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International Journal of Laboratory Hematology The Official journal of the International Society for Laboratory Hematology

ORIGINAL ARTICLE

INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Association of mean platelet volume and platelet count with the development and prognosis of ischemic and hemorrhagic stroke J. DU* ,† , Q. WANG*, B. HE † , P. LIU † , J.-Y. CHEN † , H. QUAN*, X. MA*

*Department of Neurology, The Nuclear Industry 416 Hospital, Chengdu, Sichuan, China † Department of Health and Social Behavior, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China Correspondence: Prof. Xiao Ma, Ph.D., Department of Health and Social Behavior, 17 South Renmin Road, Section 3, West China School of Public Health, Sichuan University, Chengdu, Sichuan 610041, China. Tel.: +862885422114; Fax: +862885501295; E-mail: maxiao8293846@ 163.com

doi:10.1111/ijlh.12474

Received 26 July 2015; accepted for publication 31 December 2015 Keywords Ischemic stroke, hemorrhagic stroke, mean platelet volume, platelet count, prognosis

S U M M A RY Introduction: Mean platelet volume (MPV) and platelet (PLT) count are the two major parameters that reflect the functions and activities of PLTs. The associations of MPV and PLT count with the occurrence and prognosis of stroke have not been fully clarified. This study aimed to investigate the association of MPV and PLT count with the development and prognosis of first-ever ischemic and hemorrhagic stroke in order to provide evidence for early diagnosis and treatment of both strokes. Methods: This study included 281 first-ever ischemic stroke and 164 first-ever hemorrhagic stroke patients between 2010 and 2012. All participants received routine blood tests within 2 h after ission and were categorized into good or poor prognosis group based on the Modified Rankin Scale (mRS) score. MPV and PLT counts were transformed into categorical variables and their association with the occurrence and prognosis of both strokes was evaluated by multivariate logistic regression. Results: The risk of ischemic and hemorrhagic stroke in MPV group (>13 fL) was 22.17 and 5.21 times higher compared with normal MPV group. The PLT count was positively correlated with the risk of ischemic stroke, but negatively correlated with the risk of hemorrhagic stroke. MPV and PLT count was not correlated with the prognosis of either stroke. Conclusions: Increased MPV is an independent risk factor for both strokes. Elevated PLT count increases the risk for ischemic stroke, but decreases the risk for hemorrhagic stroke. However, neither MPV nor PLT count has significant association with the prognosis of either stroke.

INTRODUCTION As a major component of the blood-vascular axis responsible for preventing hemorrhage, platelet (PLT) © 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

is crucial in the development of ischemic stroke due to its participation in thromboemboli that may initiate the symptoms of stroke [1, 2]. Activated PLTs initiate the formation of a hemostatic plug and provide a scaf233

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fold for the activation of coagulation [3, 4]. Moreover, PLT dysfunction has been found to be associated with spontaneous intracerebral hemorrhage [5, 6]. The importance of abnormal PLT for the onset of acute cerebrovascular disorders has recently received increasingly more attention [2, 7]. Mean platelet volume (MPV) and PLT count are the two major parameters that reflect the functions and activities of PLTs. MPV, which describes the mean volume (size) of platelets, is an indicator that represents megakaryocytic hyperplasia and metabolism, and platelet production in bone marrow, and indicates the age of circulating platelets. MPV has been identified as an independent risk factor for cerebral infarction [8], and a higher MPV is detected in patients with acute stroke, myocardial infarction, diabetes, hypercholesterolemia as well as smokers compared with normal subjects [8, 9]. PLT count is a parameter reflecting the production and aging of platelets [10]. As two indicators that demonstrate platelet functions, MPV and PLT count have been reported to play important roles in the development and prognosis of ischemic and hemorrhagic stroke [11, 12]. However, the associations of MPV and PLT count with the occurrence, severity and prognosis of stroke have not been fully clarified. In this case–control study, we evaluated the association of MPV and PLT count with the development and prognosis of first-ever ischemic and hemorrhagic stroke to provide evidence for early diagnosis and treatment of ischemic and hemorrhagic stroke, and to improve their prognosis.

SUBJECTS AND METHODS Study subjects Patients with first-ever ischemic or hemorrhagic stroke who were itted to our hospital between October 2010 and January 2012 were enrolled in this study. The average time elapsed from stroke onset to ission was 6 h. Subjects without any cardiovascular or cerebrovascular diseases who were itted to our hospital during the same time period were selected as controls. Any subject with pregnancy, infection, reactive airway diseases, tumor, cerebral trauma, arteriovenous malformation or bleeding caused by other factors, inflammation, hematologic disease, or undergoing

treatment with lipid-lowering drugs, angiotensin-converting enzyme inhibitors or anticoagulant drugs was excluded from the study. All participants signed the informed consent, and the study was approved by the ethical review committee of the hospital. Collection of baseline characteristics, medical history, and disease-related data The demographic and clinical characteristics were collected via a questionnaire, including the risk factors for cardiovascular and cerebrovascular diseases, previous disease history (hypertension, hyperlipemia, diabetes, and heart disease), and therapy. The cause of ischemic stroke was categorized based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) rating system [13]. The cerebral infarct size was measured at 3 days after enrollment by computed tomography (CT) [14] or magnetic resonance imaging (MRI) scan [15]. Those with the largest diameter of ≥3 cm were defined as large infarcts, whereas those with the largest diameter of <3 cm were considered as small infarcts. The intracerebral hemorrhage volume was determined using the formula ABC/2 [16]. While a hemorrhage volume of ≥30 mL indicated a large hemorrhage, while a volume of <30 mL was defined as a small hemorrhage. All measurements were performed with a blind method. Blood investigation All subjects received routine blood testing within 2 h after ission to the hospital. MPV and PLT count were measured within 30 min after venipuncture with a Sysmex XS-2000i autoanalyzer (Sysmex Corporation, Kobe, Japan). The parameters were set according to the index of adults in Sichuan province described in National Guideline for Clinical Laboratory Procedures (Third Edition) [17]. Treatment of stroke The acute ischemic stroke patients without indications for thrombolysis were given aspirin at 300 mg/d for 3 days, and 100 mg/d 3 days afterward. Those with indications for thrombolytic therapy were given an intravenous injection of recombinant tissue-type plasminogen activator (rTPA, 0.9 mg/kg) and long-term aspirin therapy (100 mg/d) at 24 h after thrombolysis. © 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

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The cardiogenic ischemic stroke patients with international normalized ratio (INR) of 2–3 were given warfarin, and those rejecting determination of INR were given aspirin (100 mg/d). Mannitol or furosemidum was given to lower the intracranial pressure. The hemorrhagic stroke patients with brainstem hemorrhage, cerebral hemorrhage of <30 mL, or cerebellar hemorrhage of <10 mL were intravenously injected with citicoline sodium (0.75 mg/d) for 10 days, and those with cerebral hemorrhage of >30 mL, cerebellar hemorrhage of >10 mL or subarachnoid hemorrhage underwent surgical therapy, mannitol or furosemidum treatment to lower the intracranial pressure, and an intravenous injection of citicoline sodium (0.75 mg/d), and vitamin C (3 g/d) for 10 days. All patients with acute ischemic stroke were intravenously istered with edaravone at a daily dose of 60 mg 12 h apart for successive 10 days following ission. The patients with carotid artery plaques and/or low-density lipoprotein cholesterol (LDL-C) concentration of >3.12 mmol/L were orally given rosuvastatin at a daily dose of 10 mg. Antihypertensive agents and antidiabetic drugs were given to lower blood pressure and blood glucose level. Assessment of neurological impairment and clinical outcomes Neurological impairment at presentation was assessed by the National Institutes of Health Stroke Scale (NIHSS) [17], and the clinical outcomes were evaluated with the Modified Rankin Scale (mRS) at 30 days after treatment [18]. Statistical analysis Categorical variables were expressed as frequency and percentage, and analyzed by chi-square tests. Mea-

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surement data were presented as mean standard deviation (SD), and compared by t-tests. To evaluate the associations of MPV and PLT count with the development and clinical outcome of stroke, MPV and PLT count were transformed into categorical variables using the normal ranges of MPV (9.4–12.5 fL) and PLT (100–300 9 109/L) as the cutoff value [17], and then included in a multivariate logistic regression model. All statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). A P value <0.05 was considered statistically significant.

R E S U LT S General characteristics Based on the selection criteria, a total of 445 cases were selected for the study including 281 cases of firstever ischemic stroke and 164 cases of first-ever hemorrhagic stroke. The general information of study subjects was summarized in Table 1. The mean age of the controls was similar to that of ischemic and hemorrhagic stroke patients (both P values >0.05). A higher incidence of diabetes, hyperlipemia, and heart disease was observed in ischemic stroke patients compared with the controls (P < 0.05), whereas the prevalence of hypertension was significantly higher in hemorrhagic stroke patients (75.6%) than that (45.5%) in the controls (v2 = 21.22, P < 0.001). Therefore, the history of diabetes, hyperlipemia, and heart disease was involved as confounding variables in the multivariate logistic regression model to evaluate the association of MPV and PLT count with the development of ischemic stroke, whereas history of hypertension was used as a confounding variable in the regression analysis to assess the association of MPV and PLT count with the development of hemorrhagic stroke.

Table 1. Clinical characteristics of patients and control subjects

No. Age (years) Male, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Heart disease, n (%) Hypertension, n (%)

Control group

Ischemic group

P

Hemorrhagic group

P

200 65.76 12.95 112 (56) 39 (19.5) 52 (26) 34 (17) 91 (45.5)

281 66.33 11.02 146 (52) 117 (41.6) 123 (43.8) 92 (32.7) 121 (43.1)

0.005 0.416 0.000 0.007 0.000 0.323

164 65.66 10.39 85 (51.8) 39 (23.8) 43 (26.2) 31 (18.9) 124 (75.6)

0.002 0.300 0.412 0.368 0.389 0.008

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

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Of the 281 patients with ischemic stroke, 200 cases were classified according to the TOAST system, including 82 cases (41%) caused by large-artery atherosclerosis, 42 cases (21%) caused by small-vessel occlusion, 44 cases (22%) caused by cardioembolism, 18 cases (9%) of other determined etiology, and 14 cases (7%) of undetermined etiology. Cerebral infarct size was measured in 183 cases, including 114 cases (62.3%) with small infarcts and 69 cases (37.7%) with large infarcts. Among the 164 hemorrhagic stroke patients, intracerebral hemorrhage volume was determined in 57 cases, including 27 cases (47.4%) with large hemorrhages and 30 cases (52.6%) with small hemorrhages. Association of MPV and PLT count with the development of ischemic and hemorrhagic stroke After the confounding factors were controlled, multivariate logistic regression analysis revealed a reduction in the risk of ischemic (OR = 0.06; 95% CI, 0.02– 0.18) and hemorrhagic stroke (OR = 0.05; 95% CI, 0.01–0.2) in subjects with MPV of <9.4 fL than those with normal range of MPV and an increase in the risk

of ischemic (OR = 22.17; 95% CI, 7.86–62.53) and hemorrhagic stroke (OR = 5.21; 95% CI, 1.62–16.74) in subjects with MPV of >12.5 fL as compared to those with normal range of MPV. In addition, the rise of PLT count was found to increase the risk of ischemic stroke (OR = 4.49; 95% CI, 1.49–13.53; P = 0.008), whereas the decrease of PLT count reduced the risk of hemorrhagic stroke (OR = 1.97; 95% CI, 1.08–3.62; P = 0.03) (Table 2). Changes of MPV, PLT count, and NIHSS score in ischemic and hemorrhagic stroke patients with good and poor prognosis The clinical outcomes were evaluated using the Modified Rankin Scale (mRS) at 30 days after treatment. Of the 281 ischemic stroke patients, 66 had no mRS scores, 129 had good prognosis (<4), and 86 had poor prognosis (≥4). Among the 164 patients with hemorrhagic stroke, 31 had no mRS scores, 78 had good prognosis (<4), and 55 had poor prognosis (≥4). There were no significant differences in gender, previous history of diabetes, hyperlipidemia, hypertension, and heart diseases, alcohol consumption, or smoking between the subjects with

Table 2. Association of MPV and PLT count with the risk of ischemic and hemorrhagic stroke detected by multivariate logistic regression analysis

Parameter

No. cases in controls

109 Normal range (9.4–12.5) Reduction 57 (<9) Elevation 34 (>13) PLT Normal 137 (9109/L) range (100–300) Reduction 29 (<100) Elevation 34 (>300) MPV (fL)

No. cases detected in ischemic stroke subjects OR (95% CI)†

No. cases detected in hemorrhagic stroke OR (95% CI)‡ P value subjects

P value

128

1.00

–

88

1.00

–

0.06 (0.02–0.18)

<0.001

40

0.05 (0.01–0.20)

<0.001

22.17 (7.86–62.53) <0.001

36

5.21 (1.62–16.74)

0.006

90

1.00

40 113 190

–

1.00

–

31

0.76 (0.43–1.36)

0.36

42

1.97 (1.08–3.62)

0.03

60

4.49 (1.49–13.53)

0.008

32

1.42 (0.29–6.96)

0.66

MPV, mean platelet volume; PLT, platelet. †The controlled variables involve history of hyperlipidemia, diabetes, and heart diseases. ‡The controlled variable is history of hypertension.

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

J. DU ET AL. | MPV AND PLT COUNT IN STROKE

poor and good prognoses (P > 0.05). MPV in the ischemic stroke patients with poor prognosis was significantly higher compared with those with good prognosis (P < 0.01). However, no association was detected between PLT count and the prognosis of ischemic stroke (P = 0.051). In the hemorrhagic stroke patients, no correlation was observed between MPV and PLT, and the prognosis (P = 0.14 and 0.15, respectively). The ischemic and hemorrhagic stroke patients with higher pretreatment NIHSS scores were found to have a significantly poorer prognosis (P < 0.001) (Table 3). Therefore, NIHSS score, as a confounding variable, was included in the multivariate logistic regression model to assess the associations of MPV and PLT count with the prognosis of ischemic and hemorrhagic stroke.

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domly chosen for the known risk factors and compared with the control subjects with the same risk factors but without any defined vascular diseases. Our findings showed that a decline in MPV reduced the risk of ischemic stroke (OR = 0.06), whereas an elevated MPV increased the risk of ischemic stroke (OR = 22.17). The elevation of MPV has been found to significantly increase the risk of ischemic stroke [20]. As an important indicator that describes platelet function and activity, MPV is found to be positively associated with platelet reactivity. Large platelets, which contain more high-density granules and have higher activity, are much easier to form thrombi [21, 22]. The size of platelets is determined during the production of progenitor cells and does not change after being released into the circulatory system. Therefore, the hypercoagulable state caused by large platelets occurs before the onset of ischemic stroke [1]. Therefore, it seems plausible to infer that the elevation of MPV may increase the risk of ischemic stroke. To our knowledge, there are few reports evaluating the role of MPV in hemorrhagic stroke. Currently, the association of MPV alteration with hemorrhagic stroke remains controversial. No clear association between MPV and the risk of hemorrhagic stroke has been detected in some studies [20, 23, 24]. Our findings showed that the reduction of MPV may decrease the risk of hemorrhagic stroke (OR = 0.05), whereas elevated MPV may increase the risk of hemorrhagic stroke (OR = 5.214). It has been shown that the patients with reduced MPV have a higher likelihood of bleeding than those with elevated MPV, suggesting that MPV may be used to measure the tendency of bleeding, and serve as a parameter for assessing early-stage recovery of the hematopoietic function of bone marrow [25]. Nevertheless, it is possible that raised MPV is a response to bleed in the hemorrhagic cohort. In addition, the measure-

Association of MPV and PLT count with the prognosis of ischemic and hemorrhagic stroke After NIHSS score was controlled, no significant association was detected between MPV and PLT count, and the prognosis of ischemic and hemorrhagic stroke (P > 0.05). No analyses were performed due to too few cases with declined MPV or increased PLT count (Table 4).

DISCUSSION It has been known that platelets play an important role in the pathophysiology of ischemic stroke by developing intravascular thrombus after erosion or rupture of atherosclerotic plaques [1], while thrombocytopenia occurs concurrently with cerebral hemorrhage [19]. MPV and PLT count have been considered an index of the functions of platelets. In this study, 281 patients with first-ever ischemic stroke and 164 patients with first-ever hemorrhagic stroke were ran-

Table 3. Comparison of MPV, PLT count, and NIHSS score in ischemic and hemorrhagic stroke patients with good or poor prognoses Ischemic stroke

Hemorrhagic stroke

Parameter

Good prognosis

Poor prognosis

MPV PLT NIHSS score

13.05 1.10 174.89 75.49 11.66 4.58

13.87 1.27 151.13 64.83 21.52 2.64

t 4.32 1.96 17.96

P

Good prognosis

Poor prognosis

<0.001 0.051 <0.001

12.23 1.25 148.93 83.83 12.48 5.07

12.63 0.75 126.18 49.74 20.41 3.62

MPV, mean platelet volume; PLT, platelet; NIHSS, National Institutes of Health Stroke Scale.

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

t

P 1.50 1.47 7.16

0.14 0.15 <0.001

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Table 4. Association of MPV and PLT count with the prognosis in patients with ischemic and hemorrhagic stroke assessed by multivariate logistic regression analysis Ischemic stroke Good prognosis

Parameter MPV (fL)

PLT (9109/L)

Normal range (9.4–12.5) Reduction (<9) Elevation (>13) Normal range (100–300) Reduction (<100) Elevation (>300)

Hemorrhagic stroke

Poor prognosis

OR (95% CI)

P value

Good prognosis

Poor prognosis

OR (95% CI)

P value

64

49

1.00

–

39

21

1.00

–

64

37

0.39

39

34

0

0

0

0.70 (0.15–3.21) –

0.64

1

1.68 (0.51–5.54) –

101

36

1.00

0.70

28

17

1.00

–

26

48

47

38

2

3

0

1.03 (0.28–3.81) –

0.97

2

1.41 (0.24–8.39) –

–

–

–

–

MPV, mean platelet volume; PLT, platelet.

ment of immature platelet fractions might provide additional value to this study. Further studies are needed to investigate the role of MPV in hemorrhagic stroke and the underlying mechanisms. The present study demonstrated that a higher PLT count increased the risk of ischemic stroke (OR = 4.49), whereas lower PLT count reduced the risk of hemorrhagic stroke (OR = 1.97). Aberrant elevation of PLT is found to promote thrombus formation, thereby increasing the risk of ischemic stroke, while the aberrant PLT reduction causes the impairment of coagulation function, thereby resulting in cerebral hemorrhage. It has been shown that increased capillary fragility and thrombocytopenia may occur concurrently with cerebral hemorrhage despite that the exact mechanism of hemorrhage is unclarified [19]. The role of MPV and PLT count in the prognosis of stroke has not been elucidated. Elevated MPV has been shown to be associated with poor prognosis in patients with acute ischemic stroke [2, 26], but other studies identified no significant correlation between MPV and the prognosis of stroke [27]. PLT count has been identified as a good predictor for hemorrhagic stroke-induced death within 24 h of stroke onset, and significantly reduced PLT count is detected in ischemic stroke patients with poor prognosis or subjects who died of ischemic stroke [28]. Our findings showed that MPV

was correlated with the prognosis in patients with ischemic stroke, and those with elevated MPV had poorer outcomes. In addition, there was a significant difference in the degree of pretreatment neurological deficit between the patients with good and poor prognoses, and more severe neurological deficit was observed in patients with poor prognosis, as shown by greater pretreatment NIHSS score found in patients with poor prognosis. A higher NIHSS score indicates a more severe neurological deficit. It is therefore speculated that the association between elevated MPV and prognosis in patients with ischemic stroke may be affected by the severity of pretreatment stroke. Our findings revealed no significant associations of MPV and PLT count with the prognosis of ischemic and hemorrhagic stroke, after the variable pretreatment NIHSS score was controlled. This study was primarily limited by its small sample size of some subgroups (e.g., subjects with elevated MPV or PLT count). A larger sample with more evenly distributed subjects across subgroups would have benefited our results. Furthermore, this study did not detect the associations of MPV and PLT count with stroke prognosis, which might be due to the limitation of sample size. Further large scale, multicenter studies are required to assess the role of MPV and PLT count in the prognosis of stroke. Patients without any cardiovascular or cerebrovascular diseases who were itted to our © 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 233–239

J. DU ET AL. | MPV AND PLT COUNT IN STROKE

hospital during the same time period were selected as controls. Another possible improvement to the study could have been mentioning the details for the reasons of their hospitalization and the treatment they received before blood sample collection. In addition, MPV and PLT counts were transformed into categorical variables in this study. It could be useful to find out whether the results are unchanged if continuous variables of MPV and PLT count are used instead of categorical variables. In summary, elevated MPV is an independent risk factor of both ischemic and hemorrhagic stroke. Elevated PLT count is a risk factor of ischemic stroke, and reduced PLT count is a risk factor of hemorrhagic

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CONFLICT OF INTERESTS The authors declare no conflict of interests.

FUNDING Scientific Research Projects funded by the Department of Public Health of Sichuan Provine (Project No. 100182).

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