Chapter 1

A Brief History of Blood Transfusion

Kim A. Janatpour ● Paul V. Holland

EARLY HISTORY with a contumacious and violent fever.” The boy had been
treated with multiple bleeds, following which “his wit
Since the beginning of human history, blood has been rec- seemed wholly sunk, his memory perfectly soft, and his
ognized as a vital force, the essence of life. Prehistoric man body so heavy and drowsie that he was not fit for any thing.”
created cave drawings showing individuals bleeding from Denis attributed these symptoms to the bloodletting he had
traumatic wounds. In the Bible, Leviticus states “the life of received. As treatment, Denis exchanged 3 ounces of the
the flesh is in the blood.” The Chinese Huang Di Nei Ching boy’s blood for 9 ounces of lamb’s blood. Denis chose ani-
(770–221 BC) held that blood contained the soul. Blood mal blood because he believed it purer than that of humans
played a central theme in ancient rituals. Egyptians and due to man’s “debauchery and irregularities in eating and
Romans took blood baths for physical and spiritual resto- drinking” and reasoned that if man could use animal milk
ration,1 and Romans even drank the blood of fallen gladia- as nutrient, animal blood would be safe. Following the infu-
tors in the belief that the blood could transmit the gladiator’s sion of lamb’s blood, the patient complained about “a great
vitality. Precolumbian North American Indians bled the body heat along his arm,” but otherwise suffered no ill effects.
“of its greatest power” as self-punishment. In the Middle Denis subsequently performed such transfusions on three
Ages, the drinking of blood was advocated as a tonic for more patients, the last of which resulted in the first mal-
rejuvenation and for the treatment of various diseases.2 Pope practice suit for blood transfusion.4 Antoine Mauroy was
Innocent VIII drank the blood from three young boys in a 34-year-old madman who was brought to Denis after he
1492. Unfortunately, the boys and the Pope died. 2 The idea was found wandering the streets of Paris in the winter of
that infusion of blood could be beneficial did not emerge 1667. Mauroy had suffered for years from severe “phren-
until the 17th century. sies,” during which he would beat his wife, strip off his
From the time of Hippocrates (c. 450 BC), disease clothes, and run through the streets, setting house fires. At
was believed to be caused by an imbalance of the four this time, blood was believed to affect one’s temperament
humours—blood, phlegm, yellow bile, and black bile. Of and character; therefore, it was reasoned that blood transfu-
these, blood was the most important (Galen [130–201 aD] sion could be used to treat mental ailments. Denis’s patron,
really advanced the humoural theory). The most popu- Monsieur de Montmort, proposed transfusing Mauroy to
lar treatment for most ailments, even as late as the 18th allay the “heat of his blood.”5 Denis transfused Mauroy with
century, was blood letting (Fig. 1–1). Without the correct calf ’s blood, hoping that the calf ’s docile nature would be
understanding of blood circulation, intravenous blood imparted to Mauroy. Although the patient complained of
infusion could not even be imagined. This changed in 1628 heat moving up his arm, he tolerated the transfusion well. A
with William Harvey’s description of the circulatory system. few days later, a second, larger transfusion was performed.
Harvey’s identification of separate yet connected arterial This time, however, the patient complained “of great pains
and venous systems in his De Motu Cordis paved the way for in his kidneys, and that he was not well in his stomack,
an entirely new arena of blood investigation.3 that he was ready to [choak] unless they gave him his lib-
In 1656, Christopher Wren used a quill with an attached erty.”6 The transfusion was quickly discontinued, after
bladder to demonstrate that the intravenous injection of which the patient vomited and passed urine “black as soot.”
substances into animals had systemic effects.1,2 In 1666, Miraculously, the patient not only survived this hemolytic
Richard Lower successfully transfused blood from one dog transfusion reaction, but also appeared to be cured, show-
to another, which led Samuel Pepys to speculate on the ing “a surprising calmness, and a great presence of mind …
potential benefits of human transfusion, stating that “bad and a general lassitude in all his limbs.” In fact, upon seeing
blood” might be mended by “borrowing” blood “from a his wife a few days later, Mauroy greeted her tenderly, relat-
better body.”3 ing “with great presence of mind all that had befallen him.”
Denis was astonished—the man who “used to do nothing
but swear and beat his wife” had dramatically, almost magi-
THE FIRST ANIMAL-TO-HUMAN cally, been cured.7
TRANSFUSIONS Also, later in 1667, Richard Lower successfully transfused
a Cambridge University student described as “cracked a little
The first published animal-to-human transfusion was per- in the head” with sheep’s blood.3,4 A bitter debate followed
formed June 15, 1667, by Jean Baptiste Denis, a physician to between Denis and Lower as to who could claim to have dis-
Louis XIV, on a 16-year-old boy who had been “tormented covered blood transfusion.4
Although a select group of scientists was excited about the concept of transfusion, others were adamantly opposed to the
practice. Denis, in particular, suffered harsh criticism from his peers. With this intense debate and criticism as the backdrop,
Mauroy suffered a relapse; his wife begged Denis to transfuse her husband again. Denis found the patient to be very ill, so
was hesitant to perform the transfusion, but reluctantly agreed. Before the transfusion began, how- ever, Mauroy died and
his widow refused to allow Denis to examine the body. The widow had been offered money from Denis’s rivals to charge
him with murder; she offered to drop the matter if Denis would agree to support her financially. Denis refused, and the case
went to court. Denis was exonerated when it was discovered that Mauroy had been poisoned with arsenic by his wife.
Nonetheless, although Denis was acquitted of malpractice, the general opposition to transfusion ultimately led the French
and English courts, and much of the rest of Europe, to ban all human transfusions.1,4,5,7,8
FIRST HUMAN-TO-HUMAN TRANSFUSION

After being banned for more than 150 years, the use of blood transfusion was revived during the late 18th century. A foot-
note in an American journal indicates that the first human- to-human transfusion had been performed by Philip Syng
Physick, the “Father of American Surgery,” in 1795, although this has never been confirmed.5,9 In 1816, John Henry
Leacock, a Barbados physician, presented his dissertation“On the Transfusion of Blood in Extreme Cases of Haemorrhage.”
Leacock subsequently performed and published a set of ani- mal experiments that proved that the donor and recipient must
be of the same species.10
Although Leacock apparently went no further with the experiments, his work inspired James Blundell, an obstetri- cian and
physiologist at Guy’s Hospital in London, to carry out additional investigations. At the time, obstetricians could only stand
by and watch helplessly as patients exsanguinated postpartum. Blundell was convinced that blood transfusion
could save patients’ lives. His extensive experimentation con- firmed Leacock’s findings that blood could be used to treat
hemorrhagic shock, but only blood from the same species could be used. Recognizing the potentially serious risks of
transfusion, Blundell began attempting human-to-human transfusion in cases that were otherwise hopeless. Over a decade,
he performed 10 such transfusions, all without suc- cess. However, in August 1825, Blundell successfully trans- fused a
woman dying from postpartum hemorrhage with blood from her husband. Other successes followed, includ- ing three cases
of postpartum hemorrhage, and a young boy who was hypovolemic following amputation of his leg.11 Subsequently, other
reports of transfusion followed from Europe and then the United States, where it was reported that transfusion was used by
the Union Army during the American Civil War.5,9
Significant progress in understanding the basis for the incompatibility between species was made by Emil Ponfick and
Leonard Landois in the late 1800s.8 The first revela- tion came from Ponfick, who observed red cell lysis in the blood of a
woman who died after receiving a transfusion of sheep blood. From animal experiments, Ponfick found that incompatible
transfusions were associated with hem- orrhage and “congestion” of the kidneys, lungs, and liver. He also recognized that
the red urine that transfused ani- mals excreted was caused by hemoglobinuria, not hema- turia. Landois’s observation that
human red cells would lyse when mixed in vitro with the sera of other animals set the stage for the study of the
immunologic basis of blood incompatibility.8

DISCOVERY OF ABO BLOOD GROUPS

Before 1901, the prevailing belief was that all human blood was the same. However, this changed in 1901 with
Karl Landsteiner’s landmark discovery of ABO blood groups.12 Landsteiner, an Austrian immunologist, noticed that
human blood mixed in test tubes with other speci- mens of human blood sometimes resulted in agglutination. By
incubating red cells from some individuals with serum from others, he identified agglutination patterns, leading to the
initial identification of three blood groups, A, B, and C (C was later renamed O).3,13 In 1902, Alfred Decastello and
Adriano Sturli, two of Landsteiner’s former students, found the fourth blood group, AB.3 Landsteiner also contributed
to forensic science by developing a method for blood typing of dried blood specimens.14
Interestingly, the importance of the blood groups was not immediately recognized; blood group typing did not
become part of routine practice for several years. Richard Weil, a pathologist at the German Hospital in New York,
was the first to perform ABO typing and began compat- ibility testing in 1907; he was also the first to suggest inheri-
tance of ABO types.5 Also in 1907 and 1910, respectively, Jan Jansky of Czechoslovakia and Moss of the United
States independently identified four human blood groups.3 However, the Roman numeral systems that Jansky and
Moss each used for designating the four blood groups were completely reversed. Tremendous confusion ensued with
the three different nomenclatures. Finally, in 1927, the American Association of Immunologists adopted a new
classification scheme proposed by Landsteiner, the current ABO terminology.
The discovery of blood groups led Ludvig Hektoen of Chicago to advocate selecting donors by blood group and
crossmatching.8 In 1913, Reuben Ottenberg conclusively demonstrated the importance of compatibility testing in his
report of 128 cases of transfusion. 15 However, even as recently as 1937, some suggested that crossmatching was unnecessary
if the selection of donors was restricted to individuals of the same blood group.5
The inheritance pattern of blood groups was finally proved by Felix Bernstein in 1924. 3 Sadly, differences in race
distribution of blood groups were manipulated and misused in Germany during World War I (WWI) and World
War II (WWII), during which time blood group B was deemed a marker for Slavic or Jewish race, and blood group A
was considered associated with intelligence and industry. In the 1950s in Louisiana, it was a misdemeanor for a
physician to give blood from a black donor to a white person without consent. In the United States, segregation of
blood by race existed until the 1960s.3
 DISCOVERY OF RH BLOOD GROUPS

Although a major discovery in transfusion medicine, ABO blood group typing was not sufficient to prevent many
fatal hemolytic transfusion reactions. In 1939 Philip Levine pub- lished a case report of post-transfusion hemolysis in
a blood group O patient who received blood from her blood group O husband. Levine found that incubation of the
patient’s serum with her husband’s red cells resulted in agglutination. Additionally, the woman’s serum was found to
agglutinate 80 of 104 other samples of ABO-compatible blood. The name of the offending antibody came from
parallel experiments conducted by Landsteiner and Alex Wiener in which anti- bodies produced by immunization of
rabbits and guinea pigs with blood from rhesus monkeys caused red cell agglutina- tion of 85% of humans tested. Those
individuals whose red cells were agglutinated by these antibodies were classified as rhesus (Rh) positive.3 Levine was able
to show that Rh anti- bodies were the main cause of serious hemolytic disease of the newborn (erythroblastosis fetalis).16
Later, it was appre- ciated that the Rh system is composed of numerous alleles. The current system of nomenclature—c, C,
d, D, e, E—was proposed in 1944 by Cambridge geneticist Sir Ronald Fisher. Subsequent development of Rh immune
globulin (RhIG) for prevention of hemolytic disease of the newborn was a major advance. The use of the antiglobulin test,
first described by Carlo Moreschi in 1908 and rediscovered in 1945 by Robin Coombs, Rob Race, and Arthur Mourant,
allowed the iden- tification of many other blood group antigens in the decades that followed.3,17

BLOOD COAGULATION, PRESERVATION, AND STORAGE

Despite some successes by Blundell and contemporaries, transfusions often failed to save lives, and remained a rarity
until the early 20th century. Clotting remained a significant problem. A variety of devices, involving valves, syringes,
and tubing, were invented to facilitate the collection and infu- sion of blood from one individual to another, including
two invented by Blundell—the “Gravitator” and the “Impellor.” The impellor consisted of a double-walled funnel in
which the outer compartment was filled with warm water. The donor blood flowed into the funnel, was sucked into a
syringe, and was forced along tubing into a cannula inserted into the patient’s vein by means of two oppositely acting
spring valves below the funnel8 (Fig. 1–2). Gesellius used an equally complex device, in which the donor’s back was lanced
multiple times and capillary blood extracted using suction cups5,8 (Fig. 1–3). James Aveling used a simpler method for
direct blood transfusion from a donor using two silver can- nulae, inserted into the recipient and donor, and connected
by rubber tubing with a compressible bulb in the middle to promote and sustain flow.11 The Aveling device is featured
in the first known photograph of an actual blood transfu- sion, taken at Bellevue Hospital in New York City in the
1870s9 (Fig. 1–4). In 1908, Alexis Carrel, a French researcher working at the Rockefeller Institute for Medical Research
in New York, perfected a surgical technique for the direct anas- tomosis of donor artery to recipient vein. 3 Although
highly effective at providing blood to the patient without clotting, performance of this technique required tremendous
skill. Further, it required donors willing to undergo the painful procedure. It was also impossible to accurately
estimate the amount of blood passed from donor to recipient; donors often became hypotensive or recipients developed
circulatoryoverload.3CITRATE ANTICOAGULATION

A chemical approach to anticoagulation was first attempted by Braxton Hicks, a 19th-century obstetrician, who experi- mented with
phosphate of soda. Unfortunately, none of the four patients in whom it was used survived.8 Other sub- stances used in
anticoagulation attempts included sodium bicarbonate, ammonium oxalate, arsphenamine, sodium iodide, sodium sulfate, and
hirudin.8 Surprisingly, these initial attempts did not include sodium citrate, which had long been used in laboratories as an
anticoagulant.8 The 1% concentration of citrate commonly used in the labora- tory, however, was toxic to humans.3 Nonetheless, in
1914 Albert Hustin reported the first human transfusion using citrated blood.8 In 1915, Richard Lewisohn of the Mount Sinai
Hospital in New York proved that a 0.2% sodium citrate solution was effective as an anticoagulant for blood, while having no
toxicity even when as much as 2500 mL of citrated blood were transfused.3 Also in 1915, Richard Weil, an American pathologist,
found that citrated blood could be refrigerated for several days before use.18 Lewinsohn and Weil, as well as Rous and Turner, found
that addition of dex- trose to citrate would preserve blood for up to 2 weeks 1,5 (Fig. 1–5). This permitted the first transfusion of stored
blood in WWI by an American army physician, Oswald Robertson,who transfused 20 casualties on 22 occasions during the bat- tle of
Cambrai in November 1917. Nine of the 20 recipients lived.19 The primary disadvantages of the Rous-Turner solu- tion were that it
was difficult to prepare and required a large volume of preservative solution in relation to the amount of blood. However, it remained
the only anticoagulant–preser- vative solution available through most of WWII.5 Acid citrate dextrose (ACD), developed in 1943 by
Loutit and Mollison, allowed for blood to be stored for up to 3 to 4 weeks,20 could be autoclaved, and had the advantage of being easier to
prepare,

ADVENT OF BLOOD BANKS

The first blood donor service was established in 1921 by Percy Oliver, Secretary of the Camberwell Division of the British Red
Cross.3 At this time, donors generally came from an unreliable supply; most from the patient’s family and friends, or from indigents.
Sometimes, no compatible donor could be found. On one such occasion, Oliver was contacted

during, or after a disease process and/or its treatment. The

benefits of transfusion today far outweigh
. The use of blood and its components temporarily
replaces what may be lost or not produced before,