting his throat to let out his old blood, replacing it with a brew of herbs and offal from birds and mammals so that body and mind were returned to a more youthful state.’ It was believed that the weak would gain strength by bathing in or drinking the blood of the strong. Thus Pliny and Celsus described the custom of people rushinginto the arena to drink the blood of dying gladi- ators.* Crile3 quotes from Ore to the effect that “the ancient Egyptians knew about it and practiced it from allusions made in their history. In the ‘Book of Wisdom’ of Tanaquila, the wife of Tarquin, mention is made of the custom, and Herophilus clearly refers to it in his treatise on a n a t ~ m y . ” ~ Galen, a Greek physician (c. 129-c.200 AD), believed that four fundamental humors-phlegm, blood, yellow bile, and black bile-were responsible for health and illness. It is difficult to understand why his empirical principles influenced medical practice for at least 15 centuries. Bleeding to let out “bad

From the Hoxworth Blood Center, Research Department, Cincin- nati, Ohio.

Received for publication December 22, 1995; revision received July 16, 1996, and accepted August 29, 1996.

Presented in part at the Fifth Regional Congress of the Inter- national Society of Blood Transfusion, Venice, Italy, July 2-5, 1995.

TRANSFUSION 1997;37:550-563.

blood,” as recommended by Galen, was practiced well into the 18th century. Some believe that George Washington’s death was hastened by excessive bleeding by his physicians.

The oft-cited earliest transfusion is that of the aged Pope Innocent VIII in 1492. Actually, it appears that the Pope was given a draught of the blood of three boys,5 whose lives were sacrificed in vain.6The fate of the physician responsible is un-

A less plausible version of this event was recorded by Pasquale Villari.6 According to Villari, the Pope, who had had an apoplectic stroke the year before,

... had for some time fallen into a kind of somnolency, which sometimes was so profound that the whole court believed him to be dead. All means to awaken the exhausted vitality had been resorted to in vain, when a Jewish doctor proposed to do so by the transfusion, by a new instrument, of the blood of a young person; an experiment which hitherto had been only been made on animals. Accordingly, the blood of the decrepit old Pontiff was passed into the veins of a youth, whose bloodwas transferred into the veins of the old man.The experiment was tried three times, and at the cost of the lives of three boys, probably from air getting into their veins, but without any effect to save that of the Pope.

Keynes also cites a similar story from Morte d’Arthur.’ It cannot be established who conceived the idea oftrans-

fusing blood. It has been suggested that it may have been Hieronymus Cardanus (1505-1576), to whom I can find no reference other than mention by Wiener2 and Kilduffe and DeBakey.* K e y n e ~ , ~ Wiener, and Kilduffe and DeBakey give credit to Magnus Pegelius for suggesting the possibility of transferring blood from the blood vessels of one individual to those of another. According to Gesellius,Io Pegelius was Pro- fessor at Rostock in 1604 when he published his book, Thesau- rus rerum selectarum magnarum, dignarum, utilium, suavium pro generis humani salute oblatus. This could not be verified, but according to Ullersperger,” “[Tlhe idea and theory of transfusion, etc., appertains by full right to Magnus Pegel,” whose work “obtained the privilege of being printed already in 1593, under the Emperor Rodolphus 11, but was not published before 1604.”

Andreas Libavius’* was the first to definitely advocate blood transfusion, describing a technique that remained in

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HISTORY OF TRANSFUSION MEDICINE

use through the fourth decade of the 20th century. In 1615, he wrote as follows (translated byWiener2):

Let there be a young man, robust, full of spirituous blood, and also an old man, thin, emaciated, his strength exhausted, hardly able to retain his soul. Let the performer of the operation have two silver tubes fitting into each other. Let him open the artery of the young man, and put into it one of the tubes, fastening it in. Let him immediately open the artery of the old man and put the female tube into it, and then the two tubes being joined together, the hot and spirituous blood of the young man will pour into the old one as it were from a fountain of life. and all of his weakness will be dimelled.

It is doubtful that Libavius ever carried out the procedure he proposed.13 It is not possible to ascertainwhether he was Ital- ian, German, Belgian, or Dutch. Keynesg states that Libavius was an Italian, whereas White and Weinstein14 state that he was a chemist from a city named Halle. I wondered about the geographic location of H d e . To my surprise, I found four cit- ies by that name in the National Geographic Atlas: one near Bieleford in western Germany, another in the Brabant near Brussels, a third close to Antwerp, and the last, called Halle an der Saale, near Leipzig, Saxony, in eastern Germany. I favor the latter because it appears in bolder type than the others. My choice is as authentic as the reader’s and that of the historians. In fact, Maluf15 agreesthat Libavius (1546-1616) was from Halle in Saxony and that he was a chemist and physician and director of the college at Coburg.

It is generally believed that the concept of transfusing blood could not have developed before the announcement by William Harvey (1578-1657) of his description of the circulation, in 1616, and its formal publication in 1628.There is much question as to who performed the first transfusion, and some doubt can be cast on credit for the discovery of the circulation. Andrea Cesalpino (1519-1603), an Italian, appears to be a strong contender for having preceded Harvey. He used the expression‘%irculation,” had ideas about the greater and lesser circulations, and proposed that fine vessels (capillaries) connected the arterial and venous systems.16 Usually not mentioned is the fact that, after finishing at Cambridge, Harvey went to Padua for his medical training (1598- 1602) at the elite Universitas Juristarum. His teacher was Hieronymus Fabricius ofAquapendente (1537-1619), an authorityon theveins ofthe human body. It is said that Harveyused Fabricius’s description of the valves of the veins to support his circulation theory. Thus, Harvey’s great contribution was based on excellent work previously done by Italian colleagues.

We are now ready to speculate on the validity of the claims that were made regarding the performance of the first trans-

at the University of Padua, mentioned in 1628 the possibility of using transfusions as a method for prolonging life,17 but there is no evidence that he ever did it. A serious contender for priority appeared to be Francesco Folli of Florence. He published the first book on transfusion, in which he claimed to be the originator of blood transfusion.’* He stated that he had read Harvey’s book and conceived the idea that the transfusion of blood could be used to cure diseases and to rejuve- nate the aged. In 1645, in Pisa, he had observed Siamese twins joined together by their livers. Only one of the twins was able to eat and drink, and his nourishment supported his brother, which suggested to Folli that nature had provided an example of blood transfusion. Harvey’s discovery of the circulation clinched the idea. Folli describes the apparatus required for a transfusion, and its use. He even postulated the presence of 20 young men to use as donors so that the patient could be given fresh blood over an extended period. At the end of the book, he confesses that he never performed the procedure. He states: “Finally, I know that I have said too much concerning the manner of carrying out the operation, not having made the experiment ... but I have done it solely, so that every one, simple and ignorant, could understand, be inspired, and make the experiment with the least possible expense, and to this end only I have written in the vulgar tongue.”’*

The credit for the first successful transfusion from one animal to another must be given to Richard Lower (1631- 1691). After years of experimentation and physiologic studies, his first attempts to transfuse blood from the jugular vein of one dog to another failed, because of clotting in the tubes.Ig In a demonstration at Oxford in February 1665, he exsanguinated a medium-sized dog through a jugular vein “until it was quite clear from its howls and struggles that its strength was nearly gone.” He then introduced blood by connecting in succession the cervical arteries of two large mastiffs to the jugular vein of the first dog and actually performed an exchange transfusion, removing blood when it was evident that the first dog was overfilled, leaving the donor animals lifeless. He was clearly exhilarated by this success, because he wrote, “[Olnce its jugular vein was sewn up and its binding shackles cast off, and, apparently oblivious to its hurts, [the dog] soon began to fondle its master and to roll on the grass to clean it- self of b l o ~ d . ” ~ ~ ( p l ~ ~ )

This event marked one of the earliest of bitter battles over priority of which I am aware. I thought that a little more detail would amuse the reader. In his treatise, published in 1669, Lower states that he had been requested to acquaint the Royal Society with the procedure of the whole experiment and that his report had been published in the Philosophical Transac- tions of the society in December 1666. He goes on:

fusion. Harvey had pumped water into the circulation of a dead man, but there is no indication that he ever considered the possibility of blood transfusion. Sir Christopher Wren, as- sisted by Robert Boyle, used quills to inject various medica- ments into the veins of animals. Johannes Colle, a professor

Thereafter talk of it wandered across to nations abroad and to France, where, attracted by the novelty of the thing, some began to follow it up more thoroughly, to extend and embellish it by other further experiments, and to apply to the use of man that which I had only

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accomplished in animals. This is seen clearly in their writings published for the first time in the following March, 1667. So far so good, and all credit to that nation for their activity in the embellishment and extension of natural knowledge and of medicine. But as this recent discovery of blood-transfusion is now a general subject of conversation, and a certain Denis, Professor of Phi- losophy and Mathematics, seeks in a recently published letter to deprive me of priority in the discovery of this experiment, and to claim it for himself, let me be permitted to insert here the letter of the Honourable Boyle [the Secretary of the Royal Society] to me and my reply to it, so that the reader may see how rightly or wrongly Denis so a ~ t e d . ’ ~ ( p ’ ~ ~ )

The publication of the Denis contribution was delayed because, at the time it was received, Boyle, the editor, was im- prisoned in the Tower of London.

There seems to have been no idea at the time of how to apply this new knowledge. Lower claims to have cured mange by transfusing the blood of a healthy dog. I also read in one of Jean-Baptiste Denis’s reports that he failed to transmit mange to a healthy dog by transfusion. Samuel Pepys, with his usual light touch of humor, on hearing about these events, quips in his diary on November 14,1666:

[Hlere Dr. Croone told me that at the meeting at Gresham College tonight, which, seems they now have every Wednesday again, there was a pretty experiment of the blood of one dogg let out, til he died, into the body of another on one side, while all his own run out on the other side. The first died upon the place, and the other very well and likely to do well. This did give occasion to many pretty wishes, as of the blood of a Quaker to be let into an Archbishop and such like; but as Dr. Croone says, may if it takes, be of mighty use to man’s health, for the amending of bad blood by borrowing from a better body.20

If all the possible contenders were still alive, further claims of prioritywould be made, and, in the present litigious world, lawsuits would follow regarding who it was first entertained the idea and who exactly performed the first human transfusion. Folli could possibly claim both distinctions. Francis Potter has been reported to have entertained the no- tion of curing diseases by transfusing blood from one man to another.” Although credit for the first human transfusions is usually given to Jean-Baptiste Denis (1635-1704), others, as already indicated, might also make the claim. In Germany in 1664 Johann-Daniel Major made the first successful intrave- nous injections in man and, if his writings (published in 1667) are correct, he is probably the first to have performed transfusions in man.22 Doan, in an article inPhysiologicu1 Re~iews,’~ stated that Major reported transfusing his teacher, Professor Doctor Johan Michaelis of Leipzig, for paralysis in October 1666. Denis knew of the animal transfusions, reported more than 10 years before, by don Robert de Gabets, a Benedictine

monk. Another predecessor was Claude Tardy (1667), of the Faculty of Medicine in Paris, who wrote the first book on the utility of transfusion. He reasoned that transfusions should work better in man than in animals and considered those from vein to vein more convenient and less dangerous than those from artery to vein. While recognizing the use of animals as donors, in a letter to Le Breton, also of the Faculty of Medicine in Paris, Tardy admitted that the blood of man is better for transfusion than that of animalsz4 Others have been mentioned as having performed animal-to-animal transfusions during this period. Those to whom there are specific references are Johann-Daniel Major, mentioned above (Chirurgiu Infusoriu, Cologne, 16671, and Johann-Sigmund Elsholtz (Clysrnaticu Nova, Berlin, 1665 and 1667), both cited by P e ~ m e r y . ~ ~ - ~ ~ Thus, there was much information, including Denis’s own animal experiments, before he and his colleague Emmerez performed their first well-documented transfusion of animal blood into a human.

Farr,28 reported in a detailed study that, at age 32, Denis was a brilliant young man, who had obtained a Bachelor of Theology degree and then studied medicine at Montpellier. It should be noted that he was a professor of philosophy and mathematics at Montpellier and physician to Louis xn! He was a member of a group of scientists and philosophers who met weekly at the Quai des Augustins, in the home of Henri de Montmort, Counsellor of State and first Master ofRequests to Louis xn! Montmort apparently had taken Denis (not Denys, as pointed out by Farr) as a protegC and encouraged him to experiment with blood transfusion. I suspect that these connections shielded him from the disapprobation of the members of the French Academy when he performed his first daring experiment, on June 15,1667. This would also explain why the recorded description of his first human transfusions was in a letter to M o n t m ~ r t . ~ ~ The patient was a youth of 15 with a longstanding fever, who had been bled 20 times by his physicians: “[Hlis wit seem’d wholly sunk, his memory per- fectly lost, and his body so heavy drowsie that he was not fit for anything.” Accordingly, he was bled of about 3 oz and received in exchange about 9 oz, from the carotid artery of a lamb connected to an arm vein. To my surprise, Denis reported that afterwards the boy had“a clear and smiling coun- tenance,” although during the procedure he had felt “a very great heat along his arm.” On July 24,1667, Denis administered a transfusion to Baron Bond, son of the Prime Minister of Sweden, without curing him. Other transfusions, to a paid volunteer and a moribund patient, were without immediate, dire consequences. The next subject, which some historians count as his fourth, although my research indicates that it was at least the fifth, proved to be of great historical significance. For this reason, and because of the case’s strangeness, I will recount it in more detail.

The patient, Antoine Mauroy, was a 34-year-old newly- wed male house-servant, who had a tendency to run away from his home and spend his time in debauchery in Paris. Henri de Montmort felt sorry for Mauroy’s wife and asked



Denis whether he could help: calf’s blood, because of the gentle nature of a calf, might dampen Mauroy’s spirits. On December 19,1667, at 6AM, he received 5 or 6 oz of blood from the femoral artery of a calf, which was connected to his arm vein. The patient seemed to improve and became quieter. On the Wednesday before Christmas, the procedure was repeated. This time, the patient felt a sensation of heat traveling up his arm during the passage of the arterial blood through his vein; he also had pain in the region of his kidneys and an oppres- sive sensation in his chest. On the day before Christmas, he had nasal bleeding and dark, bloody urine. I believe that this may be the first reported incompatible transfusion reaction. Amazingly, the patient survived and, after 2 months, again became maniacal. His wife insisted on another transfusion, which was attempted but was unsuccessful because of the noncooperation of the patient. The patient died the following night without having received the third transfusion. Re- portedly, members of the Faculty of Medicine, who were op- posed to transfusion and hated Denis, bribed Mauroy’s wife to state that he had died during the transfusion. Denis was tried for manslaughter but was exonerated. It was later ru- mored that Mauroy’s wife had been poisoning him with ar- senic and that that was the actual cause of his death.28 This cannot be substantiated.

Lowerlg was not to be outdone. On November 23, 1667, he and Edmund King performed a human transfusion before the Royal Society in England. The subject was Arthur Coga, aged 32, an indigent Bachelor of Divinity from Cambridge, brother of the Master of Pembroke College. He, variously described as a“harmless lunatic” and an“eccentric scholar,” was given 9 to 10 oz of blood from the artery of a sheep. The man was said to have “found himself very well” afterward. On No- vember21,1667, Pepys noted in his diary: “Amongthe rest they discourse of a man that is a little frantic, that hath been a kind of minister ... that is a poor debauched man that the College have hired for 20s. [20 shillings] to have some of the blood of sheep run into his body” On November 30, Pepys dined at a house of entertainment (which sounds sort of bawdy to this writer) and noted (as quoted in great detail by Keynes):

The events in Paris, described above, were used by Denis’s enemies as an excuse to issue the Edict of Chiitele~~O which banned the practice of transfusion in man without the approval of the Faculty of Medicine in P a r i ~ . ~ ! ~ ~ Similar actions by the magistrates in Rome and by the Royal Society have been implied but not ~pecified.~’ Undoubtedly, lives were saved by such bans. It should be said, nevertheless, that there had been similar activity, if not as popularized, elsewhere, especially in Italy. Cassini and Griffone had niade many successful experiments in animals, with the latter reporting the restoration of hearing to an aged deaf dog through transfusion. Manfredi (1668) had put the operation into practice?* These unfortu- nate events led to the essential abandonment of the study of the physiology of the circulatioii and of experimentation for approximately 150 y e a r ~ . 3 ~ - ~ ~

The activity during the 18th century is summarized briefly by Crile.3The surgeons Kaufman and Purman, in Frank- furt an der Oder, supposedly cured a leper in 1683 by a transfusion oflambs blood. Ettenmuller of Leipzig, in 1682, recommended small amounts of lamb’s blood given repeatedly for fevers, scurvy, and hypochondriasis. Nuck, in his book, Operu- tions et Experimenta C h i r u r g i ~ a , ~ ~ included a history of blood transfusion and stated that it should not be forbidden because it might be of great value in wounds accompanied by consid- erable hemorrhage. He may have been the first not to approve usingthe blood ofanimals. In 1749, Cantwell, a member of the Faculty of Paris, expressed a similarly dissenting opinion that transfusion should not be forbidden in desperate cases, because it occasionally had been proved to be of value.28

Michele Rosa, in 1788, published experiments demon- strating that an animal in severe shock could not be resusci- tated by the transfusion of serum: the transfusion of whole blood was necessary.36 These observations coincided with, and were supported by, the discovery of the importance of oxygen to sustain life. The “dephlogisticated air” of Joseph Priestly (1733-1804) was shown by Lavoisier in 1777 to be a definite substance, which he called oxygen and which was used to ignite carbon.

The leap into the 19th century, and to the pioneering studies of James Blundell (1790-18771, was truly long. I was unable to obtain any of the original writings of this illustrious physiologist and physician, except for an unsigned note3’ in The Lancet describing the successful transfusion of “a delicate woman, 25 years of age,” for postpartum hemorrhage, with 8 oz of “pabulum vitae [blood], procured from the arm of Mr. Davies [one of the surgical participants],. . .injected at differ- ent times-the whole operation occupying upwards of three hours.” Very good accounts of Blundell’s work are given by Doan, Keynes, Maluf, and M ~ h r e . ~ ~ He was aroused by the plight of women who went into shock and died of postpartum

But here above all, I was pleased to see the person who had his blood taken out. He speaks well, and did this day give the Society a relation thereof in Latin, saying that he finds himself much better since, and as a new man, but he is cracked a little in his head, though he speaks very reasonably and very well. He had but 20s. 120 shillings] for his suffering it, and is to have the same again tried upon him: the first sound man that ever had it tried on him in England and but one that we hear of in France, which was a porter hired by the v i r t ~ o s o s . ~ ( p ~ ~ ~

~~

Sources differ on what happened after this. Some say that the procedure was repeated without harm or positive effect, and others say that Coga was uncooperative and refused further transfusion.

hemorrhage. He performed ex.tensive animal experiments before embarking on the clinical use of transfusion, which he felt should be limited to the treatment of hemorrhage. He was saved from the error of using animal blood by the observation


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of a colleague, Dr. John Leacock, that the blood of any species might be harmful to any other species. Leacocks paper,39 ema- nating from Barbados, was based on studies performed in Edinburgh, where Blundell was a c~n tempora ry .~~ The credit for the first transfusion of human blood was established on December 22, 1818, when Blundell reported to the Medico- Chirurgical Society of London on the transfusion he had performed with the celebrated surgeon, Henry Cline. The patient, moribund because of an obstruction ofthe outlet of the stom- ach, was given 12 to 14 oz of blood from several donors and, after temporary improvement, relapsed and died.41-43 It is difficult to ascertain if Blundell was ever clinically successful, except in the 1829 case already mentioned. Keynes states:

“In 1824 he recorded six operations, including the one already mentioned ... but his attempts were uniformly unsuccessful in saving life owing to the fact that at least two of his patients were already dead when he transfused them, and the remainder too ill for recovery to be p~ssible.”~(p*~)

In contrast, Doan reports that six of nine transfusions in desperate cases were s u c ~ e s s f u l . ~ ~ Both Doan and Keynes cite the same references. In his first transfusions, Blundell used a brass syringe, which he filled from the donor’s vein, and then injected the blood into the patient’s vein. Later, he invented an instrument called the “Impellor,” described and depicted in his 1824 book42 (Fig. 1). It consisted of a double-walled funnel, in which the outer compartment was filled with warm water. The blood of the donor was allowed to run into the funnel, was sucked into the syringe on the right, and was forced along the tubing and cannula inserted into the patient’s vein by means of two oppositely acting spring valves below the funnel. The Impellor has usually been shown attached to the upper part of a chair by means of a screw and clamp. The do- nor was obliged to sit in the chair in proximity to the patient. Clumsy as the device appears to us today, it remained in use until the latter part of the 19th century. Perhaps this is not as surprising as the failure of the profession to heed Blundell’s warning about the danger of using animal blood. I found in Keynes a quotation from Blundell’s 1834 book, sufficiently amusing to risk repeating it:

[Flor the original operation the presence of some animal in the bed-chamber was necessary; what then was to be used in an emergency? A dog, it is true might have come when you whistled, but the animal is small; a calf or a sheep might, to some, have appeared fitter for the purpose; but it would not run upstairs. In this condition of it, the operation, a little more than a name, was great in its danger, but of small advantage in those very cases of sudden bleeding in which it seemed most required.42

Again, the question of priority has been raised by S ~ h m i d t , 4 ~ * ~ ~ who has discovered that a footnote by the edi- tors of the PhiladelphiaJournal of the Medical and Physical Sci- ences credits the transfusion of human blood to a Dr. Philip

Syng Physic in 1795. This footnote reads, “Thirty years ago, the experiment of the transfusion of blood under precisely the same circumstances as above, was performed by Dr. Physic.” The statement was never supported by any further details, nor was it ever retracted by Dr. Physic. Nevertheless, the credit is still properly due Dr. Blundell, who did much research and preparation for his clinical experiment^.^^

Blundell’s warnings about the dangers of transfusing animal blood to humans were not generally heeded throughout much of the remaining years of the 19* century As late as 1874, two treatises, by Franz GeselliusIo and Oscar H a ~ s e , ~ ~ advo- cated the use of lambs blood. The problem of clotting made all techniques used in those days difficult.This may have been the reason for the rarity of transfusions until the early part of the 20th century.

Two French physiologic chemists, Jean Louis Prevost (1790-1850) and Jean Baptiste Andre Dumas (1800-1884), found that the whipping of blood resulted in the deposition of the fibrin on the churning device. They noted that the defibrinated blood was as effective in resuscitating animals as untreated blood.47 Defibrinated blood appears to have more or less achieved acceptance as a safe alternative to unaltered blood, but acceptance was not general. Gesellius was an op- ponent of its use and sought to introduce what he called capillary blood, which he obtained by a device that punctured the skin of the donor’s back in many places simultaneously. The blood was sucked from the punctured skin into a receptacle, from which it was transfused (Fig. 2). I am certain you have seen this illustration previously and wondered how it worked. I still wonder that any human donor would be willing to un- dergo such torture, especially in those days when anesthetics had not been discovered. Physicians with such retrogressive viewpoints certainly held up progress in the development of blood transfusion. Keynes states that the last sentence of

Fig. 1. Cross-section of the Impellor showing syringe and valve mechanism for changing direction of flow. Blood is impelled by “long strokes and sharp movements.” (From Kilduffe RA, DeBakey M. The blood bank and the technique and therapeutics of transfusions. St. Louis: C.V. Mosby, 194227)



Gesellius’s book announced his conviction that “Die Lamm- blut-Transfusion wird in der Medicin eine neue Aera-die Blutspendende-inaugurizen [Lambs blood transfusions will inaugurate a new area of blood dona t i~ns ] . ” ’~ We should be grateful that the convictions of such as Hasse and Gesellius did not prevail.

One might wonder how successful transfusions, even those with human blood, were possible without the most basic information about the ABO blood groups. A few simple calculations reveal that, even when there was no knowledge of the blood group of either the donor or the recipient, by chance, 64.4 percent of transfusions would pass as compatible. These calculations are shown (Table l), with the percent- ages for the prevalence of the blood groups in whites taken from the American Association of Blood Banks’ Technical Manual.48

The contributions of Blundell were significant. However, the turning point in understanding the underlying reasons for the contraindication for using animal blood in human transfusions resulted from the observations of Ponfick and Landois. On May 28, 1874, Ponfick read before the Association of Bal- tic Physicians a paper describing the dangers of heterologous transfusions. He reported that a 36-year-old woman in severe shock, who had been given a direct artery-to-vein transfusion from a sheep for 1 to 2 minutes, promptly became comatose and died in 20 minutes. He had observed residues of lysed red cells in her serum taken at He noted that, after the transfusion of sheep’s blood to dogs, cats, and rabbits, those animals had difficulty in breathing; they then defecated, had convulsions, and died within 2 hours. At autopsy, their hearts were dilated, there were hemorrhages in the lungs and along the serosal surfaces, the kidneys were enlarged and congested, and the livers were dark and hemorrhagic. If the animals survived long enough, they passed bloody urine. He recognized that the bloody urine was due to hemoglobinuria and not hematuria. He ascribed the cause ofdeath, in the animals that survived the acute episode, as “secretory insufficiency” of the kidneys, and he was the first to note that the brown masses found in the tubules were hematin, or degenerated hemoglobin.50

Apparently, it was at this time that light was beginning to dawn on the real problems involved in heterologous transfusions. P a n ~ m , ~ ’ Landois and E ~ h l e n b e r g , ~ ~ and L a n d ~ i s ~ ~ , ~ ~ showed that an exsanguinated animal could be saved by the transfusion of blood from the same species, but that it would die if blood from another species was used. Their observations on hemoglobinuria and the appearance of the organs, especially the kidneys, after heterologous transfusions in animals were much the same as Ponficks. Landois suggested that the hyper- kalemia from lysed red cells was a possible contributor to rapid death. Per-

Fig. 2. Apparatus for capillary blood transfusion devised by Gesellius. (From Wiener AS. Blood groups and transfusion. Sprin@eld: Charles C. Thomas, 1943:52)

haps his most important observation was that human red cells would lyse when mixed in vitro with the sera of other animals. These observations, however, did not explain why homolo- gous (allogeneic) transfusions in man could also be followed by dangerous and even fatal reactions. The records indicate that human transfusions were performed only rarely until Landsteiner demonstrated that the serum of a normal human being can agglutinate the red cells of another. Previous observ- ers had characterized the phenomenon as a manifestation of disease. Landsteiner based his observation that there were three blood groups-A, B, and 0-on examination of the in- teractions of the cells and sera of 6 people initially (later extended to 22 p e ~ p l e ) . ~ ~ . ~ ~ Shortly afterward, von Decastello and S t ~ r l i , ~ ’ also working in Vienna, reported finding AB, the least frequent of the blood groups, which Landsteiner had not observed. Some have claimed that Samuel G. Shattock made the discovery of the human blood groups simultaneously with Landsteiner, but I could not find any substantiation of this in a paper by Shattock available to me.58

TABLE 1. Chance of compatible transfusion without donor selection Blood tvpe (freauencv)

Blood tvoe Freauencv’ 0 0.45 A 0.40 6 0.1 1 AB 0.04 Comoatible

0 0.45 0.2025 0.1800 0.0495 0.0180 0.4500 A 0.40 0.1800 0.1600 0.0440 0.0160 0.1760 B 0.1 1 0.0495 0.0440 0.0121 0.0044 0.0165 AB 0.04 0.0180 0.0160 0.0044 0.0016 0.0016 ComDatible 0.2025 0.3400 0.0616 0.0400 0.6441 ’ t 0.6441 x 100 = 64.41 percent.

Frequency in whites in US population.


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Evidently, Landsteiner realized the importance of his discovery in relation to blood transfusions, but it seems that blood group matching was not put into practice immediately. There is no documented evidence of how rapidly the matching of the blood groups and crossmatching were put to use in Europe. The first paper advocating the practice of selecting donors by blood group and crossmatching was by Ludvig Hektoen of Chicago, who stated: “It may be pointed out, however, that the possible danger indicated can be avoided by the selection of a donor whose corpuscles are not agglutinated by the serum of the recipient and whose serum does not agglutinate the corpuscles of the latter; that is to say, donor and recipient should belong to the same blood g r o ~ p . ” ~ ~ ( p ’ ~ ~ ~ )

Reuben Ottenberg is usually given the credit for introduc- ing Hektoen’s precept into regular practice. He performed extensive studies of isoagglutinationm and, with Kaliski, published reports of experiences with 128 cases of transfusion.61 Surprisingly, although careful pretransfusion testing was strongly urged in both papers as a way to prevent hemolytic transfusion accidents, it was stated that positive agglutination tests “need not be regarded as an absolute contraindica-

At that time, Ottenberg believed that, in a very anemic patient, the offending antibodies could be swamped by massive amounts of donor blood. This was no longer the practice in his service when I was an intern in 1937. In fact, having no blood bank in those days, Ottenberg’s policy was, as far as possible, to use group 0 donors exclusively.

It seems inevitable that confusing terminologies are introduced whenever some classification is needed. This was true of the blood groups, which Landsteiner had simply designated A, B, and C (for 0). The logical designation of the fourth group, discovered by von Decastello and Sturli, was AB. But no! That would have been too simple. JansW2 introduced a numerical code that designated group 0 as IV and group AB as I. Moss, in 1910, introduced another nomenclature in which I and IV were i n t e r ~ h a n g e d . ~ ~ When ordering blood, one had to tell which nomenclature was used. Fortu- nately, A and B had the same numbers in both systems. I re- member, after establishing the Junior League Blood Center in Milwaukee in 1947, that we received an order for IV 0 blood. Four units of group 0 blood were sent. The technologist from the hospital called later, asking why we had shipped 4 units when only 1 had been ordered-her hospital was still usingthe Jansky terminology. I am sure that mistakes more serious than that occurred.

A committee of distinguished experts, appointed and serving under the aegis of the American Medical Association, made the following recommendation: ‘Rs further confusion and the possibility of accident may be avoided by the use of one classification, it is recommended unanimously on the basis of priority that the Jansky classification be adopted.64(p130) Unfortunately, the recommendation was not adopted universally, even with the footnote, “Reprints of this article will be sent by the JOURNAL on receipt of 4 cents in postage.” The so-called Landsteiner universal 0, A, B, AB clas-

sification-labeling code was promulgated by the appropriate regulatory agencies. Similarly, seat belts and helmets will not be worn when indicated until there are universal laws that are strictly enforced.

Epstein and Ottenbere5 were the first to suggest that blood groups were inherited. In 1910, von Dungern and Hirszfeld‘j6 published a more definitive report, based on a study of 72 families with 102 children, showing that the A and B agglutinogens were inherited as Mendelian dominants in- dependently of each other. A mathematician, Bernstein, subsequently established that the inheritance of the ABO agglutinogens depended on three allelic genes.67

At this point, most transfusions were given by direct methods. Blundell‘s Impellor was in use until the early part of the 20th century. Many devices, using valves, syringes, and tubing to connect the veins of donor and recipient, were proposed. Crile devised a cannula, through which the vein of the recipient was drawn and then cuffed back over the cannula. The artery of the donor was drawn over the vein, forming a continuous closed endothelial surface.68 This required a skill- ful surgeon and a strongly motivated donor. Somehow, the blood had to be kept from clottinglong enough to make indi- rect transfusions possible. One method was to line with par- affin the container into which the blood was collected, as recommended by Kimpton and Brown69 (Fig. 3).

The use of defibrinated blood has already been mentioned. Many attempts were made to find a suitable antico- agulant. The following remarks must be prefaced by stating that none of those attempts could have been satisfactory, or the history of blood transfusion would have had a faster course. Major, who has been mentioned as a candidate for having performed the first transfusion in man, used ammonium sulfate.23 Braxton-Hicks, a man whose name is familiar to all physicians, had found Blundell’s methods unsatisfactory because of clotting. He used sodium phosphate to anticoagu- late blood for obstetrical patients in the “Maternity Charity” of Guy’s Hospital and stated that “the solution entirely pre- vented coagulation, and rendered, as before mentioned, the operation simple and easy, and its performance ~ a l m . ” ~ ~ ( P ~ ~ ) Unfortunately, none of the four patients in whom it was used survived.70 Doan mentions several of these attemptsz3 Neudorfer (1860) suggested the use of sodium bicarbonate. Tzanck (1922), a dermatologist and syphilologist, who was one of the founders of the International Society of Blood Transfu- sion, found sulfarsenol as effective as sodium citrate. Brines (1926) reported the successful use of ammonium oxalate and arsphenamine. Norton (1924) recommended the use of sodium iodide, and MacCraken and Abelman (1926) recommended sodium sulfate. Hirudin had been suggested by many workers, but had to be eliminated because it could not be obtained at sufficient purity to be nontoxic.

The time at which these purported anticoagulants were suggested is rather surprising, in view of the fact that H ~ s t i n , ~ ] A g ~ t e , ~ ’ L e w i s ~ h n , ~ ~ , ~ ~ and Wei175 had already reported the efficacy of sodium citrate. Sodium citrate was being used to



Fig. 3. The Kimpton-Brown tube. (From Keynes G . Blood transfusion. London: John Wright & Sons, 1949:36)

flush syringes in the Unger syringe founvay valve m e t h ~ d ~ ~ , ~ ~ and the Lindeman multiple-syringe t echn iq~e .~Wha t seems more puzzling is why the use of sodium citrate had not been introduced earlier. In the latter part of the 19th century, it had been discovered that calcium was connected with the clotting of blood. Nicolas Maurice Arthus, a professor at the Swiss Uni- versity at Fribourg, reported with his colleague C. Pages in 1890 that blood could be permanently kept liquid by the addition of any of the soluble salts of oxalic acid.79 Citrates, being relatively nontoxic, were soon adopted by physiologists for use in their experiments. In 1894, Sir Almroth E. Wright re- marked that the physiologist knows of at least a half-dozen methods by which the coagulability of blood can be indefi- nitely postponed, by the use of compounds that render a por- tion of the lime (calcium salts) unavailable for coagulation. “Either oxalic, citric, tartaric or malic acids, or the soluble salts of these acids are at our disposal for this purpose.”80 It also amazed me to read, in a paper by Satterlee and Hooker dis- cussing the use of hirudin (which they spelled herudin) in transfusion, the following: “Oxalated, citrated and fluorided plasmas are well known in the physiologic laboratories, and sodium citrate is reported to have been used as an anticoagu- lant for small quantities of transfused blood.”81[p1781) These authors expressed the opinion that decalcification produced by a chemical reaction is theoretically undesirable and could be avoided by the use of hirudin.Thus, fame and fortune were alienated.

These events stirred another controversy over priority, this time in regard to the use of citrate in the practice of transfusion. G.A. Rueck wrote in the April 15, 1916, issue of the Medical Record, “In January, 1915, R. Lewisohn of New York reported on a new method of blood transfusion, claiming the transfusion of blood treated with sodium citrate as his inven-

tion, but giving some credit to Hustin andWeil.”82(P688) Further- more, Rueck castigatedweil for claiming, in a presentation to the New York Academy of Medicine on December 17, 1914, that he had been the first to use sodium citrate and for not mentioning Hustin of Brussels, who had published his find- ings in April 1914. Apparently, Wright’s work was unknown to the authors mentioned above. Lewisohn was awarded the prestigious Landsteiner Award of the American Association of Blood Banks in 1955 and prouclly displayed a vial of the first sodium citrate solution that he had prepared.

There were still problems with transfusions. Febrile reactions were reported in about 10 percent of the patients observed by Ottenberg and Kaliski.G1 The doubters blamed this on the citrate. The problem was solved by Florence Seibert, who demonstrated that microgram quantities of filterable residues of bacteria remaining after autoclaving were pyro- genic. We now refer to these pyrogens as endotoxins, and, as Seibert indicated, gram-negative bacilli are the most frequent culprits. It is interesting to note that this workwas the basis of Seibert’s doctoral dissertation at Yale, later published in the American Journal ofPhy~iology.~~ She was given the American Association of Blood Banks John Elliott Memorial Award in 1962 for this landmark observation. We still encounter non- hemolytic febrile reactions, but the problem of endotoxins has essentially been eliminated by ciuefd avoidance of the growth of bacteria in solutions and equipment before sterilization.

Rous and Turner of the Rockefeller Institute reported in 1916 that, although human red cells would hemolyze when suspended in isotonic (3.8%) sodium citrate for 1 week, they would remain intact for 4 weeks in a mixture of three parts of blood, two parts of isotonic citrate, and five parts of isotonic (5.4%) d e x t r o ~ e . ~ J ~ In rabbits, they demonstrated that such cells circulated when introduced into the circulation. It is of interest to note that this important information was buried, left unheeded, or ignored for over a quarter of a century. (An aside: Peyton Rous was the discoverer of the Rous sarcoma virus, for which he belatedly received a Nobel Prize at the age of 89.)

Wartime, at least since the Franco-Prussian War of 1870, has been a stimulus for interest in the value of blood transfusion in the management of casualties. J. Bruce Robertson and C. GordonWatson of the Canadian Medical Corps reported on their field experiences inWorldWar 1.86-88 Citrate was the anti- coagulant in several dozen instances when the Lindeman syringe cannula and the Unger founvay stopcock methods of direct transfusion were used. The most significant step was made by Oswald H. Robertson, then at US Army Base Hospi- tal No. 5.89 It may be said that he organized the first blood bank, although I was able to find no evidence that any of the 44 units of blood that he used in 38 transfusions were actually stored. The autoclaved collection set that he devised, which consisted of integral donor collection tubing with needle, administration set, and collection bottle (Fig. 41, was very muchlike those used in many blood banks decades later. Up to 800 mLof blood was collected into 160 mL of 3.8-percent sodium itr rate.^^


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Credit for the establishment of the first blood bank in which blood was stored under refrigeration, between 4 and 6% before transfusion is usually given to Bernard Fantus, at the Cook County Hospital in Chicago. The blood was collected in chilled 500-mL flasks containing 70 mL of 2.5-percent sodium citrate. Two test tubes were attached to the flask for the collection of 5 mL of clotted blood for typing and performance of theWassermann test. Prior to administration, the blood was warmed in water, “which would not feel too hot for the hand.”g0 In this 1937 article, Fantus gave Yudin credit for establishing that cadaver blood can be preserved for weeks in a fit condition for transfusion. In fact,Yudin credited the experimental basis for the use of cadaver blood to Shamov, who was working in Kharkov in the Soviet Union.g1 This technique, which depends on the postmortem dissolution of fibrin clots by fibrinolytic enzymes, was applied fairly extensively byYudin at the Sklyfasovsky Institute in M0scow.9~ Thus, the credit for establishing the first blood bank should perhaps be given to Yudin, although the stored blood was not collected into citrate from living donors. The use of cadaver blood in the So- viet Union received much publicity, and cadavers were believed by many to be the major source of blood there. Actually, not many more than 40,000 (200-mL) units were used, most of them at the Sklyfasovsky Institute. In 1967, I witnessed the elaborate procedure, which required the use of an operating room, a well-trained staff, and extensive laboratory studies. The expense and the scarcity of suitable cadavers make this procedure impractical.

When I visited the Cook County Hospital Blood Bank in 1949, they were still collecting blood into 3.8-percent citrate, the shelf life of which was limited to 4 or 5 days. Before the blood was transfused, it was poured through gauze (to screen out clots) into a salvarsan flask (a cylindrical flask with an outlet at the bottom to which rubber tubing was attached,

ROBER-EON. 19 LO n

Citrate solution to rucipient I

Fig. 4. The OH Robertson flask. (From Kilduffe RA, DeBakey M. The blood bank and the technique and therapeutics of transfusions. St. Louis: C.V. Mosby, 1942:380.)

with a needle at the end for entering the patient’s vein; salvarsan is the chemical that was added to the flask). They had not yet caught up to the development of ACD solution that took place in Great Britain in the early 194Osg3 The pressure for storing blood in anticipation of need was great. It was already known that adding glucose to the citrate would prolong the useful shelf life of blood kept under refrigeration. Unfor- tunately, when the glucose-citrate mixtures were autoclaved, the glucose caramelized, which changed the color of the solution to various shades of brown. Acidification, by the use of an acid salt of sodium citrate, eliminated this problem and, serendipitously, made possible the extension of the blood storage to 21 days. In the United States, the preference has been to use trisodium citrate and to acidify to pH 5.0 by adding citric acid. There were two formulations of this solution, known as ACD-A and ACD-B. The former was used in the proportion of 15 mL per 100 mL of blood and the latter in the proportion of 25 mL per 100 mL. The total amount of the ingredients added was the same; only the amount of water in the ACD-B was greater. After long discussions in the early 1960s, the Bu- reau of Biologics of the National Institutes of Health (now the Food and Drug Administration) accepted the recommendation of the Blood Transfusion Committee of the National Re- search Council (which this writer chaired) to abandon ACD- B and to standardize the unit of donated blood at 450 f 45 mL.

Knowledge of the intermediary metabolism of the red cell was increasing. Some of the earliest studies were reported in July 1947.94-108 The story of these efforts is interesting and would require a separate article to do it justice. Greenwalt and Jamieson provide a reviewlog of the major developments in red cell metabolism and the methods used for blood preservation. Preliminary studies made possible the small steps that have led to modern red cell preservation methods. Knowing that low pH was good for the maintenance ofATE but bad for that of 2,3 DPG, John G. Gibson I1 and colleague^,'^^-^^^ developed CPD, improving the maintenance of 2,3 DPG by the addition of phosphate to raise the pH of the solution to 5.6. It is worth noting that, at that time, the importance of 2,3 DPG for oxygen transport was unknown, although the presence of large amounts of it in red cells had been recognized for over 30 years.”’ The role of 2,3 DPG was discovered by Chanutin and Curnishl12 and the Benesches113 in 1967.

The next major advance in red cell preservation came when the work of Nakao et al.I14 suggested that the addition of adenine enhanced the maintenance of AT€! Subsequently, Simon et performed studies that established that the addition to blood collected in ACD of adenine at a final con- centration of 0.5 pmol per mL would support longer maintenance ofATP and satisfactory red cell survival after storage for as long as 42 days. The next step forward came about when it dawned on us that it was counterproductive, during the preparation of packed red cells, to remove with the plasma the ingredients just added to the blood in the preservative solution for storage. That led us to the use of additive solutions, which was introduced by Hogman et al.II6



This innovation made it possible to store red cells at a lower hematocrit and with better flow properties, which made red cells (vs. whole blood) more acceptable to surgeons. The use of additive solutions permitted the extension of the storage shelf life of the component to 42 days. One feature, which I have not seen enunciated, is that the introduction of a num- ber of variants of the additive formulation is possible, without the lengthy and expensive collection of new information for the approval of the licensing agencies for the other blood components and derivatives, as long as the initial unit of blood was collected in an already approved medium. Much more could be told about the evolution of red cell preservation, enough to make up a long chapter in a work on the gradual development of knowledge about the metabolism and mem- brane structure of the red cell and the largely empirical changes in the improvement of its storage.

It is not always possible to recount the history of a subject in exact chronological order. At this point, it is necessary to step back to consider one of the most decisive factors in the development of blood banking. Without the discovery and patenting of the plastic container by Carl Walter in 1950, component therapy would not have been developed, nor would the technologies involved in the creation of the various sepa- ration devices used in the preparation of single-donor components and the related therapeutic procedures have been possible. One example of the impact of the introduction of multiple connected plastic containers is the change I was able to make in the 12 years of my tenure as Director of t h e h e r i - can Red Cross Blood Program (1967-1978). The use of packed red cells increased from 0.8 percent to 88 percent. The enor- mous increase in the harvesting of recovered plasma was an economic bonanza. In today’s climate, it would not be possible to meet the still-escalating demand for platelet concen- trates without the availability of plastic containers.

A complete history of blood transfusion would require several volumes. Time and space prevent the mention of more than a few high points of recent interest.The subjects of platelets, white cells, plasma, and plasma derivatives can be only briefly mentioned.

During World War 11, the use of liquid and lyophilized plasma was introduced. The credit for the earliest studies is usually given to John Elliott and his c ~ l l e a g u e s . ~ ~ ~ J ~ ~ In the early 1940s, Edwin J. Cohn and coworkers developed methods for the fractionation of plasma proteins that, with modifica- tions by other distinguished scientists, remain the basic procedures still in use.119J20 Human albumin and plasma were the major resuscitative fluids used in the first-line management of shock duringWorldWar II.IZ1 Under the direction of Charles R. Drew, the “Plasma for Britain” program was successfully implemented.’21 For reviews of these subjects, see White and Weinstein14 and Kendrick.IZI

The development of oxygen-carrying blood substitutes, including hemoglobin solutions, encapsulated hemoglobin preparations, and the perfluorochemicals, has a long history of its own. Suffice it to say here that, after many decades of

experimentation and failed clinical trials, it is still unlikelythat a useful product will become available soon.122 Supposedly, a Phase 111 clinical trial of one henioglobin preparation has been approved by the US Food and Drug Administration.

The undesirability of white cells in transfusion components has been recognized for over four decades. The first filter to reduce white cell contamination in blood, designed to prevent febrile transfusion reactions, was reported in 1962, and it was subsequently marketed as the Leukopak filter by the Baxter Corpora t i~n . ’~~ White cell reduction in all cellular components is likely to become the standard practice within the next few years. It is predictable that filtration, shortly after collection and before storage, will prove to be the most desirable procedure. Recent reviews of this subject are avail-

It is difficult for the historian to decide where history ends and the future begins. The involvement of transfusionists in therapeutic apheresis and the processing and transfusion of autologous and unrelated-donor bone marrow have become major activities.IZ6 The collection of progenitor cells from pe- ripheral blood and the collection, manipulation, and storage of cord blood may eventually replace the use of bone marrow in the management of hematologic and other malignancies and the heritable abnormalities of the hematopoietic, immu- nologic, and reticuloendothelial systems. The use of growth factors (cytokines) is increasing. The recombinant form of erythropoietin has almost eliminated the need for red cell transfusions in dialysis patients and will find broader uses in the management of patients chronic anemia. Granulocyte- macrophage-colony-stimulating factor and granulocyte- colony-stimulating factor are being used for combatting neutropenia associated with chemotherapy and bone marrow transplantation. Thrombopoietin for the management of thrombocytopenia should shortly become available for clinical tria1.lZ7

Other developments that lie on the border between the past and future include cellular biotherapy using autologous lymphokine-activated killer cells and tumor-infiltrating lym- phocytes. Somatic gene therapy is not yet history but should become part of the future documentation of the activities of a modern transfusion service. I t involves the insertion (trans- duction) of desired genes into blood cells for therapeutic pur- poses. 128~129

able, 124.125

ACKNOWLEDGMENTS

The author thanks Billie Broaddus, Director, Cincinnati Medical Heritage Center, for invaluable assistance in locating historical referencesI3O; Paul J. Schmidt, MD, for the references to the first human transfusion; and Margaret 0’ Leary for her help in organiz- ing the chaos.

REFERENCES 1. Ovid. Metamorphosis, vol VIl:333-4; trans F.J. Miller. Cited by

Keynes G, ed. Blood transfusion. London, John Wright & Sons, 1949:3.


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2. Wiener AS. Blood groups and transfusion. 3rd ed. Springfield, IL: C.C. Thomas, 1943:3-6,50-9.

3. Crile GW. Hemorrhage and transfusion. New York D. Appelton and Company, 1909:151-6.

4. Ore PC. Etude historique, physiologique et clinique sur la transfusion du sang. 2nd ed. Paris: Balliere, 1876. Cited by Crile GW. Hemorrhage and transfusion. New York D. Appelton and Company, 1909, p 151; Doan C. The transfusion problem. Physiol Rev 1927;7(1), p 7; Keynes G. Blood transfusion. London: John Wright & Sons, 1949, p vii; and Kilduffe RA, DeBakey M. The blood bank and the technique and therapeutics of transfusions. St. Louis: C.V. Mosby Com- pany, 1942, p 17.

5. Mathew AH. Life and Times of Roderigo Borgia, 191266. Cited by Keynes G, p 3; and Kilduffe and DeBakey, p 18.

6. Villari P. The history of Girolamo Savanarola and his times, vol 1; translated by Leonard Horner. London: Longmans, Roberts & Green, 1863:144. Cited by Kilduffe and DeBakey, p 17.

7. Malory T. Morte d’Arthur, Bx. XVII, Ch. 10-12, 1485. Cited by Keynes, p 3.

8. Kilduffe RA, DeBakey M. The blood bank and the technique and therapeutics of transfusions. St. Louis: The C.V. Mosby Company, 194217-45.

9. Keynes G. The history of blood transfusion. In: Keynes G, ed. Blood transfusion. London: John Wright & Sons, 1949:3-40.

10. Gesellius F. Die Transfusion des Blutes. Eine historische, krit- ische und physiologische Studie. Leipzig: F. Wagner, 1873. Cited by Keynes, p 4; and Maluf NSR. History of blood transfusion. J Hist Med Allied Sci 1954;9:79.

11. Ullersperger JB. Ancient transfusion and infusion compared with modern transfusion, infusion and hypodermic or sub- cutaneous injections; translated by Charles F. Wittig. Phila- delphia, from Chaille SE. Miscellanies, 1867-69. Cited by Kilduffe and DeBakey, p 18.

12. Libavius A. Appendix necessaria syntagmatis arcanorum chymicorum contra. Frankfurt: Heningum Sheunemanum, 1615;rV:8. Cited by Drinkard WB. History and statistics of the operation of transfusion of blood. Richmond Louisville Med J 1972;13(1), p 22; Keynes, p4; Maluf, p 59; and Wiener, p 50 (translation).

13. Scheel P. Die Transfusion des Blutes und Einsprutzung der Arzeneyen in die Adern, historisch und in Rucksicht auf die practische Heilkunde bearbeitet. 2 vols. Copenhagen: F. Brunner, 1802-03. Cited by Doan, p 5; Kilduffe and DeBakey, p 17; Maluf, p 72; and Wiener, p 50.

Preparation, storage, administration and clinical results including a discussion of shock etiology, physiology, pathology and management. Baltimore: Williams & Wilkins, 1947:l-19.

15. Maluf NS. History of blood transfusion. J Hist Med Allied Sci

16. Lyons AS, Keiner M. Circulation of the blood. In: Lyons AS, Petrucelli RJ Znd, eds. Medicine: an illustrated history. New York Abrams. 1978:437-59.

14. White CS, Weinstein JJ. Blood derivatives and substitutes.

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17. Colle J. Methodus facile parandi incunda, tuta et nova medi- camenta. Venetiis 1628;7:170. Cited by Keynes, p 4; Kilduffe and DeBakey, p 18; and Maluf, p 60.

18. Folli F. Stadera medica, nella quale oltre la medicina infusoria, ed altre novita, si bilanciano le ragioni favore voli e le contrarie alla transfusion del sangue. Florence: [no publisher named], 1680. Cited by Keynes, p 5; Kilduffe and DeBakey, p 19; and Maluf, p 60.

colour of the blood and on the passage of the chyle into the blood.] Translated by Franklin KJ. In: Franklin KJ, ed. Special Edition, The Classics of Medicine Library, Birmingham, AL: Gryphon Editions, 1989.

20. Pepys S. The diary of Samuel Pepys, vols rV to VI (1664-1667); vols VII to VIII (1667-1660) Wheatley HB, ed. London: G Bell and Sons, 1928. Cited by Doan, p 3; Keynes, p 15; Kilduffe and DeBakey, p 22; and Maluf, p 65.

21. Franklin KJ. Preface. [A treatise on the heart on the movement and colour of the blood and on the passage of the chyle into the blood.] In: Franklin KJ, ed. Special Edition, The Clas- sics of Medicine Library. Birmingham AL.: Gryphon Editions, 1989:xvi.

22. Major JD. Chirurgia infusoria. Kiloni [Cologne]:[no publisher named], 1667. Cited by Doan p 3; and Peumery JJ. Les origines de la transfusion sanguine I. Clio Med 1974;9, p 137.

23. Doan C. The transfusion problem. Physiol Rev 1927;7(1):1-84. 24. Tardy CL. Traite de I’ecoulement du sang d’un homme dans

les veins d’un autre et de ses utilites, Paris, mars 1667; Lettre Ccrite a M. Le Breton pour confirmer les utilites de la transfusion du sang et repondre a c e u qui les etendent trop, Paris 30 octobre 1667. Cited by Doan, p 4; Kilduffe and DeBakey, p 20; and Peumery p 236.

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25. Peumery JJ. Les origines de la transfusion sanguine I. Clio

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27. Peumery JJ. Les origines de la transfusion sanguine 111. Clio

28. Farr AD. The first human blood transfusion. Med Hist

29. Denis JB. Lettre Ccrite a Monsieur De Montmort ... touchant une nouvelle manigre de guCrir plusieurs maladies par la transfusion du sang, confirmhe par deux exp6riences faites sur des hommes [A letter.. .concerning a new way of curing sundry diseases by the transfusion of blood, confirmed by two experiments on men]. Paris: Chez Jean Cusson, 25 June 1667. Cited by Doan, p 4; Farr, p 144; Keynes, p 12, and Peumery, p 218.

30. Le lieutenant criminel. La sentence rendue au Chatelet le 17 avril 1668. [Court judgment against Denis at Chatelet, which banned transfusions on humans without the permission of the Faculty of Medicine in Paris, on pain of prison.] Cited by Peumery, p 132-3; and Crile, p 155.

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AUTHORS

Tibor J. Greenwalt, MD, Deputy Director, Research Department, Hoxworth Blood Center, 3130 Highland Avenue, PO Box 670055, Cincinnati, OH 45267-0055. [Reprint requests]


a short history of transfusion medicine

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