Platelet pals: How blood cells shape the future of the aorta

This is an invited commentary on Pratama MY et al. ¹² Altered platelet phenotype in patients with type II endoleaks following abdominal aortic aneurysm repair. Vasc Med 2025; 30: 39–48.

Platelets are the most abundant circulating cells and were once thought to function solely as mediators of hemostasis and thrombosis. Over the last two decades, it has become evident that platelets also act as circulating biosensors, capable of detecting external signals and adapting to the physiological conditions of the diseased individual they circulate in, despite being anucleate. ¹ For example, platelet surface receptors, which are common pharmacological targets in patients with atherosclerotic arterial disease, appear to become sensitized to certain receptor agonists—especially a protease-activated receptor 1 (PAR1) agonist following a myocardial infarction (MI).^2,3 Conversely, altered platelet receptor sensitivity to antagonists has been observed in patients with diabetes, where the P2Y₁₂ receptor adopts a different conformation, rendering it less responsive to inhibition by clopidogrel but not ticagrelor. ⁴ Lastly, vascular specialists are acutely aware that patients with symptomatic peripheral artery disease (PAD) ought to be treated with an antiplatelet medication to decrease the risk of MI and stroke. Several groups have now reproducibly demonstrated that platelets isolated from patients with PAD have increased platelet reactivity, which may constitute enhanced thrombotic risk.^5–8

Platelets are sensitive to external forces, especially through cell surface glycoprotein 1bα (GP1bα), glycoprotein VI (GPVI), and the αII/β3 integrin (also known as the GPIIb/IIIa receptor). This stimulus, referred to as biomechanical platelet activation, occurs in the absence of cell surface agonists and usually in conditions of disturbed blood flow (d-flow). D-flow is commonly associated with severe atherosclerosis and arterial aneurysmal disease. Patients with abdominal aortic aneurysms (AAAs), where luminal thrombus frequently occurs, partly due to d-flow circulation, exhibit increased platelet reactivity. ⁹ In the longest propensity-matched observational study of patients with AAA, 3435 patients evaluated by serial duplex ultrasound over 10 years revealed that aspirin restricted aneurysm growth based on annualized diameter compared to patients not taking aspirin. ¹⁰ Interestingly, this protective effect of aspirin on AAA growth was observed in men but not in women and was extinguished by ongoing tobacco use. The protective effect of aspirin may be due to preventing the release of platelet-derived mediators of aortic remodeling, yet antiplatelet therapy for patients with aortic disease carries only a class IIb recommendation in the recent American Heart Association/American College of Cardiology (AHA/ACC) guidelines. ¹⁰

The most feared consequence for patients with AAA is aortic rupture. To prevent aortic rupture, endovascular abdominal aortic repair (EVAR) is sometimes employed. EVAR is minimally invasive, it offers a faster recovery time than open aneurysm repair, and it remains an option for asymptomatic patients with favorable aortic anatomy when an AAA reaches 5.0 cm for women and 5.5 cm for men. A known complication of EVAR is a type II endoleak, in which blood flows in a retrograde manner into the aneurysmal sac from small aortic branch vessels. A low platelet count after EVAR was reported as a risk factor associated with type II endoleaks. ¹¹

In this issue of Vascular Medicine, Pratama and colleagues tested the hypothesis that mean platelet volume (MPV), a surrogate parameter sometimes used to signify changes in platelet reactivity or immature platelets, might predict type II endoleaks in patients with AAA who have undergone EVAR. ¹² Over an observational period of 8 years, the authors followed 146 patients consecutively (90 with type II endoleaks and 56 with matching demographics and clinical characteristics) after EVAR for AAA. Intuitively, patients with a larger number of lumbar arteries more frequently developed type II endoleaks (hazard ratio [HR] 1.19; 95% CI 1.05–1.36, p = 0.009) and those on dual antiplatelet therapy (DAPT) also developed more type II endoleaks after evaluation by multivariate regression analysis (HR 2.34; 95% CI 1.30–4.21, p = 0.005).

Curiously, in this cohort, patients with a higher MPV (10.3 vs 10.0 fL, p = 0.04) were more likely to have type II endoleaks when evaluated by multivariate regression analysis (HR 1.42; 95% CI 1.11–1.81, p = 0.005) as did patients with type II diabetes (HR 2.03; 95% CI 1.05–3.92, p = 0.035). ¹² Previous studies have demonstrated MPV may serve as a useful indicator of altered platelet function and thrombotic risk in patients with AAA. ¹³ Though MPV is a parameter typically overlooked on a patient’s complete blood count by clinicians, these data suggest elevated MPV could be useful in predicting type II endoleaks. A limitation of this study is shown by the area under the curve (AUC) of 0.70 for MPV when examined by receiver operator characteristic (ROC) curve analysis, suggesting a modest balance in sensitivity and specificity (62% and 65%, respectively) for MPV in predicting type II endoleaks post-EVAR. ¹² Nonetheless, the authors of this study should be congratulated for providing a risk probability score for the development of type II endoleaks using a logistic regression model that incorporates clinical variables contributing the most to risk of type II endoleaks following EVAR: DAPT at the time of hospital discharge, diabetes, MPV, and the number of lumbar arteries. This decision tool could be useful for clinicians who may decide on a personalized imaging or antiplatelet medication protocol to mitigate the risk for type II endoleaks.

Although the authors do not specifically comment on this, increasing MPV with presumably inhibited platelets in patients taking DAPT is somewhat unexpected if increased MPV truly is a marker associated with more reactive platelets in aortic aneurysmal disease. ¹⁴ In addition, data in the current study revealed that employing fenestrated endovascular repair (fEVAR) did not result in a similar increase in MPV, as was noted with EVAR, suggesting that biomechanical forces exerted on platelets could be more favorable with fEVAR. Mechanisms behind this observation require careful investigation and raise the tantalizing possibility that deleterious platelet-derived mediators that contribute to aortic remodeling may be impacted by the mechanical features of the synthetic graft used in percutaneous procedures for aortic repair. The biophysical properties of blood flow and aortic elastography are both emerging and are burgeoning areas of investigation that hold promise for determining the impact of internal and external stressors on the aortic wall. This could in turn lead to improved prediction of acute aortic syndrome, thereby offering an opportunity for earlier intervention.