Blood Groups
-
• List the blood group systems. Describe the ABO
system, Rh system State the Landsteiner's Law
• Describe the mode of inheritance of blood groups
• Discuss the importance of blood groups
, Discuss the importance and the methods of cross
matching: direct and indirect
• List the physiological basis of the symptoms and
treatment of Rh incompatibility (erythroblastosis
fetalis)
• List the hazards of blood transfusion
• Describe the complications of mismatched blood
transfusion
• Describe how blood is stored and discuss the changes
that occur in stored blood
i d!•titJiVl•1ii§;Jt.JAAB19Mt1n•
• Agglutinin: The antibody corresponding to the aggluti-
nogen; found in the plasma
• Agglutinogen: Antigen; referred to here as the antigen
on RBCs that causes blood agglutination
Multiplicity of Antigens in the Blood
Cells
At least 30 commonly occurring antigens and hundreds of
other rare antigens, each of which can at times cause antigen-
antibody reactions, have been found on the surfaces of the cell
membranes of human blood cells. Most of the antigens are
weak and therefore are of importance principally for studying
the inheritance of genes to establish parentage.
Two particular types of antigens are much more likely than
the others to cause blood transfusion reactions. They are the
0-A-B system of antigens and the Rh system.
~ A-B Blood Types
A AND B ANTIGENS-AGGLUTINOGENS
Two antigens-type A and type B-occur on the surfaces of the
red_blood cells in a large proportion of human beings. It is these
an11gens (also called agglutinogens because they often cause
blo_od cell agglutination) that cause most blood transfusion re-
actJo ns. Because of the way these agglutinogens are inherited,
people may have neither of them on their cells, they may have
one, or they may have both simultaneously.
Major 0-A-B Blood Types. In transfusing blood from one
:~e
Person to another, the blood of donors and that of recipients
nor~ally classified into four major 0-A-B blood types, as
own m Table 28.1, depending on the presence or absence of
the two agglutinogens, the A and B agglutin_ogens. When neither
A nor B agglutinogen is present, the blood _is type 0. When only
type A agglutinogen is present, the blood ~s type A. When only
type B agglutinogen is present, the blood 1s typ~ B. When both
A and B agglutinogens are present, the blood 1s type AB. The
reciprocal relationship between agglutinogens on the red ~loo~
cells and agglutinins in the serum is at the core of Landstemer s
laws. The first law states that if an agglutinogen is present on the
red cells, the corresponding agglutinin must be absent from the
plasma. The second law states that if an agglutinogen is absent
on the red cells, the corresponding agglutinin must be present
in the plasma.
Genetic Determination of the Agglutinogens. The ABO
blood group genetic locus has three alleles, which means three
different forms of the same gene. These three alleles, JA, 18, and 1° ,
determine the three blood types. We typically call these alleles
"A," "B;' and "O;' but geneticists often represent alleles of a gene
by variations of the same symbol. In this case, the common
symbol is the letter "I," which stands for "immunoglobulin."
The type O allele is either functionless or almost function-
less, so it causes no significant type O agglutinogen on the cells.
Conversely, the type A and type B alleles do cause strong agglu-
tinogens on the cells. Thus, the O allele is recessive to both the A
and B alleles, which show co-dominance.
Because each person has only two sets of chromosomes, only
one of these alleles is present on each of the two chromosomes
in any individual. However, the presence of three different al-
leles means that there are six possible combinations of alleles,
as shown in Table 28 .1, are 00, OA, OB, AA, BB, and AB. These
combinations of alleles are known as the genotypes, and each
person is one of the six genotypes.
One can also observe from Table 28.1 that a person with gen-
otype 00 produces no agglutinogens, and therefore the blood
type is 0. A person with genotype OA or AA produces type A
agglutin~gens and therefore has blood type A. Genotypes OB
and BB give type B blood, and genotype AB gives type AB blood.
Relative Frequencies of the Different Blood Types. The
prevalence o! the different. blood types among one group of
persons studied was approXImately the following:
0 47%
A 41 %
B 9%
AB J% --, '1D.>IC 8ld..8f ·
TABLE 28.1 Blood Types with their Genotypes and their
Constituent Agglutinogens and Agglutinins
§ e~~typas c:>1aoa IVl'lA,c: 4.oalutinnnAn~ l.
Agglutinins
00 0
Anti-A and Anti-B
OAorAA A
A Anti-B
OB or BB B
B Anti-A
AB AB A and B
 ~ -r .1''....
170 ~ _JV'""
SECTION III Blood and Its Constituents

has few, if any, agglutinins, show·

It is obv;oo, horn these '""'""'" that the O md A •~"" ever. Also, the neo_nate ccurs almost entirely after birth. Ing th,
occur frequently, whereas the B gene occurs infrequently. T ese agglutinin formation o 1
P">pon,oo, "''l' by global regioas a,d et m,ctt,es: f hav 1

• 1 . • · A recent
multi<en1<i, st,dy io lodia sho"ed that the pmpo<tmo, t ,)
0 1
ABO blood groups were 37, 32, 23% and 8% for the O, B,A an
AB blood groups respectively.
AGGLUTININS
\Vhen ty~e A ?gglutinogen is not present in a person's red _blood
cells, antibodies known as anti-A agglutinins develop m the
plasma. Also, w?en type Bagglutinogen is not present in the r~d
blood cells, antibodies known as anti-B agglutinins develop m
the plasma.
Thus, referring once again to Table 28.l, note that type 0
blo?d, although containing no agglutinogens, does contain both
ant,~A and anti-B agglutinins. Tyµe A blood contains type A~g-
glutinogens and anti-B agglutinins, and type B blood contains
type B agglutinogens and anti-A agglutinins. Finally, type AB
blood contains both A and Bagglutinogens but no agglutinins.
Titer of the Agglutinins at Different Ages. Immediately
after birth, the quantity of agglutinins in the plasma is almost
zero. Two to 8 months after birth, an infant begins to produce
agglutinins-anti-A agglutinins when type A agglutinogens
are not present in the cells, and anti-B agglutinins when type
B agglutinogens are not present in the cells. Fig. 28.1 shows the
changing titers of the anti-A and anti-B agglutinins at different
ages. A maximum titer is usually reached at 8-10 years of age,
and this titer gradually declines throughout the remaining years
of life.
Origin of Agglutinins in the Plasma. The agglutinins are
gamma globulins, as are almost all antibodies, and they are
produced by the same bone marrow and lymph gland cells
that produce antibodies to any other antigens. Most of them
are immunoglobulin M (IgM) and immunoglobulin G (IgG)
molecules.
But why are these agglutinins produced in people who do
not have the respective agglutinogens in their red blood cells? A
potential answer to this question is that small amounts of type
A and B antigens enter the body in food, in bacteria, and in
other ways, and these substances initiate the development of the
anti-A and anti-B agglutinins.
For instance, infusion of group A antigen into a recipient
having a non-A blood type causes a typical immune response
with formation of greater quantities of anti-A agglutinins than
Ill
400
C:
c
;::
.:! 300
Cl
the
N PROCESS IN TRANSFUSION
AGGLUTlNATI O glu
REACTIONS . . Ty\
. atched so that anti-A or anti-B agl
When bloods are _mi~:th red blood cells that contain~1asll\, ag!
agglutinins are rnixe t'vely the red cells agglutinate as a or i
• respec 1 • res \
agglutmogen~, . tt ching themselves to the red blood U1 R
of the agglutm~s 1 1-~s have ~ nding sites (IgG~ ) tel~.
Because t!1e agg ~ ~ e a single agglutinin can attach t0 \-!_0 A
binding sites (lg cells 'at the same time, thereby causii tv;o S;
d
or more re ~otogether by the agglutinin. This binding c~ the f
cells to be bot which is the process of "agglutination,, ~ses
the cellls to c umlupg, small blood vessels throughout the circ~at en
these c umps P d ·h h · . ory
. ensuing hours to ays, e1t er p ys1cal diston·
system. Dunng . h' bl d 11 Ion
of the cells or attack by phagocytic w ite ~o ce s destroys the
b an es of the agglutinated cells, releasing hemoglobin int
mem r which is called "
the plasma, Iys1s· " of th e re d bl
. oo~s. 0
Acute Hemolysis Occurs in Some Transfusion Reactions.
Sometimes, when recipient and donor _bloods ~re mismatched,
immediate hemolysis of RBCs occur~ m the circulating blood_
In this case, the antibodies cause lys1s of the RBCs by activat-
ing the complement syste~ and forming_ a me~brane attacl:
complex (also called cytolytic complex) that mserts itself into the
lipid bilayer of the cell membranes; this insertion creates mem-
brane pores that are permeable to ions and causes osmotic \ysis
of the cells, as described in Chapter 25. Immediate intravascular
hemolysis is far less common than agglutination followed by
delayed hemolysis because not only does there have to be ahigh
titer of antibodies for lysis to occur, but also a different type of
antibody seems to be required, mainly the lgM antibodies; thes,
antibodies are called hemolysins.
BLOOD TYPING
Before giving a transfusion to a person, it is necessary to deter-
mine the blood type of the recipient's blood and the blood type of
the donor blood so that the bloods can be appropriately matched.
This process is called blood typing and blood matching, and these
procedures are performed in the following way: The red bl~
cells are first separated from the plasm.a and diluted with saline 1·
solution. One portion is then mixed with anti-A agglutinin and
anoth:r portion with anti-B agglutinin. After several minutes.
the mixtures are observed under a microscope. If the red blood
th have b_ecome clumped-that is, "agglutinated"-one kno,~
cells
at an antibody-antigen reaction has resulted. .
. Table 28.2 lisJs the presence (+) or absence (_) of agg\ullDl;
hon of the four types of red blood cells. Type O red blood cell

-..
Cl
a,

200
GI
;:: TABLE 28.2

.
GI
Cl
a,
GI
>
ct
0 ' I I I I I I I I I 7
Red Blood Cell Types
0 10 20 30 40 50 60 70 80 90 100
0 A.nti-A.
I
Age of person (years) Anti-B
A
Fig. 28.1 Average titers of anti-A and anti-8 agglutinins in the plas- B
mas of people with different blood types. +
AB
+
+
+

haw no agglutinogcn~ and therefore do not react with either
the anti-A or the ant1-B agglutinins. Type A blood has A ag-
,)utinogens and therefore agglutinates with anti-A agglutinins.
~ype B blood has B agglutinogens and agglutinates with anti-B
agglutinins. Ty_µe AB blood has both A_ a~1d B agglutinogens and
agglutinates with both types of agglutmms.
RH Blood Types
Along ~ith the_ 0-A-B blood type system, the Rh blood type
system 1s also important when transfusing blood. The major
difference between the 0-A-B system and the Rh system is the
following: In ~e 0-A-B system, the plasma agglutjnins respon-
sible for _causmg transfusion reactions develop spontaneously,
whereas m the Rh system spontaneous agglutinins almost never
occur. Instead, the person must first be massively exposed to an
Rh antigen, such as by transfusion of blood containing the Rh
antigen, before enough agglutinins to cause a significant trans-
fusion reaction will develop.
Rh Antigens--"Rh-Positive" and "Rh-N egative" People.
There are six common types of Rh antigens, each of which is
called an Rh factor. These types are designated C, D, E, c, d, and
e. A person who has a C antigen does not have the c antigen, but
the person missing the C antigen always has the c antigen. The
same is true for the D-d and E-e antigens. Also, because of the
manner of inheritance of these factors, each person has one of
each of the three pairs of antigens.
The type D antigen is widely prevalent in the population
and considerably more antigenic than the other Rh antigens.
Anyone who has this type of antigen is said to be Rh-positive,
whereas a person who does not have type D antigen is said to be
Rh-negative. However, it must be noted that even in Rh-negative
people some of the other Rh antigens can still cause transfusion
reactions, although the reactions are usually much milder.
About 85% of all white people are Rh-positive and 15% are
Rh-negative. In American blacks, the percentage of Rh-positives
is about 95%, whereas in African blacks, it is virtually 100%.
Over 95% of Native Americans and Asians living in China, Japan
and Korea are also Rh positive and it is estimated that the world-
wide frequency of Rh-positive and Rh-negative blood types are
95% and 6%, respectively. In India_n~ 95% are Rh-positiYe.
RH IMMUNE RESPONSE
Formation of Anti-Rh Agglutinins. When red blood cells
containing Rh factor are injected into a person whose blood
does not contain the Rh factor-that is, into an Rh-negative
person-anti-Rh agglutinins develop slowly, reaching maxi-
mum concentration of agglutinins about 2-4 months later.
This immune response occurs to a much greater extent in some
people than in others. With multiple exposures to the Rh factor,
an Rh -negative person eventually becomes strongly "sensitized"
to Rh factor.
Characteristics of Rh Transfusion Reactions. lf an Rh-
negative person has never before been exposed to Rh-positive
~lood, transfusion of Rh-positive blood into that person will
likely cause no immediate reaction. However, anti-Rh anti-
bodies can develop in sufficient quantities during the next 2-4
":eeks to cause agglutination of the transfused cells that are still
c_irculating in the blood. These cells are then hemolyzed by the
tissue macrophage system. Thus, a delayed transfusion reaction
occurs, although it is usually mild. Upon subsequent transfu-
....._____
28 Blood Groups 171
sion of Rh -positive blood into the same person, wh_o is now_al-
ready immunized against the Rh factor, the transfuswn reaction
is greatly enhanced and can be immediate and as severe as a
transfusion reaction caused by mismatched type A or B blood.
-9, Erytl1roblastosis Feta/is ("Hemolytic Disease of the New-
born.") Rh incompatibility is a condition that develo ps wh_en
an Rh-negative pregnant woman has a baby in her womb w1!.b
Rh-positive blood This leads to a condition called erythroblas-
tosis fetalis, which is a disease of the fetus and newborn child
characterized by agglutination and phagocytosis of the fetus's
red blood cells. In most mstances of erythroblastosis fetalis, the
mother is Rh-negative and the father Rh-positive. The baby has
inherited the Rh-positive antigen from the father, and the moth-
er develops anti-Rh agglutinins from exposure to the fetus's Rh
antigen. In turn, the mother's agglutinins diffuse through the
placenta into the fetus and cause red blood cell agglutination
(Fig. 28.2). It is important to note that this condition does not
affect the first child, since sensitization to the Rh antigen occurs
during parturition of the first child. However, if the Rh-negative
mother was earlier sensitized to the Rh antigen (by, eg, an earlier
blood transfusion with Rh-positive blood), then even the first
child can be affected.
Incidence of the Disease. An Rh-negative mother having her
first Rh-positive child usually does not develop sufficient anti-
Rh agglutinins to cause any harm. However, about 3% of second
Rh-positive babies exhibit some signs of erythroblastosis fetal is;
about 10% of third babies exhibit the disease; and the incidence
rises progressively with subsequent pregnancies.
Effect of the Mother's Antibodies on the Fetus. After anti-
Rh antibodies have formed in the mother, they diffuse slowly
through the placental membrane into the fetus's blood. There
they cause agglutination of the fetus's blood. The agglutinated
red blood cells subsequently hemolyze, releasing hemoglobin
into the blood. The fetus's macrophages then convert the hemo-
globin into bilirubin, which causes the baby's skin to become
yellow (jaundiced). The antibodies can also ~ttack and damage
other cells of the body.
Clinical Picture of Erythroblastosis. The jaundiced, erythro-
blastotic newborn baby is usually anemic at birth, and the anti-
Rh agglutinins from the mother usually circulate in the infant's
blood for another 1-2 months after birth, destroying more an d
more red blood cells.
The hematopoietic tissues of the infant attempt to repl ace the
hemolyzed red blood cells. The liver and spleen become greatly
enlarged and produce red blood cells in the same manner that
they normally do during the middle of gestation. Because of the
rapid production of red cells, many early forms of red blood
cells, including many nucleated blastic [orms~ are passed from
the bab 's bone marrow into the circulato s stem, and it is
because of the presence of these nucleated blastic re lood cells
that the disease is called erythroblastosis (etalis. tt
Although the severe anemia of erythroblastosis fetalis is usu-
ally the cause of death, many children who barely survive the
anemia exhibit permanent mental impairment or damage to
motor areas of the brain because of precipitation of bilirubin
in the neuronal cells, causing destruction of many, a condition
called ~ erus .
Treatment of N eonates with Erythroblastosis Fetalis.
One treatment for erythroblastosis fetalis is to replace the
 172 SECTION Ill Blood and Its Constituents

Rh-negative
mother Rh-positive
babY

Prevention At birth
Rh antigen by
fetomaternal

-
Anit-Rh hemorrhage
agglutinin given'
soon after first pregnancy
stops sensitization .....

!
First baby

s,"'m""'"
During pregnancy
second baby

Detection
Anti-Rh
agglutinin
Coombs test to
detect sensitization

t
Erythroblastosis fetalis

Mechanism of development of erythroblastosis fetalis and the utility of the Coombs test.
Fig. 28.2

HAZARDS OF TRANSFUSION: TRANSFUSION

!!eonate's blood with Rh-negative hJood. About 400 mL of
Rh -negative blood is infused over a period of LS or more
hours while the neonate's own Rh-positive blood is being re-
moved. This procedure may be repeated several times during
the first few weeks of life, mainly to keep the bilirubin level
low and thereby prevent kernicterus. By the time these trans-
fused Rh-negative cells are replaced with the infant's own
Rh-positive cells, a process that requires 6 or more weeks, the
anti-Rh agglutinins that had come from the mother will have
been destroyed .
Prevention of Erythroblastosis Fetalis. The D antigen of the
Rh blood group system is the primary culprit in causing im-
munization of an Rh-negative mother to an Rh-positive fetus.
1n the J 970s, a dramatic reduction in the incidence of erythro-
blastosis fetalis was achieved with the development of Rh im-
munoglobulin globin, an anti-D antibody that is administered
~1yh1' to the expectant mother starting at 28-30 weeks of gestation.
The anti-D antibody is also administered to Rh-negative wom-
en who deliver Rh-positive babies to prevent sensitization of
the mothers to the D antigen. This greatly reduces the risk of
developing large amounts of D antibodies during the second
pregnancy.
The mechanism by which . .
Rh 1mmunoglobuhn . globin
prevents sensitization of the D anti?en is ~ot co~_.12Jetely un-
REACTIONS RESULTING FROM MISMATCHED
BLOOD TYPES
If donor blood of one blood type is transfused into a recipienl
who has another blood type, a transfusion reaction is likely to
occur in which the red blood cells of the donor blood are ag-
glutinated. It is rare that the transfused blood causes agglutina-
tion of the recipient's cells, for the following reason: The plasma
portion of the donor blood immediately becomes diluted byall
the plasma of the recipient, thereby decreasing the titer of the
infused agglutinins to a level ·usually too low to cause agglu-
tination. Conversely, the small amount of infused blood does
not significantly dilute the agglutinins in the recipient's plasma.
Therefore, the recipient's agglutinins can still agglutinate th,
mismatched donor cells.
All tr~nsfusi~n reactions eventually cause either immedi_at,
hemolysis resultu~g from hemolysins or later hemolysis resul_ong
from phagocytosis of agglutinated cells. Transfusion reacnons
can be ~emolyti~ or nonhemolytic (Table 28.3). In hemolytic
~ransfusion reactions, the hemoglobin released from the red cells
is then _converted by the phagocytes into bilirubin and later ex·
creted m ~e bile by the liver, as discussed in Chapter 69. The
concentration of _bilirubin in the body fluids often rises high
:~~u!~ntob cause Jaimdice-that is, the person's internal tiSS j0

derstood, but one effect of the antJ-D antibody 1s to inhibit liver funct _eco~e colored with yellow bile pigment. However
antigen-induced B lymphocyte antibody production in the 10n 1s normal th bi! . d lJl!O
the intesh- b ' e e pigment will be excrete d .
expectant mother. The administered. a_nti-D antibody also at- Lu,es y way of th li . all oe>
not appear in an aduJ e ver bile, so jaundice usu Yload
taches to D-antigen sites on Rh-pos1uve fetal red blood cells are hemolyz d • t person unless more than 400 mL ofb
that ma Y cross the Jacenta and ~nter _t~e ~ir~ulation of tht: ex- e m 1ess than a da .
~ t b _ e r e o v 111__Lc:11c1lf!
• I:_,-,a,_C--
- g w1tn the unmune response Acute Kidney Failu y. one ol
the most lethal ffi re After Transfusion Reactions. .11,rt,
e ects of transfusion recactions is kidney fai
t ~
 28 Blood Groups 173

•
Type
HEMOLYTIC
Immediate
Types of Transfusion Reactions
Cause

ABO incompatibility
Clinical Features

Ranges from fever,

chills to shock,
BOX 28.1 EFFECTS OF STORAGE OF BLOOD ON RBCS

renal failure
Delayed Rh incompatibility,
Recurrent anemia,
secondary or delayed may be fever
response to RBC
antigen
NONHEMOLYTIC
Febrile reaction Contamination of Fever and chills
stored blood with
endotoxin or due to
cytokines that are
released on storage
which can begin within a few minutes to a few hours and con-
tinue until the person dies of acute renal failure.
The kidney shutdown seems to result from three causes:
First, the antigen-antibody reaction of the transfusion reaction
releases toxic substances from the hemolyzing blood that cause
powerful renal vasoconstriction. Second, loss of circulating
red cells in the recipient, along with production of toxic sub-
stances from the hemolyzed cells and from the immune reac-
tion, often causes circulatory shock. The arterial blood pressure
falls very low, and renal blood flow and urine output decrease.
Third, if the total amount of free hemoglobin released into the
circulating blood is greater than the quantity that can bind with
"haptoglobin" (a plasma protein that binds small amounts of
hemoglobin), much of the excess leaks through the glomerular
membranes into the kidney tubules. If this amount is still slight,
it can be reabsorbed through the tubular epithelium into the
blood and will cause no harm; if it is great, then only a small
percentage is reabsorbed. Yet water continues to be reabsorbed,
causing the tubular hemoglobin concentration to rise so high
that the hemoglobin precipitates and blocks many of the kidney
tubules. Thus, renal vasoconstriction, circulatory shock, and
renal tubular blockage together cause acute renal shutdown. If
the shutdown is complete and fails to resolve, the patient dies
within a week to 12 days, as explained in Chapter 84, unless he
or she is treated with an artificial kidney.
STRUCTURAL CHANGES
• RBCs tending to lose their shape and becoming spherical
• Loss of membrane flexibility-not deformable and likely to be
removed quickly from circulation
• Loss of membrane stability
BIOCHEMICAL CHANGES
• Decreased glycolysis
• Reduced glutathione
• Depletion of ATP and adenine
COLLECTION OF BLOOD FOR TRANSFUSION,
ITS STORAGE, AND CHANGES THAT OCCUR
DURING STORAGE
Blood is often collected from donors for transfusion into those
that need it. Typically, about 450 mL of blood is collected from
a vein (usually the antecubital vein) from a healthy donor who
has been screened for diseases such as HIV, malaria, hepatitis,
and syphilis, which could be transmitted during transfusion.
When the blood that is collected is used for transfusion back
into the donor (eg, after surgery), it is called an autologous do-
nation. The blood is collected from the donor's vein into a flex-
ible plastic bag, which already has a solution of chemicals in
it. These chemicals are sodium citrate, which binds to calcium
in the blood and prevents clotting, phosphate buffers to buffer
the pH of the collected blood as well as to provide a source of
phosphate, dextrose to provide an energy source, and adenine to
provide the substrate for adenosine triphosphate (ATP) synthe-
sis. By using these chemicals, the storage of blood can be pro-
longed to up to 35 days at 4°C.
However, blood that is stored in this fashion for several days
does not escape changes. Several changes do occur: red blood
cells can become spherical due to metabolic changes, with an as-
sociated change in cell rigidity, leading to a fairly large destruc-
tion of the transfused RBCs in the body of the recipient. Within
the red blood cell, there is a reduction in ATP as well as 2,3-di-
phosphoglycerate levels. Granulocytes lose their phagocytic and
bactericidal properties within 4-6 hours, while platelets could
become nonfunctional within 36-48 hours. Other changes with
regard to the level of clotting factors also occur. Finally, the po-
tassium levels in the stored blood can also increase due to loss of
potassium from the RBC into the plasma (Box 28.1).

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