The reported prevalence of patients not achieving an adequate antiplatelet effect under aspirin varies greatly, due to difference in laboratory assessment. To date, there is no universally accepted cut-off value of each method[8]. In this study, we used aggregometry tests as a surrogate measure of aspirin response, which are still considered as the gold standard for aspirin testing. LTA-AA located in the upper quartile were defined as HTPR.
HTPR has been found to be correlated with clinical events. It is of great importance to investigate the factors influencing HTPR. Elderly patients represent a challenging population for the optimal management of antiplatelet therapy. Few studies have specifically addressed the problem of platelet aggregation in elderly patients receiving antiplatelet therapy, with contrasting results[9, 14–16]. In our study, patients in the HTPR group were older. There was a positive linear correlation between age and platelet aggregation rate. However, the ADAPT-DES study addressed that despite being associated with older age, HTPR did not modify the adjusted relative risks of ischemic events associated with age[15]. Elderly patients also represent a category where other factors, such as frailty, comorbidities or lower body weight, have an intrinsic high risk of hemorrhage[17]. Indeed, future detailed mechanistic research is needed to address the relationship of platelet changes with aging and the pathophysiological basis of the antiplatelet response. At present, antiplatelet strategies in elderly patients with ASCVD should be cautiously driven by an individualized approach, balancing bleeding and thrombotic risk.
The prothrombotic status associated with aging could be even more enhanced among chronic kidney disease (CKD) patients, displaying an intrinsic higher platelet activation induced by chronic low-grade inflammation and vascular injury[18]. Even in the absence of cardiovascular disease, patients with CKD have an increased risk of thrombosis, the dominant pathophysiology of which is likely to be abnormalities of platelet function[19]. To date, few studies have been conducted regarding the role of renal function on platelet reactivity. Conflicting results were reached, and most of them were conducted among patients receiving clopidogrel in association with aspirin[20–23]. However, there is evidence of overlap in the anti-platelet effects of aspirin and P2Y12 antagonist[11]. Therefore, we aimed to evaluate the impact of renal function on HTPR in patients receiving aspirin as monotherapy. Patients with end-stage renal disease were excluded because they are likely to suffer from multiorgan damage potentially confounding the results[24]. Our study revealed that HTPR was more common in patients with mildly/moderately decreased eGFR than in those with preserved renal function. eGFR was an independent factor of HTPR. The further mechanism of platelet hyperactivity in patients with impaired renal function might be relevant to the accumulation of uremic toxins, such as indoxyl sulfate[25] and homocysteine[26]. Furthermore, pre-activation of platelets in CKD[27] may play a role in the pathogenesis of insufficient platelet inhibition by aspirin in patients with impaired kidney function.
It is well known that elevated uric acid is associated with impaired renal function. Hyperuricemia is a condition characterized by impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses[28]. Moreover, elevated uric acid has been reported to upregulate the expression of platelet-derived growth factor and the production of tissue factor in vascular smooth muscle cells[29], which link uric acid to inflammation and therefore to platelet hyperreactivity. In this study, we found an increasing tendency of serum uric acid levels in the HTPR group, but without statistical significance, although we still know little about the mechanisms that drive these changes.
Platelet-leukocyte interactions may mitigate aspirin’s suppressive effect on platelet function by enhancing thromboxane formation independent of platelet COX-1[30, 31]. Platelets might also be an amplificatory factor in various inflammatory circumstances. Activated platelets release a wide range of inflammatory mediators and induce the expression of these mediators in monocytes/macrophages and granulocytes[32]. Monocytes/macrophages are important sources of TXA2 and have the capacity to synthesize TXA2 through the COX-2 pathway, which has a higher threshold of inhibition by aspirin than the COX-1 pathway[33]. Faraday et al. demonstrated a strong association between blood leukocyte count and increased platelet reactivity in vitro and in vivo[34]. In view of this, we excluded patients with acute or chronic inflammatory diseases in our study. There were no differences in leukocyte counts, neutrophil counts or C-reactive protein levels between the HTPR group and the non-HTPR group. However, we observed significantly higher neutrophil percentages and C-reactive protein levels in patients with moderate renal impairment than in those with mild renal impairment. This may indicate the importance of chronic low-grade inflammation as a factor contributing to HTPR in CKD patients. Furthermore, higher values of MPV and MPV/PLT ratio were considered possible biomarkers in inflammatory processes, CKD and ASCVD, which is partially in line with our study[35–38].
Acid suppression with PPIs can increase the potential for mucosal esterases to hydrolyze aspirin to its inactive form. A reduction in gastric absorption thus results in an increased drug load within the small intestine, where hydrolysis by esterases prior to absorption may reduce bioavailability[39]. This could explain the finding in our study where PPI medication was more common in the HTPR group. However, the consequences of concurrent PPI therapy with aspirin are not clear, as pharmacokinetic and pharmacodynamic studies designed to address this question have been inconsistent, although the weight of evidence appears to suggest no significant interaction[40, 41]. The current evidence therefore is in favor of PPI prescription in those who are at risk of gastrointestinal bleeding, with the additional benefit that a reduction in dyspepsia may improve adherence[42, 43].