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The use of blood as a product can be traced back to the 17th century, although the greatest advances in its therapeutic was prompted by the worldwide conflicts of the first half of the 20th century. Here, Anthony J Harding puts transfusion science into historical perspective.
There are numerous Biblical references to blood, which was considered as the very essence of life and synonymous with the same. Jehovah Witnesses quote Leviticus1 on the forbidding of eating (taking) blood from another as a key element of their stance against human blood transfusion.
One of the earliest accounts of the circulation of blood was by the Arabic scholar, mathematician and physician Ibn-al- Nafis2 who, in 1260 AD, described the 'minor circulation' of blood in the body. This was more than 250 years before William Harvey described the continuous circulation of blood around the body in 1616,3 which he published in 1628.4
The advent of the understanding of human anatomy and the circulation of blood gave rise to experimentation in transfusion techniques involving animal-to-animal and animal-to-human procedures. This eventually resulted in human-to-human transfusion.
In 1657, Dr (later Sir Christopher) Wren,5 now better known as the renowned Architect, performed a series of experiments involving the injection of various fluids into the veins of animals, with mixed results. Subsequently, in 1665, at a meeting of the Royal Society of London – of which Wren was a founder member – he demonstrated the transfusion of blood from one animal to another.
Although Lower and King performed the first animal-to-human transfusion in England, the first ever transfusion was performed by the Frenchman Jean-Baptiste Denis, five months earlier in June 1667 in Paris.8 Amazingly, Denis had commented on the potential of transfusion not only to replace blood loss but also to treat disease.
More importantly, he also considered that transfusions "ought to be done with blood of the same species". However, owing to the perceived risk to the donor, he later rejected this policy in favour of using animal blood.
The resultant fatal reactions recorded by Denis led to the transfusion of blood to humans being prohibited in France and subsequently in England. Thus, blood transfusion fell into disrepute and neglect for 148 years.
Nineteenth century revivalists
James Blundell9 graduated from Edinburgh in 1813, became an obstetrician of note at Guy’s Hospital in London and is credited with reintroducing blood transfusion into medical practice. Blundell reported favourably on the benefit of transfusion in cases of post-partum haemorrhage in 1828. He was clearly influenced by, and generously acknowledged, the earlier work of John Henry Leacock,10 also a graduate of Edinburgh, whose dissertation in 1816 established the principle that donor and recipient must be of the same species.
Blundell accepted this principle and reported his results of injecting human blood using a syringe. He later devised an apparatus, known as Blundell's Impellor, which consisted of a funnel and pump for the collection of donor blood for indirect transfusion into the veins of a patient. The invention of the hypodermic syringe by Alexander Wood in 1853 provided an important aid to transfusionists and led to the development of new devices to carry out transfusions.
In 1864 Dr Roussel in France and Dr James Aveling in London both used India rubber tubes to carry out direct human-to-human transfusions. James Aveling's apparatus consisted of two silver tubes that were used to enter the donor and recipient blood vessels, connected to a length of India rubber tubing, with a stopcock at both ends and a bulb in the middle. When squeezed, the bulb acted as a pump to expedite the flow of blood.
The main problem that stood in the way of the development of blood transfusion was the tendency for the blood to clot and to block the tubes or apparatus connected to the recipient. In 1873, Sir Thomas Smith of St Bartholomew's Hospital, London, is reported to have successfully transfused blood from which the clot had been removed (ie defibrinated blood). Attempts by Dr James Braxton-Hicks at Guy’s Hospital in 1883–84 to overcome this problem using sodium phosphate mixed with the blood as an anticoagulant resulted in the deaths of the patients.
In the last decade of the 19th century there was considerable debate about the benefit of using blood rather than saline. George Washington Crile11 carried out studies in 1898 to compare the efficacy of blood versus saline in maintaining blood pressure in shock. His conclusions kept alive the quest to find better and safer ways of transfusing blood, which did not became apparent until well into the second decade of the new century.
Identification of human blood types and groups
A considerable amount of work involving immune practice and reactions took place in the latter part of the 19th century. Physiologists had shown that blood from another species could destroy the cells of transfused subjects. It was noted that a similar reaction, the agglutination of cells, could occur between the blood of individuals of the same species. Karl Landsteiner (1868–1943), through his elucidation of different blood groups in humans, demonstrated that this was a normal phenomenon.
In 1901, Landsteiner12 described three different human blood types, A, B and 0. The following year, Alfred von Decastello and Adriano Sturli13 defined a fourth type, AB.
Landsteiner suggested his findings might be applicable to blood transfusion practice. It is now astonishing that this idea was not adopted until more than a decade later. During this period, other blood type designations were described in Czechoslovakia by Jansky14 in 1907 and in the United States by Moss15 in 1910. Both were in use as much as Landsteiner's and were still used three decades later (Table 1).
Despite these advances, surgeons continued to perform transfusions without any preliminary ‘cross-agglutination' testing. Direct transfusion (artery to vein) as described by Carrel16 and Crile17 were still the methods usually employed. Pretransfusion testing did not become normal practice until indirect transfusion became popularised by the use of sodium citrate anticoagulation and collection of donor blood, which occurred after 1915.
The ABO blood group system originally designated by Landsteiner remains the principal donor–recipient matching criteria for human blood transfusion.
Blood group classiflcation
Without doubt, Karl Landsteiner is best known for his groundbreaking work on the ABO blood group system. His work on the identification and elucidation of other blood group systems is also without parallel. In 1927, Landsteiner and Levine18 proposed a new blood group system after the identification of two new genes, which they called M and N. The system was later extended after Sanger and Race19 identified the related S and s genes in 1947. Additionally, in 1927, Landsteiner and Levine20 discovered the Pp antigens of the P blood group system.
In 1940, Landsteiner (now aged 72) and Alexander Wiener described the first Rhesus (Rh) blood group. This initiated work on unravelling what is probably the most complex blood group system known.
Karl Landsteiner had many facets to his knowledge, one of the most important being his understanding of immunochemistry. His book entitled The specificity of serological reactions, first published in 1936, is a testament to his unique contribution to our understanding of antigen–antibody reactions and their importance in blood transfusion.
Effective blood transfusion
Throughout the 20th century, milestones in the advancement of blood transfusion are synchronised with the onset of military conflict around the world. The practice of blood transfusion advanced with the outbreak of the First World War, mainly due to the new knowledge of matching different blood groups and the use of an anticoagulant that facilitated indirect transfusion. Prior to this, transfusion was only possible using defibrinated blood, as described by Moss21 in 1914, and by direct donor-to-patient techniques.
In 1914, the Belgian Adolph Hustin22 discovered that sodium citrate in tolerable quantities could anticoagulate blood for transfusion. Further work by Luis Agote23 in Argentina and Richard Lewisohn24 in the USA in 1915 showed that sodium citrate would effectively anticoagulate blood at a concentration that could be transfused without harming the recipient.
Until this time, blood transfusion on the battlefield was only practicable with a ready supply of donors close to the patients. However, tank warfare changed the mobility of battle and required a stock of blood to be established, enabling a supply to be available whenever and wherever needed.
The practice of blood transfusion was favoured by the American and the Canadian surgeons arriving at the Western Front to cope with the increasing number of casualties suffered in France and Belgium. The beneficial effect in combating blood loss in major trauma was soon recognised and adopted by British and French surgeons. As a result, the establishment of the first bank of stored blood was described by Oswald H Robertson25 in 1918. He stored blood for up to 21 days to treat haemorrhagic shock suffered in battlefield injuries.
Robertson also recognised the advantages of adding glucose to blood, but it was 20 years later before his observation was fully appreciated in the development of large-scale blood storage during the Spanish Civil War between 1937 and 1939. The subsequent publication of the effectiveness of transfusion, by army surgeons, resulted in its introduction to civilian medical practice.
A period of problems and confusion
It is a strange facet of scientific discovery that rarely does it result in an early change of practice or a benefit to society. This is exemplified in transfusion practice during the interwar years.
The discovery of ABO blood groups by Landsteiner in 1900 and subsequent work by Jansky in 1909 and Moss in 1910 did not result in the adoption of a common blood group nomenclature until 1939. Confusion caused by blood donors being grouped using the Jansky system when the Moss system was in widespread use represented a potential for mismatched transfusion.
The availability of citrate-treated, anticoagulated blood for indirect transfusion, following the work of Hustin, Agote and Lewisohn, failed to persuade physicians and surgeons to relinquish direct person-toperson transfusion. A high incidence of febrile reactions, a lack of donor panels and the medical profession's reluctance to change all contributed to the slow adoption of indirect transfusion techniques.
Ottenburg and Kaliski26 in 1913 described the beneficial outcome of pretransfusion compatibility testing or 'cross matching' in 128 patients at Mount Sinai Hospital in New York. Sadly, however, this did not become a regular procedure worldwide until many years later. Lewisohn and Rosenthal27 in 1933 showed that bacterial contamination and inadequately cleaned transfusion equipment were the causes of many transfusion reactions.
The common practice of only using group O (universal donor) by hospitals and clinicians and the use of cut-down procedures for venesection resulted in a rapid decline of available donors.
The reliability of blood group procedures was also in question due to the cost and availability of reliable antisera for blood group typing. The Burroughs Company was the only commercial source in the UK at that time. This resulted in attempts to produce homemade antisera from staff and donor samples, which resulted in unreliable and potentially dangerous reagents being used when only tile grouping techniques prevailed.
Differing views and practices prevailed until the imminent threat of war in 1939, despite the monumental work of Percy Lane Oliver28 and Geoffrey Keynes29 in establishing donor panels and in advocating of ethical standards of practice in respect of blood donors.
Onset of the Second World War
The Spanish Civil War gave rise to a fresh approach to blood transfusion, hastened by the threat of large numbers of civilian and military casualties. There was a major initiative to increase the number of blood donors and to establish large-scale blood banks to ensure adequate supplies.
One of the other outcomes of this period was the introduction by Jorda30 of adding glucose to the citrate anticoagulant for blood collection, although Robertson had suggested this as early as 1918. This was found to improve the viability of transfused red cells and thus increase the benefit of transfusion.
In 1938 the Ministry of Defence established a committee in London to consider how blood transfusion support would be provided to military hospitals in the event of war. This led to the formation of the Army Blood Transfusion Service and the opening of the Army Blood Supply Depot (ABSD) in 1939, which was the first military transfusion service in the world.
Such was the demand at the outbreak of war that the ABSD processed more than 33,000 donations in its first year – six times more than the busiest civilian service prior to the war. The ABSD went on to produce all dried products, crystalloids and grouping sera, as well as all the equipment for collecting and administering blood.
New understandings of old problems
The discovery of the Rh blood groups by Landsteiner and Wiener31 in 1940, and the related work done previously by Levine and Stetson32 in 1939, was the most important and significant advance in blood grouping and transfusion since the discovery of ABO groups, 40 years before. Landsteiner and Wiener reported the results of immunising guinea pigs and rabbits with the red cells of rhesus monkeys. The immune antibody produced was found to agglutinate the red cells of approximately 85% of random people tested.
Earlier, in 1939, Levine and Stetson were investigating intra-uterine death associated with severe anaemia. They reported a case where anaemia was due to antibodymediated cell destruction caused by the passage of maternal antibody into the fetal circulation. They clearly described a case of haemolytic disease of the newborn (HDN). The antibody identified was not named. Also, Wiener and Peters33 recognised that the anti-Rh antibody could be a cause of haemolytic reactions to blood transfusion, establishing a key principle in transfusion and a landmark medical discovery.
In 1941, Levine, Katzin, Vogel and Burnham34-36 described the aetiology of erythroblastosis fetalis (or HDN), showing that incompatibility between mother and fetus was the cause. They also found the causative antibody had the same specificity as the anti-Rh antibody described by Landsteiner and Wiener.
Pioneers of blood group science
Robert Race and Ruth Sanger are undoubtedly the most well-known names in blood group science in the period following the Second World War up to 1980. Their contribution to the understanding of blood groups is probably only exceeded by the earlier work of Landsteiner.
Robert Race worked at the Galton Serum Laboratory before he and Arthur Mourant moved, in 1946, to the Lister Institute of Preventive Medicine in London. Race became director of the Medical Research Council Blood Group Research Unit and Mourant became director of the Blood Group Reference Laboratory. Their partnership and cooperation resulted in many significant contributions to the knowledge and practice of blood group science.
In 1947 Robert Race was joined by Ruth Sanger, who became his wife. Together they wrote Blood groups in man.37 First published in 1950, it ran to seven editions and was subsequently translated into many languages. This work became the standard reference book on the subject for several decades.
In their early work on the Rh blood group system, Race and Sanger, inspired and supported by Professor Ronald Fisher in the UK, differed with Wiener in the USA. These differences reached the point of acrimonious exchanges in the scientific press about the mode of genetic inheritance.
Robin Coombs, working with Race and Mourant, developed the antiglobulin test (Coombs’ test), used for the detection of 'incomplete' antibodies. The test has become a standard technique in blood group serology and is described in three landmark publications.38-40
Development of plasma drying and fractionation
The ability to preserve therapeutic antisera by drying, which was developed in the late 1930s, gave rise to the introduction of freeze-drying processes. Although originally not intended for human plasma, experimental batches were tested and proved safe when transfused to human recipients.
Once again, the wartime situation in 1939 led to a demand for plasma supplies to treat military and civilian casualties. This accelerated the effort to find a large-scale process to satisfy the immediate requirements. There was a strong demand for dried plasma by the Armed Forces for use in the tropics, where it could be stored effectively without deterioration.
In the UK, the original freeze-drying plant in Cambridge was too small to meet the demands, even when supported by a second unit built by the Wellcome Foundation at Beckenham. This prompted the Army Blood Transfusion Service (ARTS) to build its own plant. During the last two years of the war, over 250,000, 400-mL bottles of freeze-dried plasma were produced. This was in addition to the supply of liquid plasma and serum, which, although still in use, were becoming less acceptable due to changes and contaminants formed during storage.
At the same time as early efforts were being made to develop techniques for storage of plasma for transfusion, research was proceeding into separating and purifying plasma protein fractions. Much of the work in the UK was carried out at the Lister Institute during the early years of the war. In 1944, Edwin Cohn41 in the USA published his classic work on the ethanol separation and purification of plasma proteins. However, much of the equipment and materials to carry out Cohn' s procedure was not available in the UK, and thus an alternative method had to be sought.
Kekwick, Mackay and Record42 in 1946, working at the Blood Products Research Unit in London, succeeded in producing fibrinogen and prothrombin from plasma separated by precipitation with ether. This pioneering work led to the production of other blood products and the foundation of the UK supply programme.
At the cessation of hostilities, the plasma processing equipment from the Army Blood Transfusion Service was moved to the Lister Institute in Chelsea. Further plants were installed at Elstree, which became the Blood Products Laboratory.
Discovery of polythene
The discovery of a new polymer by a research team at Imperial Chemical Industries (ICI) in 1930 resulted in its rapid adaptation as a new electrical insulating material. It was light, flexible and waterproof, and the company named the substance polythene.
The first reported clinical use of polythene in the UK, in 1948, was as a fine, flexible catheter for neonatal use. In 1952, Walter43 designed a polythene blood collection bag with integral donor line and giving set. Walter's invention was soon recognised and the Fenwal company was set up to massproduce the bags for use in American and Canadian hospitals. By 1960 they were in widespread use throughout North America. Owing to the adverse economic situation in the UK during this period, and disagreement among directors of the regional transfusion centres, these bags were not introduced throughout the UK until 1975.
Baxter (now owning Fenwal) in the USA, Biotest in Germany, Terumo in Japan and Tuta in Australia further developed plastic transfusion sets to enable more blood components and plasma fractions to be aseptically separated and stored for transfusion.
Age of automation
In the evolving world of biomedical science, many erstwhile manual techniques and procedures have become automated. Technical progress by equipment manufacturers and the advent of computer-based technologies produced an avalanche of new equipment from 1975 onwards. However, the field of blood group serology and transfusion was a latecomer to this changing world. Indeed, it was believed by many experienced workers that no machine could take over the highly interpretative role of the skilled serologist. This was to prove wrong.
Reports as early as 1963, by Sturgeon, Cedergren and McQuiston,44 and by Allen, Rosenfield and Adebahr,45 described the use of the Technicon autoanalyser for blood group antibody detection. In their review of the subject in 1968, Marsh, Nichols and Jenkins46 demonstrated that virtually all clinically significant blood group antibodies could be detected by automated means. The new technology was adopted by many transfusion centres for donor screening and larger hospital laboratories for antenatal screening.
In addition to the provision of blood grouping and antibody screening, an increasing requirement for microbiological screening of blood donations has become apparent. Initially, only syphilis testing was deemed necessary, to which was added screening for hepatitis B and then subsequently for cytomegalovirus, human immunodeficiency virus, hepatitis C and now variant Creutzfeldt-Jakob disease and malaria. Clearly, without the aid of technology an army of extra staff would be needed to cope with the constant increase in testing to ensure the supply of safer blood products.
1 Leviticus 17: 11-12. No soul of you must eat (take) blood and no alien resident who is residing in your midst should eat (take) blood.
2 Khairallah AA, Haddad SI. A forgotten chapter in the history of the circulation of blood. Ann Surg 1936; 104: 1–8.
3 Harvey W. Praelectiones anatomiae universalis, 1616 (Facsimile reprint of Harvey's manuscript notes for his 1616 Lumleian Lecture. London: Churchill, l886).
4 Harvey W. Exercitatio anatomic a de motu cordis et sanguinis in animalibus. Frankfurt, 1628.
5 Wren C, 1657. Described in detail by Boyle R. Some considerations touching the usefulness of experimental natural philosophy (part 2). Oxford: 1663, 63–5.
6 Lower R. The method observed in transfusing blood out of one live animal into another. Phil Trans R Soc Lond 1666; 1: 353–8.
7 Lower R, King E. An account of the experiment of transfusion practised upon a man in London. Phil Trans R Soc London 1667; 2: 557–64.
8 Denis. J-B. Lettre ecrite a Monsieur Montmort, touchant une nouvelle mannide guerir plusiers maladies par la transfusion du sang. Paris: Jean Cusson, 25 June 1667.
9 Blundell J. Successful case of transfusion. Lancet 1828 i: 431–2.
10 Leacock JH. On the transfusion of blood in extreme cases of haemorrhage (Dissertation). University of Edinburgh, 1816.
11 Crile GW. Haemorrhage and transfusion. New York: Appleton, 1909.
12 Landsteiner K. Uber Agglutinationserscheinungen normalen mensclinchen Blutes. Wiener Klinik Wochensctire 1901; 1: 5–8 (English translation in Transfusion 1961; 1: 1132–4).
13 Decastello A, Sturli A. Ueber die Isoagglutinine im Serum gesunder und kranker Menschen. Munch med Wshr 1902; 49: 1090–5.
14 Jansky J. Haematologicke, studie u. psychotiku. Sb Klin Praze 1907; 8: 85–139.
15 Moss WL. Studies on isoagglutinins and isohemolysins. Bull Johns Hopkins Hospital 1910; 21: 63–70.
16 Carrel A. The surgery of blood vessels. Bull Johns Hopkins Hospital 1907; 18: 18–28.
17 Crile GW. The technique of direct transfusion of blood. Ann Surg 1907; 46: 329–32.
18 Landsteiner K, Levine P. A new agglutinable factor differentiating individual human bloods. Proc Soc Exp Biol NY 1927; 24: 600–2.
19 Sanger R, Race RR. Subdivisions of the MN blood groups in man. Nature 1947; 160: 505.
20 Landsteiner K, Levine P. Further observations on individual differences of human blood. Proc Soc Exp Biol NY 1927; 24: 941–2.
21 Moss WL.) A simple method for the indirect transfusion of blood. Am J Med Sci 1914; 147: 698–703.
22 Hustin A. Principe d'une nouvelle methode de transfusion. Journal of Medicine, (Brussels) 1914; 2: 436.
23 Agote L. Nuevo procedimiento para la transfusion de la sangre. Ann Inst Clin Med 1915; 1: 24–31.
24 Lewisohn R. Blood transfusion by the citrate method. Surg Gynaecol Obstet 1915; 21: 37–47.
25 Robertson OH. Transfusion with preserved red blood cells. BMJ 1918; 1: 691–5.
26 Ottenburg R, Kaliski DJ. Accidents in transfusion; their prevention by preliminary blood examination based on an experience of one hundred and twenty-eight transfusions. JAMA 1913: 61: 2138–40.
27 Lewisohn R, Rosenthal N. Prevention of chills following transfusion of citrated blood. JAMA 1933; 100: 466–9.
28 Oliver PL. A plea for a national blood transfusion conference. BMJ 1936; 2: 1032–3.
29 Keynes G. Blood donors. BMJ 1924; 2: 613–4.
30 Jorda FD. The Barcelona Blood Service, Lancet 1939; i: 773–5.
31 Landsteiner K, Wiener AS. An agglutinable factor in human blood recognised by immune sera for Rhesus blood. Proc Soc Exp Biol NY 1940; 43: 223.
32 Levine P, Stetson RE. An unusual case of intragroup agglutination. JAMA 1939; 113: 126–7.
33 Wiener AS, Peters HR. Haemolytic reactions following transfusions of blood of the homologous group, with three cases in which the same agglutinogen was responsible. Ann Int Med 1940; 13: 2306–22.
34 Levine P, Katzin EM, Burnham L. Isoimmunisation in pregnancy its possible bearing on the aetiology of erythroblastosis foetalis. JAMA 1941; 116: 825–7.
35 Levine P, Vogel P, Katzin EM, Burnham L. Pathogenesis of erythroblastosis foetalis: statistical evidence. Science 1941; 94: 371–2.
36 Levine P, Burnham L, Katzin EM, Vogel P. The role of isoimmunisation in the pathogenesis of erythroblastosis foetalis. Am J Obstet Gynecol 1941; 42: 925–37.
37 Race RR, Sanger R. Blood groups in man. Oxford: Blackwell Scientific Publications, 1950.
38 Coombs RRA, Mourant AE, Race RR. Detection of weak and 'incomplete' Rh agglutinins: a new test. Lancet 1945; ii: 15.
39 Coombs RRA, Mourant AE, Race RR. A new test for the detection of weak and 'incomplete' Rh agglutinins. Br J Exp Pathol 1945; 26: 255–66.
40 Coombs RRA, Mourant AE, Race RR. In vivo isosensitisation of red cells in babies with haemolytic disease. Lancet 1946; i: 264–6.
41 Cohn EJ. Blood, blood derivatives and blood substitutes. Proc Am Phil Soc 1944; 88: 159–73.
42 Kekwick RA, Mackay ME, Record BR. The fractionation of human plasma with ether. Nature 1946; 157: 629.
43 Walter CW, Murphy WP. A closed gravity technique for the preservation of whole blood in ACD solution utilising plastic equipment. Surg Gynaecol Obstet 1952; 94: 687–92.
44 Sturgeon P, Cedergren B, McQuiston D. Automation of routine blood typing procedures. Vox Sang 1963 Jul-Aug; 20: 438-51.
45 Allen FH Jr, Rosenfield RE, Adebahr MR. Kidd and Duffy blood typing without Coombs serum. Adaptation of the autoanalyzer hemagglutination system. Vox Sang 1963 Nov-Dec; 76: 698–706.
46 Marsh WL, Nichols M, Jenkins WJ. Automated detection of blood group antibodies. J Med Lab Technol 1968; 25: 335–42.
This article was published in the November 2005 issue of The Biomedical Scientist is based on information contained in the booklet that accompanied the IBMS Historical Section’s exhibition at the Biomedical Science Congress in 2003.
Tags: Transfusion Science