This is the largest study to date of the relationship of pre- and postaspirin platelet aggregation and activation and the impact of metabolic syndrome in healthy but high-risk individuals. The results show that aspirin has an effect in all persons. Those with metabolic syndrome had greater in vitro platelet aggregability in three platelet function measures representing different cellular pathways and a higher degree of platelet activation in vivo as measured by TxM in individuals with metabolic syndrome. These increased levels of platelet activation are seen even on adjustment for fibrinogen and for hs-CRP as a measure of systemic inflammation. Our data demonstrate that each of the components of metabolic syndrome likely partially and independently contribute to increased native platelet activation before aspirin. Although aspirin effects on the odds of retained ex vivo platelet aggregation to arachidonic acid were primarily related to waist circumference, suggesting a dependence on overall body size, this was not so for TxM, which represents in vivo platelet activation. Metabolic syndrome (rather than each individual component) is associated with an impaired aspirin effect on TxM independent of BMI, suggesting that our results are not explained by any relationship between aspirin pharmacokinetics and body size.
Urinary TxM, an estimate of in vivo
activation of platelets and endothelial cells, is increased in persons with coronary artery thrombosis.12
Additionally, persistently high TxM after aspirin therapy has been shown to predict recurrent coronary artery disease events, in a graded manner within the range <15, 15–22, 22–34, and >34 ng/mmol creatinine, with an overall 80% difference in odds.13
In this context, the persistently higher TxM after aspirin therapy among persons with metabolic syndrome (36 vs. 32 ng/mmol creatinine) that we observed may suggest inadequate primary prevention that would be particularly important in a high-susceptibility group with a family history of premature CAD. Similarly, increased platelet aggregation in response to collagen, ADP, and arachidonic acid14,15
is also associated with increased risk of both myocardial infarction and stroke in aspirin-treated patients with atherosclerosis. Platelet activation has also been shown to be correlated with impaired metabolic states: Glycoproteins associated with platelet activation are elevated in persons with diabetes5,16,17
and metabolic syndrome,6
and diabetics have higher thromboxane biosynthesis.18
In our study, both in vivo
and ex vivo
measures of platelet aggregation are higher in persons with metabolic syndrome, providing support for the proposition that people with metabolic syndrome may be at higher risk of future acute coronary disease events due to an overall increase in platelet aggregability. Furthermore, the persistence of higher aggregability to ADP and higher levels of TxM suggests that this risk may not be fully nullified by preventive low-dose aspirin therapy.
Greater platelet aggregability among those with metabolic syndrome was not attributable to any single syndrome component in our study. Indeed, many of metabolic syndrome components have independent associations with one or the other aggregability and activation measure, but very few retain independent associations with postaspirin measures. Thus, it is extremely important to note that a constellation of metabolic syndrome components rather than any single component constitutes a particularly potent risk factor for increased platelet aggregability either in the native state or after aspirin therapy. Metabolic syndrome is thought to be a proxy diagnosis for insulin resistance, which, in later stages, results in β-cell failure and the inability to maintain normal fasting glucose levels. In this population, 2 of every 5 persons with metabolic syndrome were normoglycemic, presumably because the insulin resistance had not advanced to the point of β-cell failure. This suggests that even early insulin resistance may be related to increased platelet aggregability.
The primary limitation of our study, as in most others where platelet aggregation has been measured, is the lack of long-term follow-up data to determine the extent to which these ex vivo
tests confer excess risk for a thrombotic cardiovascular event, and we cannot directly estimate the extent of aspirin resistance conferred by metabolic syndrome. Thus, as have others, we have had to rely on intermediate phenotypes that reflect a prothrombotic milieu and on the ability of these measures to predict CAD events. We have not defined any threshold for aspirin resistance, although previous studies have defined aspirin resistance using different levels of platelet aggregation and activation measures. However, the differing definitions have led to wildly differing prevalence estimates from 6% to 26% (reviewed by Gasparyan et al.19
) making any comparisons difficult.
In conclusion, the constellation of symptoms that comprise the ATP III-defined metabolic syndrome is associated with greater in vivo and ex vivo native platelet reactivity in persons from families at high risk for CAD. Although platelet function may be only one of many pathophysiological pathways to disease, the ability of antiplatelet therapy to provide improved protection for high-risk persons with metabolic syndrome would be important to determine so that tailored therapeutic primary prevention approaches can be refined.