Medical Hypotheses 82 (2014) 341–345
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Mean platelet volume in children with attention deficit hyperactivity disorder Ozgur Yorbik a, Caner Mutlu b,⇑, Ilhan Asya Tanju c, Dincer Celik c, Omer Ozcan d a
Division of Child and Adolescent Psychiatry, Department of Child Development, Faculty of Health Science, Uskudar University, Istanbul, Turkey Department of Child and Adolescent Psychiatry, Bakirkoy Dr. Mazhar Osman Psychiatric and Neurological Diseases Teaching and Research Hospital, Istanbul, Turkey c Department of Pediatrics, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey d Department of Biochemistry, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey b
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Article history: Received 16 September 2013 Accepted 3 January 2014
a b s t r a c t The mean platelet volume (MPV), the accurate measure of platelet size, is considered a marker and determinant of platelet function. MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease. After reviewing literature, we hypothesized that attention deficit hyperactivity disorder (ADHD) in childhood may be a risk factor for coronary heart disease (CHD) in adulthood. The aim of this study was investigation of MPV and platelet count (PLT) in children with ADHD and healthy subjects. The MPV and the PLT were measured in 70 children with ADHD (aged 6–16 years), and compared with 41 healthy controls. The MPV was found to be significantly increased in ADHD group compared to control group (p = .006). There was no significant difference in the PLT between groups (p > .05). To our knowledge, this was the first study of investigating the levels of MPV and PLT in children with ADHD. Although significance and cause of increased MPV level in ADHD remain unclear in present study, further studies are warranted to investigate relationships among MPV, ADHD in childhood and CHD in adulthood. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The typical characteristics of Type A behavior pattern (TABP) includes extremes of competitiveness, aggressiveness, impatience, easily aroused hostility, rapid speech and movements, and time urgency. It was reported that hyperactive boys had higher Type A scores than their comparison peers [1]. Even if it is thought that TABP and hyperactivity have similar configuration correlates [1], TABP and hyperactivity do not differentiated clearly and to some extent they partially overlap in children [2]. Also, TABP and hyperactivity were found to have considerable stability over time [2]. Furthermore, it is considered that TABP is unrelated to physiologic coronary risk factors such as elevated serum cholesterol levels, blood pressure and body mass index (BMI); and appears to be as stable as these risk factors in children and adults [3]. TABP is an indirect risk factor of coronary heart disease (CHD), by attracting potential triggers in early manifestation of cardiac events [4]. It was reported that children with childhood hyperactivity might envisage intima media thickness in adulthood [5]. Subjects with ADHD is associated with elevated BMI compared to controls ⇑ Corresponding author. Address: Bakırköy Prof. Dr. Mazhar Osman Ruh Sag˘lıg˘ı ve _ Sinir Hastalıkları E. A. Hastanesi, Bakırköy, 34147 Istanbul, Turkey. Tel.: +90 505 8343797; fax: +90 212 5729595. E-mail address: [email protected] (C. Mutlu). 0306-9877/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2014.01.001
[6,7]. The risk of cardiovascular events rises with increasing BMI [8]. Although it was unknown the relationship between ADHD in childhood and CHD in adulthood, at least two cases with ADHD using methylphenidate was associated with myocardial infarction, albeit concomitant use of other drugs [9,10]. The relationship between TABP and ADHD, the role of TABP in early manifestation of cardiac events and possibility of intima media thickness in adulthood of hyperactive children may suggest that risk of coronary artery disease may increase in ADHD although there is no published literature about that issue. The MPV, the accurate measure of platelet size, has been considered a marker and determinant of platelet function. Larger platelets have more granules, aggregate more rapidly with collagen, have higher thromboxane A2 levels and express more glycoprotein Ib and IIb/IIIa receptors than smaller platelets [11]. It was found that larger platelets were hemostatically more reactive than platelets of normal size, increasing the propensity to thrombosis [12]. Accumulating data has shown that elevated MPV is associated with acute myocardial infarction (AMI), and MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease [13,14]. Also, it is stated that higher MPV is observed in patients with coronary risk factors including hypercholesterolemia, hypertension (HT), obesity, smoking and diabetes mellitus (DM) [13]. These observations suggest a common mechanism by which these risk factors may increase the risk of CHD [13].
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Similarly, elevated MPV may play a role at increased risk of coronary artery disease in people with TABP. The aim of present study is to investigate MPV and PLT in children with ADHD and healthy subjects. It was hypothesized that children with ADHD have elevated MPV and PLT levels, compared to healthy controls. To our knowledge, this is the first study of investigating the levels of MPV and PLT in children with ADHD. Methods Subjects Seventy drug-free subjects, aged 6–16, who were admitted to GATA Medical Academy and diagnosed as ADHD according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria [15] were included in this study. Patients were assessed using parent completed the Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSMIV-S) [16]. Forty-one mentally and physically healthy subjects that had similar socio-demographic characteristics were included in the study as a control group. All subjects in the study were outpatients and Caucasians. Subjects who had seizure disorders, mental retardation, autistic disorder, organic brain damage, psychotic disorder, conduct disorder, elevated blood pressure or HT, hypercholesterolemia, any other acute or chronic physical illnesses, a history of any drug use during the last month or smoking were excluded from the study. Written informed consent was obtained from parents of all subjects. Ethic Committee approved this study. Height, weight, platelet count and MPV were measured and recorded for each subject. The reference range for MPV was between 6.9 and 10.8 fL. There was no child who had an elevated MPV for age. Blood analysis Blood samples were drawn after a fasting period of 12 h. In fasting venous blood samples collecting with K3EDTA containing sterile Vacutainer tubes, complete blood counts including MPV were determined by using Abbott Sapphire Automated Hematology Analyzer (Abbott Laboratories, Abbott Park, IL, USA) with its own commercial kits. In order to measure MPV more reliable and to minimize the potential influence of anticoagulant (EDTA) on the MPV, blood samples were analyzed within 60 min after venipuncture. Statistical analysis Measures of MPV and PLT in the children with ADHD and control subjects were compared by using two-tailed t-test. The comparison of sex in groups was performed by using Chi square test. Results were considered significant, when the p value was .05). ADHD group consisted of 21 girls and 49 boys and control group 14 girls and 27 boys. No significant difference was found in the female/ male ratio between ADHD group and control group (p > .05). The MPV was found to be significantly increased in ADHD group compared to control group (8.35 ± 0.82 vs. 7.90 ± 0.82 fL; p = .006) (Table 1). There was no significant difference in PLT and BMI between groups (both p value >.05).
Discussion The findings of present study indicate that the children with ADHD may have increased levels of MPV in the absence of related factors, such as elevated blood pressure or HT, hypercholesterolemia and obesity. To the best of our knowledge, this is the first study investigating the levels of MPV and PLT in ADHD. MPV is considered to be an indicator of platelet activation, and to be important in the pathophysiology of CHD [13,17]. CHD is a manifestation of atherosclerosis which is known to begin in childhood. For atherosclerosis, there are behavioral risk factors (such as hyperactivity, anger, hostility, depression, Type A behavior) that may originate in early childhood and traditional risk factors (such as smoking, obesity, dyslipidemia, DM, HT) which may be a link through which early life behavioral risk factors affect later atherosclerosis [5]. In researches, atherosclerosis is widely assessed by non-invasive markers, such as carotid artery intima media thickness (cIMT) [18]. cIMT is significantly higher in pediatric populations with increased cardiovascular risk factors, such as obesity, insulin dependent DM, dyslipidemia and HT, compared with healthy populations [19]. Conversely, no association between cIMT and non-alcoholic fatty liver disease (NAFLD) was found in children and adolescents [20]. These findings confirm early vascular damages in pediatric populations with an increased future risk for CHD [19]. Moreover, relationship between behavioral and traditional risk factors is intriguing. Childhood hyperactivity predicts adulthood cIMT after adjustment for childhood and adulthood risk factors for atherosclerosis in women [5]. Motor activity, even hyperactivity, in childhood was found to increase significantly with the ApoE phenotypes in the order of E2/2, E3/2, E4/2, E3/ 3 and E4/4 [21]. Total cholesterol levels and ApoE phenotype in childhood correlate with arterial atherosclerotic findings [22]. It was reported that childhood hyperactivity correlated with apolipoproteins A-I and B (with high B and low A-1) [23] and precursors of insulin resistance syndrome [24]. Also, childhood hyperactivity was shown to predict young adulthood obesity [25]. MPV is also thought to be able to reflect atherosclerosis [13]. Previous studies reported controversial results about the relationship between MPV and cIMT. Arslan et al. [26] found that MPV and the left cIMT were significantly higher in obese adolescents than the healthy controls. MPV was found to significantly correlate with cIMT in obese adolescents, independently of fatty liver grade, relative weight, total cholesterol and homeostasis model of assessment of insulin resistance [26]. Similarly, Yarlioglues et al. [27] reported a positive correlation between MPV and cIMT in 80 newly diagnosed adult hypertensive patients. On the contrary, Kilciler et al. [28] reported no relationship between MPV and carotid atherosclerosis in adult patients with NAFLD. While Arslan et al. [26] suggested that MPV might be used as a possible indicator of subclinical atherosclerosis in obese adolescents, Kilciler et al. [28] suggested that MPV might not be involved in the mechanism of increased cardiovascular risk in adults with NAFLD in the absence of other metabolic risk factors such as hypertension, diabetes and obesity. There are numerous studies investigating the relationship between MPV and risk factors for CHD, including DM [29–32], HT [32–36], hypercholesterolemia [37–39], smoking [40,41], obesity [26,35,42,43] and metabolic syndrome (MetS) [44,45]. Several studies demonstrated that MPV increased in the presence of DM [29–32] and in patients with impaired fasting glucose (although less than that in diabetic subjects) [46,47]. It was showed that no change in MPV between Type 1 and Type 2 diabetes [29]. It is suggested that the increase in MPV may occur due to the diabetic state
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O. Yorbik et al. / Medical Hypotheses 82 (2014) 341–345 Table 1 MPV, PLT, BMI and age in children with ADHD and healthy controls. Children with ADHD (n = 70)
MPV (fL) PLT (109) BMI (kg/m2) Age (years)
Healthy controls (n = 41)
p
Mean
SD
Mean
SD
8.35 301.4 17.97 9.9
.82 81.3 2.69 2.4
7.90 315.4 17.75 9.5
.82 88.2 3.14 2.7
itself [29,30,32]. In diabetes, MPV is thought to be disassociated with vascular complications [32,48]. The mechanisms of increased MPV in DM are considered to be osmotic swelling, a shorter life span for platelets and producing larger platelets induced by insulin [30]. A relationship between blood pressure and MPV was reported by studies [33,34,36], although sometimes this relationship was not confirmed [32,35]. Increased MPV is associated with prehypertension in a cross-sectional study including Chinese adults that are free of cardiovascular disease, hypertension and diabetes [36]. Hypertensive patients have significantly higher platelet volume [33,34]. While mean systolic blood pressure in people with prehypertension was found to be increased significantly with increasing MPV [36], MPV was shown to be positively correlated with ambulatory diastolic blood pressure in essential HT and white coat HT groups [34]. Higher MPV in HT may be associated with multiple factors like atherosclerotic lesions due to HT [49]. Platelet size was found to increase in patients with hypercholesterolaemia in several studies [37–39], while no relationship was reported by other studies [42,44]. Although no correlation was found between the changes in MPV levels and the changes in plasma lipids after treatment [14], MPV was positively correlated with triglyceride levels [26]. No significant difference was found for MPV between the smoking and non-smoking young healthy male subjects possibly in the early period of atherosclerosis [41]. In the elderly, MPV was the highest in the atherosclerotic smokers, compared to non-smoking and non-atherosclerotic groups [40]. It is suggested that smoking may lead to the acceleration of atherosclerosis and may increase platelet consumption in atherosclerotic vessels [40]. No significant difference was found in BMI between children with ADHD and healthy controls in the present study. On the contrary, various studies suggested that children and adults with ADHD had increased BMI [6,7]. Children and adolescents with ADHD, not using medication, was found to be approximately 1.5 times the odds of being overweight [50]. BMI was reported to have an increasing effect on MPV in the obese patients, independently in the presence of other cardiovascular risk factors or of hematological and renal diseases [42]. It is suggested that higher MPV levels in obese individuals may be a possible cause for increased risk of atherosclerosis [42]. Percent body fat was found to be independently associated with MPV in elderly population [35]. Also, there is a positive correlation between body mass index (BMI) and MPV [26,42]. Arslan and Makay [43] suggest that MPV may be used as a follow-up marker in patients with NAFLD at the point of atherosclerosis. A cluster of atherosclerotic risk factors given above is MetS. Adult patients with MetS have significantly increased MPV. It was reported that MPV was significantly correlated and independently associated with components of MetS including blood pressure, waist circumference, BMI and fasting plasma glucose [44]. Also a significant difference was found between the patients, having MetS, with CHD and the ones without CHD. MPV values are suggested to be associated with atherosclerotic process rather than the severity of the CHD in adults [44]. Conversely, MPV was found
.006 .389 .721 .434
to be significantly lower in pre-pubertal children with MetS, especially in girls [45]. Also, it was demonstrated that MPV was negatively correlated with fasting blood glucose, low density lipoprotein-cholesterol and low density lipoprotein-cholesterol/ high density lipoprotein-cholesterol ratio in girls after adjusting for confounding factors [45]. The authors suggest that MPV can be another feature of MetS in pre-pubertal girls and might be used as a surrogate marker for MetS in clinical settings [45]. Compared to controls, higher MPV values in children with ADHD in the absence of cardiovascular risk factors given above suggest that there can be a different mechanism leading to increased MPV in ADHD. MPV is increased when both platelet production and destruction are stimulated (for example by chronic hypoxia, administration of anti-platelet) [51], when platelet turnover increases (for example in patients with diabetes or smokers) [40,52], and when systemic platelet activation (for example in the course of vessels wall disease, in progression of atherosclerosis) or systematic inflammation occur (for example in obesity) [26]. It is thought that these mechanisms are most probably mediated by cytokines, including interleukin 3 (IL-3), thrombopoietin (TPO) and in particular interleukin 6 (IL-6) [53,54]. MPV was found to be positively associated with levels of TPO and IL-6 [13]. Oades et al. [55] reported that some normalized cytokine values, including IL-2, IL-6, IL-10, IL-13 and IL-16, tended to be higher in the ADHD than in the control group. It is thought that the increased circulating levels of IL-6 and other similar cytokines may affect megakaryopoiesis [54]. In the present study, higher MPV in children with ADHD may be due to higher levels of cytokines, in particular IL-6. Unlike the MPV values, no significant difference was found in PLT between children with ADHD and healthy controls in the present study. Similar results were reported for the patients with HT [34], obesity [56], atherosclerotic renal artery stenosis [57] and heterozygous thalassaemia [58]. Experimental studies in animal models have demonstrated that when acute platelet destruction occurs in the absence of platelet production, an increase in MPV but no change in PLT occurs [14]. But, several studies have reported that increases in MPV are often associated with decreases in PLT [43,59–61]. Although the relationship between MPV and PLT has not been clearly understood yet [13], increased MPV and normal PLT in our study may suggest possible atherosclerotic changes beginning and being asymptomatic in children with ADHD. At least two case reports have noted an association with myocardial infarction and use of methylphenidate complicated by concomitant use of other drugs (e.g. pseudoephedrine for the one, bupropion and erythromycin for the other) in patients with ADHD [9,10]. Accumulating risk factors in ADHD may be important for myocardial infarction in ones who use methylphenidate. Although there is no study investigating the relationship between CHD and ADHD, the possible role of MPV on reflecting atherosclerosis, the role of childhood hyperactivity on prediction of adulthood cIMT and our finding of increased MPV in children with ADHD suggest a potential relationship between CHD and ADHD. Despite the findings, some limitations should be noted for the present study. Firstly, the study sample was relatively small to
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draw definite conclusions. Secondly, we could not measure inflammatuar markers, including the levels of IL-3, TPO, in particular IL-6 which are positively associated with MPV [13]. In order to elucidate the cause of increased MPV values, further studies with more participants in both sex are required to assess whether MPV in patients with ADHD is associated with other factors such as levels of cytokines mentioned above; whether subtypes of ADHD can affect MPV values; whether levels of MPV can differ in patients with ADHD in presence of comorbid vascular risk diseases; and whether levels of MPV can differ after treatment of ADHD. In conclusion, this study suggested that children with ADHD were associated with increased MPV levels. Significance and cause of increased MPV values in ADHD remain unclear in this study. Previous studies suggested that elevated MPV might be related to CHD. We speculated that ADHD in childhood might be a risk factor for CHD in adulthood. Further studies are warranted to investigate relationships between ADHD in childhood and CHD in adulthood. Conflict of interest Ozgur Yorbik, Caner Mutlu, Ilhan Asya Tanju, Dincer Celik and Omer Ozcan declare no financial and personal relationships with other people or organizations for this work. Role of funding source None. References [1] Whalen CK, Henker B. Type A behavior in normal and hyperactive children: multisource evidence of overlapping constructs. Child Dev 1986;57(3):688–99. [2] Nyberg L, Bohlin G, Hagekull B. Assessing Type A behavior in children: a longitudinal exploration of the overlap between Type A behavior and hyperactivity. Scand J Psychol 2004;45(2):145–56. [3] Weidner G, McLellarn R, Sexton G, Istvan J, Connor S. Type A behavior and physiologic coronary risk factors in children of the family heart study: results from a 1-year follow-up. Psychosom Med 1986;48(7):480–8. [4] Gallacher JE, Sweetnam PM, Yarnell JW, Elwood PC, Stansfeld SA. Is Type A behavior really a trigger for coronary heart disease events? Psychosom Med 2003;65(3):339–46. [5] Keltikangas-Järvinen L, Pulkki-Råback L, Puttonen S, Viikari J, Raitakari OT. Childhood hyperactivity as a predictor of carotid artery intima media thickness over a period of 21 years: the cardiovascular risk in young Finns study. Psychosom Med 2006;68(4):509–16. [6] Hubel R, Jass J, Marcus A, Laessle RG. Overweight and basal metabolic rate in boys with attention-deficit/hyperactivity disorder. Eat Weight Disord 2006;11(3):139–46. [7] Strimas R, Davis C, Patte K, Curtis C, Reid C, McCool C. Symptoms of attentiondeficit/hyperactivity disorder, overeating, and body mass index in men. Eat Behav 2008;9(4):516–8. [8] Gelber RP, Gaziano JM, Orav EJ, Manson JE, Buring JE, Kurth T. Measures of obesity and cardiovascular risk among men and women. J Am Coll Cardiol 2008;52(8):605–15. [9] Gandhi PJ, Ezeala GU, Luyen TT, Tu TC, Tran MT. Myocardial infarction in an adolescent taking Adderall. Am J Health Syst Pharm 2005;62(14):1494–7. [10] Jiao X, Velez S, Ringstad J, Eyma V, Miller D, Bleiberg M. Myocardial infarction associated with Adderall XR and alcohol use in a young man. J. Am. Board Fam. Med. 2009;22(2):197–201. [11] Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983;32(5):443–60. [12] Thompson CB, Jakubowski JA, Quinn PG, Deykin D, Valeri CR. Platelet size and age determine platelet function independently. Blood 1984;63(6):1372–5. [13] 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;8:148–56. [14] Vizioli L, Muscari S, Muscari A. The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases. Int J Clin Pract 2009;63(10):1509–15. [15] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Mean platelet volume in children with attention deficit hyperactivity disorder Ozgur Yorbik a, Caner Mutlu b,⇑, Ilhan Asya Tanju c, Dincer Celik c, Omer Ozcan d a
Division of Child and Adolescent Psychiatry, Department of Child Development, Faculty of Health Science, Uskudar University, Istanbul, Turkey Department of Child and Adolescent Psychiatry, Bakirkoy Dr. Mazhar Osman Psychiatric and Neurological Diseases Teaching and Research Hospital, Istanbul, Turkey c Department of Pediatrics, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey d Department of Biochemistry, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey b
a r t i c l e
i n f o
Article history: Received 16 September 2013 Accepted 3 January 2014
a b s t r a c t The mean platelet volume (MPV), the accurate measure of platelet size, is considered a marker and determinant of platelet function. MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease. After reviewing literature, we hypothesized that attention deficit hyperactivity disorder (ADHD) in childhood may be a risk factor for coronary heart disease (CHD) in adulthood. The aim of this study was investigation of MPV and platelet count (PLT) in children with ADHD and healthy subjects. The MPV and the PLT were measured in 70 children with ADHD (aged 6–16 years), and compared with 41 healthy controls. The MPV was found to be significantly increased in ADHD group compared to control group (p = .006). There was no significant difference in the PLT between groups (p > .05). To our knowledge, this was the first study of investigating the levels of MPV and PLT in children with ADHD. Although significance and cause of increased MPV level in ADHD remain unclear in present study, further studies are warranted to investigate relationships among MPV, ADHD in childhood and CHD in adulthood. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The typical characteristics of Type A behavior pattern (TABP) includes extremes of competitiveness, aggressiveness, impatience, easily aroused hostility, rapid speech and movements, and time urgency. It was reported that hyperactive boys had higher Type A scores than their comparison peers [1]. Even if it is thought that TABP and hyperactivity have similar configuration correlates [1], TABP and hyperactivity do not differentiated clearly and to some extent they partially overlap in children [2]. Also, TABP and hyperactivity were found to have considerable stability over time [2]. Furthermore, it is considered that TABP is unrelated to physiologic coronary risk factors such as elevated serum cholesterol levels, blood pressure and body mass index (BMI); and appears to be as stable as these risk factors in children and adults [3]. TABP is an indirect risk factor of coronary heart disease (CHD), by attracting potential triggers in early manifestation of cardiac events [4]. It was reported that children with childhood hyperactivity might envisage intima media thickness in adulthood [5]. Subjects with ADHD is associated with elevated BMI compared to controls ⇑ Corresponding author. Address: Bakırköy Prof. Dr. Mazhar Osman Ruh Sag˘lıg˘ı ve _ Sinir Hastalıkları E. A. Hastanesi, Bakırköy, 34147 Istanbul, Turkey. Tel.: +90 505 8343797; fax: +90 212 5729595. E-mail address: [email protected] (C. Mutlu). 0306-9877/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2014.01.001
[6,7]. The risk of cardiovascular events rises with increasing BMI [8]. Although it was unknown the relationship between ADHD in childhood and CHD in adulthood, at least two cases with ADHD using methylphenidate was associated with myocardial infarction, albeit concomitant use of other drugs [9,10]. The relationship between TABP and ADHD, the role of TABP in early manifestation of cardiac events and possibility of intima media thickness in adulthood of hyperactive children may suggest that risk of coronary artery disease may increase in ADHD although there is no published literature about that issue. The MPV, the accurate measure of platelet size, has been considered a marker and determinant of platelet function. Larger platelets have more granules, aggregate more rapidly with collagen, have higher thromboxane A2 levels and express more glycoprotein Ib and IIb/IIIa receptors than smaller platelets [11]. It was found that larger platelets were hemostatically more reactive than platelets of normal size, increasing the propensity to thrombosis [12]. Accumulating data has shown that elevated MPV is associated with acute myocardial infarction (AMI), and MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease [13,14]. Also, it is stated that higher MPV is observed in patients with coronary risk factors including hypercholesterolemia, hypertension (HT), obesity, smoking and diabetes mellitus (DM) [13]. These observations suggest a common mechanism by which these risk factors may increase the risk of CHD [13].
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Similarly, elevated MPV may play a role at increased risk of coronary artery disease in people with TABP. The aim of present study is to investigate MPV and PLT in children with ADHD and healthy subjects. It was hypothesized that children with ADHD have elevated MPV and PLT levels, compared to healthy controls. To our knowledge, this is the first study of investigating the levels of MPV and PLT in children with ADHD. Methods Subjects Seventy drug-free subjects, aged 6–16, who were admitted to GATA Medical Academy and diagnosed as ADHD according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) criteria [15] were included in this study. Patients were assessed using parent completed the Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSMIV-S) [16]. Forty-one mentally and physically healthy subjects that had similar socio-demographic characteristics were included in the study as a control group. All subjects in the study were outpatients and Caucasians. Subjects who had seizure disorders, mental retardation, autistic disorder, organic brain damage, psychotic disorder, conduct disorder, elevated blood pressure or HT, hypercholesterolemia, any other acute or chronic physical illnesses, a history of any drug use during the last month or smoking were excluded from the study. Written informed consent was obtained from parents of all subjects. Ethic Committee approved this study. Height, weight, platelet count and MPV were measured and recorded for each subject. The reference range for MPV was between 6.9 and 10.8 fL. There was no child who had an elevated MPV for age. Blood analysis Blood samples were drawn after a fasting period of 12 h. In fasting venous blood samples collecting with K3EDTA containing sterile Vacutainer tubes, complete blood counts including MPV were determined by using Abbott Sapphire Automated Hematology Analyzer (Abbott Laboratories, Abbott Park, IL, USA) with its own commercial kits. In order to measure MPV more reliable and to minimize the potential influence of anticoagulant (EDTA) on the MPV, blood samples were analyzed within 60 min after venipuncture. Statistical analysis Measures of MPV and PLT in the children with ADHD and control subjects were compared by using two-tailed t-test. The comparison of sex in groups was performed by using Chi square test. Results were considered significant, when the p value was .05). ADHD group consisted of 21 girls and 49 boys and control group 14 girls and 27 boys. No significant difference was found in the female/ male ratio between ADHD group and control group (p > .05). The MPV was found to be significantly increased in ADHD group compared to control group (8.35 ± 0.82 vs. 7.90 ± 0.82 fL; p = .006) (Table 1). There was no significant difference in PLT and BMI between groups (both p value >.05).
Discussion The findings of present study indicate that the children with ADHD may have increased levels of MPV in the absence of related factors, such as elevated blood pressure or HT, hypercholesterolemia and obesity. To the best of our knowledge, this is the first study investigating the levels of MPV and PLT in ADHD. MPV is considered to be an indicator of platelet activation, and to be important in the pathophysiology of CHD [13,17]. CHD is a manifestation of atherosclerosis which is known to begin in childhood. For atherosclerosis, there are behavioral risk factors (such as hyperactivity, anger, hostility, depression, Type A behavior) that may originate in early childhood and traditional risk factors (such as smoking, obesity, dyslipidemia, DM, HT) which may be a link through which early life behavioral risk factors affect later atherosclerosis [5]. In researches, atherosclerosis is widely assessed by non-invasive markers, such as carotid artery intima media thickness (cIMT) [18]. cIMT is significantly higher in pediatric populations with increased cardiovascular risk factors, such as obesity, insulin dependent DM, dyslipidemia and HT, compared with healthy populations [19]. Conversely, no association between cIMT and non-alcoholic fatty liver disease (NAFLD) was found in children and adolescents [20]. These findings confirm early vascular damages in pediatric populations with an increased future risk for CHD [19]. Moreover, relationship between behavioral and traditional risk factors is intriguing. Childhood hyperactivity predicts adulthood cIMT after adjustment for childhood and adulthood risk factors for atherosclerosis in women [5]. Motor activity, even hyperactivity, in childhood was found to increase significantly with the ApoE phenotypes in the order of E2/2, E3/2, E4/2, E3/ 3 and E4/4 [21]. Total cholesterol levels and ApoE phenotype in childhood correlate with arterial atherosclerotic findings [22]. It was reported that childhood hyperactivity correlated with apolipoproteins A-I and B (with high B and low A-1) [23] and precursors of insulin resistance syndrome [24]. Also, childhood hyperactivity was shown to predict young adulthood obesity [25]. MPV is also thought to be able to reflect atherosclerosis [13]. Previous studies reported controversial results about the relationship between MPV and cIMT. Arslan et al. [26] found that MPV and the left cIMT were significantly higher in obese adolescents than the healthy controls. MPV was found to significantly correlate with cIMT in obese adolescents, independently of fatty liver grade, relative weight, total cholesterol and homeostasis model of assessment of insulin resistance [26]. Similarly, Yarlioglues et al. [27] reported a positive correlation between MPV and cIMT in 80 newly diagnosed adult hypertensive patients. On the contrary, Kilciler et al. [28] reported no relationship between MPV and carotid atherosclerosis in adult patients with NAFLD. While Arslan et al. [26] suggested that MPV might be used as a possible indicator of subclinical atherosclerosis in obese adolescents, Kilciler et al. [28] suggested that MPV might not be involved in the mechanism of increased cardiovascular risk in adults with NAFLD in the absence of other metabolic risk factors such as hypertension, diabetes and obesity. There are numerous studies investigating the relationship between MPV and risk factors for CHD, including DM [29–32], HT [32–36], hypercholesterolemia [37–39], smoking [40,41], obesity [26,35,42,43] and metabolic syndrome (MetS) [44,45]. Several studies demonstrated that MPV increased in the presence of DM [29–32] and in patients with impaired fasting glucose (although less than that in diabetic subjects) [46,47]. It was showed that no change in MPV between Type 1 and Type 2 diabetes [29]. It is suggested that the increase in MPV may occur due to the diabetic state
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O. Yorbik et al. / Medical Hypotheses 82 (2014) 341–345 Table 1 MPV, PLT, BMI and age in children with ADHD and healthy controls. Children with ADHD (n = 70)
MPV (fL) PLT (109) BMI (kg/m2) Age (years)
Healthy controls (n = 41)
p
Mean
SD
Mean
SD
8.35 301.4 17.97 9.9
.82 81.3 2.69 2.4
7.90 315.4 17.75 9.5
.82 88.2 3.14 2.7
itself [29,30,32]. In diabetes, MPV is thought to be disassociated with vascular complications [32,48]. The mechanisms of increased MPV in DM are considered to be osmotic swelling, a shorter life span for platelets and producing larger platelets induced by insulin [30]. A relationship between blood pressure and MPV was reported by studies [33,34,36], although sometimes this relationship was not confirmed [32,35]. Increased MPV is associated with prehypertension in a cross-sectional study including Chinese adults that are free of cardiovascular disease, hypertension and diabetes [36]. Hypertensive patients have significantly higher platelet volume [33,34]. While mean systolic blood pressure in people with prehypertension was found to be increased significantly with increasing MPV [36], MPV was shown to be positively correlated with ambulatory diastolic blood pressure in essential HT and white coat HT groups [34]. Higher MPV in HT may be associated with multiple factors like atherosclerotic lesions due to HT [49]. Platelet size was found to increase in patients with hypercholesterolaemia in several studies [37–39], while no relationship was reported by other studies [42,44]. Although no correlation was found between the changes in MPV levels and the changes in plasma lipids after treatment [14], MPV was positively correlated with triglyceride levels [26]. No significant difference was found for MPV between the smoking and non-smoking young healthy male subjects possibly in the early period of atherosclerosis [41]. In the elderly, MPV was the highest in the atherosclerotic smokers, compared to non-smoking and non-atherosclerotic groups [40]. It is suggested that smoking may lead to the acceleration of atherosclerosis and may increase platelet consumption in atherosclerotic vessels [40]. No significant difference was found in BMI between children with ADHD and healthy controls in the present study. On the contrary, various studies suggested that children and adults with ADHD had increased BMI [6,7]. Children and adolescents with ADHD, not using medication, was found to be approximately 1.5 times the odds of being overweight [50]. BMI was reported to have an increasing effect on MPV in the obese patients, independently in the presence of other cardiovascular risk factors or of hematological and renal diseases [42]. It is suggested that higher MPV levels in obese individuals may be a possible cause for increased risk of atherosclerosis [42]. Percent body fat was found to be independently associated with MPV in elderly population [35]. Also, there is a positive correlation between body mass index (BMI) and MPV [26,42]. Arslan and Makay [43] suggest that MPV may be used as a follow-up marker in patients with NAFLD at the point of atherosclerosis. A cluster of atherosclerotic risk factors given above is MetS. Adult patients with MetS have significantly increased MPV. It was reported that MPV was significantly correlated and independently associated with components of MetS including blood pressure, waist circumference, BMI and fasting plasma glucose [44]. Also a significant difference was found between the patients, having MetS, with CHD and the ones without CHD. MPV values are suggested to be associated with atherosclerotic process rather than the severity of the CHD in adults [44]. Conversely, MPV was found
.006 .389 .721 .434
to be significantly lower in pre-pubertal children with MetS, especially in girls [45]. Also, it was demonstrated that MPV was negatively correlated with fasting blood glucose, low density lipoprotein-cholesterol and low density lipoprotein-cholesterol/ high density lipoprotein-cholesterol ratio in girls after adjusting for confounding factors [45]. The authors suggest that MPV can be another feature of MetS in pre-pubertal girls and might be used as a surrogate marker for MetS in clinical settings [45]. Compared to controls, higher MPV values in children with ADHD in the absence of cardiovascular risk factors given above suggest that there can be a different mechanism leading to increased MPV in ADHD. MPV is increased when both platelet production and destruction are stimulated (for example by chronic hypoxia, administration of anti-platelet) [51], when platelet turnover increases (for example in patients with diabetes or smokers) [40,52], and when systemic platelet activation (for example in the course of vessels wall disease, in progression of atherosclerosis) or systematic inflammation occur (for example in obesity) [26]. It is thought that these mechanisms are most probably mediated by cytokines, including interleukin 3 (IL-3), thrombopoietin (TPO) and in particular interleukin 6 (IL-6) [53,54]. MPV was found to be positively associated with levels of TPO and IL-6 [13]. Oades et al. [55] reported that some normalized cytokine values, including IL-2, IL-6, IL-10, IL-13 and IL-16, tended to be higher in the ADHD than in the control group. It is thought that the increased circulating levels of IL-6 and other similar cytokines may affect megakaryopoiesis [54]. In the present study, higher MPV in children with ADHD may be due to higher levels of cytokines, in particular IL-6. Unlike the MPV values, no significant difference was found in PLT between children with ADHD and healthy controls in the present study. Similar results were reported for the patients with HT [34], obesity [56], atherosclerotic renal artery stenosis [57] and heterozygous thalassaemia [58]. Experimental studies in animal models have demonstrated that when acute platelet destruction occurs in the absence of platelet production, an increase in MPV but no change in PLT occurs [14]. But, several studies have reported that increases in MPV are often associated with decreases in PLT [43,59–61]. Although the relationship between MPV and PLT has not been clearly understood yet [13], increased MPV and normal PLT in our study may suggest possible atherosclerotic changes beginning and being asymptomatic in children with ADHD. At least two case reports have noted an association with myocardial infarction and use of methylphenidate complicated by concomitant use of other drugs (e.g. pseudoephedrine for the one, bupropion and erythromycin for the other) in patients with ADHD [9,10]. Accumulating risk factors in ADHD may be important for myocardial infarction in ones who use methylphenidate. Although there is no study investigating the relationship between CHD and ADHD, the possible role of MPV on reflecting atherosclerosis, the role of childhood hyperactivity on prediction of adulthood cIMT and our finding of increased MPV in children with ADHD suggest a potential relationship between CHD and ADHD. Despite the findings, some limitations should be noted for the present study. Firstly, the study sample was relatively small to
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draw definite conclusions. Secondly, we could not measure inflammatuar markers, including the levels of IL-3, TPO, in particular IL-6 which are positively associated with MPV [13]. In order to elucidate the cause of increased MPV values, further studies with more participants in both sex are required to assess whether MPV in patients with ADHD is associated with other factors such as levels of cytokines mentioned above; whether subtypes of ADHD can affect MPV values; whether levels of MPV can differ in patients with ADHD in presence of comorbid vascular risk diseases; and whether levels of MPV can differ after treatment of ADHD. In conclusion, this study suggested that children with ADHD were associated with increased MPV levels. Significance and cause of increased MPV values in ADHD remain unclear in this study. Previous studies suggested that elevated MPV might be related to CHD. We speculated that ADHD in childhood might be a risk factor for CHD in adulthood. Further studies are warranted to investigate relationships between ADHD in childhood and CHD in adulthood. Conflict of interest Ozgur Yorbik, Caner Mutlu, Ilhan Asya Tanju, Dincer Celik and Omer Ozcan declare no financial and personal relationships with other people or organizations for this work. Role of funding source None. References [1] Whalen CK, Henker B. Type A behavior in normal and hyperactive children: multisource evidence of overlapping constructs. Child Dev 1986;57(3):688–99. [2] Nyberg L, Bohlin G, Hagekull B. Assessing Type A behavior in children: a longitudinal exploration of the overlap between Type A behavior and hyperactivity. Scand J Psychol 2004;45(2):145–56. [3] Weidner G, McLellarn R, Sexton G, Istvan J, Connor S. Type A behavior and physiologic coronary risk factors in children of the family heart study: results from a 1-year follow-up. Psychosom Med 1986;48(7):480–8. [4] Gallacher JE, Sweetnam PM, Yarnell JW, Elwood PC, Stansfeld SA. Is Type A behavior really a trigger for coronary heart disease events? Psychosom Med 2003;65(3):339–46. [5] Keltikangas-Järvinen L, Pulkki-Råback L, Puttonen S, Viikari J, Raitakari OT. Childhood hyperactivity as a predictor of carotid artery intima media thickness over a period of 21 years: the cardiovascular risk in young Finns study. Psychosom Med 2006;68(4):509–16. [6] Hubel R, Jass J, Marcus A, Laessle RG. Overweight and basal metabolic rate in boys with attention-deficit/hyperactivity disorder. Eat Weight Disord 2006;11(3):139–46. [7] Strimas R, Davis C, Patte K, Curtis C, Reid C, McCool C. Symptoms of attentiondeficit/hyperactivity disorder, overeating, and body mass index in men. Eat Behav 2008;9(4):516–8. [8] Gelber RP, Gaziano JM, Orav EJ, Manson JE, Buring JE, Kurth T. Measures of obesity and cardiovascular risk among men and women. J Am Coll Cardiol 2008;52(8):605–15. [9] Gandhi PJ, Ezeala GU, Luyen TT, Tu TC, Tran MT. Myocardial infarction in an adolescent taking Adderall. Am J Health Syst Pharm 2005;62(14):1494–7. [10] Jiao X, Velez S, Ringstad J, Eyma V, Miller D, Bleiberg M. Myocardial infarction associated with Adderall XR and alcohol use in a young man. J. Am. Board Fam. Med. 2009;22(2):197–201. [11] Martin JF, Trowbridge EA, Salmon G, Plumb J. The biological significance of platelet volume: its relationship to bleeding time, platelet thromboxane B2 production and megakaryocyte nuclear DNA concentration. Thromb Res 1983;32(5):443–60. [12] Thompson CB, Jakubowski JA, Quinn PG, Deykin D, Valeri CR. Platelet size and age determine platelet function independently. Blood 1984;63(6):1372–5. [13] 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;8:148–56. [14] Vizioli L, Muscari S, Muscari A. The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases. Int J Clin Pract 2009;63(10):1509–15. [15] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.
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