How Does Platelet Dysfunction Affect CMD Risk Across Age, Sex, and BMI Groups: A Comprehensive Review

Introduction: Cardiometabolic diseases (CMD) are a group of interconnected metabolic and cardiovascular disorders influenced by genetic, environmental, and lifestyle factors, representing a major cause of global mortality [1]. Metabolic dysfunctions such as obesity, type 2 diabetes, and dyslipidemia contribute to vascular complications including heart failure and hypertension [2]. Recent studies identify platelet dysfunction as a key mediator linking metabolic dysregulation, inflammation, and thrombosis [3]. Platelets are anucleate fragments derived from megakaryocytes that maintain vascular integrity through hemostasis and thrombus formation [4]. Under metabolic stress conditions such as hyperglycemia and oxidative stress, platelets become aberrantly activated, exhibiting enhanced adhesion, aggregation, and cytokine secretion [3]. Due to limited data on platelet-based studies assessing CMD risk variables [5], we hypothesized that platelet activation markers would amongst males, older individuals, and those with a high BMI. This investigation therefore aims to evaluate the correlation of platelet activation markers with CMD risk across demographic groups, clarifying their role as potential early biomarkers of CMD progression. Methods: This comprehensive review categorized a variety of studies regarding platelet biomarkers and their roles in cell-signalling pathways by sex, BMI, patient/control, and age groups. Statistical associations were correlated between biomarkers of interest including P-selectin, soluble CD40 ligand (sCD40L) platelet-derived extracellular vesicles (pEV), mean platelet volume (MPV), platelet phospholipid eicosapentaenoic acid (EPA) fraction, and the cardiometabolic outcomes they produce. Statistical analyses included multivariate linear regression models to identify independent predictors of CMD risk, furthermore analysis of variance (ANOVA) to test group differences, using a significance of p<0.05 and p<0.001. Results: As anticipated, elevated MPV values correlated more strongly with vascular inflammation and atherosclerosis in older individuals and males. Meanwhile, platelet phospholipid EPA fraction had a negative correlation in older females, rather than males. Additionally, pEV had a greater influence on cardiometabolic dysregulation among high-risk groups which included older individuals with a high BMI, rather than amongst females. Similarly, sCD40L levels were significantly higher in overweight individuals, whereas P-selectin did not increase with age as we had hypothesized. Implications: Our findings highlight platelet dysregulation biomarkers as potential early predictors of CMD risk, specifically amongst various demographics as preventative interventions.