Clinical Interventions in Aging

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The mean platelet volume on admission predicts

unfavorable stroke outcomes in patients treated
with IV thrombolysis

Jacek Staszewski, Aleksandra Pogoda, Kamila Data, Klaudia Walczak, Maciej

Nowocień, Emilia Frankowska & Adam Stępień

To cite this article: Jacek Staszewski, Aleksandra Pogoda, Kamila Data, Klaudia Walczak,
Maciej Nowocień, Emilia Frankowska & Adam Stępień (2019) The mean platelet volume on
admission predicts unfavorable stroke outcomes in patients treated with IV thrombolysis,
Clinical Interventions in Aging, , 493-503, DOI: 10.2147/CIA.S195451

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Open Access Full Text Article Original Research

The mean platelet volume on admission predicts

unfavorable stroke outcomes in patients treated
with IV thrombolysis
This article was published in the following Dove Medical Press journal:
Clinical Interventions in Aging

Jacek Staszewski 1 Purpose: The role of biomarkers in the prediction of acute ischemic stroke (AIS) outcome
Aleksandra Pogoda 1 or response to thrombolytic therapy (with recombinant tissue plasminogen activator [rt-PA])
Kamila Data 1 remains limited. The aim of this study was to evaluate whether mean platelet volume (MPV)
Klaudia Walczak 1 could predict short-term functional outcome in patients with AIS following rt-PA treatment.
Maciej Nowocień 2 Patients and methods: This was a retrospective analysis of 237 AIS patients (mean age
71.04±0.8 years, 50.6% women) consecutively admitted to a tertiary care center between
Emilia Frankowska 2
2011 and 2015.
Adam Stępień 1
Results: The mean MPV in the cohort was 9.8±0.35 fL (lowest tertile ,7.29 fL, median
1
Clinic of Neurology, Military 7.29–8.8 fL, and highest tertile .8.8 fL). Patients in the lowest tertile compared to median
Institute of Medicine, Warsaw, Poland;
2
Department of Radiology, Military and highest tertiles were less often dependent (modified Rankin scale [mRS] $3) at admission
Institute of Medicine, Warsaw, Poland (87.2% vs 96.1% and 96.1%, respectively, P=0.04) and less often had a poor stroke outcome
(mRS 4–6) at discharge (28.2% vs 55.3% and 44.7%, P,0.01). However, there was no significant
difference between tertiles with regard to AIS etiology, CT (Alberta Stroke Program Early CT)
score, frequency of stroke due to large artery occlusion, risk of secondary hemorrhage, and early
neurologic deterioration. Multivariable analysis after adjustment for confounders showed that
patients in the second and third tertiles had a significantly higher risk of poor stroke outcome
(OR =1.9, 95% CI =1.01–4), lack of early improvement (OR =1.91, 95% CI =1.05–3.47), lower
chance of good outcome (mRS 0–2; OR =0.38, 95% CI =0.18–0.78), or minor stroke at discharge
(OR =0.47, 95% CI =0.26–0.84). Receiver operating characteristic analysis for prediction of
poor stroke outcome showed that the optimal cut-off point of MPV was 8.8 fL (area under the
curve 0.586 [0.512–0.659], P=0.03) with a sensitivity of 82.7% and a specificity of 43.9%.
Conclusion: Disabling or fatal ischemic stroke in thrombolyzed patients was observed more
often in patients with high admission MPV. The prognostic value of MPV was independent of
other well-defined individual risk factors.
Keywords: acute ischemic stroke, rt-PA, prognosis, MPV, biomarker, platelet activity,
reperfusion

Introduction
Thrombolytic therapy (with recombinant tissue plasminogen activator [rt-PA]) is an
effective treatment for acute ischemic stroke (AIS). The efficacy of rt-PA has been
reported to be related to the location of the occlusion, collateral blood supply, and
Correspondence: Jacek Staszewski clot-specific factors such as size, composition, and origin of the thrombus; however,
Clinic of Neurology, Military Institute
of Medicine, Szaserow 128, 04-141
reliable predictors of early and late outcomes as well as predictors of intracranial
Warsaw, Poland hemorrhage in patients who receive rt-PA in AIS are unknown.1 The ideal marker of
Tel +48 6181 8419
Fax +48 22 810 6100
reperfusion would help predict when standard rt-PA therapy will not lead to prompt
Email [email protected] artery recanalization; thus, a more specific treatment (ie, mechanical thrombectomy)
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could be immediately adopted in such cases. Unfortunately, was applied and treatment was allowed up to 4.5 hours after
clinical and laboratory predictors of failed thrombolysis have onset provided that there were no contraindications in either
not been identified because the mechanisms underlying acute situation.10 Patients treated with intra-arterial thrombolysis or
occlusion and the variable response to lytic therapy are still thrombectomy were excluded from this analysis. We also did
largely unknown. not include patients with autoimmune disorders, immunosup-
Hyperactive platelets play a pivotal role in thrombus pression, sepsis, thrombocytopenia, acute leukemia, aplastic
formation and propagation, leading to acute thrombotic anemia, or drug-induced marrow hypoplasia because these
events.2 Larger platelets generally contain more dense diseases could significantly influence MPV and increase
granules, express more glycoprotein IIb/IIIa receptors, have the risk of rt-PA complications. All patients received a
more thromboxane A2, and aggregate more rapidly with standardized stroke diagnosis according to the national and
collagen. The mean platelet volume (MPV) is an index of international guidelines – this consisted of clinical examina-
platelet size that correlates with platelet activation, and its tions, cerebral imaging (computed tomography [CT] scans),
precise measurement may provide clues to pathways that and carotid/vertebral and transcranial ultrasonography.11
can be targeted for interventions aimed at stroke prevention We conducted this study in accordance with the Declaration
or treatment. of Helsinki. The electronic database was decoded and patient
However, most clinical studies on MPV in cardiovascular identification data were scrambled to ensure confidentiality;
disease have been performed in patients with coronary artery informed consent was thus exempted. This study was
disease (CAD) in whom MPV was predictive of the infarct- evaluated and approved by the Institutional Review Board
related artery patency and mortality following acute myo- of Wojskowy Instytut Medyczny w Warszawie.
cardial infarction.3,4 Although patients with AIS differ from Blood samples for MPV and other biochemical markers
those with CAD in their risk factor profile, underlying vessel were drawn from the antecubital vein at baseline within a
pathology, and acute treatment, platelets with an increased mean of 14±7 minutes of sampling after admission to the
MPV led to the occurrence of AIS due to carotid stenosis Emergency Department (a mean of 2.36+0.33 hours after
or cardioembolism.5 Previously published studies have also stroke onset); samples were assessed by a Sysmex XN-1000
shown that an increased MPV was seen in AIS subjects vs hematology autoanalyzer. Samples for MPV were collected
controls.6 The MPV has been proposed as a predictor of in EDTA, and MPV was measured in units of fL (normal
outcome in patients with AIS treated with aspirin; however, range, 7.5–11.5 fL). CT scans were performed immediately
the value of MPV in predicting stroke outcome and risk of at admission and 24 hours after rt-PA or earlier in case of
secondary hemorrhage in patients receiving reperfusion neurologic deterioration (mean 23±3.5 hours) to rule out
therapy remains unclear.7–9 intracranial bleeding. The severity of stroke was assessed
We hypothesized that an elevated MPV level before immediately at admission, at 1, 24, and 72 hours after rt-PA
initiation of rt-PA treatment may be associated with worse treatment, and at discharge by a trained and certified senior
AIS outcome than in patients with lower platelet volume. neurologist in the National Institutes of Health Stroke Scale
The goal of this study was to investigate whether there is (NIHSS).12 To measure global disability and functional
an association between MPV and short-term prognosis in dependence at admission and discharge, we used the modi-
patients with AIS following intravenous (IV) thrombolytic fied Rankin scale (mRS) which ranges from 0 (no symptoms)
treatment. We also examined the association between base- to 6 (death).
line MPV measurement and levels of neurologic deficit,
early radiologic signs, and AIS etiology. Study endpoints
An excellent functional outcome was defined as mRS
Patients and methods discharge score #1; a favorable outcome was defined as
Study population discharge mRS score #2; and poor stroke outcome was
This was a retrospective study of 237 patients consecutively defined if it caused dependence (mRS 3–5) or death during
admitted to a tertiary care center over 5 years (01.01.2011– hospitalization. Lack of early improvement was defined as
31.12.2015) due to AIS. a difference of 3 points or less between the NIHSS score
All patients were treated with standard-dose of IV rt-PA at baseline and at 24 hours.13 Early neurologic deteriora-
according to the National Institute of Neurological Disorders tion (END) was defined as worsening of NIHSS $4 points
and Stroke schedule and criteria, except that no age restriction within the first 72 hours after acute stroke compared with

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baseline NIHSS.14 Symptomatic intracerebral hemorrhage cholesterol $3.6 mmol/L, high-density lipoprotein (HDL)
(sICH) was defined according to the European Cooperative cholesterol #1.0 mmol/L, any use of lipid-lowering drugs,
Acute Stroke Study-III criteria (intracerebral hemorrhage or any self-reported history of dyslipidemia. Carotid artery
combined with clinical deterioration of $4 points on NIHSS stenosis was recognized if either occlusive or stenotic ($50%
or death) and it was divided into hemorrhagic infarct type 1 diameter reduction) vascular disease judged to be due to
(HI1): small petechiae along the periphery of the infarct; atherosclerosis was found in the clinically relevant or not
hemorrhagic infarct type 2 (HI2): confluent petechiae relevant extracranial arteries.
within the infarcted area without a space-occupying effect; The presence of hyperdense middle cerebral artery (MCA)
parenchymal hematoma type 1 (PH1): bleeding #30% of sign on admission CT was recorded – this refers to focal
the infarcted area with a mild space-occupying effect; and increased density of MCA on CT and is a direct visualization
parenchymal hematoma type 2 (PH2): bleeding .30% of of thromboembolic material within the lumen. The Alberta
the infarcted area with a significant space-occupying effect.15 Stroke Program Early CT Score (ASPECTS) has been used
Remote parenchymal hematoma (PHr), solitary or multiple, to quantify early ischemic change on baseline CT brain scans
was defined as hemorrhages that appear in brain regions of acute stroke patients.20 For each of the ten areas, a point
without visible ischemic damage, remote from the area of was subtracted if there was evidence of early signs of brain
ischemia causing the initial stroke symptoms.16 ischemia there (eg, reduced attenuation or hypodensity, loss
Minor ischemic stroke (IS) was defined as a discharge of gray–white matter differentiation, focal swelling, obscu-
NIHSS score #4 and major stroke as NIHSS .4 in accor- ration of the lentiform nucleus, or insular ribbon sign). Old
dance with previous studies.17 infarcts were ignored. A scan with no ischemia in the MCA
territory was scored 10, and a scan with diffuse involvement
Relevant covariates of all MCA territories was scored 0. Intracranial large artery
The Causative Classification of Stroke (CCS) method was occlusion (LAO) was suspected in patients with baseline
used to classify stroke etiology in accordance with the Stop NIHSS $9 (within 3 hours of stroke onset) or NIHSS $7
Stroke Study Trial of Org 10172 in Acute Stroke Treatment (within 6 hours) based on the European consensus statement.21
criteria.18 These criteria integrate the results of clinical
evaluations, brain imaging, vascular/heart examinations, Statistical analyses
and work-up for uncommon causes of stroke. Strokes All data were first analyzed for normality of distribution
were categorized into one of the four following categories: using the Kolmogorov–Smirnov test of normality. The results
cardioembolism, large-artery atherosclerosis, small-vessel are shown as the mean ± SD or as counts and percentages.
occlusion (lacunar stroke), and other (determined etiologies Baseline characteristics of individuals were summarized
or cryptogenic). If multiple potential causes existed, then the according to the tertile distribution of MPV. The clinical
patient was assigned to the undetermined cause group. The characteristics of the three groups were compared using one-
CCS has good to excellent intra- and inter-rater reliability.19 way ANOVA for continuous variable; the chi-squared test
The time of symptom onset, sex, age, history of anti- was used to compare the categorical parameters. Compari-
thrombotic medication, hypertension, diabetes mellitus, sons between normally distributed continuous variables were
current smoking, dyslipidemia, atrial fibrillation (AF), CAD, made using ANOVA with post-hoc analysis of least signifi-
moderate or heavy alcohol consumption ($2 standard alco- cant difference, and the Kruskal-Wallis test with Bonferoni’s
holic drinks per day), body mass index, previous stroke or post hoc adjustment was used for nonparametric distributed
transient ischemic attack, serum glucose, and BP were rou- variables. Pearson’s correlation coefficients were calculated
tinely collected on admission. Hypertension was defined as to evaluate the relationships between MPV and admission
systolic blood pressure (SBP) $140 mmHg or diastolic blood clinical and laboratory variables (mRS, NIHSS, SBP, DBP,
pressure (DBP) $90 mmHg, any use of antihypertensive CT score, morphology, and biochemistry parameters). The
drugs, or any self-reported history of hypertension. Diabetes distribution of total cholesterol and TG was skewed; hence,
mellitus was defined as a fasting glucose level $7.0 mmol/L, we conducted Pearson’s linear correlation analysis using
a non-fasting glucose concentration $11.1 mmol/L, any use log-transformed values instead of the raw data. To measure
of glucose-lowering drugs, or any self-reported history of the strength of the relationship between MPV and discharge
diabetes. Dyslipidemia was defined as a serum triglyceride NIHSS, mRS, CT ASPECTS score, and other baseline labo-
(TG) level $1.7 mmol/L, low-density lipoprotein (LDL) ratory variables, we used the partial correlation coefficient

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controlled for potential confounders selected based on clini- Results

cal plausibility and previous literature reviews and known During the 5 years of this study, 237 patients underwent IV
to influence stroke course and linked with high MPV (age, thrombolysis (mean age 71.04±0.8 years, 50.6% women,
sex, time to rt-PA treatment, and admission NIHSS).22,23 A mean onset to treatment 2.9±0.1 hours). Most patients were
multivariable analysis adjusted for the same confounders functionally dependent at admission (n=214; 93%) and had
was performed to assess the effect size and independent severe neurologic deficit (mean NIHSS score 11.8±3.7).
relationship between MPV and the stroke outcome. The The admission CT scan showed early stroke signs in 33
ORs and 95% CIs for the upper two tertiles relative to the patients (14.3%), and hyperdense MCA sign was found in
lowest tertile were calculated. To evaluate the MPV power 35 patients (15.2%). Symptomatic secondary hemorrhage
to predict poor stroke outcome, we also used receiver operat- was found in 27 patients (11.7%). The in-hospital mortality
ing characteristic (ROC). The best cut-off for maximizing rate was 13.5%. Of those who survived, 34% (n=67) were
sensitivity and specificity according to the Youden index dependent at discharge. Clinical and imaging characteristics
criterion was established.24 Statistical significance was set at of the cohort are presented in Table 1.
P-value ,0.05 for all analyses. The statistical analyses were The mean admission MPV in the cohort was 9.8±0.35 fL.
performed with the STATISTICA 17.0 software (StatSoft There were significant differences between MPV tertiles (low-
Inc., Tulsa, OK, USA). est ,7.29 fL, median 7.29–8.8 fL, and highest tertile .8.8 fL)

Table 1 Main characteristics of the study population

Characteristics Lowest tertile Median tertile Highest tertile P-value for difference
(n=78) (n=76) (n=76) across tertiles
MPV range (fL) ,7.29 7.29–8.8 .8.8
Demographic data
Age (years) 68.6 (12.1)** 69.8 (13.8) 74 (11.1) 0.02
Females 37 (47.4) 47 (61.8)# 32 (42.1) 0.04
Vascular risk factors
Carotid artery stenosis 21 (27) 20 (26) 26 (34) 0.5
Diabetes 9 (11.5)** 18 (23.7) 20 (26.3) 0.04
Hypertension 54 (69.2) 58 (76.3) 57 (75) 0.5
Chronic heart failure 4 (5.1) 13 (17.1) 10 (13.2) 0.04
Coronary artery disease 20 (25.6) 16 (21.1) 20 (26.3) 0.7
Atrial fibrillation 14 (17.9)*,** 29 (38.2) 29 (38.2) ,0.01
Hyperlipidemia 27 (34.6) 19 (25) 19 (25) 0.36
IMT (mm) 1.09 (0.24) 1.09 (0.29) 1.1 (0.2) 0.8
Current smoking 23 (29.5) 11 (14.5) 13 (17.1) 0.05
Chronic kidney disease 3 (3.8) 5 (6.6) 4 (5.3) 0.6
Peripheral atherosclerosis 21 (26.9) 20 (26.3) 26 (34.2) 0.4
Previous stroke/TIA 11 (14.1) 12 (15.8) 10 (13.2) 0.8
Previous antithrombotic therapy a
29 (42) 27 (38) 33 (48) 0.2
Baseline CT
ASPECTS score 9.6 (1.1) 9.65 (0.88) 9.8 (0.4) 0.4
ASPECTS ,10 10 (14.7) 12 (19.4) 11 (15.3) 0.7
Hyperdense MCA sign 12 (15.4) 18 (23.7)# 5 (6.6) 0.01
Symptomatic ICH 8 (10.3) 8 (10.5) 11 (14.5) 0.05
HI1 6 (7.7) 2 (2.6) 3 (3.9)
HI2 0 0 4 (5.3)
PH1 2 (2.6) 4 (5.3) 1 (1.3)
PH2 0 2 (2.6) 3 (3.9)
PHr1 0 1 (1)b 1 (1)b
PHr2 0 0 1 (1)b
(Continued)

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Table 1 (Continued )
Characteristics Lowest tertile Median tertile Highest tertile P-value for difference
(n=78) (n=76) (n=76) across tertiles
Stroke etiology
Lacunar stroke 13 (16.7) 12 (16) 9 (12.2) 0.5
Cardioembolic stroke 23 (29.5) 31 (41.3) 27 (36.5) –
Large atherothrombotic stroke 37 (47.4) 24 (32) 31 (41.9) –
Other 5 (6.4) 9 (11.8) 9 (11.8) –
Baseline biochemical and other variables
Onset to treatment (hours) 2.78 (1.12) 2.85 (0.97) 2.95 (1.07) 0.6
Onset to blood draw (hours) 2.2 (0.3) 2.5 (0.2) 2.4 (0.5) 0.5
eGFR (mL/min/1.73 m ) 2
85.8 (41.2)** 72.8 (31.6) 58.2 (24.7) ,0.001
Creatinine (mg/dL) 0.93 (0.26)** 0.97 (0.44) 1.19 (0.9) 0.01
Blood glucose (mg/dL) 119.8 (44) 123.1 (35.6) 141.5 (77.1) 0.03
Fibrinogen (mg/dL) 354.9 (109) 367 (127) 347 (111) 0.6
WBC (103/µL) 8.4 (2.9) 9.07 (4) 9 (3.1) 0.4
PLT (10 /µL)
3
229.6 (68.7) 228.3 (76) 218 (74.3) 0.5
Total cholesterol (mg/dL) 182.1 (40.8)** 168.3 (41) 158.1 (40.6) ,0.01
LDL (mg/dL) 110.9 (39.8) 103 (34.4) 102.3 (35.5) 0.3
SBP (mmHg) 152 (25) 154 (30) 159 (23) 0.2
DBP (mmHg) 84.9 (13.4) 87.2 (18.8) 86.3 (14.2) 0.6
Neurologic status
Admission GCS 13.4 (2.48) 12.7 (2.7) 13.2 (2.5) 0.3
mRS 4.05 (1.11)* 4.43 (0.89) 4.36 (0.89) 0.03
Dependence (mRS $3) 68 (87.2)*,** 73 (96.1) 73 (96.1) 0.04
NIHSS 10.4 (5.1)* 12.5 (6.1) 12.4 (6) 0.03
Large artery occlusion 55 (70.5) 60 (78.9) 56 (73.7) 0.4
Symptomatic intracerebral hemorrhage 8 (10.3) 8 (10.5) 11 (14.5) 0.6
Early neurologic deterioration 11 (14.1) 14 (18.4) 11 (14.5) 0.7
Discharge mRS 2.29 (1.8)*,** 3.57 (1.9) 3.2 (1.9) ,0.001
NIHSS 3.9 (4.1)* **
,
6.8 (5.9) 5.7 (5.5) ,0.01
Favorable outcome (mRS #2)* 56 (71.8)*,** 34 (44.7) 42 (55.3) ,0.01
Poor outcome (mRS $3) 22 (28.2)* ** ,
42 (55.3) 34 (44.7) ,0.01
Excellent outcome (mRS #1) 33 (42.3)* ** ,
16 (21.1) 20 (26.3) 0.01
Minor stroke (NIHSS #4) 51 (65.4)*,** 31 (40.8) 38 (50) ,0.01
Death 6 (7.7) 13 (17.1) 12 (15.8) 0.17
Length of hospitalization (days) 11.7 (4.6) 17.4 (16.7) 14.5 (11.8) 0.01
Lack of early improvement 23 (29.5)*,** 34 (44.7) 38 (50) 0.02
Notes: Values represent the mean (±SD) for continuously distributed data or number (%) for categorical data. P-values were calculated using the ANOVA and chi-squared
tests. aData available from 208 patients (68 for first tertile, 71 for second tertile, and 69 for third tertile). bWith concomitant local PH2. *P,0.05 between tertiles 1 and 2,
**P,0.05 between tertiles 1 and 3, #P,0.05 between tertiles 2 and 3.
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; CT, computed tomography; eGFR, estimated glomerular filtration rate; MPV, mean platelet volume;
GCS, Glasgow Coma Scale; HI, hemorrhagic infarct; ICH, intracerebral hemorrhage; IMT, intima–media thickness; LDL, low-density lipoprotein; MCA, middle cerebral
artery; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PH, parenchymal hematoma; PHr, parenchymal hematoma; PLT, platelet; TIA, transient
ischemic attack; WBC, white blood cells.

with regard to demographic data, frequency of vascular risk total cholesterol vs patients in the median or highest MPV
factors, and neurologic status at admission and discharge. tertiles. They had lower admission NIHSS scores, were less
Patients in the lowest tertile were younger; had lower often dependent, and rarely experienced early improvement
prevalence of diabetes, chronic heart failure, and AF; had following rt-PA treatment; they had favorable stroke outcome
lower levels of glucose and creatinine; and had higher at discharge with a lower mean mRS and NIHSS. There
values for estimated glomerular filtration rate (eGFR) and were only few differences between patients in the median

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and highest tertiles – those in the median tertile were more (Figure 1). Patients in the second and third tertiles had a sig-
often women and were more likely to have a hyperdense nificantly higher risk of poor stroke outcome (OR =1.9, 95%
MCA sign. However, there were no significant differences CI =1.01–4.2), lack of early improvement (OR =1.9, 95%
between tertiles with regard to AIS etiology, frequency CI =1.04–3.5), lower chance of favorable outcome (OR =0.37,
of carotid artery stenosis, antithrombotic treatment, CT 95% CI =0.18–0.75), or minor stroke at discharge (OR =0.57,
ASPECTS score, frequency of stroke due to LAO, and risk 95% CI =0.27–0.99) vs patients in the first tertile. They also
of END. Also, the difference between the risk of sICH and had a lower chance of excellent stroke outcome (OR =0.52,
the subtype distribution of all hemorrhage types did not reach 95% CI =0.26–1.02). The risk of END, sICH, or death was
statistical significance. similar across all tertiles of MPV. Lower chance of favorable
There was a weak linear positive correlation between outcome and lack of early improvement were significantly
MPV and age, creatinine, glucose levels, SBP at admission, related to second and third MPV tertiles after adding other
and mRS at discharge. There was a negative correlation confounders also (stroke etiology, diabetes, and AF) into the
between MPV and eGFR and total cholesterol at admission multivariate model. ROC analysis for prediction of poor stroke
(Table 2). Similarly, after correcting for confounders, MPV outcome showed that the optimal cut-off point of MPV was
correlated with eGFR, creatinine, glucose, total cholesterol, 8.8 fL (area under the curve 0.586 [0.512–0.659], P=0.03) with
and discharge mRS. Among the variables available on admis- 82.7% sensitivity and 43.9% specificity (Figure 2).
sion, only age (OR =1.003, 95% CI =1.01–1.05), diabetes
(OR =1.5, 95% CI =1.2–1.9), AF (OR =1.4, 95% CI =1.2–1.6), Discussion
cardioembolic stroke (OR =1.8, 95% CI =1.4–4.2), mRS This study found that MPV may be an early and easily
(OR =6.5, 95% CI =3.5–11.7), and NIHSS (OR =1.2, 95% measured predictor of prognosis in AIS patients treated
CI =1.1–1.3) were significantly related to poor outcome in with rt-PA. We demonstrated that patients in the medium
univariate analysis. Multivariable analysis after adjustment for and upper tertiles of MPV had a higher risk of poor stroke
age, sex, delay to rt-PA treatment, and baseline NIHSS showed outcome and a lower chance of excellent outcome follow-
significant correlations between MPV and clinical outcomes ing rt-PA treatment. Moreover, patients in the lowest tertile
of MPV were less often dependent at admission and scored
Table 2 Correlation and partial correlation analysis between lower on admission mRS and NIHSS. However, the MPV
tertiles of MPV as well as clinical and biochemical parameters was not predictive of stroke etiology, LAO, early stroke
Variables r P-value ra P-valuea radiological signs, and risk of complications (sICH or END)
Age 0.18 ,0.01 – – following rt-PA therapy. As MPV has been considered to
Onset to treatment 0.05 0.14 – – reflect platelet activity, our findings provide further evidence
Admission NIHSS 0.1 0.05 – – that platelet activation plays a role in the course of hyperacute
Admission mRS 0.1 0.07 0.19 0.06 AIS following rt-PA treatment.
eGFR -0.29 ,0.001 -0.2 0.04 Thrombolytic therapy with rt-PA is a standard treatment
Creatinine 0.15 ,0.01 0.21 0.04 for patients with AIS, and it has a Class 1A recommenda-
Glucose 0.16 0.01 0.24 0.02 tion according to current guidelines.25 In the last decade,
Fibrinogen -0.06 0.2 0.01 0.8 there has been an increased focus on early identification of
WBC 0.06 0.18 0.17 0.09 accurate markers of thrombolytic success and identification
PLT -0.08 0.1 -0.1 0.3 for patients at risk of developing complications following
Total cholesterol -0.17 ,0.01 -0.2 0.04 rt-PA therapy. Such markers could help to stratify which
LDL -0.05 0.3 -0.12 0.1 patients are likely to benefit from selective use of additional
SBP 0.11 0.03 0.05 0.6 interventions, for example, mechanical thrombectomy. There
DBP 0.04 0.4 0.04 0.6 are several well-established predictors of poor outcome fol-
CT ASPECTS score 0.01 0.9 0.07 0.5 lowing rt-PA therapy, for example, long onset to treatment
Discharge mRS 0.16 ,0.01 0.29 ,0.01 time, elderly age, high admission NIHSS score, high blood
Discharge NIHSS 0.1 0.06 0.14 0.18 glucose, and early hypodensity area on neuroimaging.26
Notes: Coefficients (r) and P-values are calculated using the Pearson’s correlation Other parameters, for example, high SBP, AF, weight, and
model. aAdjusted for age, time to treatment, and admission NIHSS.
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; CT, computed severe stroke at admission, increase the risk of intracranial
tomography; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein;
MPV, mean platelet volume; mRS, modified Rankin Scale; NIHSS, National Institutes
hemorrhage.27,28 Most of these factors, however, provide
of Health Stroke Scale; PLT, platelet; WBC, white blood cells. only an approximation of the efficacy and safety of rt-PA

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Dovepress Staszewski et al

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P56±

P56±

P56±

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2GGVUDWLRDQG&, ORJVFDOH
Figure 1 Associations between tertiles of MPV and clinical outcomes.a
Note: aAdjusted by age, sex, onset to treatment, and baseline NIHSS.
Abbreviations: MPV, mean platelet volume; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; sICH, symptomatic intracerebral hemorrhage.

therapy and are not predictive of outcome for an individual Our results suggest that patients within middle or high
patient – there remains a substantial need to develop a simple tertiles of MPV on admission represent the highest risk for
and quick tool that could help clinicians predict stroke out- larger infarcts on admission and worse outcome following
come at bedside. rt-PA therapy; however, the MPV was not predictive of
hemorrhagic complications or early neurologic deteriora-
tion. The relationship between MPV and poor AIS outcome
52&
 has been previously described, but only a few studies have
evaluated the prognostic value of MPV in patients treated
 with rt-PA.29–32 An association between lower MPV and
improvement in the NIHSS and mRS scores at 24 hours
6HQVLWLYLW\

 and 3 months after discharge from the hospital was recently
shown by İnanç et al,9 but no correlations were found with
neurologic deterioration, and the results were not controlled

for important confounders such as admission stroke severity
and timing of MPV measurement after stroke.8 du et al

039 demonstrated that elevated admission MPV was correlated
5HIHUHQFHOLQH with poor prognosis at 30 days, but the association was

      not significant after adjusting for pretreatment NIHSS;
±VSHFLILFLW\ other confounders were not assessed, and the number of
patients who received rt-PA in that cohort was not stated.33
Figure 2 ROC curve for baseline MPV.
Abbreviations: MPV, mean platelet volume; ROC, receiver operating characteristic. Most studies on patients who received antiplatelet therapy

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Staszewski et al Dovepress

demonstrated the association between MPV and worse Our data showed that larger MPV predicted poor stroke
functional status or higher mRS scores at 24 hours and at outcome and more severe stroke at admission, and these
3 months post-admission.34,35 Muscari et al revealed that results confirm previous reports showing the association
patients with MPV in the highest quantile had .2-fold between MPV and a larger admission infarct volume on CT
higher risk of in-hospital dependence or death than groups brain scans.49 Activated platelets are probably implicated
with MPV in the lowest quantile.36 Contrasting results have both in the pathophysiology of stroke and stroke develop-
also been published. Ciancarelli et al found no relationship ment. They play an important role in plaque destabilization,
between MPV values at baseline and NIHSS and mRS at thrombus formation, and progression.50 Platelets express
2 months, but they revealed that MPV decreases following and secrete many substances that are crucial mediators of
8 weeks of neurorehabilitation.37 Ntaios et al described no prothrombotic state and atherosclerosis, linking hemostasis
significant difference in the frequency of minor strokes and and immunity in both directions. Larger platelets contain
good functional outcome at 3 and 12 months across MPV more thrombotic substances (platelet factor 4, P-selectin,
quartiles.38 The exact mechanism by which MPV might influ- platelet-derived growth factor) and show decreased inhibition
ence stroke outcome is unknown and multiple mechanisms of aggregation by prostacyclin and greater aggregability in
may be involved. MPV is associated with platelet activity, response to ADP in vitro.51 They can aggravate clot forma-
aggregation, thromboxane B2 release, and increased expres- tion through the platelet/fibrinogen interactions and regulate
sion of the platelet adhesion molecule glycoprotein IIb/IIIa, inflammatory reactions and endothelial permeability, which
and several clinical studies reported that an elevated MPV is may influence both short- and long-term course of stroke.52,53
associated with different thromboembolic diseases. The platelets’ involvement in the interplay between throm-
Some studies revealed that high MPV results from com- bosis, inflammation, and hemostasis is likely complex, yet
bined stroke risk factors and simply reflects an increased extremely important in each disease process. Several of
platelet activity representing the pre-stroke status, decreased the proinflammatory mediators implicated in IS (eg, IL-6,
HDL levels, hypertension, and advanced age of patients; it IL-8, IL-1β, and monocyte chemotactic protein 1) induce
might also represent inflammatory status.34,39 Progressive platelet activation (and thus, MPV) and platelet–leukocyte
impairment of endothelial function plays a crucial role in aggregation, and they promote a variety of responses that
the aging process, and therefore leads to the production of favor coagulation and thrombosis.54,55 These interactions are
large platelets. An increase in MPV has also been reported critical for hemostasis and the function of endothelial cells,
to be associated with race, sex, obesity, smoking, and glu- and they have been suggested as important factors contribut-
cose and creatinine levels, with an inverse correlation with ing to plaque rupture, thrombus formation, and unfavorable
eGFR; this is similar to our data.40–42 An inverse relationship prognosis after AIS.56,57
normally exists between MPV and the platelet count within However, it is not clear whether MPV could be increased
the normal range – this probably contributes to the mainte- secondary to the extent of acute brain injury after IS. Here,
nance of normal hemostatic function. Moreover, we found both admission and discharge mRS and NIHSS scores were
that total cholesterol levels were independently associated the highest in medium and upper tertiles of MPV; however,
with MPV – this agrees with some studies that demonstrated MPV remained significantly correlated with discharge
binding of LDL, very low-density lipoprotein, and LDL to neurologic status also after adjustment for admission mRS,
the platelet surface; in vitro, LDL stimulated platelet aggre- and it did not differ between patients with early CT signs of
gation similar to common platelet agonists.43 brain ischemia. This could also suggest that activated plate-
There are multiple studies with conflicting results lets may contribute to reperfusion injury and “no reflow”
describing relations between MPV and symptomatic carotid phenomenon after AIS and play a more important role in
artery stenosis or artery plaques.44–46 However, we found no collateral circulation and in microvessels, which has been
differences in MPV tertiles between patients with significant shown in animal models.58
carotid artery stenosis or between patients with different The MPV is widely available, cheap, and available before
stroke etiology; these data correspond to O’Malley et al rt-PA therapy as a part of morphology assessment; however,
who reported high values of MPV in all subtypes of IS.47 numerous other biomarkers have been studied to improve
Although MPV was higher in patients with AF, this agreed early diagnosis or predict clinical outcome and response
with previous studies that demonstrated the association to stroke therapy, but currently none of these has sufficient
between MPV and markers of left atrial stasis in patients accuracy for routine clinical practice. Many studies revealed
with AF.48 that CRP (C-reactive protein) correlated with the infarct size,

500 submit your manuscript | www.dovepress.com Clinical Interventions in Aging 2019:14

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Dovepress Staszewski et al

risk of hemorrhage, or worse prognosis; but this association studied in a Polish population. We found that high MPV
was weak or insignificant after adjustment for age or stroke values on admission were closely associated with stroke
severity.59–61 Studies also showed a decrease in fibrinogen outcome at discharge in patients who received rt-PA therapy
level following rt-PA therapy, which was associated with the in AIS. In conjunction with other laboratory tests or radio-
risk of sICH and poor prognosis at 3 months.62 Also, higher logical data, MPV measurements that are already available
matrix metallopeptidase-9 (MMP-9) and copeptin levels were in routine laboratories may represent one of the easiest mea-
shown to be associated with infarct volume, stroke severity, surements to be used as a prognostic marker and help with
and clinical outcomes.63–65 Other studies demonstrated decision making and selecting optimal treatment strategies
that elevated brain natriuretic protein and D-dimer levels without adding economic burden. The combination of MPV
were associated with increased stroke mortality, but other with stroke scores including vascular risk factors as well
studies found no such association.66–69 Furthermore, MMP-9 as clinical and imaging data could increase the predictive
and S-100B concentrations were related to the risk of hem- value for early risk of recurrence, early death, and progres-
orrhagic complications after thrombolysis; however, their sive stroke after IS. However, the methodological problems
use is still limited by a lack of availability and high cost.70 involved in obtaining an accurate MPV result must be con-
sidered and the results should be carefully standardized.73
Limitations Our results should be verified in a prospective study with a
This study has several limitations. It was limited by the larger sample size to clarify the role of MPV during AIS and
absence of a control group, and its retrospective and single- how patients with high MPV should be handled regarding
center design may have led to bias; thus, our findings should optimal stroke management including reperfusion therapy.
be considered as hypothesis generating at best. We were It is important to note that MPV could give some informa-
also unable to explore the exact mechanism of MPV in the tion regarding the thrombocytes’ activation, but the final
course of stroke. Furthermore, it is unclear how our findings evidence will be the functional tests for platelet activity;
might impact treatment because our analyses were limited therefore, further investigations are required to elucidate
to short-term in-hospital outcomes, while prognostic stroke the precise mechanisms through which circulating platelets
studies used the mRS as the primary outcome measure after affect the prognosis in AIS.
3 months.71 Prospective studies with long-term follow-up
data or imaging approaches in both the hyperacute and sub- Conclusion
acute stages would provide more reliable findings. Another Disabling or fatal IS in thrombolyzed patients was observed
limitation is that we did not have data on the pre-stroke more often in patients with high admission MPV. The
use of antithrombotic drugs from all patients or lipid- prognostic value of MPV was independent of other well-
lowering drugs, and we did not routinely perform exams to defined individual risk factors. It is not clear if MPV has a
assess leptomeningeal collateral circulation, reperfusion/ direct contribution to AIS outcomes; therefore, further studies
recanalization, and infarct volume, which are important are needed to explain the underlying mechanism.
variables influencing short-term outcome in patients treated
with IV rt-PA. An additional important limitation is that the Disclosure
normal ranges for the MPV can be influenced by factors The authors report no conflicts of interest in this work.
such as the anticoagulant used in the collection tube and
the delay in time from sampling to analysis; however, this References
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