DOI 10.
1515/cclm-2013-0168 Clin Chem Lab Med 2013; 51(8): 1545–1553
Review
Massimo Franchini* and Giancarlo Maria Liumbruno
ABO blood group: old dogma, new perspectives
Abstract: Human blood group antigens are glycoproteins
and glycolipids expressed on the surface of red blood cells
and a variety of human tissues, including the epithelium,
sensory neurons, platelets and the vascular endothelium.
Accumulating evidence indicate that ABO blood type is
implicated in the development of a number of human dis-
eases, including cardiovascular and neoplastic disorders.
In this review, beside its physiologic role in immunohe-
matology and transfusion medicine, we summarize the
current knowledge on the association between the ABO
blood group and the risk of developing thrombotic events
and cancers.
Keywords: ABO blood group; cancer; cardiovascular dis-
orders; thrombosis; von Willebrand factor.
*Corresponding author: Massimo Franchini, Department of
Transfusion Medicine and Hematology, Azienda Ospedaliera Carlo
Poma, Mantova, Italy, E-mail: massimo.franchini@aopoma.it
Giancarlo Maria Liumbruno: Immunohematology, Transfusion
Medicine and Clinical Pathology Units, “San Giovanni Calibita”
Fatebenefratelli Hospital, AFAR, Rome, Italy
Introduction
The antigens of the ABO blood group system were first
discovered and the knowledge of their structure and func-
tion has greatly improved thanks to more than a century
of research [1]. ABO blood groups are defined by carbo-
hydrate moieties on the extracellular surface of the red
blood cell (RBC) membranes [1]. However, along with
their expression on RBCs, ABO antigens are also highly
expressed on the surface of a variety of human cells and
tissues, including the epithelium, sensory neurons, plate-
lets, and the vascular endothelium [2]. The clinical sig-
nificance of the ABO blood group system extends beyond
transfusion medicine as several reports have suggested an
important involvement in the development of neoplastic
and cardiovascular disorders [3, 4].
In this review, we summarize the current knowledge
on the ABO blood group system, focusing in particular on
its role in the pathogenesis of human diseases.
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
The ABO blood group system
History and evolutionary considerations
At the beginning of the last century, the Austrian scien-
tist Karl Landsteiner noticed that if six sera (including his
own one and those of five colleagues) were mixed sepa-
rately with their saline RBC suspension, visible aggluti-
nation and hemolysis occurred [5]. The results of these
early experiments led to the identification of three of the
four phenotypes of the ABO blood group system, the first
genetic polymorphism discovered in humans. The first
three blood groups discovered were A, B and C (subse-
quently renamed O from the German word “ohne” which
means “without”) [1]. Landsteiner showed that the serum
contained antibodies to the antigen(s) lacking from the
RBC of the individual subject. Group A RBCs possessed an
A antigen and contained anti-B in the serum that aggluti-
nated group B RBCs. The serum from people with group B
RBCs (and, therefore, the B antigen) contained anti-A and
caused agglutination of the group A RBCs. The third ABO
group (group O) did not show evidence of any antigens on
the RBC, however, the serum contained antibodies to both
the A and B antigens.
In 1902, the fourth ABO group, group AB, was discov-
ered by two of Landsteiner’s associates, von Decastello
and Sturli [6]. Group AB RBCs possessed both the A and
B antigens and lacked all ABO antibodies in the serum.
Therefore, based on RBC agglutination patterns, people
could be divided into four major groups: A, B, AB, and
O. An inverse reciprocal relationship exists between the
presence of A and B antigens on RBCs and the presence of
anti-A, anti-B, or both, in sera (Table 1). These antibodies,
directed against missing A and B antigens, are known as
isohemagglutinins. They are usually IgM type and are not
present in newborns but appear after the first few months
of life or, if they are present, are of maternal origin. They
were initially called naturally occurring antibodies as
they were thought to originate without antigenic stimula-
tion. However, it is now known that this is not the case. In
fact, it is believed that the immunizing sources for such
naturally occurring antibodies are gut and environmental
1546 Franchini and Liumbruno: ABO blood group

Lapps
Incidence (%)

[11]

18.2
36.1
18.5
4.8
6.2
6.2
Table 1 Serologic reactions of the ABO blood groups.

Blood Red blood Antibodies contained

Bengalese
[11]

22
22.2
1.8
38.2
14.8
0.9
group cell antigens in serum

A A Anti-B
B B Anti-A
O None None

Vietnamese
[11]

45
21.4
0
29.1
4.5
0
AB A and B Anti-A, Anti-B, Anti-A,B

bacteria, such as Enterobacteriaceae, which have been

Aboriginals
Australian

[11]

44.4
55.6
0
0
0
0
shown to have ABO-like structures on their lipopolysac-
charide coats [7, 8]. Therefore, endogenous synthesis of
anti-A and anti-B can begin as early as 3–6 months and
almost all children have the appropriate isohemagglu-

South

Indians [11]
American

100
0
0
0
0
0
tinins in their sera at 1 year [9]. The titers of anti-A and
anti-B increase during early childhood and reach adult
levels by 5–10 years. Furthermore, ABO antigens can be
detected on RBCs of embryos as early as 5–6 weeks of ges-

Europeans
[10]

44
33
9
10
3
1
tation, but the amount of ABO antigens on cord RBCs is
less than that on adult erythrocytes; with increasing age
more A and B antigen is present on RBCs and a normal
ABO expression is usually observed by 2–4 years.

Taiwanese
Chinese
[13]

42.4
25.6

25.8
6.2
The frequency of ABO blood groups varies greatly
in different races and populations. In most populations,
about 50% are Group O, followed closely by group A,
with groups B and AB showing a much lower incidence. Indians) [12]
Navajo (North
American

73
27

0
0
In many non-European populations, group B has higher
frequencies (e.g., 26% of the Chinese population) [10] or is
even the commonest group (38.2% of the Bengalese popu-
lation) [11], while the incidence of group A shows a cor-
responding marked reduction. In some populations, such
Blackfoot

Indians) [12]
(North American

17
82

0
1
as the Blackfoot (North American Indians) the frequency
of group A is 82% [12], and in the Lapp population there
Table 2 ABO phenotype incidence in selected populations [9–13].

is a relatively high frequency of A2. In the Australian Abo-

riginal population, only groups O and A1 are found and
South American Indians all belong to group O [11]. The
frequencies of ABO phenotypes in a few selected popula-
USA African
ethnicity [9]

49
27

20
4

tions are reported in Table 2 [9–11, 13]; further data on the

racial and ethnic distribution of ABO blood types sorted
by population groups can also be found at the Bloodbook.
com website [12].
USA European
ethnicity [9]

45
40

11
4

The ABO blood group system also has a key role in

genetics, anthropology, and population studies. The
concept of evolutionary selection based on pathogen-
driven blood group changes is also supported by studies
on the genetic characterization of the ABO blood group in
A1B
A2B

the Neanderthals [14] and ancient Egyptian mummies [15].

A1
A2
Phenotype

These studies suggest a potential selective advantage of

the O allele influencing the susceptibility to several dif-
AB

ferent pathogens responsible for diseases, such as severe

O

B
A

Brought to you by | University of Newcastle, Australia

Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM

malaria [16], Helicobacter pylori infections [17], and severe
forms of cholera [18]. The positive selective pressure could
have been caused by the absence of the A and B antigens
(that can be used as receptors by infectious agents) and
by the presence of anti-A and anti-B antibodies. Therefore,
the study of the evolution of the ABO blood groups can
contribute to the determination of when during human
history the different alleles emerged, and can help to
identify the selective forces that might have acted on the
different alleles.
Genetic inheritance and biochemistry
Fundamentally, the ABO blood group system consists of
three alleles: two co-dominant A and B alleles, and one
silent and recessive O allele. Inheritance of the ABO genes
follows Mendelian principles. The system is controlled by
a single gene located on the terminal portion of the long
arm of chromosome 9 (9q34.2); the ABO gene is quite
large and consists of 7 exons spread over 18 kilobases at
the chromosomal locus [19]. This gene encodes a glyco-
syltransferase enzyme that adds a sugar residue to a
carbohydrate structure called the H antigen. In fact, the
antigens of the ABO, H, and also those of Lewis I, and P
blood group systems, are defined by small carbohydrate
epitopes on glycoproteins and glycolipids. Therefore, ABO
expression is also regulated by the H gene that is respon-
sible for the synthesis of the H antigen substrate, the pre-
cursor of A and B antigens. The ABH antigens also occur
as soluble glycoprotein antigens in secretion that include
saliva, tears, breast milk, and seminal fluid.
The presence of ABH antigens in the secretion is con-
trolled by a Se gene. This salivary secretor characteristic
was found to be inherited as a dominant Mendelian trait
[20]. Secreted antigens are absent when two se genes
are inherited (20% of the population). The H antigen is
present in the membrane of RBCs and also of most epi-
thelial and endothelial cells. People lacking the H gene
do not have H-bearing structure on the erythrocyte mem-
brane and do not express A or B antigens; these individu-
als are homozygous for the Bombay gene (hh) and have the
rare Oh phenotype [21], the so-called Bombay phenotype,
which was recognized in 1952 [22]. The A allele codes for
an enzyme that adds a N-acetyl galactosamine to the sub-
terminal galactose of H antigen, while the B allele, which
differs from the former by four amino acid changes, codes
for an enzyme that adds a D-galactose to the same subter-
minal galactose. In group AB individuals, both A and B
structures are synthesized. The O allele occurs most fre-
quently in modern humans and carries a human-specific
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
Franchini and Liumbruno: ABO blood group 1547
inactivating mutation, which produces a non-functional
enzyme, thus the H antigen remains without further modi-
fication on the surface of the cells [23, 24].
ABO subgroups
ABO subgroups are distinguished by decreased amounts
of antigens on RBCs and, in secretors, present in the
saliva. A subgroups are more frequent than B subgroups
[25]. The two principal A subgroups are A1 and A2. RBCs
from A1 and A2 subjects both react strongly with anti-A rea-
gents in direct agglutination tests. The serologic distinc-
tion between A1 and A2 is based on the agglutination of A1
RBCs but not A2 with anti-A1 lectin from Dolichos biflorus
seeds. Approximately 80% of blood type A or AB are clas-
sified as A1 or A1B. The remaining 20% are either A2 or A2B.
Subgroups weaker than A2 are not frequent, and are char-
acterized by a decreasing number of A antigen sites on the
RBCs and a reciprocal increase in H antigen activity. Sub-
groups Aint, A3, Ax, Aend, Am, and Ael are met only rarely in
transfusion practice, and the last four cannot reliably be
identified on the basis of blood typing tests alone.
B subgroups are even less common than A subgroups
and, similarly, are classified by the amount of B antigen,
which decreases in the order B, B3, Bx, Bm, and Bel [26].
ABO blood group testing and
clinical importance
ABO testing
The ABO group system was the first of the 33 current blood
group systems [27] to be identified, and is the most signifi-
cant for transfusion medicine practice as accurate testing
of the blood donor and recipient for ABO compatibility is
fundamental for the prevention of hemolytic transfusion
reactions (HTRs). The determination of the ABO type of
transfusion therapy candidates and blood donors has a
key role in guaranteeing the safety of blood transfusion.
The ABO blood group test is performed in two steps. The
forward type is commonly carried out through murine
monoclonal reagents to establish whether A or B antigens
are present on the RBCs. The reverse type is a comple-
mentary test based on the inverse reciprocal relationship
between the presence of A and B antigens on erythrocytes
and the presence of naturally occurring antibodies in
their sera. Therefore, by knowing which ABO antigens are
1548 Franchini and Liumbruno: ABO blood group
present on the RBCs and which antibodies are contained
in the serum, the ABO type of recipients can be deter-
mined, thus allowing compatible blood components to be
supplied.
Routine grouping of donors and patients must
include both RBC and serum tests, each serving as a
check on the other. However, according to the Italian
Standards of Transfusion Medicine, recently translated
into English and freely available at the Italian Society of
Transfusion Medicine and Immunohaematology (SIMTI)
website [28], the ABO blood group of donors who have
not already been typed “shall be determined on RBCs
using the anti-A, anti-B, and anti-A, B reagents” and
“in serum/plasma using at least A1 and B erythrocytes”,
while “unequivocally identified donors who have already
been typed for the ABO and RhD systems” shall be typed
through RBC testing “using at least anti-A and anti-B rea-
gents”. In addition, “for ABO blood group determination
in serum/plasma, it may also be advisable to use A2 and/
or O erythrocytes, in order to identify weak phenotypes or
antibodies against ABH specificities”. The same applies
to patients. Only RBCs are tested when blood grouping is
performed on samples from infants < 4 months of age.
At present, ABO typing reagents are produced from
monoclonal antibodies derived from cultured cell lines
and they agglutinate most antigen-positive erythrocytes
even without centrifugation. On the contrary, anti-A and
anti-B antibodies in the sera of most patients and donors
are usually too weak to agglutinate RBCs without cen-
trifugation or incubation. Both tests can be carried out
through slide, tube, microplate or column agglutination
techniques.
ABO discrepancies
Technical errors and several clinical conditions or diseases
can lead to discrepancies between erythrocyte and serum
results in ABO grouping [9]. Technical errors include:
specimen mix-up, too heavy or too light RBC suspension,
failure to add reagents, missed observation of hemolysis,
failure to comply with the manufacturer’s instructions,
under- or over-centrifugation of test samples, incorrect
interpretation or recording of the test results, contami-
nated reagents or dirty glassware, and expired or other-
wise inactive reagents. ABO typing discrepancies may be
caused by intrinsic problems with either RBCs or serum
and can be classified in five categories: i) weak/missing
RBC reactivity, resulting from weak ABO subgroup inherit-
ance, leukemia/malignancy, transfusion, transplantation,
and excessive soluble blood group substance; ii) extra
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
RBC reactivity, caused by autoagglutinins/excess proteins
coating RBCs, non-specific RBC aggregation due to abnor-
mal concentrations of serum proteins or infused macro-
molecular solutions, pH- or reagent-dependent antibody,
or rouleaux, transplantation, acquired A antigen [group
O or group B people with activation of the Tn cryptanti-
gen (namely N-acetyl galactosamine) usually associated
with bacterial or viral infections], acquired B-like antigen
(usually found in A1 individuals with diseases of the
lower intestinal tract, carcinoma of the colon or rectum,
intestinal obstruction, gram-negative septicemia, or gan-
grene of the lower extremities and more commonly due
to deacetylation of the A antigen by microbial enzymes)
[29], and out-of-group transfusion; iii) mixed-field RBC
reactivity for recent transfusion, transplantation, foeto-
maternal hemorrhage, and chimerism; iv) weak/missing
serum reactivity, due to age ( < 4–6 months old or elderly
persons), ABO subgroups, hypogammaglobulinemia, and
transplantation; v) extra serum reactivity, caused by cold
auto- or allo-antibodies, antibodies to reagent constitu-
ent, excess serum protein, transfusion of plasma, trans-
plantation, or infusion of intravenous immunoglobulin.
ABO clinical importance
ABO incompatibility is also the cause of other severe dis-
eases, such as hemolytic disease of the fetus and newborn
(HDFN), and HTRs, and plays an important role in solid
organ and hematopoietic transplantation.
HDFN as a result of ABO incompatibility between
mother and baby is a relatively common event in group O
mothers carrying a group A or B fetus. It may occur in the
first or in any subsequent pregnancy and in the usual sce-
nario, is caused by naturally occurring A, B IgG antibodies
crossing the placenta [1]. However, despite the prevalence
of ABO, HDFN is nearly always mild and hemolysis of fetal
RBCs only rarely causes severe anemia. Several reasons
can be listed for the paradoxical mildness of this disease:
i) there are a smaller number of A and B antigenic sites on
the fetal RBC membrane; ii) anti-A and anti-B are mostly
IgM, which does not cross the placenta; iii) the small
amount of antibody is neutralized by a myriad of tissue
and soluble antigens.
The interaction between preformed antibodies and
RBC antigens is the immunologic basis for acute HTRs.
Life-threatening HTRs are associated with transfusion
of ABO-incompatible RBCs or ABO-incompatible plasma
that result in acute intravascular hemolysis. Although
rare, the most common circumstance is when group
O platelets from donors with high titers of anti-A are
 Franchini and Liumbruno: ABO blood group 1549

transfused to group A patients [30, 31]. ABO incompati- against blood group antigen(s) present on the recipient’s
bility because of clerical errors are still one of the main (group A) RBCs]; iii) incompatible bidirectionally (donor
risks for major morbidity and mortality associated with is group A and recipient is group B). Some evidence sug-
transfusion therapy [32]. gests that ABO-incompatible transplants may be associ-
ABO compatibility is also important for platelet ated with increased complications, but only in a selected
transfusion [33]. In fact, platelets express ABO antigens group of patients [36]. Immune hemolysis remains a
on a large number of platelet glycoproteins and glycoli- major complication in transplantation of ABO-incom-
pids and routine transfusion of ABO-incompatible plate- patible solid organs [37], a relatively recent strategy that
lets can be associated with cumulative adverse effects, has met with moderate success. However, the results can
including decreased post-transfusion recovery, increased also be improved by aphaeretic treatment together with
platelet utilization, incompatible platelet crossmatches, immunosuppressive therapy and reach outcomes similar
HLA alloimmunization, and ABH-specific refractoriness to those of normal ABO-compatible transplants [38].
[34]. The criteria for blood-group compatibility for the
transfusion of RBCs, plasma, and platelets are reported
in Table 3 [33, 35]. The role of the ABO blood group
The clinical significance of anti-A and anti-B is also
important in both solid organ and hematopoietic trans-
in human diseases
plantation. ABO compatibility is not critical in the selec-
There is a high amount of clinical data documenting the
tion of potential hematopoietic stem cell transplantation
involvement of ABO blood groups in the development of
donors because pluripotent and early-committed hemat-
various human disorders. However, the more consistent
opoietic progenitor cells (HPCs) lack ABO antigens.
data come from studies analyzing the association with
Therefore, engraftment of HPCs is uninhibited even in
malignancies and cardiovascular diseases.
the presence of circulating ABO antibodies. However,
ABO incompatibility, which is present in 20%–40% of
donor/recipient pairs, influences transfusion decisions The ABO blood group and cancer
and can fall into one of three categories: i) incompat-
ible in the major crossmatch [the (group O) recipient A number of epidemiological studies have reported an
has antibodies against blood group antigen(s) present association between ABO blood groups and risk of devel-
on the donor’s (group A) RBCs]; ii) incompatible in the oping certain malignancies, especially gastric and pancre-
minor crossmatch [the (group O) donor has antibodies atic cancers.
In a combined analysis published more than fifty
Table 3 Selection criteria of the ABO phenotype of red cell units to years ago on gastric cancer cases in 15 study locations
transfuse. in the USA, Europe and Australia, a significant positive
association was reported between non-O blood group and
ABO phenotype ABO phenotype of the units to select for risk of gastric cancer with an odds ratio (OR) of 1.24 [95%
of the recipient transfusion (in order of preference) confidence interval (CI): 1.18–1.30] for patients with blood
Red blood Plasma Platelets group A compared to those with blood group O [39]. More
cells recently, the large Scandinavian Donations and Transfu-
O O O, A, B, AB O, A, B, AB sions study, involving more than one million donors, who
A A, O A, AB A, AB (O after were followed for up to 35 years, demonstrated a similar
plasma removal and magnitude of association with blood group A (OR 1.20,
resuspension in 95% CI: 1.02–1.42) [40]. In a case-control study published
additive solutions)a
last year by Wang et al. [41], the risk of gastric cancer
B B, O B, AB B, AB (O after
plasma removal and
in group A was significantly higher than that in non-A
resuspension in groups (OR 1.34, 95% CI: 1.25–1.44). Conversely, individu-
additive solutions)a als with blood group O showed a reduced risk of gastric
AB AB, A, B, O AB AB (A, B, O after cancer compared with non-O groups (OR 0.80, 95% CI:
plasma removal and 0.72–0.88). These findings were replicated in a meta-
resuspension in
analysis made by the same authors combining their data
additive solutions)a
with those from the PubMed database [41]. Interestingly,
a
This could conversely be negative for high titer anti-A/A,B. the authors also found that subjects with blood type A are

Brought to you by | University of Newcastle, Australia

Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
1550 Franchini and Liumbruno: ABO blood group
more prone to H. pylori infection than other ABO blood
type individuals.
In the multinational Pancreatic Cancer Cohort Con-
sortium (PanScan) I genome-wide association study, 1896
individuals with pancreatic cancer and 1939 controls were
genotyped, and a significant association was reported for
rs505922, a single-nucleotide polymorphism (SNP) which
maps to the first intron of the ABO gene [42]. This associa-
tion was also replicated in an independent sample of 2457
affected individuals and 2654 controls from the PanScan II
study [42]. A combined analysis of these groups yielded a
multiplicative per-allele OR of 1.20 (95% CI: 1.12–1.28), thus
supporting earlier epidemiologic evidences that people
with blood group O may have a lower risk of pancreatic
cancer than those with groups A, B or AB. Using SNP geno-
type data to determine serotype status, Wolpin and col-
leagues reported that, compared to individuals with blood
group O, participants with blood groups A, AB or B were
more likely to develop pancreatic cancer [adjusted hazard
ratios for incident pancreatic cancer were 1.32 (95% CI: 1.02–
1.72), 1.51 (95% CI: 1.02–2.23), and 1.72 (95% CI: 1.25–2.38),
respectively] [43]. The age-adjusted incidence rates for pan-
creatic cancer per 100,000 person-years were 27 for partici-
pants with blood type O, 36 for those with blood type A, 41
for those with blood type AB, and 46 for those with blood
type B, respectively [43]. The relevance of the interaction of
the ABO blood group and H. pylori infection for the develop-
ment of pancreatic cancer was recently analyzed by Risch
et al. in a case-control study involving 373 case patients and
690 gender- and age-matched control subjects [44]. Inter-
estingly, they reported that the increased risk of pancreatic
cancer among the individuals with non-O blood group was
even higher if they were also seropositive for CagA-negative
H. pylori (OR 2.78, 95% CI: 1.49–5.20).
Finally, data from large prospective cohort studies
indicate that the ABO blood group is associated with the
risk of developing skin, ovarian and lung cancers [45–47],
while no association was found with colorectal and breast
cancers [48, 49].
The ABO blood group and cardiovascular
disorders
It has been known for approximately 50 years that the ABO
blood group has a profound influence on hemostasis, as
it has been a major determinant of von Willebrand factor
(VWF) and, consequently, of factor VIII (FVIII) plasma
levels [50–52]. In particular, VWF levels are approxi-
mately 25% higher in individuals who are a blood group
other than O [53]. The presence of ABH structures in VWF
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
N-linked oligosaccharides provides the molecular basis
for the ABO regulation of VWF levels [54]. The active ABO
A and B glycosyltransferase enzymes, found in the Golgi
of endothelial cells, generate terminal carbohydrate mod-
ifications, that is, A and B antigens, on the existing VWF
“H” oligosaccharides, whereas the enzymatically inactive
ABO O protein cannot modify these VWF H antigens [55].
The addition of A or B terminal carbohydrate antigens
to VWF in endothelial cells might influence circulating
VWF levels and function by several mechanisms, includ-
ing the alteration of the rate of VWF synthesis and/or
secretion, the regulation of VWF proteolysis by a disinte-
grin and metalloproteinase with a thrombospondin type
1 motif, member 13 (ADAMTS13), the modulation of VWF
clearance, the modification of VWF biological activity or
perhaps a combination of such events [56].
Based on these experimental findings, in the last three
decades several clinical studies have assessed whether
the ABO blood group could influence the risk of develop-
ing arterial or venous thrombotic events [4]. In 2008, Wu
et al. performed a systematic review and meta-analysis of
studies reporting the association of non-O blood groups
with a variety of vascular disorders [57]. Among these
pathologies, significant risk could be calculated for periph-
eral vascular disease (OR 1.45; 95% CI, 1.35–1.56), myocar-
dial infarction (OR 1.25; 95% CI: 1.14–1.36), ischemic stroke
(OR 1.14; 95% CI: 1.01–1.27) and venous thromboembolism
(VTE) (OR 1.79; 95% CI: 1.56–2.05). These latter findings
were replicated in a more recent meta-analysis performed
by our group on a larger number of studies and VTE cases
(38 studies with 10,305 VTE cases) [58]. Indeed, we found
a prevalence of non-O blood group significantly higher
in VTE patients compared with controls with a result-
ing pooled OR of 2.08 (95% CI: 1.83, 2.37; p < 0.00001).
Finally, another recent publication including two pro-
spective cohort studies and a meta-analysis confirmed the
positive association between non-O blood group and the
risk of coronary heart disease (RR 1.11; 95% CI: 1.05–1.18;
p < 0.001) [59]. The same results emerged in a retrospective
case-control study conducted by our group [60].
Conclusions
As well as its essential role in immunohematology and
transfusion medicine, a consistent amount of clinical
data have documented that the ABO blood group plays a
key role in the risk of developing thrombosis, especially
VTE. Further studies are needed to better clarify the
pathogenic mechanisms of the interaction between the
ABO blood group and hemostasis and their clinical and

therapeutic implications. Additional studies will also
help us to clarify the link between the ABO blood group
and the risk of cancer.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated
that there are no conflicts of interest regarding the publica-
tion of this article.
References
1. Storry JR, Olsson ML. The ABO blood group system revisited: a
review and update. Immunohematology 2009;25:48–59.
2. Eastlund T. The histo-blood group ABO system and tissue
transplantation. Transfusion 1998;38:975–88.
3. Franchini M, Capra F, Targher G, Montagnana M, Lippi G.
Relationship between ABO blood group and von Willebrand
factor levels: from biology to clinical implications. Thromb J
2007;5:14.
4. Franchini M, Favaloro EJ, Targher G, Lippi G. ABO blood group,
hypercoagulability, and cardiovascular and cancer risk. Crit Rev
Clin Lab Sci 2012;49:137–49.
5. Landsteiner K. Zur kenntnis der antifermentativen, lytischen
und agglutinierenden wirkungendes des blutserums und der
lymphe. Zentralbl Bakteriol 1900;27:357–63.
6. Decastello A, Sturli A. Über die isoagglutinine im serum
gesunder und kranker menschen. Munch Med Wochenschr
1902;49:1900–5.
7. Springer GF. Blood-group and Forssman antigenic determinants
shared between microbes and mammalian cells. Prog Allergy
1971;15:9–77.
8. Daniel-Johnson J, Leitman S, Klein H, Alter H, Lee-Stroka A,
Scheinberg P, et al. Probiotic-associated high-titer anti-B
in a group A platelet donor as a cause of severe hemolytic
transfusion reactions. Transfusion 2009;49:1845–9.
9. Cooling L. ABO, H, and Lewis blood groups and structurally
related antigens. In: Roback JD, Grossman BJ, Harris T, Hillyer
CD, editors. Technical manual, 17th ed. Bethesda: AABB,
2011:363–87.
10. Napier JAF, editor. Handbook of blood transfusion therapy, 2nd
ed. Chichester: John Wiley & Sons Ltd, 1995:15.
11. Mollison PL, Engelfriet CP, Contreras MK, editors. Blood
transfusion in clinical medicine, 9th ed. Oxford: Blackwell
Scientific Publications, 1993:150.
12. Bloodbook.com. Racial and ethnic distribution of ABO blood
types. Available from: http://www.bloodbook.com/world-abo.
html. Accessed on 3 April, 2013.
13. Lin-Chu M, Broadberry RE, Chang FJ. The distribution of blood
group antigens and alloantibodies among Chinese in Taiwan.
Transfusion 1988;28:350–2.
14. Lalueza-Fox C, Gigli E, de la Rasilla M, Fortea J, Rosas A,
Bertranpetit J, et al. Genetic characterization of the ABO blood
group in Neandertals. BMC Evol Biol 2008;8:342.
15. Crainic K, Durigon M, Oriol R. ABO tissue antigens of Egyptian
mummies. Forensic Sci Int 1989;43:113–24.
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
Franchini and Liumbruno: ABO blood group 1551
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Received March 5, 2013; accepted April 8, 2013; previously pub-
lished online May 7, 2013
16. Fry AE, Griffiths MJ, Auburn S, Diakite M, Forton JT, Green A,
et al. Common variation in the ABO glycosyltransferase is
associated with susceptibility to severe Plasmodium falciparum
malaria. Hum Mol Genet 2007;17:567–76.
17. Borén T, Falk P, Roth KA, Larson G, Normark S. Attachment of
Helicobacter pylori to human gastric epithelium mediated by
blood group antigens. Science 1993;262:1892–5.
18. Swerdlow DL, Mintz ED, Rodriguez M, Tejada E, Ocampo C,
Espejo L, et al. Severe life-threatening cholera associated with
blood group O in Peru: implications for the Latin American
epidemic. J Infect Dis 1994;170:468–72.
19. Yamamoto F. Review: ABO blood group system – ABH
oligosaccharide antigens, anti-A and anti-B, A and B
glycosyltransferases, and ABO genes. Immunohematology
2004;20:3–22.
20. Schiff F, Sasaki H. Der Ausscheidungstypus ein auf Serolo-
gischem Wege Nachweirbares Mendelndes merkaml. Klin
Wochenschr 1932;11:1426–9.
21. Kelly RJ, Ernst LK, Larsen RD, Bryant JG, Robinson JS, Lowe
JB. Molecular basis for H blood group deficiency in Bombay
(Oh) and para-Bombay individuals. Proc Natl Acad Sci USA
1994;91:5843–7.
22. Bhende YM, Deshpande CK, Bhatia HM, Sanger R, Race RR,
Morgan WT, et al. A “new” blood group character related to the
ABO system. Lancet 1952;1:903–4.
23. Yamamoto F, Clausen H, White T, Marken J, Hakomori S.
Molecular genetic basis of the histo-blood group ABO system.
Nature 1990;345:229–33.
24. Kermarrec N, Roubinet F, Apoil PA, Blancher A. Comparison of
allele O sequences of the human and non-human primate ABO
system. Immunogenetics 1999;49:517–26.
25. Beattie KM. Discrepancies in ABO grouping. In:
American Association of Blood Banks, editor. A seminar on
problems encountered in pretranfusion tests. Washington,
DC: American Association of Blood Banks, 1972:
129–65.
26. Hosoi E. Biological and clinical aspects of ABO blood group
system. J Med Invest 2008;55:174–82.
27. International Society of Blood Transfusion (ISBT). Blood
Group Terminology. Table of blood group systems. Available
from: http://www.isbtweb.org/fileadmin/user_upload/
WP_on_Red_Cell_Immunogenetics_and/Table_of_blood_
group_systems_v3.0_121028.pdf. Accessed on 2 March,
2013.
1552 Franchini and Liumbruno: ABO blood group
28. Società Italiana di Medicina Trasfusionale e Immunoematologia
(SIMTI), editor. Standards of Transfusion Medicine, 2nd ed.
Milan: SIMTI Servizi srl, 2010:156. Available from: http://www.
simti.it/pdf/Standard_EN_protetto.pdf. Accessed 2 Mar, 2013.
29. Gerbal A, Maslet C, Salmon C. Immunologic aspects of the
acquired-B antigen. Vox Sang 1975;28:398–403.
30. Josephson CD, Mullis NC, Van Demark C, Hillyer CD. Significant
numbers of apheresis-derived group O platelet units have
“high-titer” anti-A/A,B: implications for transfusion policy.
Transfusion 2004;44:805–8.
31. Sapatnekar S, Sharma G, Downes KA, Wiersma S, McGrath C,
Yomtovían R. Acute hemolytic transfusion reaction in a pediatric
patient following transfusion of apheresis platelets. J Clin Apher
2005;20:225–9.
32. Bolton-Maggs PH, editor, Cohen H, on behalf of the Serious
Hazards of Transfusion (SHOT) Steering Group. The 2011 Annual
SHOT Report (2012). Available from: http://www.shotuk.
org/wp-content/uploads/2012/07/SHOT-ANNUAL-REPORT_
FinalWebVersionBookmarked_2012_06_22.pdf. Accessed on 4
April, 2013.
33. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G,
Italian Society of Transfusion Medicine and Immuno-
haematology (SIMTI) Work Group. Recommendations for
the transfusion of plasma and platelets. Blood Transfus
2009;7:132–50.
34. Cooling L. ABO and platelet transfusion therapy.
Immunohematology 2007;23:20–33.
35. Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G.
Recommendations for the transfusion of red blood cells. Blood
Transfus 2009;7:49–64.
36. Tormey CA. Transfusion support for hematopoietic stem cell
transplant recipients. In: Roback JD, Grossman BJ, Harris T,
Hillyer CD, editors. Technical manual, 17th ed. Betheshda:
AABB, 2011:687–705.
37. Yazer MH, Triulzi DJ. Immune hemolysis following
ABO-mismatched stem cell or solid organ transplantation. Curr
Opin Hematol 2007;14:664–70.
38. Sassi M, Maggiore U, Buzio C, Franchini M. Immunohaemato-
logical and apheretic aspects of the first kidney transplant from
a living, ABO-incompatible donor carried out in Italy. Blood
Transfus 2011;9:218–24.
39. Clarke CA. Blood group and disease. In: Steiberg AG, editor.
Progress in medical genetics, Vol. 1. New York: Grune and
Stratton, 1961:81–119.
40. Edgren G, Hjalgrim H, Rostgaard K, Norda R, Wikman A,
Melbye M, et al. Risk of gastric cancer and peptic ulcers in
relation to ABO blood type: a cohort study. Am J Epidemiol
2010;172:1280–5.
41. Wang Z, Liu L, Ji J, Zhang J, Yan M, Zhang J, et al. ABO blood
group system and gastric cancer: a case-control study and
meta-analysis. Int J Mol Sci 2012;13:13308–31.
42. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS,
Petersen GM, Arslan AA, et al. Genome-wide association study
identifies variants in the ABO locus associated with suscep-
tibility to pancreatic cancer. Nat Genet 2009;41:986–90.
Brought to you by | University of Newcastle, Australia
Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM
43. Wolpin BM, Chan AT, Hartge P, Chanock SJ, Kraft P, Hunter DJ,
et al. ABO blood group and the risk of pancreatic cancer. J Natl
Cancer Inst 2009;101:424–31.
44. Risch HA, Yu H, Lu L, Kidd MS. ABO blood group, Helicobacter
pylori seropositivity, and risk of pancreatic cancer: a
case-control study. J Natl Cancer Inst 2010;102:502–5.
45. Xie J, Qureshi AA, Li Y, Han J. ABO blood group and incidence of
skin cancer. PloS One 2010;5:e11972.
46. Gates MA, Wolpin BM, Cramer DW, Hankinson SE, Tworoger SS.
ABO blood group and incidence of epithelial ovarian cancer. Int J
Cancer 2011;128:482–6.
47. Lee JS, Ro JY, Sahin AA, Hong WK, Brown BW, Mountain CF,
et al. Expression of blood-group antigen A – a favorable
prognostic factor in non-small-cell lung cancer. N Engl J Med
1991;324:1084–90.
48. Khalili H, Wolpin BM, Huang ES, Giovannucci EL, Kraft P,
Fuchs CS, et al. ABO blood group and risk of colorectal cancer.
Cancer Epidemiol Biomarkers Prev 2011;20:1017–29.
49. Gates MA, Xu M, Chen WY, Kraft P, Hankinson SE, Wolpin BM.
ABO blood group and breast cancer incidence and survival.
Int J Cancer 2012;130:2129–37.
50. Preston AE, Barr A. The plasma concentration of factor VIII in the
normal population. Br J Haematol 1964;10:238–45.
51. Moeller A, Weippert-Kretschmer M, Prinz H, Kretschmer V.
Influence of ABO blood groups on primary hemostasis.
Transfusion 2001;41:56–60.
52. O’Donnell JS, Lasffan MA. The relationship between ABO
histo-blood group, factor VIII and von Willebrand factor.
Transfus Med 2001;11:343–51.
53. Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR.
The effect of ABO blood group on the diagnosis of von
Willebrand disease. Blood 1987;69:1691–5.
54. Matsui T, Titani K, Mizuochi T. Structures of the asparagine-
linked oligosaccharide chains of human von Willebrand factor.
Occurrence of blood group A, B, and H(O) structures. J Biol Chem
1992;267:8723–31.
55. Sodetz JM, Pizzo SV, McKee PA. Relationship of sialic acid to
function and in vivo survival of human factor VIII/von Willebrand
factor protein. J Biol Chem 1977;252:5538–46.
56. Jenkins PV, O’Donnell JS. ABO blood group determines plasma
von Willebrand factor levels: a biologic function after all?
Transfusion 2006;46:1836–44.
57. Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups
and vascular disease: a systematic review and meta-analysis.
J Thromb Haemost 2008;6:62–9.
58. Dentali F, Sironi AP, Ageno W, Turato S, Bonfanti C, Frattini F,
et al. Non-O blood type is the commonest genetic risk factor
for VTE: results from a meta-analysis of the literature. Semin
Thromb Hemost 2012;38:535–48.
59. He M, Wolpin B, Rexrode K, Manson JE, Rimm E, Hu FB, et al. ABO
blood group and risk of coronary heart disease in two prospective
cohort studies. Arterioscler Thromb Vasc Biol 2012;32:2314–20.
60. Franchini M, Rossi C, Mengoli C, Frattini F, Crestani S, Giacomini I,
et al. ABO blood group and the risk of coronary artery disease. J
Thromb Thrombolysis 2012; DOI: 10.1007/s11239-012-0836-1.
 Franchini and Liumbruno: ABO blood group 1553

Dr. Massimo Franchini was born in Verona (Italy) in 1966. After
graduating in Medicine from the University of Verona (Italy) in
1991, he specialized in Hematology at the same university in 1995.
He worked at the Immunohematology and Transfusion Medicine
of the University Hospital of Verona until 2008 when he became
Head of Transfusion Center of the University Hospital of Parma
(Italy). Currently, he is Head of the Department of Hematology and
Transfusion Medicine of the city Hospital of Mantova (Italy) and is
associate editor of Blood Transfusion and Seminars in Thrombosis
and Hemostasis.
Dr. Giancarlo Maria Liumbruno was born in Mogadishu (Somalia) in
1961. After graduating in Medicine from the University of Pisa (Italy)
in 1985, he specialized in Clinical Pathology (Immunohematology
branch) at the same University in 1993. In 1995, he attained the
diploma “Certificat d’Université d’Enseignement Européen de
Transfusion Sanguine” at the Louis Pasteur University, Strasbourg
(France) and in 2000 a Masters in “Healthcare management:
principles, tools, methods” at the University of Florence (Italy).
Currently, he is Head of the Immunohematology and Transfusion
Medicine and Clinical Pathology Units at the “San Giovanni Calibita”
Fatebenefratelli Hospital, Rome (Italy) and is associate editor of
Blood Transfusion and member of the editorial board of the Journal
of Blood Transfusion.

Brought to you by | University of Newcastle, Australia

Authenticated | 134.99.128.41
Download Date | 9/24/13 2:43 PM