Current Pharmaceutical Design, 2011, 17, 47-58 47

Mean Platelet Volume: A Link Between Thrombosis and Inflammation?

Armen Yuri Gasparyan1*, Lilit Ayvazyan2, Dimitri P. Mikhailidis3 and George D. Kitas1,4

1
Clinical Research Unit, Russells Hall Hospital, Dudley Group of Hospitals NHS Foundation Trust, Dudley, West Midlands, UK,
2
Department of Medical Chemistry, Yerevan State Medical University, Yerevan, Armenia, 3Department of Clinical Biochemistry
(Vascular Prevention Clinic), Royal Free Hospital, University College London Medical School, University College London (UCL),
London, United Kingdom, 4Arthritis Research UK (AR UK) Epidemiology Unit, University of Manchester, Manchester, United
Kingdom

Abstract: Platelet activation is a link in the pathophysiology of diseases prone to thrombosis and inflammation. Numerous platelet mark-
ers, including mean platelet volume (MPV), have been investigated in connection with both thrombosis and inflammation. This review
considers MPV as a prognostic and therapeutic marker as well as the factors influencing its measurement. Established cardiovascular risk
factors, such as smoking, hypertension, dyslipidemia, and diabetes, can influence MPV, depending on confounding factors. Low-grade
inflammation is one such factor. Evidence, particularly derived from prospective studies and a meta-analysis, suggest a correlation be-
tween an increase in MPV and the risk of thrombosis. High MPV associates with a variety of established risk factors, cardio- and cere-
brovascular disorders, and low-grade inflammatory conditions prone to arterial and venous thromboses. High-grade inflammatory dis-
eases, such as active rheumatoid arthritis or attacks of familial Mediterranean fever, present with low levels of MPV, which reverse in the
course of antiinflammatory therapy. Lifestyle modification, antihypertensive, lipid-lowering and diet therapies can also affect MPV val-
ues, but these effects need to be investigated in large prospective studies with thrombotic endpoints.
Keywords: Platelets, mean platelet volume, arterial thrombosis, venous thromboembolism, inflammation, rheumatic disease, prognosis.

INTRODUCTION
Recent advances in clinical laboratory techniques have opened
new horizons for a better understanding of the role of platelets in
thrombosis, immunity, inflammation and angiogenesis [1-4]. As a
result, platelet activation is now viewed as a therapeutic target in
atherothrombosis [5], hypertension [6] and diabetes [7]. Experimen-
tal and clinical evidence has also been suggestive of the involve-
ment of platelet-derived agents in inflammatory disorders, such as
systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)
and associated thrombotic complications [8-11]. There is, however,
no strong evidence supporting the use of antiplatelet therapy in
inflammatory disorders. This might be, at least partly, due to the
diversity of pathways activating platelets and lack of tools for plate-
let function monitoring in these disorders.
This review examines the evidence for the use of mean platelet
volume (MPV), a readily available marker of platelet activation, in
the assessment of prothrombotic and pro-inflammatory potentials in
several clinical conditions. We also consider factors confounding
changes in MPV.
SEARCH STRATEGY
We searched Medline/PubMed, Scopus, EMBASE, DARE, and
Web of Science (1983-2010) using terms mean platelet volume or
MPV in combination with thrombopoiesis, platelet function,
methods, flow cytometry, automated hematology analyzer,
thrombosis, cardiovascular risk, smoking, hypertension,
diabetes, dyslipidemia, obesity, coronary artery disease,
heart failure, stroke, venous thrombosis, inflammatory dis-
orders, rheumatic disease, antiplatelet agents, treatment, and
genetics. The preference was given to the sources published
within the past 5 years and to the large clinical studies focusing on
the role of MPV in thrombosis and inflammation. Highly-cited old
publications on thrombopoiesis and platelet size heterogeneity were
*Address correspondence to this author at the Dudley Group of Hospitals
NHS Trust (Teaching Trust of University of Birmingham, UK), Russells
Hall Hospital, North Block, Clinical Research Unit, Dudley, West Midlands
DY1 2HQ, United Kingdom; Tel: +44-1384-244842;
Fax: +44-1384-244808; E-mails: a.gasparyan@gmail.com;
armen.gasparyan@dgoh.nhs.uk
also reviewed and cited. The reference lists of the selected sources
were searched to identify relevant original papers and reviews.
REGULATION OF THROMBOPOIESIS AND THE PLATE-
LET SIZE
Steady-state megakaryocytopoiesis contributes to the circulat-
ing blood by producing disc-shaped anucleate particles measuring
1-2 m in size, with a lifespan of 8-10 days [12]. These particles,
called platelets, are cytoplasmatic fragments of megakaryocytes,
and their morphology and functional capacities are determined by 2
sets of factors: those affecting the process of megakaryocytopoiesis
and the circulation of platelets. The first set of factors is thought to
have more pronounced impact on the size of platelets and their
function [13]. The morphology of platelets remains fairly constant
during their life-span [13]. In other words, the regulation of platelet
function and aging, primarily aimed at maintaining platelet mass
(platelet count multiplied by MPV) and persistent hemostatic poten-
tial, is dependent on the ploidy (ability to reduplicate DNA) and
maturity of thrombopoietic progenitors [14].
Several hormonal and immune agents influence the maturation
of thrombopoietic cells and release of platelets into the circulation.
Of these, thrombopoietin, granulocyte-macrophage colony-stimu-
lating factor, interleukin (IL)-1, tumor necrosis factor (TNF)-alpha,
and IL-6 are important [15]. In steady-state conditions, throm-
bopoietin levels are affected by gender (significantly higher in
males) and platelet count (slightly higher in subjects with lower
platelet count) but not by reticulated (large) platelet count and MPV
[16]. In stress conditions, however, a positive correlation between
thrombopoietin, ploidy of platelet progenitors, functional activity
and high platelet count is more apparent [17].
The regulation of megakaryocytopoiesis is programmed to meet
demands for activated platelets in physiological and pathological
conditions, resulting in time-dependent changes of platelet indices
[18]. This process can be thrombopoietin-dependent and independ-
ent [19]. The interpretation of the resultant changes in platelet indi-
ces, however, is not always straightforward, considering the com-
plexity of inflammatory and immune mechanisms involved.
The frequently described inverse relationship between platelet
count and MPV in physiological and some pathological conditions

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48 Current Pharmaceutical Design, 2011, Vol. 17, No. 1
reflects the tendency to maintain hemostasis by preserving a con-
stant platelet mass [18]. This inverse relationship is often seen in
inflammatory disorders, where enhanced thrombopoiesis increases
the quantity of circulating platelets, and large amount of highly
reactive large-sized platelets migrate to inflammatory sites, where
they are intensely consumed [14]. Importantly, defective throm-
bopoiesis and enhanced destruction and swelling of circulating
platelets in an environment rich in activating agents can affect the
relationship between platelet count and MPV.
Circulating platelets contain matrix ribonucleic acid, mitochon-
dria, alpha- and dense granules which provide mechanisms of self-
regulation by shape-change and release of biologically active sub-
stances [20]. Rapid (minutes-hours) shifts in platelet indices, in-
cluding an increase of MPV, may take place as a result of the syn-
thesis of prothrombotic and pro-inflammatory agents in platelets,
degranulation of alpha-granules, and release of highly reactive
platelets from stores (the spleen). The crucial role of stores in de-
termining reactive changes of platelet indices is confined to exer-
cise-induced stress and activation of the sympathetic nervous sys-
tem [21, 22].
METHODOLOGICAL CHALLENGES IN PLATELET SIZE
QUANTIFICATION
MPV is measured by cell counters employing impedance and
optical effects [23]. The discordance between the results of differ-
ent and even the same cell counters limits the interchangeable use
of MPV [24]. This can explain, at least partly, why hematological
laboratories sometimes do not display the MPV and some other
indices of platelet function.
Inaccurate measurement of platelet indices may be due to inap-
propriate blood sampling and storing. The platelet indices have
been shown to be sensitive to the differences in blood sample anti-
coagulation, storage temperature and delays in processing. In par-
ticular, the time-dependent swelling of platelets in samples antico-
agulated with ethylenediaminetetraacetic acid (EDTA) can result in
an artefactual increase of MPV and misinterpretation of pro-
thrombotic changes [25]. Storage-dependent changes are also char-
acteristic for other simultaneously measured indices, such as mean
platelet component (MPC; reflects density and platelet degranula-
tion) and platelet distribution width (PDW; relates to the platelet
pseudopodia and shape change) [25].
It is widely accepted that platelet swelling in test tubes can be
minimized by rapid processing of samples (within less than 1 h) or
by using tubes with sodium citrate (time-dependent changes are
more characteristic for EDTA) [26]. Notably, within the first hour
of sampling, MPV values of EDTA samples are at least 9% higher
than those of citrated samples [27].
Earlier, it was suggested using tubes with high concentration of
sodium citrate to obtain more reliable measures of MPV [28]. This
recommendation, however, did not meet routine practice demands;
instead, most laboratories continue relying on EDTA as a standard
hematological anticoagulant by further shortening processing times
and by adding MPV stabilizers in standard tubes [29]. For example,
it was shown that wortmanin and tyrphostin (ED-WORTY) solution
used as additives to EDTA blocks platelet signaling pathways and
preserves samples, allowing reliable measurement of MPV and
other platelet indices within 6 h of sampling [29].
Another challenging factor is a poor correlation of MPV with
simultaneously measured indices (i.e., PDW and MPC) and with
the results of other platelet function tests [30]. The lack of agree-
ment may reflect differences in the assessed pathways of platelet
activation, poor laboratory standardization as well as diurnal varia-
tion of MPV in both physiological and pathological conditions [31].
One recent study suggested recording both MPV and PDW to
provide more reliable information [32]. An argument against this,
however, is the fact that of all the variables produced by automated
Gasparyan et al.
cell counters only MPV is well-standardized. Moreover, the prog-
nostic value of PDW is not well explored; the reliability of PDW as
a marker of platelet activation is still questioned [33].
Finally, automated cell counters allow calculating platelet-large
cell ratio, which may provide additional information on the pre-
dominant size of circulating platelets, particularly in conditions
associated with platelet count changes (for example, in reactive
thrombocytosis due to inflammation). In one large laboratory study,
this parameter was positively correlated with MPV and PDW, and it
was shown to be affected by platelet count (an increase of the ratio
in thrombocytopenia and a decrease in thrombocytosis) [34].
PLATELET SIZE AND PROTHROMBOTIC RISK FAC-
TORS
The effects of established cardiovascular risk factors and their
combinations on platelet morphology and thrombogenesis have
been investigated.
Smoking
Cigarette smoking and exposure to nicotine exert a range of
effects on platelet function, which were confounded by age, sex,
duration of smoking and other risk factors. For example, a double-
blind, placebo-controlled study comparing response to chewing
nicotine gum over 30 min in non-smoking hypertensive and nor-
motensive middle-aged men reported an increase of platelet count
and MPV only in hypertensive subjects [35].
A study with young (median age 22.8 years) male subjects
failed to reveal any association between smoking status and MPV
[36], which was apparent in another study with older subjects of
both sexes (mean age 36 years) exposed to smoking over 3-45 years
(an increase of MPV in smokers) [37]. In the latter study, MPV
elevation was shown to be part of smoking-induced low-grade in-
flammation, measured by high-sensitivity C-reactive protein
(hsCRP).
The gender differences in the response of platelets to smoking
may contribute to the risk of thrombosis. Postmenopausal women in
general [16, 38] and smokers in particular [39] present with a high
quantities of large platelets that correlate with an increase of other
markers of platelet activation. In a study with 27 monozygotic,
predominantly female twin pairs (mean age 47.4 years) with a life-
long discordance for smoking, co-twins exposed to this risk factor
had a higher MPV, which was independently associated with athe-
rosclerotic lesions in the carotid arteries [40].
There is evidence from a study of 121 subjects exposed to long-
term smoking (20 cigarettes/day for at least 5 years) suggesting
positive effects of smoking cessation on platelet size (a decrease of
MPV within several months) and their responsiveness to anti-
aggregating agents [41].
Hypertension
The course of hypertension is characterized by platelet activa-
tion primarily due to the effects of sympathetic and renin-
angiotensin systems, shear stress, increased production of reactive
oxygen species, altered regulation of calcium signaling, endothelial
dysfunction and decreased bioavailability of nitric oxide [6]. The
additive effect of comorbid conditions and other risk factors such as
diabetes and hypercholesterolemia further contribute to the altera-
tion of platelet morphology and enhanced risk of thrombosis [6].
With a one exception [42], an increase of MPV in hypertension
has been reported in numerous studies. The observed association
was stronger with the advance of hypertension and presence of
target organ damage: a higher MPV was noted in patients with es-
tablished hypertension compared with those with white coat hyper-
tension [43] or prehypertension [44]. Likewise, those with a higher
blood pressure during night-time (non-dipper hypertensives) had a
higher MPV than dippers [45]. The MPV elevation in adult non-
Mean Platelet Volume
dippers was shown to be part of low-grade inflammation, with a
correlation between MPV and hsCRP (r<0.482; P<0.002) [46].
One well-designed study comparing groups of healthy controls,
patients with hypertension and those with malignant or treatment-
resistant hypertension revealed a stepwise increase of MPV with
elevation of systolic blood pressure and target organ damage [47].
Apparently, left ventricular hypertrophy, retinopathy, myocardial
infarction (MI), and stroke, complicating the course of hyperten-
sion, further disturb the megakaryocytopoiesis and present with a
much higher MPV [48-50].
Blood pressure control over a sufficiently long period (at least
5-6 months) was associated with decreasing MPV and related risk
of thrombosis. Lifestyle modification appeared to be useful for
correcting blood pressure and MPV in prehypertension [51], while
more aggressive antihypertensive therapy was suggested for hyper-
tension [52, 53]. Newly diagnosed, drug-nave hypertensive sub-
jects with a high MPV were shown to respond to 6-month amlodip-
ine- [52] or nebivolol-based therapy [53] with a significant decrease
of MPV and other indices of platelet activation.
Diabetes
Disturbances in endothelial and platelet function coupled with
injurious effects of hyperlipidemia on the vascular wall trigger dia-
betic vasculopathy and thrombosis [54]. Numerous factors are re-
sponsible for platelet activation and release of proinflammatory and
prothrombotic agents in diabetes. Of these, systematic inflamma-
tion, oxidative stress, altered calcium metabolism, decreased
bioavailability of nitric oxide, and increased phosphorylation of
cellular proteins are important [55]. Diabetic platelets are hyperac-
tive, hyposensitive towards the anti-aggregatory effects of prosta-
cyclin and nitric oxide, and produce large amounts of thromboxane
A2, thus attenuating the antiplatelet effects of aspirin and clopi-
dogrel [7, 56, 57].
In a large series of case-control and cohort studies, platelet acti-
vation in diabetes has been linked to the production of large plate-
lets, shape change and enlargement of circulating platelets. Notably,
in one of the earliest studies, MPV correlated with blood glucose,
glycated hemoglobin (HbA1c) and urinary 11-dehydro-thromboxane
B2 (a metabolite of thromboxane A2) levels [58]. An increase of
MPV and its correlation with blood glucose and HbA1c were also
noted in prediabetic subjects with impaired fasting glucose and
impaired glucose tolerance [59, 60]. With the advance of insulin
resistance and transition from prediabetes to diabetes, the elevation
of MPV reaches its highest level [61] and remains fairly constant
and independent of age, sex and duration of diabetes [62, 63].
Within diabetic subjects, MPV was found to be greater in those
with microangiopathy (i.e., retinopathy, microalbuminuria), in-
flammation, nephropathy, atherosclerotic vascular disease and heart
failure [64-66].
Therapeutic options for decreasing MPV and attenuating the
associated risk of thrombosis in diabetes have not been specifically
addressed. It seems, however, plausible to decrease MPV by im-
proving glycemic control (HbA1c <7%) [68].
Dyslipidemia and Obesity
Hypercholesterolemia is an established vascular risk factor,
which interacts with a wide range of inflammatory and pro-
thrombotic agents and contributes to atherogenesis [69]. Notably,
dyslipidemia triggers release of CD40 ligand, IL-1beta, platelet
factor (PF)-4 and other chemokines from platelets [69]. The over-
production of platelet cytokines in dyslipidemia mobilizes progeni-
tors from the bone marrow and causes thrombocytosis [70]. Platelet
activation and changes in MPV values are not entirely related to the
quantitative shifts in cholesterol metabolism; qualitative modifica-
tions in platelet membrane phospholipids also play a role [71].
Current Pharmaceutical Design, 2011, Vol. 17, No. 1 49
In animal models of alimentary hypercholesterolemia, a choles-
terol-rich diet enhanced megakaryocyte ploidy and led to reactive
thrombocytosis, with a decrease in platelet size [72, 73]. A similar
pattern of changes in platelet count and MPV was noted in patients
with hypercholesterolemia undergoing coronary artery bypass sur-
gery [74]. In subjects with hypercholesterolemia and unaltered
platelet count, an increased ploidy of megakaryocytes, enhanced
expression of platelet glycoprotein IIIa and elevated MPV were
noted [75]. The effect of dyslipidemia on MPV in apparently
healthy subjects is probably time-dependent, as it was shown that
diet-induced hypercholesterolemia has no effect on platelet count
and MPV over a 2-month period [76]. In contrast, uncontrolled
primary dyslipidemia, fatty liver disease, and obesity are all found
to be associated with elevated MPV [77-79]. Furthermore, when
dyslipidemia (hypertriglyceridemia) and abdominal obesity com-
bine with elevated blood pressure and hyperglycemia, MPV eleva-
tion becomes more expressed and dependent on metabolic status
[80, 81]. Insulin resistance was shown to trigger the MPV elevation
prior to clinical manifestation of the metabolic syndrome [80]. Fur-
thermore, a study with 207 patients with the metabolic syndrome
reported that waist circumference and fasting blood glucose con-
tribute to the elevation of MPV more significantly than angi-
ographically documented coronary artery disease (CAD) [81].
Lipid-lowering and weight-reducing therapies have been shown
to exert both increasing and decreasing effects on MPV. In one
longitudinal study with 55 hyperlipidemic subjects, cholesterol-
lowering diet high in plant sterols, soy protein, viscous fibers, and
almonds slightly increased MPV (0.160.07 fl; P=0.033) at the end
of a 12-month period [82]. An increase in MPV was also observed
with short-term dietary supplementation of cod liver, olive or whale
oil [83, 84] and n-3 polyunsaturated fatty acids [85]. It was pointed
out that negative consequences of weight-reducing therapies, in-
cluding the rise of MPV, are often due to low calorie [86] or purely
vegetarian diets [87]. The positive, decreasing effect of drug thera-
pies on MPV in metabolic disorders was recorded in only few small
studies with rosuvastatin [78], gamma-tocopherol [88] or doxazosin
[89]. Obviously, more prospective studies with thrombotic end-
points are warranted to assess the prognostic role of MPV values in
these disorders.
PLATELET SIZE IN PROTHROMBOTIC DISEASES
Evidence derived from both retrospective and prospective stud-
ies suggests that large platelets and high MPV, in particular, are
predictors of thrombotic events in several predominantly arterial
disorders [90].
Cardiovascular Disease
Experimental and clinical evidence supports the concept that
the main triggers of platelet activation, enlargement and involve-
ment in acute coronary syndromes are factors affecting the matura-
tion and ploidy of megakaryocytes [91]. A variety of inflammatory
cells and bioactive agents, such as IL-6 and CRP, alter the mor-
phology and reactivity of platelets released from the bone marrow
several weeks before thrombotic coronary events [91]. Actually, a
high MPV is detectable from the first hours of the destabilization of
CAD and onset of MI [92-95].
In a large comparative study with subgroups of patients (n=981)
differing in the extent (one-, two- and three-vessel disease) and
stability of CAD (stable, unstable angina and angina requiring ur-
gent percutaneous coronary intervention [PCI]), differences in
MPV values were noted only between patients with stable and un-
stable angina [96]. Patients requiring PCI had the highest MPV
(10.41.03 fl).
Another comparative study with patients with stable CAD
(n=185) and those who suffered MI (n=188) highlighted the impor-
tance of MPV monitoring [97]. In this study, the highest quintile of
MPV (>11.6 fl) was associated with the greatest risk of MI (ad-
50 Current Pharmaceutical Design, 2011, Vol. 17, No. 1 Gasparyan et al.

justed Odds Ratio [OR] = 2.6, 95% Confidence Interval [CI] 1.3-
5.1). Moreover, in a cohort study (n = 282), MPV above the 10.35
fl cut-off level predicted unstable angina and MI with 78.3% sensi-
tivity and 74.6% specificity [95].
Contrasting are the results of some case-control studies that did
not detect a difference in MPV values between patients with MI and
healthy controls [98, 99], which might be due to the intense con-
sumption of large, hyperactive platelets at the sites of ongoing
thrombus formation, myocardial injury and inflammation.
The most valuable evidence in favor of MPV as a marker of
thrombosis in cardiovascular disease derived from prospective stud-
ies (Table 1). Despite some limitations due to the lack of laboratory
standardization, these studies, to a certain extent, support value of
elevated MPV in predicting recurrent MI and death in post-
infarction period [100], impaired myocardial reperfusion after
thrombolysis [101] or PCI in ST-elevation MI (no-reflow phe-
nomenon in an infarct-related artery) [102, 103] and restenosis after
PCI in angina [104-106].
Antiplatelet therapy with GPIIb/IIIa blocker abciximab was
shown to reduce the risk of short-term mortality after PCI in pa-
tients with MPV >8.95 fl (adjusted Hazard Ratio [HR] 1.44 in those
who were treated with abciximab vs 3.67 in those who were not)
[107]. Additionally, it was demonstrated that elevated MPV can
help stratify cardiovascular risk and predict thrombotic events in
those who fail to respond to aspirin therapy [108].
To sum up, a recent large meta-analysis on MPV in cardiovas-
cular disease provided evidence supporting the association of ele-
vated MPV with MI, restenosis after PCI and mortality [109]. A
pooled analysis of 3 cohort studies with a total of 3,184 patients
with MI yielded a significant mortality prediction value of high
MPV (OR 1.65, 95%CI 1.12-2.52; P=0.012) [109].
A few studies have focused on MPV in heart failure. It should
be noted that heart failure is an endpoint of untreated cardiovascular
disorders [110]. Low-grade inflammation has been shown to ac-
company heart failure [111]. Platelet size was found to be increased
in stable heart failure along with the elevation of other markers of

Table 1. Prospective Studies on MPV in Prothrombotic Disease States

Refs. P T Endpoints Main Results Antiplatelet Effects

[100] 1,716 post-MI M
24 h MI and death within 2 126 P had MI and 88 P died. Their baseline MPV and NS
aged <70 y from y fibrinogen were . P at the highest quartile of MPV were
21 centers twice more likely to develop MI or die compared to P at
the lowest quartile.

[101] 122 P with A Coronary artery oc- MPV was  in P with failed thrombolysis (P=0.019). NS
STEMI on few clusion (TIMI flow Cut-off value 8.6 fl was used. The failure was more fre-
thrombolysis min grade 0-1) and in- quent in P with MPV >8.6 fl (31.8% vs. 16%; P=0.048).
(91% M; MA hospital mortality
58.5 y)

[102] 388 P with 30 Impaired reperfusion Mortality was  at the highest tertile of MPV (10.3 fl). Abciximab
mortality in P
STEMI and PCI min (based on TIMI scale) MPV10.3 fl predicted no-reflow (adjusted OR 4.7, with MPV10.3 fl (OR 0.02,
(72.2% M; MA and 6-m all-cause 95%CI 2.3-9.9; P<0.0001) and 6-m mortality (OR 3.2, 95%CI 0.01-0.48;
60 y) mortality 95%CI 1.1.-9.3; P=0.0084). P=0.0165).

[107] 617 P with
1 h Impaired reperfusion MPV was  in P with TIMI 0-1 compared to TIMI 2-3 MPV>8.95 fl predicted
STEMI and PCI (based on TIMI scale) (median MPV 9 fl vs. 8.5 fl; P<0.0001). MPV predicted mortality in those who were
(82% M; MA 64 and 1-m mortality successful reperfusion (OR 0.63, 95%CI 0.51-0.78; not on abciximab compared
y) P<0.0001). to those who were (HR
3.67).

[122] 3,134 P (71% M; 24-48 Stroke during a mean 1fl increment of MPV was associated with a 15% P received perindopril plus
MA 65 y) with h follow-up of 3.9 y ischemic stroke RR . indapamide or perindopril.
CVD Baseline and follow-up MPV
were not different.

[126] 25,923 subjects
12 h VTE during 1994- There were 186 (42%) unprovoked events (DVT and NS
aged 25-94 y 2007 PE). Those with MPV9.5 fl had a 1.5-fold  risk of
unprovoked VTE compared to those with MPV<8.5 fl
(HR 1.5, 95%CI 1.0-2.3; P=0.04).

[127] 192 P with acute
30 1-m mortality MPV was  in non-survivors compared to survivors Aspirin intake did not differ
PE (113 F, 79 M; min (P<0.01). Kaplan-Meier curves revealed differences in 7- between survivors and non-
MA 64 y) (18% vs. 4%; P<0.01) and 30-day mortality rates (18% survivors and P with  and

vs. 7%, P<0.05) between P with MPV>10.9 fl and
10.9 MPV.
fl. MPV predicted 7- (HR 2.0, 95%CI 1.3-3.0; P<0.001)
and 30-day mortality (HR 1.7, 95%CI 1.2-2.5; P<0.01).
MPV: mean platelet volume; M: male; F: female; y: year; m: month; MI: myocardial infarction; h: hour; T: time of MPV measurement after sampling in ethylenediaminetetraacetic
acid-containing tubes; P: patient; STEMI: ST-elevation MI; MA: mean age; TIMI: Thrombolysis In Myocardial Infarction (angiographic flow grade scale); NS: not studied; PCI:
percutaneous coronary intervention; OR: Odds Ratio; CI: Confidence Interval; HR: Hazard Ratio; RR: relative risk; CVD: cerebrovascular disease; VTE: venous thromboembolism;
DVT: deep venous thrombosis; PE: pulmonary embolism; : increased or high;
: decreased or low.
Mean Platelet Volume
platelet activation [112]. The increase of platelet size was especially
expressed in decompensated heart failure and found to be predictive
of related mortality [113].
Cerebrovascular Disease
Elevated MPV is a characteristic laboratory feature of ischemic
stroke, detectable from the early hours of its onset. It is probably
present well before the acute cerebrovascular event, and it persists
during the long-term recovery period (3-6 months) [114]. A higher
MPV is associated with a larger volume of cerebral damage and
greater risk of poor outcomes (death or dependence) during the
early post-stroke period [115, 116].
In a large multi-center cross-sectional study with 776 patients
with ischemic stroke or transient ischemic attack, those within the
highest baseline quintile of MPV (11.3-15.3 fl) suffered a more
severe stroke 1 week after the admission (adjusted OR 2.2, 95%CI
1.2-4.0; P=0.013), with a modified Rankin Scale (mRS) score of 3-
6 (death or dependence) [115]. The association between high MPV
and severity of ischemic stroke was also reported in another cohort
study (n=384), which, however, did not find any differences in
relation to the cause, localization, and size of cerebral infarcts
[117]. The absence of association between high MPV and severity
and outcomes of ischemic stroke was confirmed in a recent 12-
month follow-up study [118].
Notably, the differences in MPV within the patients can be
related to an increased consumption of large platelets at the sites of
cerebrovascular thrombosis and inflammation [119, 120] as well as
to the level of hypertension. The latter turned out to be the strongest
independent determinant of MPV in stroke patients [121].
The prognostic value of MPV was investigated in a prospective
multi-center study with 3,134 hypertensive patients within 5 years
of stroke and/or transient ischemic attacks [122] (Table 1). During
the follow-up period (a mean 3.9 years), 301 ischemic, 59 hemor-
rhagic, and 42 strokes of unknown origin were registered. MPV
was associated with ischemic strokes only, with the highest number
of events at the highest quintile of MPV. When baseline and more
than 1 year on-treatment MPV measurements were compared be-
tween the treatment arms (perindopril plus indapamide vs perindo-
pril alone) there was no difference. The results of this study led to a
conclusion that MPV can serve as a prognostic marker of stroke in
high-risk patients and that angiotensin-converting enzyme (ACE)
inhibition does not provide an antiplatelet effect.
Antiplatelet therapy may seem to be a challenging task, particu-
larly given the inability of widely used aspirin at 75-300 mg/daily
dose to alter megakaryocytopoiesis and to decrease MPV in patients
with ischemic stroke [123].
Other Diseases
It has been increasingly recognized that platelets are involved in
venous thromboembolism (VTE). Activated by abnormal venous
blood flow, platelets may interact with erythrocytes, endothelial
cells, neutrophils and monocytes and released fibrinogen, tissue
factors as well as other agents resulting in venous thrombosis [124].
Relatively few studies have focused on MPV in conditions
associated with venous thrombosis and right ventricular dysfunc-
tion. Though an increase of MPV was noted in deep vein thrombo-
sis [125], pulmonary thromboembolism [126, 127] and pulmonary
hypertension [128], determinants of this marker in these disorders
are ill-defined. The Troms Study (Table 1), which is the largest
and longest population-based study on MPV, demonstrated a strong
independent association of high MPV (
9.5 fl) with venous throm-
boembolism without underlying surgery, trauma, immobilization or
cancer (adjusted HR 1.5, 95%CI 1.0-2.3; P = 0.04) [126]. MPV was
also found to be a predictor of poor outcomes in patients with acute
pulmonary embolism (a 30-day mortality adjusted HR 1.7, 95%CI
1.2-2.5; P<0.01) [127].
Current Pharmaceutical Design, 2011, Vol. 17, No. 1 51
In conclusion, elevated MPV was noted in some other disorders
frequently associated with arterial and venous thrombosis, such as
atrial fibrillation [129], mitral stenosis [130], dilated cardiomyopa-
thy [131] and thyroid dysfunction [132, 133]. It is possible that the
elevation of MPV in these conditions results from the effect of low-
grade inflammation and metabolic perturbations on thrombopoiesis.
The latter is particularly obvious in paroxysmal atrial fibrillation
associated with both elevated MPV and CRP [129].
PLATELET SIZE IN INFLAMMATORY DISORDERS
Evidence has accumulated suggesting an important role of
MPV as a marker of inflammation, disease activity and efficacy of
antiinflammatory treatment in several chronic inflammatory disor-
ders (Table 2). It would seem that the size of circulating platelets is
dependent on the intensity of systemic inflammation, with contrast-
ing features of MPV in high- and low-grade inflammatory disorders
and in the course of antiinflammatory treatment. Disease-specific
and cardiovascular confounding factors affect the direction of MPV
changes. Platelet count estimations further complicate the interpre-
tation of MPV values in thrombocytopenia.
Systemic Lupus Erythematosus (SLE)
The autoimmune reactions and abundant production of an-
tiphospholipid antibodies directed against blood cells, including
platelets, are thought to contribute to platelet activation, release of
vasoactive and thrombogenic agents and accelerated atherogenesis
in SLE [134]. Antibodies targeting platelet glycoproteins IIb/IIIa,
Ib/IX and IV were identified and linked to thrombocytopenia in
SLE [135].
In one of the earliest laboratory investigations of MPV [24], low
MPV (<7.2 fl) was recorded by 2 different hematology analyzers in
5 (14.3%) and 23 (65.7%) patients with SLE, mostly at active stage
of the disease (n=28, 80%). Unfortunately, no conclusion was made
with respect to the role of MPV, since there was no proper calibra-
tion and timing of blood samples processing.
Inflammatory Bowel Disease (IBD)
An increased P-selectin, CD40 ligand, beta-thromboglobulin,
PF-4, and platelet-leukocyte aggregates propagate intestinal in-
flammation in IBD by forming microaggregates and obstructing
mesenteric circulation [136]. Some, but not all, of these platelet
markers are associated with activity and extent of the disease [136].
Thrombocytosis with an increase in the quantity of low-sized plate-
lets is a frequent feature in both ulcerative colitis (UC) and Crohns
disease (CD) [137, 138]. Based on observational studies, MPV has
been identified as a marker of IBD activity [138] and the extent of
intestinal inflammation, assessed clinically and endoscopically
[139, 140]. Compared with acute-phase reactants, a higher predic-
tive value of MPV was demonstrated in relation to disease activity
in UC [140]. In UC and CD, MPV was inversely correlated with
acute-phase reactants, beta-thromboglobulin and PF-4 [139]. Gen-
der differences might also affect this association [141]. In patients
with UC, a low MPV was recorded in those with extraintestinal
inflammatory manifestations [140], suggesting an intense consump-
tion of large platelets.
Rheumatoid Arthritis (RA)
RA is the most common inflammatory arthritis associated with
high-grade systemic inflammation, progressive destruction of pe-
ripheral joints and extraarticular manifestations, of which acceler-
ated atherosclerosis is the main contributor to premature mortality
in these patients [142, 143]. Though it has been long known that
thrombocytosis is a frequent finding in active RA, only recently
platelet-derived microparticles and other markers of platelet activa-
tion were recognized as triggers of arthritis and an essential link
between RA and accelerated atherosclerosis [11].
52 Current Pharmaceutical Design, 2011, Vol. 17, No. 1 Gasparyan et al.

Table 2. Studies on MPV in Inflammatory Disorders

Refs. P Main Results Effects of Therapy MPV -marker of

[139] 93 with UC (33 F; CCAI>4 in active UC and CDAI>150 in active CD. In UC and CD (vs. NS Disease activity
MA 49.5 y) and healthy controls), MPV
, platelet count . MPV
in active vs. inactive
66 with CD (25 F; states. MPV was much
in UC with pancolitis vs. limited colitis and in
MA 43.3 y) CD with ileocolonic disease vs. only colonic or terminal ileal inflamma-
tion. MPV inversely correlated with CRP, ESR, beta-TG, and PF-4.

[140] 61 with UC (20 F; MPV was
in P in active compared to inactive disease (P=0.01). MPV NS Disease activity
MA 42.2 y) and endoscopic activity index correlated (r=-0.358; P=0.005). P with ar-
thritis and uveitis had much
MPV. The MPV cut-off value 8.0 fl was
highly specific (73%) for prediction of UC activity.

[141] 195 with UC (102 A significantly
MPV was in males with UC and CD. In UC male P, NS Inconclusive data
F; MA 46.4 y) and MPV correlated with CCAI (r= -0.341; P= 0.001) and CRP (r= -0.276;
76 with CD (26 F; P=0.015). In CD, MPV correlated with CDAI (r= -0.32; P<0.001) in males
MA 45.4 y) only.

[144] 32 with RA (25 F; MPV was
in RA P compared with osteoarthritis controls (P<0.001). On therapy, ESR and Inflammation
MA 49 y) Platelet count and ESR (5530.6 mm/h) were  in RA. DAS28
; MPV 
(P<0.001).

[145] 21 with RA (13 F; P with high DAS28 (mean 4.22) were eligible for anti-TNFalpha therapy. On therapy, DAS28
Efficacy
MA 56.5 y) (P<0.001); MPV 
(P<0.016).

[146] 97 with early RA MPV  in RA (P<0.004). P had also  platelet count, ESR and CRP. MPV MPV, DAS28, ESR, and Disease activity
(78 F; MA 51 y) correlated with DAS28 (r=0.27; P=0.007) only. CRP
after therapy. and efficacy

[147] 400 with RA (292 Both MPV and platelet count were  in RA compared with non-RA con- Groups with high and CV risk
F; MA 61.6 y) trols (P<0.0001). MPV
10.7 fl was more frequent in RA cohort than in low MPV did not differ
non-RA controls (21% vs. 9.2%; P<0.0001). Hypertension was a strong in terms of treatment.
predictor of high MPV (OR 2.2, 95%CI 1.3-3.7; P=0.003).

[144] 30 with AS (15 F; MPV was
in AS vs. healthy controls (P<0.001). ESR (6024.5 mm/h) ESR and BASDAI
, Inflammation
MA 36 y) and platelet count . MPV  (P<0.001),
MPV and BASDAI
correlated (r=0.507;
P=0.004) after therapy

[149] 68 with AS (22 F; MPV was  in AS vs. healthy controls (P<0.001). Platelet count, CRP and BASDAI, ESR, platelet Disease activity
MA 36.4 y) ESR . count, and MPV
after and efficacy
therapy.

[150] 20 males with P had mild to moderate disease severity, were free of CV risk factors and NS Inflammation
psoriasis (MA 23 were drug nave. MPV and CRP were  in P vs. in healthy controls. MPV
y) positively correlated with PASI.

[151] 106 with psoriasis MPV was  in P vs. healthy controls (P<0.001). P with arthritis had much NS Disease severity
(47 F; MA 41.4 y)  MPV. MPV positively correlated with PASI and duration of psoriasis.

[153] 111 children with MPV was
in attacks vs. attack-free period (P<0.001). MPV correlated NS Disease severity
FMF (52 F) with platelet count (r=-0.45; P<0.01) and FMF severity (r=-0.38; P<0.01)
but not with acute-phase reactants.

[154] 35 with FMF (16 Attacks and CV risk factors were excluded. P were on colchicine. MPV  MPV and duration of CV risk
F; MA 34 y) in P vs. healthy controls (P=0.001). therapy correlated (r=-
0.40; P=0.017)

[156] 60 with BD (29 F; MPV was  in venous thrombosis. No difference in MPV between P with NS Venous
MA 40.5 y) active and inactive BD. thrombosis
P: patients; F: females; MA: mean age; y: years; NS: not studied; UC: ulcerative colitis; CD: Crohns disease; CCAI: Clinical Colitis Activity Index; CDAI: Crohns Disease Activity
Index;
: lower (decreased); : higher (increased); CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; beta-TG: beta-thromboglobulin; PF-4: platelet factor 4; RA: rheu-
matoid arthritis; DAS28: Disease Activity Score 28; TNF: tumor necrosis factor; AS: ankylosing spondyloarthritis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index;
CV: cardiovascular; PASI: Psoriasis Area and Severity Index; FMF: familial Mediterranean fever; BD: Behet's disease.
Mean Platelet Volume
High-grade inflammation accompanies a decrease of MPV in
RA, possibly due to the increased consumption of platelets at the
sites of rheumatoid inflammation. A reverse shift of MPV results
from the suppression of inflammation by disease-modifying and
anti-TNF-alpha agents [144, 145]. Importantly, an association of
MPV with inflammatory markers and severity of RA was depend-
ent on the prevalence of cardiovascular risk factors. In one study,
where only dyslipidemia among risk factors was excluded, MPV
was significantly higher in RA patients compared with healthy con-
trols (P<0.004) [146]. Moreover, in a large cohort study, hyperten-
sion was a strong predictor of high MPV (
10.7 fl) (OR 2.2, 95%CI
1.3-3.7; P=0.003) [147].
Other Diseases
A low MPV was noted in ankylosing spondyloarthritis (AS) in
connection with a high disease activity (Bath Ankylosing Spondy-
litis Disease Activity Index [BASDAI] >4) and an intense inflam-
matory reaction [148]. It is, however, more likely to see an increase
in MPV in active AS and a decrease in response to anti-
inflammatory therapy, with a positive correlation between MPV
and BASDAI [149]. A similar increase in MPV was noted in pso-
riasis [150, 151], especially in psoriatic arthritis [151].
Familial Mediterranean fever (FMF), an autoinflammatory dis-
order characterized by febrile, short-lived (1-3 days) attacks of
polyserositis and symptom-free periods of subclinical low-grade
inflammation [152], was associated with a decrease of MPV in
attacks in pediatric patients [153]. A possible explanation could be
the consumption of large platelets at the sites of serosal inflamma-
tion, which may occur well before clinical manifestation of the
attacks. In attack-free periods in adult FMF patients, circulating
platelets tend to be larger which may be viewed as a marker cardio-
vascular risk [154].
MPV changes have also been investigated in Behets disease
(BD) [155, 156], another autoinflammatory multisystem disorder
characterized by recurrent oral and genital ulcers, eye and skin le-
sions and generalized vasculitis. BD is a model of venous thrombo-
sis, where platelet activation may play a role [157]. It was shown
that an increase of MPV may indicate the presence of venous
thrombosis [156], but MPV is an inappropriate marker of activity in
BD [155, 156].
CONCLUDING REMARKS
Understanding of the role of platelets in a variety of thrombotic
and inflammatory disorders has substantially improved, owing to
the recent advances in the quantification of laboratory markers of
platelet function. MPV has emerged as a relatively reliable marker
of thrombopoiesis and platelet function. MPV is routinely measured
by automated cell counters but sometimes disregarded because of
the inappropriate storage of blood samples and artefactual, time-
dependent changes in EDTA anticoagulated samples. As with most
platelet function tests, the reliability of the MPV quantification is
subject to preanalytical factors.
It has become evident that MPV is a reflection of both pro-
inflammatory and prothrombotic conditions, where thrombopoietin
and numerous inflammatory cytokines (e.g., IL-1, IL-6 and TNF-
alpha) regulate thrombopoiesis. The intensity of systemic inflam-
mation can be viewed as a distinctive factor for classifying condi-
tions associated with large and small-sized circulating platelets
(Fig. 1). From this standpoint high-grade inflammatory conditions
(e.g., active IBD, RA or attacks of FMF) are associated with circu-
lation of predominantly small platelets, whereas the same disorders
at remission and controlled by antiinflammatory drugs are associ-
ated with large circulating platelets (Table 1). Established cardio-
vascular risk factors, such as smoking, hypertension, diabetes, as
well as age, sex, and possibly ethnicity can modify shifts of MPV,
affecting the expected inverse relationship between MPV and plate-
let count seen in inflammatory thrombocytosis. Disease-specific
Current Pharmaceutical Design, 2011, Vol. 17, No. 1 53
pathophysiological factors (e.g., antiphospholipid antibodies in SLE
or vasculitis in BD) can also either decrease or increase MPV.
MPV has been regarded as a prognostic marker of not only
arterial but also venous thrombosis, particularly in subjects without
any provoking factors and in patients with BD. The relevant data,
however, can not explain mechanisms triggering changes of MPV
in venous thrombosis, and more specifically designed prospective
studies with better standardized laboratory tests are warranted.
In contrast to the conditions where thrombopoiesis determines long-
term changes of MPV (e.g., MI and stroke), the activation of the
sympathetic system and release of platelets from the spleen may
underlie rapid shifts in MPV values (within minutes-hours). How-
ever, the rapid increase of MPV due to the release of large platelets
from the spleen is more likely in the presence of an underlying pro-
thrombotic condition [21].
Recently, genome-wide association studies have discovered yet
another determinant of MPV, genetic polymorphisms predisposing
to thrombosis. In a population-based study, single-nucleotide poly-
morphisms of rs7961894 located on chromosome 12q24.31,
rs12485738 on chromosome 3p13-p21, and rs2138852 on chromo-
some 17q11.2 were found to account for 4-5% variation of MPV
[158]. In addition, sequence variations at the 7q22.3 region were
identified as modifiers of thrombopoiesis and MPV in another large
study [159]. Clearly, more studies are warranted to ascertain the
role of these genetic factors in the regulation of MPV in inflamma-
tion and thrombosis.
A few studies have investigated the effects of therapeutic inter-
ventions on MPV in various clinical conditions. Aspirin, with its
specific action on the arachidonic acid cascade in megakaryocytes
and platelets, was found to exert little, if any, effect on MPV [123,
160]. The failure to affect platelet size was also reported in the case
of dual (aspirin + clopidogrel) therapy [161]. It was, however,
demonstrated that purinergic receptors (P2Y1 and P2Y12) are inti-
mately involved in the control of platelet shape and volume change
[162], and it is more likely that P2Y12 receptor blockers, particu-
larly thienopyridine compounds at loading doses and novel P2Y12
blockers with an increased bioavailability, rapid onset of action and
potent inhibition of platelets, can influence MPV. A relevant exam-
ple, in this regard, is the study showing an inhibition of purinergic
and serotoninergic platelet activation and volume change within 4 h
of clopidogrel intake at a 300 mg loading dose [163].
Another potent antiplatelet agent, a GPIIb/IIIa blocker abcixi-
mab, proved to be efficient in reducing MPV and associated risk of
thrombotic events in patients with MI undergoing PCI [107].
Whether the clinically significant effect of abciximab on MPV is
dependent on platelet shape and volume regulating mechanisms, as
well as whether the positive effect on MPV is universal within the
whole group of GPIIb/IIIa blockers remain to be ascertained. At
least, an in vitro investigation with tirofiban, another GPIIb/IIIa
blocker, indicates the complexity of the raised questions: tirofiban
non-specifically inhibits platelet aggregation, the late stage of plate-
let activation, but does not exert any effect on initial platelet shape
change [164].
The results of investigations of pleiotropic antiplatelet effects of
several drugs may have implications for future therapeutic strate-
gies. Of interest, a large prospective study failed to detect the plate-
let inhibiting effect of an ACE inhibitor perindopril, based on re-
peated measurements of MPV in patients with stroke [122]. It was,
however, expected that perindopril through the activation of nitrer-
gic mechanism could suppress activated platelets and decrease
MPV. The study had some limitations inherent to the lack of labo-
ratory standardization and chosen treatment arms (perindopril plus
indapamide vs perindopril alone), which may indicate the need for
better designed investigations on the effects of ACE inhibitors on
MPV. It would be also useful to test the same pleiotropic effect of
54 Current Pharmaceutical Design, 2011, Vol. 17, No. 1 Gasparyan et al.

Cardiovascular risk factors

Smoking Hypertension Dyslipidemia

Diabetes Obesity

Low-grade inflammatory disorders High-grade inflammatory disorders

Psoriasis AS FMF BD SLE RA IBD

Low-grade systemic inflammation High-grade systemic inflammation

TNF-
IL-1 IL-6

MI Stroke Consumption of
Involvement of
large platelets large platelets at
in thrombi the sites of
inflammation

Arthritis

Venous
thrombosis MPV
MPV MPV
MPV

AS: ankylosing spondylitis; FMF: familial Mediterranean fever; BD: Behcets disease; SLE: systemic lupus erythematosus; RA: rheumatoid
arthritis; IBD: inflammatory bowel disease; IL-1: interleukin-1; TNF-
: tumor necrosis factor alpha; IL-6: interleukin-6; MPV: mean platelet
volume.

Stem cell

Megakaryoblast

Megakaryocyte

Activated platelet
Fig. (1). Possible factors affecting platelet size and its association with thrombosis and inflammation.

angiotensin II antagonists, as an in vitro investigation showed inhi-
bition of MPV increase by losartan [165].
In hypertension and conditions associated with a complex of
risk factors affecting platelets and the vasculature (e.g., the meta-
bolic syndrome), doxazosin inhibited serotonin-induced platelet
volume increase [89, 166]. In high-risk patients with dyslipidemia
and increased MPV an appropriate therapeutic option is statin ther-
apy [78], which demonstrated antagonism toward platelet perox-
isome proliferator-activated receptors [167] and independent bene-
ficial effect on thrombotic risk [168]. It is, however, relevant to
prospectively investigate an impact of different statins in various
conditions (e.g., in dyslipidemias with and without low-grade in-
flammation) on MPV and thrombosis.
The shifts in MPV in studies on lipid-lowering, weight-reducing
[78, 83-87] as well as antiinflammatory [145] therapies support the
role of this marker in monitoring therapeutic effects. It is highly
likely that the elaboration of universally acceptable standards of the
MPV measurement will allow utilizing this tool in large prospective
studies on conditions associated with both thrombosis and inflam-
mation.
ACKNOWLEDGEMENTS
AYG and GDK thank the Dudley Group of Hospitals NHS
Foundation Trust, UK (A Teaching Trust of University of
Birmingham, UK) for their support.
Mean Platelet Volume
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