Mean Platelet Volume in Acute Phase of Ischemic Stroke, as Predictor of Mortality and Functional Outcome after 1 Year

mez, MD, Jos e Carlos Ar evalo-Lorido, MD, Juana Carretero-Go  n Guti ~ o, MD, Alejandra Alvarez-Oliva, MD, Concepcio errez-Montan Jos e Mar a Fern andez-Recio, MD, and Francisco Najarro-D ez, MD

Background: Mean platelet volume (MPV) could be a predictor of prognosis after ischemic stroke. Our aim is to investigate the association of MPV with a greater mortality and morbidity (dened as readmissions) after 1 year of follow-up in patients with acute stroke, and with a poor functional outcome in these patients. Methods: Patients with ischemic stroke (N 5 379) were recruited and assessed for an average of 46.27 weeks. MPV was measured at admission. The sample was divided in thirds according with the tertiles of distribution of MPV. Univariate and multivariate analysis were performed. Results: The median (interquartile range) of MPV by third was 10 (0.7), 11(0.4), and 12 (0.8) fentoliters. Patients within highest third had a signicant higher risk of either death or readmission (odds ratio 1.3; 95% condence interval 1.00-1.7; P , .048) compared with patients within the lowest third. Functional outcome, dened as a modied Rankin Scale score of 3 to 6, was signicantly higher (P , .0004) by greater third of MPV. Conclusions: MPV may be an easily available predictor for the prognosis in patients with acute ischemic stroke. Key Words: Cerebrovascular diseaseplateletstroke. 2013 by National Stroke Association

Platelet size, measured as mean platelet volume (MPV), could be a marker of platelet activation, because large platelets are more reactive, produce more prothrombotic factors, and aggregate more easily.1 Previous studies reported an increased MPV among patients with myocardial infarction,2,3 chronic vascular disease,4,5 or vascular risk factors, such as diabetes,6 hypercholesterolemia,7 and smoking.8 Under physiologic conditions, the rate of platelet production is continuously regulated so that the circulating platelet mass (platelet count 3 MPV) is kept constant,9 and both MPV and platelet count are inversely associated.
From the Department of Internal Medicine, Zafra County Hospital, Zafra, Spain. Received July 9, 2011; revision received September 2, 2011; accepted September 9, 2011. Address correspondence to Jos e Carlos Ar evalo-Lorido, MD, Department of Internal Medicine, Zafra County Hospital, Ctra Badajoz-Granada s/n. 06300, Zafra (Badajoz), Spain. E-mail: joscarlor@gmail.com. 1052-3057/$ - see front matter 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.09.009

In addition, several studies have investigated the relationship of MPV with stroke, noticing its increase in all subtypes of ischemic stroke,10 with the capacity to predict the risk of a second stroke up to 4 years before the acute event11 or have provided some information about the prognosis after acute stroke (from 3 months to 1 year). Other studies, however, have not found any signicant relationship between MPV and stroke outcome.12 MPV is a parameter that is routinely available in many laboratories and is often disregarded. Nevertheless, an interest in MPV is increasing because it could be related to the risk and prognosis of cardiovascular diseases. Our aim in this study was to investigate the association between the MPV measured in acute phase of ischemic stroke, and a greater mortality and morbidity after 1 year of monitoring, and with a worse functional prognosis in these patients.

Methods
We included all consecutive ischemic stroke patients admitted within 24 hours after stroke in our Internal
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Table 1. Epidemiologic, clinical, and laboratory ndings by thirds* Variable N Age (y) Sex (men) Hypertension Diabetes mellitus Dyslipemia Smokers SBP (mm Hg) DBP (mm Hg) Glucose (mg/dL) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Triglycerides (mg/dL) Creatinine (mg/dL) Fibrinogen (mg/dL) NIHSS score MRS score Framingham score INDANA score MPV (fL) Platelets/mm3 TOAST Atherosclerotic Cardioembolic Lacunar Rare Unknown Antiaggregant (at admission) Acenocumarol (at admission) Statins (after stroke) Third 1 121 74 (13) 76 (62.8%) 104 (85.9%) 42 (34.71%) 57 (47.11%) 21 (17.36%) 160 (36) 90 (20) 113 (64) 185 (57) 112 (42) 41 (14) 104 (73) 1 (0.4) 355 (206) 6 (5) 2 (1) 25 (5) 4.1 (4.8) 10 (0.7) 239000 (85000) 36 (29.75%) 24 (19.83%) 49 (40.5%) 5 (4.13%) 7 (5.79%) 33 (27.2%) 3 (2.48%) 74 (61.16%) Third 2 134 76 (12) 67 (50%) 114 (85.07%) 40 (29.85%) 64 (47.76%) 29 (21.64%) 160 (40) 86 (24) 112 (59) 185 (58) 116 (52) 41 (18) 100 (56) 0.9 (0.4) 373 (152) 7 (7) 3 (2) 25 (7) 5 (6.9) 11 (0.4) 201500 (83000) 42 (31.34%) 41 (30.6%) 38 (28.36%) 4 (2.99%) 9 (6.72%) 52 (38.8%) 8 (5.97%) 85 (63.43%) Third 3 124 79 (12) 68 (54.8%) 104 (83.87%) 40 (32.26%) 56 (45.16%) 20 (16.13%) 158.5 (40) 85 (27) 115 (57) 181 (45) 115 (38) 40.5 (14) 103.5 (60) 1 (0.4) 368 (185) 9 (7) 3 (2) 25 (10) 5 (5.1) 12 (0.8) 187500 (79500) 40 (32.36%) 46 (37.1%) 33 (26.61%) 2 (1.61%) 3 (2.42%) 31 (25%) 11 (8.8%) 78 (62.9%) P value .0004 .11 .9 .7 .91 .48 .2 .02 .94 .41 .17 .53 .8 .69 .53 .005 .002 .56 .2 .000001 .0008 .062 .062 .062 .062 .062 .02 .02 .92

Abbreviations: DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; INDANA, risk stratication by INDANA Steering Committee; LDL-C, low-density lipoprotein cholesterol; MPV, mean platelet volume (in fentoliters); MRS, modied Rankin Scale; NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure; TOAST, Trial of Org 10172 in Acute Stroke Treatment. *Quantitative variables are shown as median (interquartile range). Percentages are referred to as a total of thirds.

Medicine Unit between January 1, 2005 and December 31, 2009 who signed the consent to participate in a registry under an ethics committeeapproved protocol. The diagnosis of stroke was based on the clinical evaluation and computed tomographic scan or magnetic resonance imaging scan of the brain performed in all cases within 24 hours from event. The subtypes of stroke were classied according to the TOAST classication.13 We excluded patients with intracerebral hemorrhage, subarachnoid hemorrhage, cerebral venous sinus thrombosis, late admission (.24 hours after stroke onset), patients in whom MPV was not measured on admission, or died during these, and patients that have not completed a follow-up period for 1 year. The neurologic examination included scores with the National Institutes of Health Stroke Scale score14 and the modied Rankin Scale.15 All patients underwent several laboratory investigations, and were asked for vascular risk factors or

documented treatment with antiaggregants before the index event. MPV was determined on admission, collected into ethylenediaminetetraacetic acid (EDTA) tubes, and processed within 1 hour after venipuncture. During the time between venipuncture and processing, the samples were stored at room temperature. EDTA blood samples were analyzed by both electrical impedance and optical uorescence methods in automated hematology analysis system (Sysmex XE-2100; Sysmex Corp, Kobe, Japan). A score for predicting risk of death from cardiovascular disease was obtained from each patient based on Framingham16 and INDANA scores.17 The patients were divided into thirds according with tertiles of distribution of MPV. The primary objective of our study was to determine if the higher third had a worse composite outcome of death from any cause or hospitalization after 52 weeks of follow-up. The secondary objectives were death from cardiovascular causes, including

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Table 2. Epidemiologic, clinical, and laboratory ndings of thirds excluded transient ischemic attack and deaths to analyze functional outcome Third 1 N Age (y) Sex (men) Hypertension Diabetes mellitus Dyslipemia SBP (mm Hg) DBP (mm Hg) Total cholesterol (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Tryglicerides (mg/dL) Glucose (mg/dL) Creatinine (mg/dL) Fibrinogen (mg/dL) MRS at admission NIHSS score at admission Rankin score ,2 at 1 year Rankin score $2 at 1 year 88 74 (13) 69 (68.18%) 74 (84.09%) 28 (31.82%) 41 (46.59%) 164.5 (30) 90 (20) 189 (54) 114 (38.5) 41 (12.5) 108.5 (87) 114.5 (60) 1 (0.35) 353 (204.5) 3 (1) 6 (5.5) 77 (87.5%) 11 (12.5%) Third 2 87 75 (14) 45 (51.72%) 76 (87.36%) 29 (33.33%) 45 (51.72%) 160 (40) 85 (19) 192 (64) 120 (52) 41 (14) 108 (67) 116 (73) 0.9 (0.4) 374 (142) 3 (2) 7 (7) 62 (72.09%) 24 (27.91%) Third 3 76 78 (11) 41 (53.95%) 63 (82.89%) 21 (27.63%) 32 (42.11%) 160 (30) 82 (27.5) 181 (42.5) 116 (37) 39 (15) 94 (62) 105 (45.5) 0.9 (0.4) 357 (184) 3 (2) 9 (6.5) 46 (60.53%) 30 (39.47%) P value

.04 .06 .7 .7 .46 .32 .12 .18 .22 .21 .18 .08 .84 .51 .05 .02 .0004 .0004

Abbreviations: DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; INDANA, risk stratication by INDANA Steering Committee; LDL-C, low-density lipoprotein cholesterol; MPV, mean platelet volume (in fentoliters); MRS, modied Rankin Scale; NIHSS, National Institute of Health Stroke Scale; SBP, systolic blood pressure; TOAST, Trial of Org 10172 in Acute Stroke Treatment.

heart failure, and the measurement of severity in functional status, achieved in basis to the modied Rankin Scale at 12 months in the outpatients that survived. Good functional outcome was dened as Rankin Scale score ,2, and patients with transient ischemic attack (TIA) were excluded (TIA was dened as complete disappearance of signs and symptoms within 24 hours regardless if infarction was evident on neuroimaging).

Results
A total of 687 patients with acute stroke were admitted, and 36 patients refused to have their data included in the registry. From the admitted patients, we excluded 46 because of intracerebral hemorrhage, 160 because admission after 24 hours from event, 41 because of death during hospitalization, and 52 because of a loss to follow up. Finally, we included a total of 379 patients: 211 men (55.67%) and 168 women (44.33%). MPV was observed in a normal distribution, ranging from 7.4 to 14.1 fentoliters (fL). The rst third included patients with MPV from 7.4 to 10.6 fL; the second included patients with MPV from 10.7 to 11.4 fL; the third included patients with MPV from 11.5 to 14.1 fL. The medians (interquartile range) of MPV by third were 10 (0.7), 11 (0.11), and 12 (0.8) fL, respectively. Platelet count, as expected, was inversely associated with MPV. Epidemiologic, clinical, and laboratory ndings by thirds in univariable analysis are showed in Table 1. The 3 groups were not different in terms of distribution of traditional risk factors except for age (older by consecutively group; P , .0004) and diastolic blood pressure at admission (lower while MPV increases by group; P , .02). Likewise, MPV was not different between different stroke subtypes according to the TOAST classication. We found that correlation with NIHSS score (P , .0005) and Rankin Scale score (P , .0002) were greater by third. In the subgroup of 306 patients (175 men [57.19%] and 131 women [42.81%]) without TIA, we excluded those

Statistical Analysis
Continuous parameters are reported as median (interquartile range). Categorical data and qualitative variables are expressed as percentage. The association between the thirds and clinical parameters was rst tested univariately with the Chi-square test for binary and categorical data and the KruskalWallis test for continuous variables. Multivariate analysis was performed by Cox regression model for morbidity and mortality (outcome variable) adjusted for age, diastolic blood pressure, NIHSS score, Rankin Scale score, subtypes of stroke and for antithrombotic treatment, and by logistic regression model for functional status (state variable was Rankin Scale score $2) adjusted for age, sex, and both NIHSS and Rankin Scale scores at admission. Outcomes were dened as the time to the event or at least 52 weeks of follow-up if an event did not occur. Cumulative event curves were estimated by Kaplan Meier method and compared by Cox regression test. Differences and correlations were considered signicant at P ,.05.

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Table 3. Findings of mean platelet volume according to either antiaggregant or anticoagulant drugs before admission of patients*

5 (1.32%) 11.3 (1.8) 198,000 (69,000)

Triusal

that died in the follow-up (55 patients [17.97%]). Their characteristics by thirds are presented in Table 2. The prevalence of poor functional outcome after 52 weeks grew across the greater thirds (P , .0004). After adjustment by logistic regression, the odds ratio for the worst functional outcome was 1.97 (95% condence interval 1.33-2.93; P , .0006). The percentage of patients before stroke who were taking antiaggregant treatment was 63.59%, and under anticoagulant (acenocumarol) therapy was 5.8%. Despite signicant differences in percentage (Table 1) by third of MPV, when we compared MPV in different treatment groups, we would not nd signicant differences (Table 3). The median of monitoring of patients was 46.27 weeks. Rates of mortality, cardiovascular mortality, readmission, and combined events among the entire cohort were 16.36%, 8.71%, 16.09%, and 30.08% respectively. The data on mortality, cardiovascular mortality, readmission, and combined events during monitoring are shown in Table 4 and and Figures 1 and 2. Primary end point and cardiovascular mortality were signicantly higher in patients in the highest third. In contrast, there were no signicant differences between the thirds, either in the overall mortality or in the readmissions during follow-up.
Abbreviation: MPV, mean platelet volume. *Variables analyzed by analysis of variance. MPV and platelets are showed as median (interquartile range).

P value

Aspirin 1 clopidogrel

1 (0.26%) 10.8 (0) 325,000 (0)

22 (5.8%) 11.5 (1.2) 209,500 (69,000)

Anticoagulant (Acenocumarol)

.30 .34

Discussion
Our study shows that higher MPV levels in patients with stroke are associated with either their overall morbidity and mortality and their cardiovascular mortality. Several studies have indicated that high MPV levels, representative of high platelet reactivity, are associated with overall vascular mortality in the general population,18,19 and there are other studies that suggest that MPV may represent a predictive parameter of cardiovascular risk and overall vascular mortality in the general population.20,21 In patients with a history of cardiovascular events, there are studies that show a higher mortality after myocardial infarction,22 but there are none after stroke, as we have reported here. The mechanisms by which elevated MPV might inuence the development or progression of cardiovascular disease are not completely understood. Multiple factors may be involved, such as more alpha-granules in larger platelets, increased levels of thromboxane A2, or a wider expression of adhesion receptors. These factors have a variety of atherogenic actions involved.23,24 In any case, the reasons for an increase in the size of platelets are not fully understood. It is possible that changes in the secretion and metabolism of biologically active substances during aging, diabetic changes in metabolism, high blood pressure, or an acute ischemic event, all may stimulate the bone marrow to produce large platelets.25 In our study, in accordance with other ndings, we observed a strong association between an increased MPV and older age and observed an unexpected

Antiaggregant

N MPV (fL) Platelets/mm3

249 (63.39%) 10.9 (1.5) 204,000 (87,000)

No

91 (24.01%) 11.1 (1.0) 200,000 (99,000)

Aspirin

10 (5.01%) 10.8 (1.2) 219,000 (90,000)

Clopidogrel

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301

Table 4. Results of monitoring of patients for 1 year, in univariate (third 3 v third 1) and multivariate analysis* Univariate analysis Third 1 Death Cardiovascular death Admission Primary endpoint 14 (3.69%)y 7 (1.85%)y 16 (4.22%)y 30 (7.92%)y Third 2 21 (5.54%)y 9 (2.37%)y 20 (5.28%)y 39 (10.29%)y Third 3 27 (7.12%)y 17 (4.49%)y 25 (6.68%)y 45 (11.87%)y RR (95% CI)z 1.88 (1.03-3.41) 2.36 (1.01-5.5) 1.4 (0.78-2.5) 1.46 (1.00-2.54) P value .03 .03 .25 .04 Multivatiate analysis OR (95% CI){ 1.22 (0.98-2.02) 1.6 (1.02-2.6) 1.24 (0.87-1.76) 1.3 (1.00-1.7) P value .06 .04 .22 .048

Abbreviations: CI, condence interval; OR, odds ratio; RR, relative risk. *Cox Risk Proportional regression model adjusted to age, diastolic blood pressure, National Institutes of Health Stroke Scale score, Rankin score, subtypes according to TOAST, and antiaggregant treatment at admission. yPercentages referred to total of sample. zRR (95% CI): Relative Risk with 95% of condence interval, (Third 3 vs Third 1). {OR (95% CI): Odds Ratio with 95% of condence interval.

weak association with diastolic blood pressure at admission. However, after adjustment, the relation between MPV and mortality persisted. Moreover, and regardless of assumptions about the increased size of platelets, the greater MPV was, in agreement with previous studies, associated with the worst outcome in patients with cerebrovascular events.26,27 Currently, available studies report controversial results regarding MPV and stroke outcome. Recently, Ntaios et al12 described no any association between MPV in acute ischemic stroke with regard to either its severity or its functional outcome. However, as in other earlier studies,26,27 we found a relationship between them. Although this was not a primary end point in our case, the results suggest that this relation remain to be evaluated. Likewise, and equally, we also found an association between a high MPV value and increased neurologic damage as measured by the NIHSS score, similar to that found by Muscari et al28 suggesting a correlation between NIHSS score at admis-

sion and MPV measured within 24 hours from event that may reect the severity of stroke. Finally, the limitations of this study include misclassication of both MPVand cardiovascular mortality. Misclassication of MPV is well known because of time-dependent

Figure 1. KaplanMeier curve of the primary end point showing survival probability by third, adjusted by age, diastolic blood pressure, National Institute of Health Stroke Scale and Rankin scores, stroke subtype according the Trial of Org 10172 in Acute Stroke Treatment classication, and antithrombotic treatment at admission.

Figure 2. KaplanMeier curve of global mortality (A) and cardiovascular mortality (B) by thirds. Cox regression adjusted by age, diastolic blood pressure, National Institute of Health Stroke Scale and Rankin scores, stroke subtype according the Trial of Org 10172 in Acute Stroke Treatment classication, and antithrombotic treatment at admission.

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 ALO-LORIDO ET AL. J.C. AREV 9. Jakubowski JA, Thompson CB, Vaillancourt R, et al. Arachidonic acid metabolism by platelets of differing size. Br J Haematol 1983;53:503. 10. OMalley T, Langhorne P, Elton R, et al. Platelet size in stroke patients. Stroke 1995;26:995-999. 11. Bath P, Algert C, Chapman N, et al. Association of mean platelet volume with risk of stroke among 3134 individuals with hystory of cerebrovascular disease. Stroke 2004;35:622-626. 12. Ntaios G, Gurer O, Faouzi M, et al. Mean platelet volume in the early phase of acute ischemic stroke is not associated with severity or functional outcome. Cerebrovasc Dis 2010;29:484-489. 13. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classication of subtype of acute ischemic stroke. Denitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 14. Lyden PD, Lu M, Levine SR, et al. A modied National Institute of Health Stroke Scale for use in stroke clinical trials: Preliminary reliability and validity. Stroke 2001; 32:1310-1317. 15. Hacke W, Kaste M, Fieschi C, et al. Randomized doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-1251. 16. Ivename Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults. Collective name executive summary of the third report of the National Cholesterol Education Program (NCEP), expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adults treatment Panel III). JAMA 2001;285:2486-2497. 17. Pocock SJ, McCormack V, Gueyfer F, et al. A score for predicting risk of death from cardiovascular disease in adults with raised blood pressure, based on individual patient data from randomised controlled trials. BMJ 2001;323:75-81. 18. Boos CJ, Balakrishnan B, Lip GY. The effects of coronary artery disease severity on time-dependent changes in platelet activation indices in stored whole blood. J Thromb Thrombolysis 2008;25:135-140. 19. Klovaite J, Benn M, Yazdanyar S, et al. High platelet volume and increased risk of myocardial infarction: 39531 participants from the general population. J Thromb Haemost 2011;9:49-56. 20. Chu SG, Becker RC, Berger PB, et al. Mean platelet volume as a predictor of cardiovascular risk: A systematic review and meta-analysis. J Thromb Haemost 2010;8:148-156. 21. Slavka G, Perkmann T, Haslacher H, et al. Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease. Arterioscler Thromb Vasc Biol 2011;31:1215-1218. 22. Martin JF, Bath PM, Burr ML. Inuence of platelet size on outcome after myocardial infarction. Lancet 1991;338: 1409-1411. 23. Borisoff JI, Sprouk HMH, Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med 2011; 364:1746-1760. 24. Kamath S, Blann AD, Lip GY. Platelet activation: Assessment and qualication. Eur Heart J 2001;22:1561-1571. 25. Boos CJ, Lip GY. Assessment of mean platelet volume in coronary artery diseaseWhat does it mean? Thromb Res 2007;120:11-13. 26. Greissenegger S, Endler G, Hsieh K, et al. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events? Stroke 2004;35:1688-1691.

platelet swelling in vitro using EDTA as anticoagulant. Nevertheless, we were able to adjust for this, because time from blood sampling until analysis was registered and very similar for all participants. In addition, MPV may be inuenced by various comorbidities and concomitant drug therapies. Previous in vitro studies found no effect of aspirin on platelet size29; however, it was shown that clopidogrel inhibits the adenosine triphosphateinduced increase in MPV in vitro.30 Clinical data on a possible association of MPV with various platelet inhibitors in patients do not exist. In our study, differences were not found in the MPVof patients under antiaggregant or anticoagulant therapies (Table 3), and the number of patients under other treatments including lipid-lowering drugs was not different between the thirds of MPV. As for the misclassication of cardiovascular mortality, in the hospitalized patients, there is no doubt because death was coded by one of the authors; in the outpatient groups, the codication was based on self-reports on the death certicate of National Civil Registry, which may be subject to error. Therefore, in cases where the cause was unclear, we preferred not to encode it as cardiovascular death. In conclusion, the present study is the rst to show an increase in morbidity and cardiovascular mortality in patients with high MPV after suffering a stroke. These ndings raise the hypothesis of the potential importance of MPV, a measurement easily identied during routine hematologic analysis, as a valuable predictor of mortality and worse outcome in patients with acute ischemic cerebrovascular events.

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MPV AND GLOBAL PROGNOSIS AFTER STROKE 27. Mayda-Domac F, Misirli H, Yilmaz M. Prognostic role of mean platelet volume and platelet count in ischemic and hemorrhagic stroke. J Stroke Cerebrovasc Dis 2010;19: 66-72. 28. Muscari A, Puddu GM, Cenni A, et al. Mean platelet volumen (MPV) increase during acute non-lacunar ischemic strokes. Thromb Res 2009;123:587-591.

303 29. Jagroop IA, Tsiara S, Mikhailidis DP. Mean platelet volume as an indicator of platelet activation: Methodological issues. Platelets 2003;14:335-336. 30. Jagroop IA, Mikhailidis DP. Mean platelet volume as an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol 2003; 120:169-170.