Low cardiorespiratory fitness (CRF) has long been linked to cardiovascular disease (CVD), and platelets are key mediators in atherosclerotic CVD and thrombosis. However, few prior studies have examined associations between fitness and platelets, the majority exploring platelet reactivity after acute exercise bouts and showing a transient platelet hyperreactivity phase. Studies that have looked at chronic physical activity or CRF and platelet reactivity have yielded mixed results but were limited by small sample sizes in niche patient populations and, thus, may not be relevant to the general population. Our study, published in the November 2024 issue of Medicine & Science in Sports & Exercise®, sought to identify the effects of CRF, defined via participant-measured VO2 max, on platelet reactivity traits derived from five distinct platelet function assays utilizing a broad range of platelet agonists.
Of the 126 platelet reactivity traits tested, we found 17 to be significantly associated with CRF, all in the direction of effect indicating higher CRF was associated with decreases in platelet reactivity, after adjustments for several confounding variables. It is noteworthy to add that 75 of our 126 traits trended towards significance.
While our results across a broad range of platelet function assays, and after a broad range of agonist stimulation, suggest CRF to have a global effect on platelet function, many of our strongest associated traits were derived from the Multiplate Impedance Aggregometry System, which tests platelet function in a whole-blood milieu rather than platelet-rich plasma. We find these traits to be particularly interesting, as testing platelets in whole blood allows for samples to maintain cells, proteins and additional blood components that are stripped away while preparing platelet-rich plasma and, thus, may be more representative physiologically. In the context of our results, a possible rationale for more significant traits derived from the Multiplate assay may be that CRF works mechanistically via multiple hematological systems to alter platelet reactivity. Additionally, we found platelet traits after stimulation by adenosine diphosphate (ADP) and thrombin receptor-activating peptide-6 (TRAP-6) to be responsible for our top four most significant results. Interestingly, both agonists work via pathways that are known pharmacological targets for CVD: ADP via P2Y12/P2Y1 signaling, a target for antiplatelet therapy, and TRAP-6 via PAR-1 signaling, a target for anticoagulation therapy.
While our patient sample was a bit too young, and thus underpowered, to measure prospective CVD and cardiovascular events in relation to CRF and platelet reactivity, our results certainly lend support to the encouragement of physical activity in community and clinical setting for the potential reduction of primary and secondary cardiovascular events, particularly by showing inhibition of pathways used pharmacologically. Additionally, our results lend support to the American Heart Association’s 2016 recommendation for the use of CRF as a clinical vital measurement by providing evidence for CRF’s effects on platelet reactivity. We hope the findings from our study can inspire researchers to continue identifying mechanisms by which CRF protects cardiovascular health, and better informs clinicians to advocate for and encourage fitness and physical activity.
Joseph Grech, BS, is a fourth-year medical student at the Loyola University Stritch School of Medicine applying for a residency in internal medicine. He received a Bachelor of Science in human biology from Michigan State University and has completed a postbaccalaureate research fellowship and summer research internship at the National Heart, Lung, and Blood Institute (NHLBI) in the lab of Dr. Andrew Johnson, with a research focus in platelet biology, cardiovascular epidemiology and cardiovascular omics.
Andrew D. Johnson, PhD, was trained in biomedical science, pharmacology and bioinformatics. He is a tenured senior investigator in the NHLBI’s Division of Intramural Science and based at The Framingham Heart Study where he conducts population-based research mainly centered around platelets and hemostasis.
