1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

Insufficient platelet function suppression by aspirin is a predictor of cardiovascular events in high-risk patients. The authors assessed the impact of obesity on platelet responsiveness before and after 2 weeks of aspirin 81 mg/d in 2014 people. Obese individuals had greater baseline platelet reactivity. Comparing obese and nonobese individuals after aspirin therapy, results for aggregometry to collagen were 6.7 vs 6.1 ohms, P=.008; aggregometry to adenosine diphosphate were 13.1 vs 11.8 ohms,P<.0001; aggregometry to arachidonic acid (AA) were 4.9% vs 8.3% nonzero aggregation, P=.002; urinary excretion of 11-dehydro-thromboxane B2 (Tx-M) were 4.9% vs 8.3% nonzero aggregation, P=.002; and aspirin resistance were 26.% vs 20.5%, P=.002; respectively. These remained significantly different for AA aggregation and Tx-M excretion after adjustment for covariates. Obese individuals have greater native platelet reactivity and retain greater reactivity after suppression by aspirin.

Prev Cardiol. 2010;13:56–62.©2009 Wiley Periodicals, Inc.

Most studies demonstrate a notable increase in cardiovascular risk in obese individuals,1 although the extent to which this is entirely independent of other risk factors remains unclear.2 Traditional coronary artery disease (CAD) risk factors, including hyperglycemia, hypertension, dyslipidemia, and impaired fasting glucose, all cluster strongly in obese adults.3 In addition, obesity appears to be associated with a prothrombotic state that may also enhance the susceptibility of obese people to acute cardiovascular disease events.4,5

Based on compelling evidence supporting a cardioprotective effect in persons at increased risk for a first CAD event, the United States Preventive Services Task Force currently recommends low-dose aspirin (at least 75 mg/d) for people with a projected CAD risk of ≥3% over the next 5 years.6 This recommendation is particularly relevant for individuals with clustered CAD risk factors, such as those with obesity and a strong family history of premature CAD.7

Aspirin exerts its protective effect by inhibiting platelet cyclooxygenase-1 (COX-1) and its production of thromboxane, a potent platelet activator.8 However, marked variability in aspirin’s suppressive effect on platelet function is reported for asymptomatic individuals9,10 and those with overt CAD.11,12 Furthermore, lesser suppression of collagen aggregation,4 adenosine diphosphate (ADP) and arachidonic acid (AA) aggregation,13 and urinary excretion of 11-dehydro-thromboxane B2 (Tx-M)14 is associated with increased risk of myocardial infarction, stroke, and cardiovascular death in patients with CAD.

Aspirin is commonly used in obese patients for primary and secondary cardiovascular protection, but the impact of obesity on platelet function and response to aspirin is poorly characterized. The purpose of this study was to characterize platelet responsiveness to low-dose aspirin in a large population of obese and nonobese men and women with a strong family history of premature CAD, a population at sufficiently increased risk to warrant aggressive primary prevention.15


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

Study Design and Population

This study was performed as part of a parent study, the Genetic Study of Aspirin Responsiveness (GeneSTAR), which was designed to examine the genetic determinants of platelet responsiveness to low-dose aspirin therapy. The population included 2014 apparently healthy family members of 543 unique probands with documented CAD events before 60 years of age, including siblings, adult offspring of patients and siblings older than 20 years, and the coparent of the adult offspring (543 families). Eligible participants (N=2014) were 21 years or older and had no clinical CAD, peripheral vascular disease, vascular thrombotic events, bleeding disorders, hemorrhagic events, autoimmune diseases, or serious gastrointestinal disorders. Individuals were excluded if they had a history of aspirin intolerance or allergy or abnormal blood cell counts (platelet count <100,000 per μL or >500,000 per μL, hematocrit <30%, or white blood cell count >20,000 per μL). Participants were also ineligible if they were taking anticoagulants, antiplatelet agents, or nonsteroidal anti-inflammatory drugs that could not be safely discontinued for 2 to 4 weeks. The trial was approved by the institutional review board of the Johns Hopkins University School of Medicine and was monitored by a data safety and monitoring board appointed by the National Heart, Lung and Blood Institute. Written informed consent was obtained from all participants.

Data Collection

Eligible participants self-reported their age, sex, and race and underwent a medical history and physical examination by the study nurse practitioner as previously described.16 Medication use was assessed. Blood pressure was measured at rest according to Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.17 Hypertension was considered present if the average of 4 blood pressure measurements was at least 140/90 mm Hg and/or the participant was taking an antihypertensive medication. Current cigarette smoking was defined as any smoking within the past 30 days, verified by exhaled carbon monoxide levels. All blood tests were performed after participants had fasted for 12 hours overnight. Serum glucose, total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were measured directly. Low-density lipoprotein cholesterol levels were estimated using the Friedewald formula,18 and cutpoints for abnormal lipid levels were defined according to the guidelines of the National Cholesterol Education Program Adult Treatment Panel III.19 Diabetes was defined as a glucose level of at least 126 mg/dL (6.99 mmol/L) and/or use of an antidiabetic agent.

Participants were given a 36-day supply of 81-mg aspirin tablets and instructed to take 1 tablet each day for 14 days. A subgroup of participants (n=106) was given aspirin 325 mg/d for additional 14 days followed by platelet function tests. An interviewer-administered assessment of diet and exercise with a modified 24-hour dietary recall and the Stanford 7-Day Physical Activity Recall20 were performed, and participants were instructed to maintain the same dietary and physical activity patterns during aspirin therapy. Aspirin adherence was assessed with a modified Hill-Bone compliance questionnaire21 and pill counts. Dietary supplements (eg, vitamin E) known to influence platelet function were proscribed for the week preceding the baseline measurement and during the 14 days of therapy; foods (eg, coffee, chocolate, grapes, alcohol) known to influence platelet function were proscribed for the 48 hours before the baseline measurement and 48 hours before the post-aspirin measurement.


Height was measured using a stadiometer, and weight was measured using a clinical balance scale with the participants wearing light indoor clothing. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. BMI weight classes were grouped as normal weight (<25kg/m2), overweight (25.0–29.9 kg/m2), obese I (30–34.9 kg/m2), obese II (35–39.9 kg/m2), and extremely obese (≥40 kg/m2), according to current National Institutes of Health obesity panel guidelines.22

Platelet Testing

Platelet function testing was performed at baseline and after aspirin therapy. The same technician processed the same individual’s samples on the same equipment for all studies to minimize measurement variation. The platelet technicians were blinded to the sex, race, and medical history of participants.

Blood was obtained from venipuncture and collected into vacutainer tubes containing ethylenediaminetetraacetic acid (for complete blood cell counts) or 3.2% sodium citrate (for platelet function testing and fibrinogen levels) after the first 4 mL was discarded. Platelet counts were determined by automated cell counter (ACT-Diff; Beckman-Coulter, Miami, FL). Whole blood impedance aggregometry was measured in a Chrono-Log dual-channel lumi-aggregometer (Havertown, PA) after samples were stimulated with collagen (1 μg/mL), ADP (10 μmol/L), or AA (0.5 mmol/L). Peak platelet responses within 5 minutes of agonist stimulation were automatically recorded for aggregation (in ohms). Plasma fibrinogen was measured using an automated optical clot detection device (Behring Coagulation System; Dade-Behring, Newark, DE). Urine was stored at −80°C until analyzed. Urine samples were then thawed and assayed for Tx-M using a commercially available enzyme linked immunoassay (Cayman Chemical Co, Ann Arbor, MI) with a coefficient of variation for replicate measurements of 8%. Tx-M levels were normalized to urinary creatinine levels.

Statistical Analysis

Data were analyzed using standard descriptive and multivariable methods. Distributions were examined for normality using the Kolmogorov-Smirnov statistic. Non-normal variables were appropriately transformed. Categoric variables were examined using contingency table arrays and the χ2 statistic. Analyses were carried out comparing nonobese vs all obese persons because there was a threshold effect at a BMI level of 30 kg/m2. Multivariable linear and logistic regression analyses were used to determine the independent effect of both BMI and obesity on post–aspirin therapy platelet function outcomes, controlling for potentially influential demographic and biological covariables, including age, race, sex, smoking, blood pressure, glucose level or diabetes, total cholesterol level, and fibrinogen levels. All covariates were prespecified according to the published literature on the biological determinants of platelet aggregation. Because AA causes near-complete suppression in the majority of people, post-aspirin measures are reported as the percentage of individuals with nonzero aggregation. For Tx-M, the percentage of individuals who met a common clinical definition of “aspirin resistance”14 was compared between obese and nonobese individuals following aspirin administration.

Adjustments for nonindependence of measures within families were made using the generalized estimating equations.23 Incremental multivariable regression analyses were also used to allow determination of the contribution of each variable to the total variance in each platelet reactivity outcome. All significance testing was two-tailed with an alpha of .05, and data were analyzed using SAS (version 9.1; SAS Institute Inc, Cary, NC) and SUDAAN (version 9.0.1; Research Triangle Institute, Research Triangle Park, NC).


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

Study Population Characteristics

The study population included 2014 individuals, and 41% were obese. The average BMI of obese and nonobese individuals was 36.6±6.1 and 25.3±2.9 kg/m2, respectively. Characteristics by obesity status are shown in Table I. Obese individuals were significantly more likely to be older, female, and black and less likely to smoke cigarettes. Hypertension, diabetes, and higher fibrinogen levels were also significantly more common in obese individuals. All participants returned for the 14-day follow-up, and all took a dose of aspirin in the 24 hours preceding the post–aspirin therapy measurements, as required by the protocol. Pill counts and self-reported nonadherence demonstrated that 7.7% of participants missed 1 dose and 7.4% missed 2 or more doses during the 14 days of treatment. There were no differences in any measure of adherence between obese and nonobese participants.

Table I.   Characteristics of the Study Population
 Nonobese (BMI <30 kg/m2), n=1184Obese (BMI ≥30 kg/m2), n=830 P Valuea
  1. Abbreviation: BMI, body mass index. All results are mean (SD) unless otherwise noted. at tests or χ2 on log-transformed variables.

Waist circumference, in35.1 (4.0)44.7 (5.6)<.0001
Age, y 43.5 (13.3) 45.6 (12.0).0002
Glucose, mg/dL 92.4 (24.2)100.5 (31.2).008
Total cholesterol, mg/dL198.2 (41.9)204.5 (41.6).008
Fibrinogen, mg/dL 360.9 (103.0) 437.2 (128.4)<.0001
Female, %53.062.5<.0001
Black race, %32.452.4<.0001
Current smoker, %28.422.7.004
Hypertension, %21.548.1<.0001
Diabetes, %4.114.2<.0001

Platelet Reactivity at Baseline

Obese individuals demonstrated greater ex vivo platelet activation in response to all agonists including collagen, ADP, and AA (Table II). In vivo platelet activation measured by Tx-M was also greater in obese participants. Most measures were statistically significant or near significant between the obese and nonobese groups.

Table II.   Platelet Function at Baseline and After Aspirin Among Nonobese and Obese Individuals
PhenotypeNonobesebmi <30 kg/m2 (n=1184)Obese BMI ≥30 kg/m2 (n=830) P Valuea
  1. Abbreviations: ADP, adenosine diphosphate; BMI, body mass index. All results are mean (SD) unless otherwise noted. at tests or χ2 on log-transformed variables. bUpper quartile of urinary thromboxane metabolite.9

Aggregation to collagen 1 μg/mL, ohms
 Baseline19.6 (5.5)20.2 (6.0).02
 After aspirin6.1 (5.2)6.7 (5.5).008
 Change−13.4 (6.5)−13.5 (7.0).87
Aggregation to ADP 10 μmol/L, ohms
 Baseline12.4 (5.8)13.0 (6.03).01
 After aspirin11.8 (6.0)13.1 (6.0)<.0001
 Change−0.538 (5.3)0.130 (4.8).003
Aggregation to arachidonic acid 0.5 mmol/L, ohms
 Baseline15.5 (6.5)16.5 (6.5).0003
 After aspirin (nonzero aggregation)4.9%8.3%.002
Urinary thromboxane B2, ng/mmol creatinine
 Baseline235.5 (581.5)254.6 (530.2).002
 After aspirin49.9 (97.3)54.4 (102.0).003
 Change−183.0 (579)−207.6 (552).013
 Aspirin resistanceb (%)20.526.4.002

Platelet Reactivity Following Aspirin

In assays directly related to COX-1 pathway (eg, AA aggregation and Tx-M), obese individuals consistently showed greater residual platelet reactivity (measured in ohms) than nonobese individuals after aspirin (Table II). Similarly, a significantly larger fraction of obese individuals had any residual platelet reactivity to AA (measured in percentage nonzero aggregation) after aspirin than nonobese individuals. Tx-M was suppressed in both groups with aspirin, but obese individuals demonstrated greater in vivo platelet reactivity after aspirin compared with nonobese individuals. A higher percentage of obese individuals met the Tx-M criteria (upper quartile) for aspirin resistance following aspirin. Similar to direct COX-1 pathway, indirect COX-1 pathways (ie, aggregation to collagen and ADP) also showed significantly greater residual platelet reactivity after aspirin in obese than in nonobese individuals. For collagen and TxM, the absolute change in platelet activation was the same or greater in obese persons compared with nonobese, while for ADP-induced platelet aggregation, there was a small increase. A BMI cutoff of 30 kg/m2 was chosen because there was a nonlinear relationship between BMI and platelet reactivity that appeared at a BMI of 29.8 kg/m2. Similar results were obtained using waist circumference instead of BMI, but the relationship was not as strong.

To determine whether the larger volume of distribution of aspirin in obese participants may have an impact on bioavailability and be responsible for increased residual platelet activity after aspirin therapy, we further increased the dosage of aspirin to 325 mg/d for 14 additional days to a randomly selected subgroup (n=106) of participants (Table III). All platelet function tests were again performed after 14 days under the same protocols. After increasing the aspirin dosage to 325 mg/d, there were marginal or no differences between obese and nonobese participants in the suppression of platelet function (Table II). Additionally, 8.7% of nonobese persons vs 10% of those who were obese demonstrated nonzero aggregation to AA 0.5 mmol/L.

Table III.   Residual Platelet Function After Aspirin 81 mg and After 325 mg/d in a Subset of Obese and Nonobese Individuals (n=106)
 After Aspirin 81 mg/dAfter Aspirin 325 mg/dP Value
  1. Abbreviation: ADP, adenosine diphosphate.

Nonzero aggregation to arachidonic acid 0.5 mmol/L
Aggregation to collagen 1 μg/ml, ohms
 Nonobese4.27 (3.90)4.53 (5.13).7542
 Obese4.17 (3.93)4.85 (4.97).4722
Aggregation to ADP 10 μmol/L, ohms
 Nonobese11.16 (5.89)11.54 (4.33).6439
 Obese11.60 (4.52)11.73 (4.61).8607
Urinary thromboxane metabolite (adjusted for creatinine)
 Nonobese67.86 (73.2)56.22 (82.5).0399
 Obese46.67 (24.4)47.76 (42.33).9798

Multivariable Analyses

In multivariable analyses, platelet reactivity before and after aspirin therapy was adjusted for baseline demographics (age, sex, and race) as well as traditional cardiovascular risk factors associated with obesity and platelet function (cigarette smoking, systolic blood pressure, fasting glucose, total cholesterol, and fibrinogen levels) (Table IV). To adjust for clinical and demographic variables, a multivariate linear regression model was constructed for baseline platelet reactivity in response to AA. Since most patients had complete suppression of AA-induced platelet reactivity after aspirin, we used absence or presence of any residual reactivity in a multivariate logistic regression model. After adjusting for clinical and demographic variables, greater BMI, as a continuous variable, remained strongly and significantly associated with higher baseline and post-aspirin aggregation to AA. When BMI was dichotomized and entered in the model as the presence or absence of obesity, the significant differences between obesity and AA-mediated platelet aggregation after aspirin therapy persisted for all platelet function variables when adjusted for the same variables as in Table IV (coefficient for obesity, 0.48; P=.0374). Similarly, after adjusting for clinical and demographic variables, higher BMI was significantly associated with higher Tx-M levels both at baseline and after aspirin (Table V). In contrast, for indirect COX-1 pathways (collagen and ADP), neither high BMI nor obesity remained significantly associated with baseline or post–aspirin platelet aggregation after adjustment for clinical and demographic variables (data not shown).

Table IV.   Multiple Linear Regression Predicting Aggregation to Arachidonic Acid (0.5 mmol/L) Before Aspirin (Model 1) and Logistic Regression Predicting the Presence of Residual Aggregation to Arachidonic Acid (0.5 mmol/L) Following Aspirin (Model 2) (N=2014)
 Model 1 Baseline: Linear RegressionModel 2 After Aspirin: Logistic Regression
β (SE)P ValueParameter Estimate (SE)P Value
  1. aAdjusted for nonindependence of families using the generalized estimating equation method.

Body mass index, kg/m2 0.05 (0.03).05 0.04 (0.01).004
Female 1.6 (0.3)<.0001−0.4 (0.2).08
Age, y−0.04 (0.01).004−0.02 (0.01).004
White race 0.6 (0.4).1−0.5 (0.2).02
Current smoker 0.8 (0.4).05 0.5 (0.2).01
Systolic blood pressure, mm Hg 0.02 (0.01).06−0.01 (0.01).3
Glucose, mg/dL 0.007 (0.005).9−0.00 (0.00).6
Total cholesterol, mg/dL−0.002 (0.004).7−0.00 (0.00).9
Fibrinogen, mg/dL  0.006 (0.002).0001  0.00 (0.00).007
Table V.   Multiple Linear Regression Models for Urinary Thromboxane Metabolites (TxM) Before and After Aspirin Therapy (N=2014)
 BaselineAfter Aspirin
β (SE)P Valueaβ (SE)P Valuea
  1. aAdjusted for nonindependence of families using the generalized estimating equation method.

Body mass index, kg/m20.02 (0.004)<.00010.01 (0.004).0009
Female sex0.2 (0.06).0010.1 (0.05).006
Age, y0.007 (0.002).0030.005 (0.002).02
White race0.07 (0.06).30.03 (0.06).6
Current smoker0.3 (0.07)<.00010.3 (0.06)<.0001
Systolic blood pressure, mm Hg−0.0006 (0.002).8−0.0007 (0.002).7
Glucose, mg/dL0.0006 (0.001).60.001 (0.0009).3
Total cholesterol, mg/dL−0.0004 (0.0007).5−0.0006 (0.0006).3
Fibrinogen mg/dL0.00004 (0.0003).9−0.0005 (0.0002).8


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

No large population-based studies to date have characterized the putative independent impact of obesity on in vivo and ex vivo platelet responsiveness to aspirin. In this study of low-dose aspirin in unaffected individuals from families with premature CAD, obese individuals had greater baseline platelet function than nonobese individuals in pathways directly and indirectly related to COX-1. After aspirin, residual platelet function remained greater for obese individuals both in vivo and ex vivo, and the association between obesity and platelet reactivity remained significant for direct COX-1 measures after adjusting for demographic and clinical covariates. Importantly, obese persons showed the same or even greater change in collagen-induced aggregation and Tx-M, respectively, with only a modest increment in ADP aggregation. This suggests that obese persons obtained a similar effect with low-dose aspirin, but it was not sufficient to overcome their higher levels of native platelet activation.

The finding that platelets from obese individuals were more reactive both at baseline and after aspirin suggests an innate hyperaggregable state in obesity that has been suggested in prior smaller studies.24–26 Although the absolute differences in platelet function between groups were generally small, they were consistent ex vivo and in vivo and across all platelet activation pathways. Furthermore, the differences between obese and nonobese individuals were sufficiently large to detect a significant difference in the proportion of individuals who met published aspirin resistance Tx-M criteria associated with clinical aspirin failure.14

Our results are consistent with those of a much smaller study involving 21 participants in which obese individuals had less suppression of platelet aggregation to AA and ADP after aspirin exposure.25 Two other smaller studies, one in patients with CAD26 and one in normal volunteers,24 demonstrated an association between participants’ weight and residual platelet function in response to enteric-coated low-dose aspirin. The authors suggested that reduced bioavailability from enteric coating may have mitigated aspirin’s suppressive effect and that this effect could lead to underdosing of obese individuals. In contrast, our findings using 81 mg/d of regular aspirin suggest that there is a threshold at the level of obesity after which platelet reactivity is higher both at baseline and after aspirin. Thus, the use of enteric-coated aspirin in the prior study cannot fully explain the differences in platelet function between obese and nonobese individuals.

Another potential explanation of post–aspirin-increased residual platelet function in obese individuals can be larger volume of distribution. However, although the design was not optimal and the sample size considerably smaller, we noted that the administration of a larger aspirin dose did not result in any further decrease in platelet function, which one would expect if the volume of distribution was the primary problem. The smaller subsample results highlight the fact that increasing the aspirin dosage above 81 mg/d to the maximal daily dose usually used clinically does not result in any further suppression of platelet function.

Previous work examining the relationship between obesity and platelet function has demonstrated higher levels of urinary Tx-M in obese women. After an average short-term weight loss of 15.3 kg, obese women had significantly lower levels of Tx-M.27 Thus, weight reduction may potentially be an effective nonpharmacologic strategy to decrease aspirin resistance in obese individuals.

Insufficient suppression of platelet function by aspirin is associated with increased future risk of myocardial infarction, stroke, and cardiovascular death in patients with atherosclerosis.12–14 Lesser suppression of in vivo platelet function is also associated with higher predicted risk of future CAD events in asymptomatic individuals. Our finding of lesser suppression of platelet function by aspirin in obese persons suggests that these individuals may receive decreased cardioprotection from low-dose aspirin. Further study is required to determine the clinical consequence of reduced platelet suppression by aspirin in patients with obesity and whether higher doses of aspirin are required in these individuals to achieve equivalent platelet suppression and/or cardioprotection than in nonobese people.

The biological mechanism for the obesity-related platelet function differences observed remains unresolved. Fibrinogen levels and all traditional known CAD risk factors are often more common in obese individuals,5 but they did not explain platelet function differences observed. Leptin is a protein hormone that regulates dietary energy intake and energy expenditure, influencing appetite and the metabolic substrate for obesity. The elevations of leptin observed in obese people are proatherogenic and have been shown to be associated with endothelial dysfunction, vascular smooth muscle cell proliferation, increased oxidative stress, and inflammation, all mechanisms involved in atherosclerotic vascular disease.28 Leptin receptors exist on human platelets,29 and in obese mice, increased leptin has been proposed as a mechanism responsible for a propensity to prothrombosis.30 Future studies will help to determine whether leptin enhances baseline platelet reactivity and diminishes aspirin responsiveness in obese individuals.

It should be noted that the highly potent impact of aspirin on platelet function, even among individuals who retain some residual platelet function post-aspirin, obviates the necessity for a control group. The COX-1 pathway is virtually totally suppressed in everyone, so that it is eminently possible to determine that aspirin has been taken. This is one of the few trial paradigms where there would be no benefit of a placebo-controlled study.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

This large study demonstrates that obese individuals have greater native platelet reactivity and retain greater residual platelet function despite aspirin treatment compared with nonobese individuals. It remains unclear whether the currently recommended low-dose of aspirin therapy provides equivalent cardioprotection to obese and nonobese patients at risk for CAD events.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References

Acknowledgments and disclosures:  This work was supported by a grant from the National Heart, Lung and Blood Institute (HL072518) and the Johns Hopkins General Clinical Research Center via a grant from the National Center for Research Resources (M01-RR000052), National Institutes of Health. Aspirin 31 mg was supplied to the study by McNeil Consumer and Specialty Pharmaceuticals, a Division of McNeil-PPC, Inc; aspirin 325 mg was supplied to the study by Bayer HealthCare, Inc. There are no financial disclosures.


  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  7. Acknowledgments
  8. References
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