Vox Sanguinis (2019) 114, 535–552

© 2019 International Society of Blood Transfusion

REVIEW ARTICLE DOI: 10.1111/vox.12786

Biologic roles of the ABH and Lewis histo-blood group

antigens part II: thrombosis, cardiovascular disease and
metabolism
Sean R. Stowell1,2 & Christopher P. Stowell3,4
1
Center for Apheresis, Center for Transfusion and Cellular Therapies, Emory Hospital, Emory University School of Medicine, Atlanta, GA, USA
2
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
3
Blood Transfusion Service, Massachusetts General Hospital, Boston, MA, USA
4
Department of Pathology, Harvard Medical School, Boston, MA, USA

Received: 30 April 2018,
revised 8 April 2019,
accepted 10 April 2019,
published online 14 May 2019
The ABH and Lewis antigens were among the first of the human red blood cell
polymorphisms to be identified and, in the case of the former, play a dominant
role in transfusion and transplantation. But these two therapies are largely twen-
tieth-century innovations, and the ABH and related carbohydrate antigens are
not only expressed on a very wide range of human tissues, but were present in
primates long before modern humans evolved. Although we have learned a great
deal about the biochemistry and genetics of these structures, the biological roles
that they play in human health and disease are incompletely understood. This
review and its companion, which appeared in a previous issue of Vox Sanguinis,
will focus on a few of the biologic and pathologic processes which appear to be
affected by histo-blood group phenotype. The first of the two reviews explored
the interactions of two bacteria with the ABH and Lewis glycoconjugates of their
human host cells, and described the possible connections between the immune
response of the human host to infection and the development of the AB-isoag-
glutinins. This second review will describe the relationship between ABO pheno-
type and thromboembolic disease, cardiovascular disease states, and general
metabolism.
Key words: blood groups, epidemiology, transfusion medicine.

blood group antigens has been studied for many years.

Introduction
Following the discovery of ABO blood groups over
100 years ago, a variety of studies sought to determine
whether different disease states are influenced by ABO
inheritance. The goal of this review and the companion
review published in an earlier issue of Vox Sanguinis is
to focus on a few of the biologic and pathologic pro-
cesses which appear to be affected by histo-blood group
phenotype. The first review described the influence of
ABH and Le (Lewis) antigens on the outcome of expo-
sure to Helicobacter pylori and Vibrio cholera, two infec-
tious micro-organisms whose association with ABO
Correspondence: Christopher P. Stowell, Blood Transfusion Service,
Massachusetts General Hospital, Boston, MA, USA
E-mail: christopherpstowell@gmail.com
In addition, the first review examined current concepts
regarding genetic and environmental factors that may
contribute to the development of naturally occurring
AB-isoagglutinins, the most common immunological
barriers to transfusion and transplantation. In this
review, we will consider the influence of ABO phenotype
on thromboembolic disease, cardiovascular disease states
and general metabolism. By contrast, the impact of the
Le phenotype has been much less well studied in these
areas. In examining potential associations between ABO
blood group expression and each of these general areas,
we will first explore the history of epidemiological asso-
ciation studies. This will be followed by a description of
more recent laboratory data that provides some mecha-
nistic insight into these associations. Finally, we will
conclude by sharing some of the challenges associated

535
536 S. R. Stowell & C. P. Stowell

with studying ABO disease associations and potential significant and favoured group O; for MI, the IRR was
research directions that may address these limitations in 1
10 (95% CI 1
05–1
14), and for cerebrovascular stroke,
the future. the IRR was 1
07 (95% CI 1
01–1
12).
In recent years, the association between non-group O
phenotype and thromboembolic disease seen in the epi-
A tripod – ABO histo-blood groups, von
demiologic studies has been reinforced by a number of
Willebrand’s factor and thromboembolic
genome-wide association studies (GWAS). A metanalysis
disease
of 12 GWAS which included 7507 subjects with VTE and
A number of epidemiologic studies carried out over the 52 632 control subjects identified nine loci associated
past 20 years have made the observation of an apparent with VTE which reached genome-wide significance, six of
association between ABO blood group and the prevalence which, including the ABO gene locus on chromosome 9,
of many thromboembolic diseases [1–4], including venous had been identified in the studies included in the analysis
thromboembolic events (VTE) [5–10], cerebrovascular and three of which were new [7]. The following year, a
ischaemic events [11–13], including recurrent stroke [14], GWAS were performed on a group of 6135 subjects with
coronary artery disease [15–17], myocardial infarction self-reported VTE and 252 827 controls, all of European
(MI) [6, 18] and atherosclerotic vascular disease [15]. In extraction, who were members of the 23 and Me cohort
general, these studies have found that individuals with of research participants [28]. In addition to confirming
non-group O phenotypes are at increased risk for throm- the association between VTE and seven previously identi-
boembolic diseases compared to those who are group O. fied loci, including the ABO gene, a new locus was found,
However, this result has not been observed in all studies, rs114209171 which is located upstream from the factor 8
including in certain specific clinical situations such as structural gene.
postsurgery [19–21], post-trauma [22], cancer [5, 23] and Several GWAS have also identified ABO blood group
diabetes mellitus [24] In addition, the magnitude of the to be a risk factor for all ischaemic stroke and large ves-
effect of ABO group on these clinical events has also var- sel stroke [13, 29–32]. A metanalysis of several of these
ied between studies. GWAS was performed on a cohort of 12 239 subjects
Two metanalyses of the epidemiologic studies have with ischaemic stroke and 62 004 control subjects who
been performed to address the possible association were contributed from 15 studies [29]. The analysis con-
between ABO blood group and thromboembolic disease. firmed the association of ABO and ischaemic stroke, and
One of these metanalyses incorporated data from 59 stud- the GWAS on this pooled data set identified two loci
ies and a total of 21 010 thrombotic events [25]. It found associated with cardioembolic stroke and two different
that the odds ratios were greater in the non-O subjects loci, including one at the 9p21 ABO gene site, with large
(compared to group O subjects) for MI (OR 1
25, 95% CI vessel stroke. Several more recent GWAS also have con-
1
14–1
36), peripheral vascular disease (1
45, 95% firmed the association between ABO genotype and all
CI 1
35–1
56), cerebral ischaemic events (OR 1
14, 95% CI ischaemic stroke [32, 33] as well as large vessel stroke
1
01–1
27) and VTE (OR 1
79, 95% CI 1
56–2
05), but not
for angina (OR 1
03, 95% CI 0
89–1
19). In a second met-
analysis of 38 studies which included 10 305 patients Table 1 Risk of venous and arterial thromboembolic events in non-group
with VTE, the risk was also found to be greater for non-O O healthy blood donors (n = 665 952)
individuals (OR 1
83, 95% CI 1
83–2
38; P < 0
00001)
Event Number IRR (95% CI)
[26]. The largest, single epidemiologic study published to
date included approximately 1
1 million blood donors in Venous
Sweden and Denmark whose data sets were linked to the All 6710 1
80 (1
71, 1
88)
comprehensive national health data registers in those Pulmonary embolism 3302 1
75 (1
64, 1
86)
countries [27] (See Table 1). The median donor follow-up Deep vein thrombosis 3514 1
92 (1
80, 2
05)
time was 12
6 years, and a total of 9170 VTEs and Other VTEs 364 1
53 (1
27, 1
85)
24 653 cardiovascular events were observed. The inci- Pregnancy-related VTEs 325 2
22 (1
76, 2
78)
dence rate ratio (IRR) for combined venous events was Arterial
Myocardial infarction 6476 1
10 (1
05, 1
14)
higher for the non-group O cohort than for the group O
Cerebrovascular stroke 4401 1
07 (1
02, 1
12)
cohort (1
80; 95% CI 1
17–1
88). The results were similar
Peripheral vascular disease 3784 1
06 (1
01, 1
12)
for deep vein thrombosis and pulmonary embolus, but
Other arterial thrombosis 672 1
55 (1
35, 1
78)
slightly higher for pregnancy-related thromboembolic
events (IRR 2
22; 95% CI 1
76–2
78). The IRRs for arterial Data from table 2 in ref. 27. The referent populations are group O blood
events were generally lower, but still statistically donors (n = 466 120).

© 2019 International Society of Blood Transfusion

Vox Sanguinis (2019) 114, 535–552
 ABH, thrombosis, CV disease and metabolism 537

<0
0001

<0
0001
[33]. One of these, the EuroCLOT study, identified a num-
ber of single nucleotide polymorphisms (SNP) associated

P
with ischaemic stroke using data from a study of healthy
twins and two large cohorts of patients with ischaemic
stroke and controls [31]. An association between four of

138
0 (133
9, 142
2)

167
0 (159
1, 175
3)

these SNPs, including one in the ABO gene, was sought
through a GWAS of an independent cohort consisting of
8884 patients with ischaemic stroke and 55 254 controls
which confirmed the association with large vessel stroke

AB
but not small vessel stroke. A second study was con-
ducted using a data set pooled from three consortia,
which included 12 389 subjects with stroke and 62 004

138
3 (135
9, 140
8)

164
1 (160
5, 167
8)

controls. It too found a significant association between

B (B,B + B,O)
the ABO locus and both ischaemic stroke and large vessel
stroke [33]. Subsequently, a metanalysis and GWAS on
data from 12 GWAS which included 10 307 subjects with
cerebral ischaemic events and 19 326 controls also found
that the ABO gene was associated with all ischaemic

Table 2 Levels of vWF antigen and FVIII activity by ABO phenotype among 11 673 subjects in the atherosclerosis risk in communities study
stroke, large vessel disease and cardioembolic stroke, but

129
8 (125
1, 137
7)

100
1 (98
1, 102
2)
A2 (A2,A2 + A2,O)
not small vessel disease [32]. It also confirmed the associ-
ation of ABO and vWF levels. The association with ABO
has also been demonstrated for recurrent ischaemic stroke
by a GWAS analysis of 1931 subjects with previous
stroke who were followed prospectively [14].
One of the several possible explanations for the patho-
physiologic link between ABO phenotype (or genotype)
127
6 (122
7, 132
6)

154
7 (139
6, 171
5)

and risk of thromboembolic disease is based on the long-
recognized correlation between ABO blood group and
level of von Willebrand’s factor (vWF) in the plasma [34–
36]. Non-group O individuals have vWF (and factor VIII)
A1A2

levels which are approximately 30% higher than O indi-

viduals, which might predispose them to pathologic clot Values were adjusted for age, gender, race, smoking, BMI, diabetes and hypertension.
formation. In a prospective epidemiologic study of risk
132
1 (130
5, 133
8)

156
2 (152
4, 160
1)

factors for atherosclerosis, ABO genotypes and plasma

A1 (A1,A1 + A1,O)

levels of vWF antigen and FVIII activity were determined

for a group of 11 673 subjects [37]. As shown in Table 2,
levels of vWF and FVIII were highest in the group AB
Values were adjusted for the above as well as % vWF antigen.

and B (BB and OB) subjects, intermediate in the A1, A1A2

and A2 phenotypes, and lowest in group O subjects. vWF
levels also showed a gene dosage effect; homozygotes for
125
1 (123
3, 126
9)

the A gene had higher levels than A,O heterozygotes

95
2 (94
2, 96
2)

(144 – 52% vs. 123 – 45%, P = 0
0001) which was also

the case comparing B homozygotes to B,O heterozygotes
(160 – 53% vs. 135 – 46%, P = 0
0042). ABO was found
Data from tables 2 and 3 in ref. 37.

to account for 15
4% of the variability in plasma vWF

O

antigen level and 10
7% of the variability in FVIII activ-

ity [38, 39]. After adjustment for vWF, however, ABO
Mean % vWF antigena

Mean % FVIII activityb

only accounted for 0
6% of the variability in FVIII activ-

ity [40].
The third leg of this tripod is the demonstration that
vWF levels are elevated in patients with thromboembolic
(95% CI)

(95% CI)
Analyte

disease [14, 41]. One study of 355 patients with venous

thromboembolic disease found that the A1 and B genes
b
a

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Vox Sanguinis (2019) 114, 535–552
538 S. R. Stowell & C. P. Stowell
were over-represented and the O1,O2 and A2 genes were
under-represented compared to their frequencies in 236
control subjects [42]. In addition, factor VIII activity and
vWF antigen were also higher in the patient cohort than
in the controls. vWF antigen and ADAMTS13 activity
were measured in a group of 94 patients with cerebral
infarcts and 103 controls [43]. The patients had higher
levels of vWF and lower levels of ADAMTS13 than the
controls. In a study mentioned previously, elevated vWF
levels were found to be associated with increased risk for
recurrent stroke as well [14].
The three-way association between ABO blood group,
vWF levels and thromboembolic disease intermeshes to
provide a plausible model to explain the increased risk of
thromboembolic disease in individuals with non-O pheno-
types, but it also begs the question of how ABO influ-
ences vWF levels. One suggestion is that ABO glycans on
vWF affect its secretion into the plasma, its clearance or
both. vWF is synthesized as a pre-pro-polypeptide
(ppvWF) of 2813 amino acids by endothelial cells and
megakaryocytes [44]. Both ppvWF and vWF are secreted,
although the latter has a longer plasma half-life. The
ratios of vWF propeptide (ppvWF) and vWF antigen sug-
gest that clearance rates are slower in the presence of A,
B or both antigens on vWF [45, 46]. In addition, there is
a correlation between increased age, and increased
plasma levels of vWF antigen, decreased ppvWF to vWF
antigen ratio, longer plasma half-life of vWF, and
increased expression of A antigen on vWF [47]. A second
study measured levels of vWF antigen and ppvWF and
performed GWAS on a group of 3238 healthy individuals
and found that SNPs in the ABO and vWF loci as well as
on 2q12 had very strong associations for vWF level, but
not for ppvWF level, suggesting that different rates of
clearance drive vWF levels and account for the correla-
tion with ABO blood group [48]. An indirect line of evi-
dence favouring this explanation comes from the
observation that the vWF levels in infants and children
do not show the same ABO dependence that is seen in
adults [49]. Because the ‘branching’ transferase (b 1,6
N-acetylglucosaminyltransferase) is not expressed in the
first few months of life and is not fully induced until
the second year [50], very few multi-antennary glycans
are made and can serve as substrates for further modifi-
cation to form A, B and H structures. As a result, the den-
sity of these antigens on cell surfaces and serum
glycoproteins is lower in infants and small children than
in the adult, making them less susceptible to glycan-dri-
ven clearance by lectin receptors such as the Ashwell–
Morell receptor [51]. Of note, one of the loci which has
been identified by a GWAS to be associated with vWF
level is the gene for CLEC4M, a protein which binds and
internalizes vWF [34, 52]. Variants in the variable
nontandem repeat region of the CLECC4M gene were
found to occur in higher frequency among patients with
vWD Type I and may contribute to the disease phenotype
[53]. vWF has been showed to bind to other galectins as
well [54].
Another possible explanation for the association
between ABO group and thromboembolic disease is that
glycosylation might affect the behaviour of vWF directly.
vWF is heavily glycosylated and is one of the few plasma
glycoproteins which carries ABH antigens [55]. The protein
has multiple domains, some of which affect some of its
intrinsic properties, such as dimerization, multimerization
and sensitivity to proteases [56], while others are involved
in its interactions with other macromolecules, such as fac-
tor VIII [57], collagen [58], platelet GpIba and GpIIbIIIa
[59, 60], P-selectin [61], and heparin [62] (See Fig. 1).
vWF has 12 potential N-glycosylation sites, all of which
are glycosylated, and is also substituted with 10 O-glycans
[63–65]. Most of the more than 300 different N-glycan
structures that can be found on vWF are biantennary, and
16% of those antennae express ABH epitopes [64].
Approximately 70% of the O-glycans are disialylated core
1 structures, some of which contain a disialosyl group
consisting of two NeuNAc residues connected in series by
an a 2–8 linkage [63]. The cluster of 4 O-glycans between
the A1 and A2 domains also include core 2 structures, and
some of them carry ABH epitopes as well [65].
Many of the glycosylation sites on vWF are located
proximal to its functional domains, including clusters of
4 O-glycans flanking the A1 domain. The presence of the
clusters of highly charged, sialylated O-glycans around
the A1 domain may affect the ability of vWF to bind to
GpIb on the surface of platelets [66]. Similarly, their pres-
ence proximal to the ADAMTS13 cleavage site affects its
susceptibility to proteolysis [67, 68]. In addition, half of
the antennae of the N-glycans are ‘capped’ with terminal
a 2,6 NeuNAc residues which are known to protect vWF
from proteolysis by serine and cysteine proteases [69],
but which increase its susceptibility to cleavage by
ADAMTS13 [70]. The rate of proteolysis of vWF by
ADAMTS13 is also affected by ABO group with higher
rates being observed in group O individuals compared to
non-O individuals [71]. Desialylation of vWF protects it
from cleavage by ADAMTS13 and also abrogates the
influence of ABO on vWF levels [70, 72]. The glycans of
vWF have also been shown to affect secretion and dimer-
ization [73], multimerization [74, 75], plasma half-life
[76] and adherence to platelets [77, 78].
Although the associations between thromboembolic
disease, vWF levels and ABO blood group have been con-
vincingly demonstrated, they are not very large, which
may explain in part why the mechanism whereby the
presence of a galactose or N-acetylgalactosamine residue
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Vox Sanguinis (2019) 114, 535–552

N 1147
N 857 N 1231 N 1515 N 1574
D’ D3 A1 A2
T 857 T 1255 T 1468 T 1477
T 1256 S 1263 S 1486 T 1487
Factor VIII Platelet GpIb ADA MTS13
P-selecn Collagen type VI
Mulmerizaon Heparin
N glycan amino O glycan amino
acid posion acid posion
Fig. 1 The functional domains and glycosylation sites of human von Willebrand’s factor (Information from refs 55–68).
on glycans expressing the H epitope alters the biology of
this glycoprotein remains unclear. vWF is a key player in
hemostasis which stands at the intersection of all three
elements of the coagulation system: platelets, plasma
clotting proteins and endothelial cells. Further insights
into its glycobiology and the role of its ABH-glycans may
help us unravel the diverse functions of this versatile gly-
coprotein.
ABH antigens and cardiovascular disease
In addition to the apparent association between ABO
blood group, vWF levels and thromboembolic disease
[79], there is evidence that ABO blood group status may
affect vascular biology independently of, or in conjunc-
tion with, alterations in hemostasis. Some of the earliest
studies examining potential associations between ABO
blood group expression and vascular disease simply eval-
uated the prevalence of ABO blood groups among outpa-
tients receiving anticoagulant therapy for antecedent
ischaemic cardiovascular events and compared these indi-
viduals to various control groups that typically consisted
of healthy blood donors [80–83]. Although the results of
such studies may be confounded by survival bias, a
higher ratio of A:O was observed for males (P < 0
001)
with preceding cardiovascular events. However, a similar
relationship was not identified for patients with aortic
valve disease, diabetes mellitus, polycythaemia or
hypothyroidism when compared to healthy blood donors
in the same geographic area. In contrast, a similar
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552
ABH, thrombosis, CV disease and metabolism 539
N 2223 N 2290 N 2357 N 2400 N 2546 N 2585 N 2790
A3 D4 B B C1 C2 CK
T 1679 T 2298
Collagen type I Platelet GpIIbIIIa Dimerization
Collagen type II
association between blood group A and prior cardiovas-
cular episodes was not observed for females (P < 0
1).
However, of the 792 patients who had a previous diagno-
sis of either myocardial infarction (632 patients) or ang-
ina pectoris (160 patients), 617 were male. These results
suggest that the apparent lack of association between
blood group A status and risk for cardiovascular events
among females may have reflected differences in study
power. When A and B subjects were combined, both men
and women had a significantly higher A+B:O ratio
(P < 0
02, and P < 0
001, respectively). The blood group
A:O and B:O ratios of all patients increased when those
with angina pectoris were excluded, suggesting a stronger
correlation with increased disease severity.
More recent studies have evaluated potential associa-
tions between ABO blood group status and vascular
disease using genome association studies. A GWAS com-
pared 12 393 individuals with coronary artery disease
(CAD) as identified by angiography with 7383 controls
and found an association between the ADAMTS7 locus
and the likelihood of having CAD (P = 4
98 9 10-13), but
no clear relationship between ABO polymorphisms and
CAD [84]. However, among patients with CAD and MI, a
significant association with the ABO locus (P = 7
62 9
10-9) was observed, with non-O patients exhibiting
greater odds of also having had a MI than blood group O
patients (OR 1
62, 95% CI 1
23–2
13). The same associa-
tion was observed when individual non-O blood group
cohorts were compared to group O, with group A (OR
1
49, 95% CI 1
11–2
00) and group B (OR 2
15, 95% CI
540 S. R. Stowell & C. P. Stowell
1
37–3
40) showing statistically significantly increased
likelihood of also having had an MI in addition to CAD,
and group AB (OR 1
65, 95% CI 0
85–3
25) showing a
trend in the same direction.
Many of the studies that examined ABO blood group
associations were retrospective in nature and therefore
may have suffered from limitations secondary to inade-
quately matched control groups. To overcome these
potential shortcomings, a prospective British study exam-
ined the relationship between ABO blood group status of
7662 men and the risk for developing ischaemic heart
disease [85]. Men ranging 40–59 years of age were ran-
domly selected from a general registry and followed for
8 years while evaluating for the development of ischae-
mic heart disease. While no difference in the prevalence
of ischaemic heart disease was observed between blood
group A or O individuals, there was a higher incidence of
ischaemic heart disease events among blood group A
individuals when compared with O (RR 1
21, 95% CI
1
01–1
46). Additionally, a reduced incidence of ischae-
mic heart disease was seen when comparing O to all other
blood groups (RR 0
82, 95% CI 0
68–0
99). Two additional
prospective cohort studies were carried out over 20 years:
the Nurses’ Health Study, which included 62 073 women,
and the Health Professionals Follow-up Study that fol-
lowed 27 428 men. Analysis of the pooled data sets from
both study populations demonstrated that when compared
to blood group O individuals, the age-adjusted hazard
ratio for CAD for blood group A was 1
06 (95% CI 0
98–
1
13), for group B was 1
11 (95% CI 1
01–1
23) and for
group AB was 1
23 (95% CI 1
10–1
37) [16]. Although
stratified analysis demonstrated that associations between
ABO blood group status and CAD were not modified by
physical activity, alcohol consumption, smoking or dia-
betes, there was a positive interaction between a
BMI > 25 kg/m2 and ABO blood type among women.
Associations not only exist between ABO blood group
status and the overall prevalence and incidence of CAD
and MI. Recent investigations have also demonstrated
that ABO blood group expression correlates with the
extent of CAD. This relationship was shown following the
analysis of angiographic results of 559 Turkish patients
from 2010 to 2012. Patients were evaluated using the
SYNTAX score to measure systematically the complexity
of coronary lesions. The results of this study demon-
strated that the frequency of non-O blood group individu-
als was increased among those patients in the upper
tertiles (more severe) SYNTAX scores (OR 2
68; 95% CI
1
65–4
35) [86]. A similar study examined a Chinese pop-
ulation using the alternative Gensini scoring system to
grade coronary atherosclerotic lesions in patients prospec-
tively enrolled prior to coronary angiography and found
that among 2919 patients examined, blood group A
individuals were more highly represented in the upper
tertiles of disease severity; blood group A was shown to
be significantly associated with mid- or high Gensini
scores as compared to the non-A blood groups (OR 1
44;
95% CI 1
16–1
80), while the blood group O phenotype
appeared to be protective (OR: 0
77; 95% CI 0
65–0
92)
[15]. Similar results were found when examining
atherosclerosis in the context of potential changes in
metabolic profiles [87].
Conflicting reports do exist, however, with respect to
ABO blood group status and its potential association with
CAD. An observational study conducted between 2009
and 2010 of 646 Croatian patients with CAD (72
4%
male) found no correlation between the number of coro-
nary arteries affected as determined by angiography, or
the number of segments narrowed >50%, with ABO blood
group [88], similar to other studies [84]. However, the
study did find that blood group AB men developed CAD
at a younger age than their non-AB counterparts [88].
Another study conducted in Bangladesh demonstrated
that among 95 patients admitted with CAD, a higher rep-
resentation of blood group O was observed when com-
pared with 95 healthy staff at the same institution(OR
2
03; 95% CI 1
13–3
67) [89]. An additional case–control
study conducted in Croatia observed that among 182
patients with acute MI and 286 healthy blood donor con-
trols, individuals with the OO genotype exhibited no dif-
ference in MI frequency when compared to all non-OO
genotype individuals (OR 1
41, 95% CI 0
94–2
11) [90].
Subgroup analysis, however, did demonstrate a slight dif-
ference in MI frequency when comparing individuals with
the A1O1 genotype vs. OO (OR 1
66, 95% CI 1
03–2
68).
The lower power and potential sampling bias of both
patients with heart disease and healthy controls may have
contributed to the differences observed in this study when
compared to other studies [15, 86, 88].
Beyond CAD, potential associations between ABO blood
group status and other forms of vascular disease have
also been examined. For example, a comparison of 1222
patients with either aortoiliac or femora-popliteal
atherosclerosis with over 250 000 healthy blood donors
found a greater number of blood group A individuals
among patients with aortoiliac or femora-popliteal
atherosclerosis than controls [91]. More detailed analysis
demonstrated that among individuals with ‘slight’ vessel
irregularities, there were also more blood group A than O
individuals. Increased A representation was similarly
observed, but to a lesser extent, among individuals with
‘moderate’ irregularities. However, a higher number of
blood group O than A individuals were noted among
patients who possessed ‘extensive’ mural irregularities but
no evidence of vessel occlusion. Similar associations
between ABO blood group status were observed following
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552

stratification of patients based on the degree of vessel
stenosis, with a higher number of blood group O patients
among those presenting with the most severe stenosis. In
contrast, a higher number of blood group A individuals
were noted among patients who presented with 1 or more
occluded vessels. No increase in blood group A individu-
als was observed among those with aneurysms [91]. More
recent studies sought to extend these findings by specifi-
cally focusing on the potential association between
abdominal aortic aneurysm (AAA) and ABO blood group
status. Evaluation of 504 patients from 1992 to 2008 who
underwent surgical AAA repair showed a very similar
ABO blood group distribution as the general Swedish
population. Further analysis likewise failed to reveal any
difference in ABO blood group status among those who
either had ruptured (n = 174) or un-ruptured (n = 330)
AAA [92].
ABO blood group status may also influence outcomes
following acute vascular injury. A prospective cohort of
critically ill patients who presented with major trauma
(732) or sepsis (976) were evaluated for possible associa-
tions between ABO blood group status and the develop-
ment of acute respiratory distress syndrome (ARDS) [93].
Results from this study demonstrated that, among trauma
patients, blood group A individuals of European descent
were more likely to develop ARDS (OR 1
88, 95% CI
1
14–3
12). A similar association with the development of
ARDS was observed among blood group A patients of
European descent who were admitted for severe sepsis
(OR 1
67, 95% CI 1
08–2
59). In contrast, ABO blood
group status failed to correlate with the development of
ARDS among patients of African descent following either
trauma or sepsis. A subsequent study conducted at the
same institution found that among 497 critically ill
trauma patients, blood group A patients of European des-
cent experienced a higher likelihood of developing acute
kidney injury (AKI) [risk difference (RD) 0
14, 95% CI
0
03–0
24], while individuals of African descent failed to
display similar associations [94]. Importantly, these asso-
ciations remained when examining only the patients with
AKI who were not transfused within 24 h of presentation
(RD 0
13, 95% CI 0
0–0
27) or who also failed to develop
ARDS (RD 0
16, 95% CI 0
03–0
29). Patients of European
descent with severe sepsis were likewise evaluated for
potential associations between ABO blood group status
and AKI. An association between blood group A and the
development of AKI (RD 0
14, 95% CI 0
04–0
23) was
also found, which was likewise maintained following
exclusion of individuals transfused within the first 24 h
of hospitalization (RD 0
13, 95% CI 0
02–0
23). However,
similar associations were not observed in patients without
concomitant ARDS (RD 0
09, 95% CI -0
03 to 0
22).
Additionally, patients of African descent did not display a
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552
ABH, thrombosis, CV disease and metabolism 541
similar association between ABO blood group status and
AKI following either trauma or severe sepsis, similar to
ARDS.
The underlying mechanisms whereby ABO blood group
antigens may influence vascular disease have been diffi-
cult to ascertain. This in part reflects challenges associ-
ated with directly examining endothelial activity and
function in vivo. As a result, insights into a possible role
for ABO glycans in vascular biology have often been
indirectly assessed by evaluating the levels of shed
endothelial adhesion molecules as surrogates for endothe-
lial activation or injury [95–102]. Taking this approach,
the Women’s Genome Health Study examined 6578 indi-
viduals for genetic factors that might correlate with alter-
ations in the levels of the soluble fragment of the
adhesion molecule ICAM (sICAM) [103]. Three SNP within
the ICAM1 locus, rs1799969, rs5498 and rs281437, were
found to be associated with sICAM levels in the plasma
(P < 5
1 9 10-8). Additional analysis of ABO gene poly-
morphisms also demonstrated a significant inverse rela-
tionship between a SNP associated with blood group A1
expression (rs507666) and levels of sICAM (P < 5
1 9
10-29). Importantly, sICAM concentrations could be strati-
fied based on ABO blood group status (A1 < A2 < O<B).
In contrast, Secretor or Lewis genotype failed to correlate
with sICAM levels [103].
ABO blood group status also appears to correlate with
the expression of other soluble vascular adhesion mole-
cules. Individuals enrolled in The Cohorts for Heart and
Aging Research in Genome Epidemiology consortium
were analysed for levels of soluble P-selectin (sP-selectin)
[104, 105], a vascular adhesion molecule, as well as
sICAM [96]. Among the 4115 patients examined, the
SELP gene (SNP rs6136) was found to be significantly
associated with sP-selectin levels (P = 4
05 9 10-61).
However, both sP-selectin (P < 1
86 9 10-41) and sICAM
levels (P = 1
22 9 10-15) were also associated with SNPs
within the ABO locus. Similar to the prior study [103],
reduced levels of sP-selectin and sICAM correlated with
SNPs associated with the A1 blood group [96]. Genetic
association analysis of 685 individuals enrolled in the
Diabetes Control and Complications Trial similarly exam-
ined genetic predictors of the level of soluble E-selectin
(sE-selectin), and another key adhesion molecule involved
in leucocyte extravasation [104, 105]. This analysis
demonstrated that the SNP rs579459 near the ABO locus
associated with blood group A expression was highly
associated with sE-selectin levels (P = 10-29). This associ-
ation was not limited to individuals with diabetes, but
was also observed among nondiabetic siblings
(P < 2 9 10-8) [95]. A recent meta-analysis examining
associations between all three markers, sICAM, sP-selectin
and sE-selection, and the rs579459 SNP, found significant
542 S. R. Stowell & C. P. Stowell
associations between reduced sICAM levels and individu-
als who were minor allele homozygotes (7
2% reduction,
95% CI 4
7–9
7% P = 1
2 9 10-4) and heterozygotes
(4
6% reduction, 95% CI 3
4–5
8% P = 1
4 9 10-8) com-
pared to major allele homozygotes among 33 671 indi-
viduals examined [97]. Of the 4921 individuals examined
for sP-selectin levels, those who were minor allele
homozygotes displayed a 18
6% reduction in sP-selectin
(95% CI 9
1–28
1% P = 7
3 9 10-14), while heterozygote
individuals displayed a 11
5% reduction (95% CI 7
2–
15
8% P = 1
7 9 10-7) when similarly compared to major
allele homozygotes. Among 2860 individuals examined
for genetic modifiers of sE-selectin levels, minor allele
homozygote individuals displayed a 43
3% reduction
(95% CI 36
9–49
3% P = 4
3 9 10-42), while heterozy-
gous individuals exhibited a 25
6% reduction (95% CI
19
0–32
2% P = 2
1 9 10-14) when compared to major
allele homozygotes [97]. An independent analysis of CAD
patients in the Audsburg study (1482 individuals) and the
LURIC study (1546 individuals) demonstrated significant
associations between 12–13 SNPs and sE-selectin levels
[98]. While the strongest correlation was observed
between SNP rs651007 (P = 1
87 9 10-103), all of the
SNPs associated with sE-selectin levels were found within
the ABO blood group gene. A similar study of 800 Chi-
nese healthy blood donors likewise demonstrated that
blood group A individuals had lower levels of sICAM and
sP-selectin when compared to blood group O individuals
[101].
The mechanisms responsible for the correlation
between ABO blood group antigen expression and vascu-
lar adhesion molecules are unknown. Endothelial cells
within most vascular beds express ABH antigens, but the
level of ABH expression can vary depending on the tissue
type and other physiologic cues, such as inflammation
[106–111]. Alterations in the expression of ABO(H)
glycans could directly influence the sensitivity of ICAM,
P-selectin and E-selection to proteolytic cleavage
[96, 112, 113]. However, less direct mechanisms may also
play a role, including altered interactions with extracellu-
lar lectins that facilitate retention at the cell surface.
Increased resident time on the cell may increase leucocyte
trafficking and subsequent activation, possibly influenc-
ing the magnitude of an inflammatory episode and its
pathophysiologic sequelae [104, 114]. ABO blood group
expression has also been shown to correlate with plasma
levels of IL-10 [115], and tumour necrosis factor [116],
which may directly or indirectly alter vascular adhesion
molecule expression. Ultimately, altered leucocyte–en-
dothelial interactions would be predicted to influence
atheroma formation by enhancing or attenuating the
rate of monocyte extravasation at endothelial sites
prone to atherogenesis [117, 118]. Recent data appear to
corroborate this notion, as endothelial cells expressing
the H antigen preferentially facilitate leucocyte rolling,
possibly through direct enhancement of vascular adhesion
molecule function [119].
Correlations between the levels of soluble vascular
adhesion molecules and ABO blood group status may also
reflect alterations in biomarker levels that occur indepen-
dent of adhesion molecule function. For example, eleva-
tions in soluble endothelial adhesion molecules may
reflect changes in their circulatory half-lives that occur
independent of endothelial cell activation, cleavage, cell
surface resident time or function [120, 121]. This is
especially important when considering that glycan deter-
minants can significantly modify the clearance of glyco-
proteins by altering the affinity for receptors responsible
for their elimination [120–122]. However, even if the
plasma half-life of vascular adhesion molecules is not
directly influenced by ABH expression, changes in vascu-
lar adhesion molecule levels may also reflect alterations
in VWF, which affects FVIII levels, platelet adhesion and
endothelial activation [37, 123–126]. Furthermore, a
recent study suggests that ABO antigen expression on a
biomarker glycoprotein may influence the ability of cer-
tain monoclonal antibodies (or other components of the
assay system) to accurately and quantitatively detect the
target analyte, as was recently shown for TNFa [116].
However, the likelihood of this type of artefact would
influence the detection of all three analytes, sICAM, sP-
selectin and sE-selectin, would seem to be low. Since
alterations in hemostasis, vascular biology and inflamma-
tion are intimately linked [127, 128], it would not be sur-
prising if ABO antigen expression impacts a variety of
factors that ultimately converge to influence the general
predisposition to vascular disease.
ABO and general metabolism
In addition to affecting hemostasis and vascular biology,
ABO associations with vascular-related complications
may independently or additionally be influenced by ABO
expression on general metabolism. In a study among 600
healthy men and 344 healthy women in South Wales,
blood group A individuals were shown to have higher
cholesterol levels than non-A individuals [129]. Among
women, the Lea phenotype also positively correlated with
elevated levels of cholesterol. In a subsequent study of
494 men, blood group A individuals exhibited higher
cholesterol levels than blood group B and O; the choles-
terol levels in the AB cohort were not significantly differ-
ent from that observed in A, B or O individuals, with B
individuals exhibiting the lowest cholesterol levels [130].
By contrast, of the 444 women evaluated in parallel,
blood group A and O individuals did not significantly
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552

differ in cholesterol levels. However, similar to men,
blood group B women had lower cholesterol than their
blood group A or O counterparts. No differences were
observed among men or women based on Lea phenotype.
With respect to TG levels, blood group A men had
higher levels than blood group O men, while blood
group B women presented with lower levels than non-B
women [130]. Lea antigen expression did impact TG
levels among men, with Lea positive men exhibiting
higher TG levels. Similar differences in TG levels with
respect to Lewis phenotype were not observed for
women. Interestingly, menopause appeared to influence
the relationship between ABO status and lipid levels, as
blood group A postmenopausal women had higher
cholesterol levels (3
08 – 0
54 g/l) than blood group A
premenopausal women (2
85 – 0
54 g/l; P < 0
01), while
AB postmenopausal women had lower TG levels
(0
85 – 0
27 mmoles/l) than AB premenopausal individ-
uals (1
14 – 0
34 mmoles/l; P < 0
02) [130].
More recent data appear to corroborate earlier studies
suggesting that ABO status may influence lipid metabo-
lism. A study of 4079 Japanese individuals demonstrated
that blood group A correlated with higher levels of total
cholesterol when compared to non-A individuals
(P < 1 9 10-5) [131]. A subsequent study of 617 Tai-
wanese subjects evaluated both cholesterol levels and
inflammatory markers and found significantly higher
total (P = 7
2 9 10-4) and low-density lipoprotein choles-
terol levels (P = 7
3 9 10-4) in blood group A individuals
when compared to non-A individuals [132]. Additional
analysis demonstrated that blood group A individuals also
had lower HDL, higher TG and higher HDL/TG ratios than
non-A blood group individuals. While sE-selectin levels
were associated with different ABO-related genetic poly-
morphisms (P values ranging from 2
65 9 10-20 to
7
76 9 10-32), less significant associations were observed
for sICAM and sP-selectin. Stratification of cholesterol
values on sE-selectin levels continued to demonstrate a
significant correlation between blood group A and lower
HDL, higher TG and higher HDL/TG ratios among men.
However, similar associations were no longer observed
for women. A study of 7723 Italian blood donors exam-
ined associations between ABO blood group status and a
variety of blood analytes found a correlation with haemo-
globin levels, platelet count, ferritin, uric acid, cholesterol
levels and various liver function tests [133]. Additional
analysis demonstrated that non-O individuals had higher
levels of LDL cholesterol than blood group O individuals.
In particular, A1 individuals had higher LDL cholesterol
and total cholesterol than A2 individuals.
Recent studies suggest that levels of proprotein conver-
tase subtilisin/kexin type 9 (PCSK9), a regulator of LDL
receptor levels and therefore general lipid metabolism
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552
ABH, thrombosis, CV disease and metabolism 543
[134], differ depending on the ABO blood group status of
an individual and therefore may play a role in ABO cor-
relations with lipid levels [135]. Non-O blood group indi-
viduals have higher levels of PCSK9 in addition to higher
levels of total cholesterol and LDL cholesterol [135]. Since
PCSK9 is a negative regulator of lipid metabolism [136],
ABO associated differences in PSCK9 levels may result in
decreased cholesterol removal and therefore higher levels
in non-O blood group individuals. The mechanism
whereby ABO blood group status affects PCSK9 levels
remains unknown. However, a direct impact of ABH
expression on PCSK9 cell surface half-life, plasma half-
life or overall level of expression may possibly play a role
[120, 121]. Additionally, a more direct impact of ABO
blood group expression may result from ABH differences
in the glycosylation of the LDL receptor itself. Prior stud-
ies demonstrated that glycosylation of the LDL receptor
can regulate LDL receptor function, suggesting that termi-
nal ABH modification, if present, could have very distinct
influences on lipid metabolism [137, 138].
Glycolipids from plasma, some of which express ABH
antigens, can be inserted into lipid carriers [139]. The
extent to which ABH-expressing glycolipids become
incorporated into lipoproteins as previously described for
RBCs [140], where they could potentially affect the clear-
ance of these particles, remains to be fully characterized.
Since humans express a series of carbohydrate binding
proteins that exhibit distinct specificity for ABH antigens
[141–145], differential recognition of ABH blood antigen-
containing glycolipids or glycoproteins with endogenous
carbohydrate binding proteins could alter particle clear-
ance and general metabolism. Alternatively, as the
ABCA2 transporter has been recently implicated in
cholesterol metabolism and is located close to the ABO
gene locus on chromosome 9, associations between ABO
blood group status and altered lipid metabolism may sim-
ply reflect linkage disequilibrium with genes more inti-
mately involved in regulating lipid levels [146, 147].
In addition to the possible impact of ABO antigen
expression and lipid metabolism, several studies also sug-
gest that ABO status may influence the development of
diabetes mellitus (DM). One study of 833 patients in
Liverpool and 5000 patients in Oxford compared the fre-
quency of ABO blood group antigens among patients with
DM to 14 252 blood donors [148]. A greater number of
blood group A individuals were observed among diabetic
men when compared to controls, while no differences in
ABO blood group distribution were observed between dia-
betic and control women. A subsequent study conducted
in Copenhagen between 1956 and 1958 compared 992
diabetic patients to 12 122 controls [149]. In contrast to
the Liverpool and Oxford diabetic populations, an excess
of blood group O individuals was discovered among the
544 S. R. Stowell & C. P. Stowell
Danish diabetic males when compared to controls; blood
group O was also over-represented among female diabetic
patients, although this trend did not reach statistical sig-
nificance. In contrast, a comparison of 865 patients with
diabetes and 11 327 controls in Belfast failed to detect an
association between ABO blood group status and diabetes
[150]. Conflicting results in many of these early studies
could reflect a lack of differentiation regarding the type
of diabetes in addition to possible inherent differences in
ABO blood group distribution among the control groups
used for comparison.
More recent studies have sought to provide some reso-
lution regarding the potential influence of ABO blood
group status on the development of DM. Examination of
patients presenting to a diabetic clinic in Hyderabad
found a higher percentage of blood group A, B and AB in
DM patients than in control individuals among the local
general population [151]. Several subsequent studies
appeared to corroborate this observation. Examination of
82 104 women followed from 1990 to 2008 for potential
associations between ABO blood group and the develop-
ment of type 2 DM found that blood group A and blood
group B individuals were at increased risk for developing
type 2 DM when compared to blood group O individuals
(A:O, HR 1
10, 95% CI 1
02–1
18; B:O, HR 1
21, 95% CI
1
07–1
36) [152]. Examination of 1633 diabetic patients
with 1650 controls in Qatar likewise found that blood
group B was more common in diabetic patients than con-
trols (P < 0
001), while blood group O was correspond-
ingly less common [153]. Segregation of patients based
on gender revealed that among males, blood group B
continued to be more common among diabetic patients
when compared to controls, while blood group A and B
were higher among female DM patients than controls.
However, similar to many of the original studies examin-
ing potential associations between ABO blood group sta-
tus and the development of diabetes, conflicting reports
continue to arise. Among 501 DM patients analysed out
of 1005 women within the Nurses’ Health Study, blood
group B individuals were actually less likely to have DM
(OR 0
44; 95% CI 0
27–0
70) when compared to non-B
blood group individuals after adjusting for several
endothelial markers (sE-selectin, sICAM), which can be
altered in DM [154, 155] and TNF-R2 [99]. A recent
review highlights many of the different outcomes
observed in these and other studies [156].
Changes in metabolism associated with diabetes,
including altered lipid profiles, have long been implicated
in the development of vascular disease [157]. Studies sug-
gesting that blood group O individuals are less likely to
develop CAD, unfavourable cholesterol profiles and dia-
betes provide a potential link between the influence of
ABO blood group inheritance on metabolism and vascular
biology that may influence vascular disease risk. While
the influence of ABO blood group antigens on DM altered
lipid metabolism, vascular adhesion molecule expression
and vWF levels may reflect discrete biological processes
influenced by the impact of these post-translational mod-
ifications on a variety of substrates, these differences may
also reflect correlations derived from a more direct, yet
incompletely explored, effect of ABO expression on a
common biological pathway.
Limitations in the examination of ABO
influence on disease
As noted previously, associations observed between ABH
antigen expression and disease outcomes may reflect a
direct or indirect impact of ABO phenotype on the
propensity of an individual to undergo a particular patho-
physiologic process. However, since the frequency of the
ABO phenotypes varies between distinct populations
[158], associations between human disease and ABO
blood group could also reflect other genetic and environ-
mental factors more commonly present in a particular
study population. This is especially problematic when a
population with a particular disease is compared to a
control population, such as a group of blood donors,
which could otherwise be genetically distinct [159]. Since
the ABO blood group was the first molecular polymor-
phism discovered in the human species, and routine clini-
cal practice often led to the determination of blood group
status among large numbers of patients (and donors), the
readily available nature of these data provided a com-
pelling opportunity to examine potential genetic predic-
tors of disease associations with relative ease. However,
issues associated with selection bias and the potential for
ABO blood group expression to be a surrogate marker for
a closely linked genetic trait directly involved in the
pathogenesis of the particular disease process have been,
and in many ways continues to be, a challenge when
interpreting many ABH disease association studies. While
more recent less biased approaches continue to identify
ABO status as an independent predictor of disease
[14, 16, 37, 85, 87, 160], the paucity of mechanistic stud-
ies that directly define the impact of ABH expression on
disease outcomes in many of these cases has continued to
make it difficult to fully interpret prior correlative data.
Efforts to directly link ABO expression to the patho-
physiology of disease have historically been challenging
in part due to the lack of suitable animal models to test
hypotheses that naturally extend from epidemiological
observational studies. Unlike many models recently devel-
oped to study the immunological consequences of expo-
sure to other alloantigens of clinical importance in
transfusion medicine [161–165], a natural, nonprimate
© 2019 International Society of Blood Transfusion
Vox Sanguinis (2019) 114, 535–552
 ABH, thrombosis, CV disease and metabolism 545

animal model system for ABO expression does not cur-
rently exist. This reflects the fact that ABO and related
antigen polymorphisms are not similarly expressed in
lower mammals, and therefore, the models that tradition-
ally have been used to study the impact of gene associa-
tions commonly conserved among mammals can be
difficult to apply to the study of ABO blood groups. This
is a significant limitation as the genetic tools and other
methods that are necessary to establish clear mechanistic
relationships are predominately limited to these types of
animal model systems. Attempts to generate ABO models
in animals commonly used to study disease processes,
such as mice, illustrate the challenges associated with
seeking to understand the function of complex carbohy-
drate antigenic determinants in general when only
expressed in certain species. As ABO antigens are carbo-
hydrates, the generation of these structures requires
expression of the glycosyltransferases responsible for
their synthesis. Mice do possess a1,2 fucosyltransferases
capable of generating the H antigen and an AB cis trans-
ferase that can add both galactose (blood group B) and
N-acetylgalactosamine (blood group A) to the H antigen
substrate [166, 167]. However, it is not clear whether
these transferases are expressed at sufficient levels or
exhibit the required activity in the relevant cell compart-
ments to human biology to generate comparable ABH
antigens. While the fucosyltransferase KO mice have been
shown to possess distinct phenotypes [166, 168], very lit-
tle A, B or H antigen can be detected in mice. Consistent
with this, intentional exposure of these mice to A or B
antigen often results in the development of anti-A and
anti-B antibodies [169, 170], suggesting that whatever
expression may occur it is insufficient to induce immuno-
logical tolerance.
In an effort to circumvent inadequate expression of A,
B and H antigens in mice, while also seeking to mirror
the location of expression thought to occur in humans,
several groups have attempted to generate transgenic ani-
mals that express a 1,2 fucosyltransferases and/or A or B
transferases under tissue-specific promoters [171–173].
These approaches have successfully resulted in the
expression of A and B antigens in different tissues. How-
ever, as these transferases are not normally expressed in
the target tissue, expression of ABH antigens likely occurs
as a result of competition with endogenous glycosyltrans-
ferases for the same glycan substrates (Fig. 2). In this set-
ting, phenotypic differences observed following ectopic
expression of these enzymes and therefore ABH antigens
may be attributable to A, B or H expression. However, it
is equally possible that changes in biology observed in
these transgenic animals reflect glycan truncations and
the loss of terminal modifications that evolved to serve
specific purposes in a particular type of cell [172]. As gly-
cosyltransferases can modify many different targets, the
impact of these altered modifications can be quite pleio-
tropic and therefore hard to fully control. Given the
unique characteristics responsible for biosynthesis of ABH
antigens when compared to other RBC blood group anti-
gens, recent approaches designed to model other RBC
alloantigens relevant to transfusion, where expression of
protein antigens largely results in the simple insertion of
another protein in the cell membrane [161–164], are not

Fig. 2 Ectopic expression of blood group antigens interferes with normal glycan biosynthesis and function. As carbohydrate structures, ABH blood group
expression requires a series of glycosyltransferases for the correct synthesis of these post-translational modifications. As these glycosyltransferases utilize
many of the same substrates that endogenous glycosyltransferases likewise modify, ectopic expression of the glycosyltransferases responsible for ABH
biosynthesis can cause premature glycan truncation and prevent otherwise normal modifications that can be critical for glycan function. As a result,
despite the ability of this approach to generate animal models that express similar A, B and H antigens found in humans, it can be difficult to decipher
whether alterations in the biology of these animals reflect ABH expression, the loss of normal glycan structures that typically decorate the cell surface
or a combination of both on evaluated outcomes (Sial = sialic acid, Gal = galactose, GlcNAc = N-acetylgalactosamine, Fuc = fucose, Man = mannose).

© 2019 International Society of Blood Transfusion

Vox Sanguinis (2019) 114, 535–552
546 S. R. Stowell & C. P. Stowell

likely be suitable for generating a similarly meaningful
ABO blood group model system. However, recent devel-
opments in the synthesis of glycolipids that bear carbohy-
drate blood group determinants, which can be inserted in
cell membranes, may provide a more attractive approach
[174, 175]. This method promises to allow A, B or H anti-
gens to be incorporated into a membrane surface without
significantly compromising the underlying biology of the
accompanying cell.
In contrast to mice, non-human primates might
seem like a logical alternative to studying the biologi-
cal significance of ABO blood group polymorphisms
at a mechanistic level [176]. However, most non-
human primates fail to express the full complement of
ABH and related blood group antigens [177]. Further-
more, the relative tissue distribution of A, B and H
histo-blood group antigens is not well understood in
either humans or non-human primates. As the expres-
sion of A or B antigens on specific glycolipids or gly-
coproteins in a given cell would be predicted to
directly regulate function and therefore potential dis-
ease associations, differences in the glycoprotein, gly-
colipid or even cellular substrates of ABH antigen
expression between human and non-human primates
may make it difficult to accurately model the impact
of ABO blood group expression in humans using non-
human primate systems. Furthermore, the significant
resources required to study non-human primates, cou-
pled with the lack of infrastructure for non-human
primate research at most institutions when compared
to other model systems, often make these types of
studies logistically and financially untenable. Single
cell in vitro studies will likely continue to be infor-
mative [119]. However, as many of the disease pro-
cesses thought to be influenced by ABH expression
are systemic in nature, an animal model that is cap-
able of recapitulating key features of ABH expression
would be extremely useful for understanding at a
mechanistic level the association between ABO blood
group status and disease.
Conclusion
In this review, we have focused on just a few of the bio-
logic and pathologic processes that appear to be influ-
enced by the ABH and related carbohydrate histo-blood
group antigens. Many more areas are the subject of active
investigation, for example the role of these and related
carbohydrate structures in carcinogenesis [178, 179]. The
application of some of the newer glycobiological strate-
gies such as glycoengineered cell lines, glycomic and gly-
coproteomic approaches, glycan microarray analysis, and
the use of synthetic glycolipids and recombinant versions
of glycosylated proteins coupled with the development of
effective animal models will undoubtedly bring new
insights into the biological roles of these structures
[180, 181]. The next decade should prove to be very
exciting for both transfusion medicine specialists and gly-
cobiologists.

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