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Review article: Platelet abnormalities in diabetes mellitus

Jos Luis Ferreiro, Joan Antoni Gmez-Hospital and Dominick J Angiolillo
Diabetes and Vascular Disease Research 2010 7: 251 originally published online 4 October 2010
DOI: 10.1177/1479164110383994
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Review article

Platelet abnormalities in diabetes mellitus

Diabetes & Vascular Disease Research

7(4) 251259
The Author(s) 2010
Reprints and permission: sagepub.
co.uk/journalsPermissions.nav
DOI: 10.1177/1479164110383994
dvr.sagepub.com

Jos Luis Ferreiro1,2, Joan Antoni Gmez-Hospital1 and

Dominick J Angiolillo3

Abstract
Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which is the main underlying factor contributing
to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the leading cause of
morbidity and mortality in patients with DM. Among factors contributing to the prothrombotic condition which characterise patients with DM, platelet hyperreactivity plays a pivotal role. Platelets of DM patients are characterised by
dysregulation of several signalling pathways leading to intensified adhesion, activation and aggregation. Multiple mechanisms
are involved in platelet dysfunction of patients with DM, which can be categorised as follows: a) hyperglycaemia, b) insulin
deficiency and resistance, c) associated metabolic conditions, and d) other cellular abnormalities.The present manuscript aims
to provide an overview on the current status of knowledge on platelet abnormalities that characterise patients with DM.
Keywords
Cardiovascular disease, diabetes mellitus, platelets

Introduction: the diabetic platelet

Accelerated atherosclerosis is the main underlying factor
contributing to the high risk of atherothrombotic events in
patients with diabetes mellitus (DM). Cardiovascular disease, particularly coronary artery disease (CAD), often presenting as an acute coronary syndrome (ACS), is the leading
cause of morbidity and mortality in patients with DM.1 Of
note, DM patients without any history of CAD have the
same cardiac mortality risk as non-DM patients with a history of myocardial infarction (MI).2 In addition, cardiovascular disease has also worse prognosis in patients with DM
as they have a higher risk of complications and recurrent
atherothrombotic events than non-DM patients.3 In fact,
DM is a strong independent predictor of short- and longterm recurrent ischaemic events, including mortality, in an
ACS scenario.4,5 Further, the concomitant presence of cardiovascular risk factors and comorbidities that negatively
impact the outcomes of ACS is higher in DM patients.6
Several factors contribute to the prothrombotic condition that characterises patients with DM, such as the following: increased coagulation, impaired fibrinolysis,
endothelial dysfunction and platelet hyperreactivity.7-9 The
latter is of particular interest, since platelets play a key role
in the formation, development and sustainment of thrombi,
which are platelet-driven processes.10 Platelets of patients
with DM are characterised by dysregulation of several
signalling pathways, and have been proven to be hyperreactive with intensified adhesion, activation and aggregation.7,11-14 Such a hyperreactive platelet phenotype may

contribute to the higher proportion of DM patients with

inadequate response to antiplatelet agents compared with
non-DM subjects.15,16 The role of antiplatelet agents in
patients with DM will be developed in detail elsewhere in
this supplement.
Multiple mechanisms caused by metabolic and cellular
abnormalities have been suggested to play a role in the
increased platelet reactivity observed in patients with DM.
These mechanisms can be grouped together into the following aetiopathogenic categories: a) hyperglycaemia, b) insulin deficiency and resistance, c) associated metabolic
conditions, and d) other cellular abnormalities (Figure 1).17
The aim of this paper is to provide an overview on the
current status of knowledge on platelet abnormalities which
characterise DM patients and to analyse the evidence
regarding their implications in platelet reactivity.

IDIBELL-Hospital Universitari de Bellvitge, Department of Cardiology,

Interventional Cardiology Unit, LHospitalet de Llobregat, Barcelona,
Spain
2
IDIBELL-Hosptal Universitari de Bellvitge, Cardiovascular Research Lab,
LHospitalet de Llobregat, Barcelona, Spain
3
University of Florida College of Medicine-Jacksonville, Jacksonville,
Florida, USA
1

Corresponding author:
Dominick J Angiolillo, University of Florida College of MedicineJacksonville, 655 West 8th Street, Jacksonville, Florida, 32209, USA.
Email: dominick.angiolillo@jax.ufl.edu

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Diabetes and Vascular Disease Research 7(4)

Figure 1. Mechanisms contributing to platelet dysfunction in patients with diabetes mellitus.

Platelet dysfunction in patients with diabetes mellitus (DM) is caused by several mechanisms, such as those due to hyperglycaemia,
insulin deficiency, associated metabolic conditions, and other cellular abnormalities. Hyperglycaemia may increase platelet reactivity
by glycating platelet surface proteins (impairing membrane fluidity and therefore increasing platelet adhesion), activating protein
kinase C (a mediator of platelet activation), inducing P-selectin (a surface adhesion protein) expression, and due to osmotic effect.
Insulin deficiency also plays an important role in platelet dysfunction by different mechanisms. Some of them have been suggested
to be IRS-dependent, such as the increased intracellular calcium concentration leading to enhanced platelet degranulation and
aggregation, while other factors are not dependent of IRS, such as the impaired response to NO and PGI2, which enhances platelet
reactivity. Metabolic conditions frequently associated with DM may per se play a role on platelet hyperreactivity, including obesity,
dyslipidaemia and enhanced systemic inflammation. Obesity, in addition to being associated with insulin resistance, contributes
to platelet dysfunction, mostly in terms of adhesion and activation, due to mechanisms such as increased cytosolic calcium
concentration and augmented oxidative stress. Abnormalities of lipidic profile, particularly hypertriglyceridaemia, also affect
platelet reactivity by different mechanisms, which include inducing endothelial dysfunction. Endothelial dysfunction is another
characteristic feature of DM, which enhances platelet reactivity by decreasing the production of NO and PGI2 and contributes to
the prothrombotic state through an increased production of TF. Patients with DM present other platelet abnormalities that can
enhance platelet adhesion and activation, such as the following: increased expression of surface proteins (P-selectin and GP IIb/IIIa),
augmented cytosolic calcium concentration, upregulation of P2Y12 signalling, increased platelet turnover, and oxidative stress, which
provokes an overproduction of reactive oxygen and nitrogen species.
ADP: adenosine diphosphate, Ca++: calcium, GP: glycoprotein, IRS: insulin receptor substrate, NO: nitric oxide, PGI2: prostacycline, PKC: protein kinase
C, ROS/NOS: reactive oxygen and nitrogen species, TF: tissue factor.
Reproduced from Ferreiro JL and Angiolillo DJ. Diabetes and anti-platelet therapy in acute coronary syndrome. Circulation 2010 (in press).17

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Ferreiro et al.

Hyperglycaemia
As per the definition of the American Diabetes Association,
Diabetes is a group of metabolic diseases characterised by
hyperglycaemia resulting from defects in insulin secretion,
insulin action, or both.18 Hyperglycaemia not only defines
DM but also plays an independent and important role in the
blood abnormalities leading to a prothrombotic state in DM
patients.19,20
Platelets from patients with type-2 DM have increased
expression of adhesion molecules. A study by Eibl and colleagues showed that platelets from DM patients have a
greater expression of platelet activation markers compared
with an age-matched non-diabetic control group.21 After
improving metabolic control during 3months, a significant
decrease in expression of platelet activation markers
(CD31, CD49b, CD62P and CD63) was noted. Further, a
significant correlation between CD62P, CD63 and HbA1C
levels observed. These findings suggest that improvement
of glycaemic control may have a beneficial effect on platelet adhesion and subsequent activation.21 Expression of
platelet surface receptors is also increased in DM patients.
In particular, expression of glycoprotein (GP) Ib and GP
IIb/IIIa, which respectively mediate binding to von
Willebrand factor and platelet-fibrin interaction, is augmented in DM patients.13,14,16
Acute hyperglycaemia results in increased platelet activation, as documented by elevated levels of surface adhesion molecules such as P-selectin22 and soluble markers of
platelet activation (e.g. soluble P-selectin and CD40 ligand).23,24 Further, levels of HbA1C and fasting glucose have
been correlated to P-selectin expression in type-2 DM
patients undergoing coronary angioplasty,25 which suggests
again that an improved glycaemic control may reduce
platelet reactivity.
In line with the above mentioned laboratory findings,
there are some clinical data that support the concept that
glucose-lowering therapy to improve metabolic control is
beneficial in DM patients with atherothrombotic complications. In the setting of ACS, the DIGAMI (Diabetes
Mellitus, Insulin Glucose Infusion in Acute Myocardial
Infarction) trial randomised patients with DM presenting
with an acute MI to intensive glucose-lowering treatment
(standard treatment plus insulinglucose infusion for 24 h
followed by multidose insulin therapy) or standard treatment. Mortality in the intensive treatment group was significantly lower than in the control group (33% vs. 44%;
RR=0.72 (95% confidence interval 0.550.92); p=0.011)
after 3.4years of follow-up.26 No differences in mortality or
morbidity (non-fatal reinfarction or stroke) were found in
the DIGAMI-2 trial among three different glucose-lowering strategies (group 1: glucoseinsulin infusion titrated by
glucose levels for at least 24 h followed by insulin-based
long-term glucose control; group 2: glucoseinsulin infusion titrated by glucose levels for at least 24hours followed

by standard glucose control; and group 3: routine metabolic

control according to local practice).27 Glucose-lowering
levels were similar among the three study groups, suggesting that the benefit of decreasing glucose levels is independent of the way it is achieved. However, the optimal
blood glucose level remains unknown. In fact, an excessive lowering of glucose has been proven to be harmful in
the ACCORD (Action to Control Cardiovascular Risk in
Diabetes Study Group) trial, which randomised DM patients
to receive an intensive glucose-lowering regimen (targeting
a glycated haemoglobin level <6.0%) or a standard regimen
(targeting a glycated haemoglobin level 7.07.9%). The
trial was interrupted prematurely after 3.5years of followup due to an increased mortality in the intensive therapy
group.28 The latter is in line with the results of the NICESUGAR (Normoglycemia in Intensive Care Evaluation
Survival Using Glucose Algorithm Regulation) trial that
randomised patients admitted to an intensive care unit to
undergo either intensive glucose control (target blood glucose range 4.56.0mmol/l) or conventional glucose control
(target of 10.0 mmol/l or less), in which mortality was
higher in the intensive glucose control group.29
Several mechanisms have been proposed to contribute to
the increased platelet reactivity caused by hyperglycaemia,
including the following: a) non-enzymatic glycation of
platelet membrane proteins that decreases membrane fluidity, which may increase platelet adhesion;30,31 b) osmotic
effect of glucose that activates platelet GP IIb/IIIa and
P-selectin expression;32 c) activation of protein kinase C, a
mediator of platelet activation;33 and d) glycation of circulating low-density lipoproteins (LDL), which increases
intracellular calcium concentration and nitric oxide (NO)
production.34 Although a description of abnormalities inducing a prothrombotic state in DM other than those which are
platelet specific goes beyond the scope of this paper, it is
worth mentioning that hyperglycaemia also promotes
thrombosis through plasmatic components. In particular,
hyperglycaemia activates coagulation by raising concentrations of procoagulant factors (e.g. tissue factor, von
Willebrand factor)35,36 and inhibits fibrinolysis by increasing
concentrations of plasminogen activator inhibitor.9

Insulin deficiency and resistance

The vast majority of DM patients can be assigned to two
broad aetiopathogenetic categories. Type-1 DM, which
accounts for only 510% of cases, results from a cellularmediated autoimmune destruction of the

-
cells of the pancreas, leading to an absolute deficiency of insulin secretion.
Type-2 DM, which accounts for around 9095% of DM
individuals, is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory
response, usually having relative (rather than absolute) insulin deficiency.18

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Diabetes and Vascular Disease Research 7(4)

Deficient insulin action is the cardinal factor for development of DM and clearly contributes to platelet dysfunction.37 Both insulin receptors (IR) and insulin-like growth
factor-1 (IGF-1) receptors are expressed in platelets.38,39
Among other effects in platelets, insulin increases surface
expression of adenylate cyclase-linked prostacyclin (PGI2)
receptor and induces the release of plasminogen activator.40,41 However, IR expression is relatively low as the
majority of its subunits heterodimerise with those of IGF-1
receptor to form insulin/IGF-1 receptor hybrids, which
eagerly bind IGF-1, but not insulin.39 IGF-1 is present in
alpha granules of platelets and high levels of its functional
receptor are expressed on the platelet surface, which may
contribute to the amplification of platelet responses. The
pathways through which IGF-1 may modulate platelet
function, however, are currently not fully elucidated. IGF-1
stimulation of platelets results in dose-dependent phosphorylation of the IGF receptor and in tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2,
stimulating their subsequent binding with the p85 subunit
of phosphoinositide-3 kinase (PI3K), leading to phosphorylation of protein kinase B, which is involved in several
cellular responses to insulin and IGF-1, including modulation of platelet reactivity.42
Several anomalies in insulin-mediated signalling pathways, which can be classified as IRS-dependent and independent factors, have been suggested to contribute to the
hampered or abolished platelet-inhibitory effect observed in
patients with insulin resistance.37,43 Among IRS-dependent
factors, insulin resistance causes an increase in intracellular
calcium concentration that leads to augmented platelet
degranulation and aggregation.44 The exact mechanism by
which the increase in calcium concentration is generated
is not yet entirely known and a number of hypotheses
have been suggested, such as IRS binding to the calciumATPase of the sarcoplasmic reticulum in an insulinregulated fashion,45 or via inhibition of cyclic adenosine
monophosphate formation by the inhibitory G-protein of
adenylyl cyclase, Gi.46 Among IRS-independent pathways
involved in platelet dysfunction due to insulin resistance,
the role of reduced platelet sensitivity to NO and PGI2 is
noteworthy, since both molecules released by the endothelium retard platelet activation; thus, an impaired response is
associated with enhanced platelet reactivity.47,48 Further, a
recent study found correlation between improvement of
insulin sensitivity, measured by the homeostasis model
assessment (HOMA) of insulin resistance, and changes of
platelet function.49
The importance of insulin resistance in platelet hyperreactivity characteristic of patients with DM is highlighted by
recent studies with thiazolidinediones in which this group
of insulin sensitisers has shown a beneficial effect on platelet function. For instance, rosiglitazone therapy has been
associated in some preliminary studies with improved

sensitivity to NO and partial normalisation of intracellular

calcium concentrations in DM patients,50 as well as with
reduced P-selectin expression in non-DM patients with
CAD.51 There are controversial data regarding the suggested
benefit of insulin-sensitiser therapy over insulin-providing
therapy in terms of atherosclerosis progression and cardiovascular outcomes. The PERISCOPE (Pioglitazone Effect
on Regression of Intravascular Sonographic Coronary
Obstruction Prospective Evaluation) trial was a prospective,
randomised, multicentre, double-blind clinical trial that
compared the effect of pioglitazone, an insulin sensitiser,
versus glimepiride, an insulin secretagogue, on progression
of coronary atherosclerosis measured by intravascular
ultrasonography in patients with type-2 DM and CAD.52
Pioglitazone therapy was associated with a significantly
lower rate of atherosclerosis progression at 18 months,
when compared with glimepiride treatment. In a substudy
of the SYMPHONY (Sibrafiban vs Aspirin to Yield
Maximum Protection From Ischemic Heart Events Postacute Coronary Syndromes) and SYMPHONY-2 trials performed in DM patients after an ACS, insulin-sensitiser
therapy with biguanide and/or thiazolidinedione was associated with a significantly lower rate of cardiovascular outcomes at 90days compared with insulin-providing treatment
with insulin and/or sulfonylurea.53 Although these studies
emphasised the important role of insulin resistance in progression of atherothrombotic disease in DM patients, these
results have not been confirmed in the recently published
APPROACH (Assessment on the Prevention of Progression
by Rosiglitazone on Atherosclerosis in Diabetes Patients
With Cardiovascular History) trial.54 In this study, the thiazolinedione rosiglitazone did not significantly decrease the
primary end point of progression of coronary atherosclerosis, measured by percent atheroma volume, more than glipizide, an insulin secretagogue, in patients with type-2 DM
and CAD.54

Associated metabolic conditions

Several metabolic conditions associated with type-2 DM
may contribute to the enhanced platelet reactivity observed
in these patients, including obesity, dyslipidaemia and
increased systemic inflammation.
Obesity is a common feature in patients with type-2 DM,
and obesity itself may be associated with some degree of
insulin resistance, which has relevant implications for platelet reactivity as described above. Nevertheless, other factors
present in obese subjects may account for platelet dysfunction, which include: a) elevated platelet count and high
mean platelet volume,55 which is related with platelet reactivity and has prognostic implications in atherothrombotic
processes such as stroke and ACS;56 b) higher serum leptin
concentration, which is associated with increased platelet
aggregability;57 c) greater cytosolic calcium concentration,58

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Ferreiro et al.
which also boosts platelet reactivity; and d) increased oxidative stress.59 Overall, these metabolic abnormalities
caused by obesity ultimately lead to enhanced platelet reactivity.60,61 Russo et al. recently observed in a population of
subjects affected with central obesity that diet-induced
weight loss restored the sensitivity to NO and PGI2 and
reduced platelet activation.49 Of note, response to antiplatelet drugs, in particular to clopidogrel, is impaired as well in
subjects with elevated body mass index.62-64
Patients with type-2 DM are prone to have dyslipidaemia,
typically manifested by elevated triglycerides and low highdensity lipoprotein (HDL) cholesterol. Hypertriglyceridaemia
is a typical manifestation that is known to induce higher
platelet activation.65
The role of triglyceride-rich very-low-density lipoprotein (VLDL) particles is not limited to platelet activation
and also affects coagulation cascade and impairs fibrinolysis, thus predisposing to atherothrombosis.66 The suggested
mechanism to explain the effects of triglycerides on platelet
function is mediated by the apoE content of VLDL particles
and their interaction with the platelet LDL receptor.67 Low
levels of HDL are associated with endothelial dysfunction,68 which increases the atherothrombotic risk in DM
patients. Further, intravenous infusion of reconstituted
HDL rapidly normalises endothelial function by increasing
NO bioavailability in hypercholesterolaemic patients.69 In
line with these findings, an interesting study recently
reported by Calkin and colleagues showed that administration of reconstituted HDL caused a reduction of platelet
aggregation in DM subjects by promoting cholesterol
efflux from platelets.70
DM is also associated with systemic inflammation.
Indeed, DM patients show higher concentrations of inflammatory, platelet activation and coagulation markers (soluble CD40 ligand, soluble P-selectin, interleukin-6, and
tissue factor) than healthy subjects.71 Further, expression of
FcgammaRIIA receptor, which is enhanced in platelets of
DM patients and contributes to platelet activation,72 has
been suggested to be modulated by inflammation.73

Other cellular abnormalities

In this section, the roles of other platelet anomalies common
in DM patients that may account for the global hyperreactivity status, including dysregulation of calcium metabolism,
oxidative stress, upregulation of P2Y12 signalling pathway
and accelerated platelet turnover, are discussed.
Impaired regulation of calcium metabolism that leads to
increased intracellular calcium levels is a major feature of
platelets from patients with DM. The mechanisms involved
in calcium signalling abnormalities present in DM are not
fully elucidated. Factors that have been proposed to play a
role in impaired calcium homeostasis and, therefore, in
platelet hyperreactivity are: a) excessive influx of calcium

through the sodium/calcium exchanger;74 b) changes in the

activity of calcium ATPases;75 c) impaired sensitivity to
insulin, which decreases sarcoplasmic endoplasmic reticulum calcium-ATPase (SERCA-2);37,50 and d) augmented
oxidative stress, which enhances calcium signalling due to
increased formation of superoxide anions and reduced
nitric oxide production.76 The final result of this altered
calcium homeostasis is an augmented concentration of
cytosolic calcium, which leads to enhanced platelet reactivity and aggregation.37,77
Modulation of platelet or vascular redox status and the
presence of reactive oxygen species can impair platelet
function and may be prothrombotic.78 DM is associated
with oxidative stress, in particular with an overproduction
of reactive oxygen and nitrogen species, as well as reduced
platelet antioxidant levels.79,80 The excessive generation of
potent oxidants, such as superoxide anions and hydrogen
peroxide, increases platelet activation.78,81 An increase in
reactive oxygen species in addition to chronic hyperglycaemia enhances production of advanced glycation end products (AGEs).82 These glycated proteins may contribute to
the development of atherosclerotic complications by activation of the receptor for AGEs (RAGE)83 and by enhancing platelet aggregation through the serotonin receptor.84
Further, endothelial function is impaired also by oxidative
stress through a reduction in production of NO and PGI2.85
This is of particular interest in patients with DM since their
platelets have diminished sensitivity to the actions of these
vasodilator molecules produced by the endothelium.47,48
The platelet adenosine diphosphate (ADP) P2Y12 receptor signalling pathway has been suggested to be upregulated in diabetic platelets, in particular those with type-2
DM.86 This suppresses cAMP concentration and, in addition to a lower responsiveness to insulin, leads to increased
adhesion, aggregation, and procoagulant activity.87 Another
abnormality in platelet surface molecules is the increased
expression of surface proteins such as P-selectin and glycoproteins Ib and IIb/IIIa, which are integrins that mediate
adhesion.60,88
An accelerated platelet turnover represented by the presence of a higher number of reticulated platelets has been
observed in patients with DM.91 Reticulated platelets are
larger and more sensitive, resulting in platelet hyperreactivity and lower response to antiplatelet therapies including
aspirin and clopidogrel.90,91 In addition, platelets of DM
patients are larger, and thus hyperreactive, as platelet size
correlates with greater platelet reactivity measured by
aggregation and total release of granular content.92

Conclusions
Patients with DM have accelerated atherosclerosis and
an elevated risk of recurrent atherothrombotic events.
Among the factors that contribute to the prothrombotic

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Diabetes and Vascular Disease Research 7(4)

Key messages

 therothrombotic events are more frequent and are

A
associated with worse prognosis in patients with DM
compared with non-DM patients.
Platelet hyperreactivity is a characteristic feature of DM
and plays a pivotal role in its overall prothrombotic state.
Several mechanisms contribute to platelet dysfunction
and affect the adhesion, activation and, aggregation phases
of platelet-mediated thrombosis.

status characterising these patients, abnormalities in platelet function play a pivotal role. These platelet abnormalities
ultimately result in a hyperreactive platelet phenotype. The
understanding of the molecular mechanisms leading to
increased platelet reactivity in patients with DM may set
the basis for targeted antiplatelet treatment strategies in this
high-risk cohort.
Funding
This work was supported by an unrestricted educational
grant from Eli Lilly and Daiichi Sankyo to University of
Sheffield to fund the activities of the European Platelet
Academy.
Conflict of interest
Dominick J Angiolillo (corresponding author) reports
receiving: honoraria for lectures from Bristol Myers
Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc;
consulting fees from Bristol Myers Squibb; SanofiAventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines
Company; Portola; Novartis; Medicure; Accumetrics;
Arena Pharmaceuticals; Astra Zeneca; Merck; research
grants from GlaxoSmithKline; Otsuka; Eli Lilly Co;
Daiichi Sankyo, Inc., The Medicines Company; Portola;
Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. Jos
Luis Ferreiro has no conflicts of interest to report. Joan
Antoni Gmez-Hospital has no conflicts of interest to
report.
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