Platelet Activation Pathways and Respiratory Morbidity in COPD

PROJECT SUMMARY / ABSTRACT Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States. Currently, the treatment of COPD relies on a stepwise algorithm of inhaler therapies without targeting systemic processes. Mounting evidence suggests that activated platelets may play a role in COPD but the mechanisms and impact of platelet activation on COPD outcomes are not known. Furthermore, it has been difficult to differentiate respiratory events from cardiovascular symptoms since COPD and cardiovascular disease (CVD) are highly comorbid. Understanding the role of platelets and potential for targeted antiplatelet therapy in COPD patients without CVD could lead to novel therapeutic options. Prior studies demonstrating an association between platelet activation and worse respiratory morbidity in COPD have employed non-specific surrogate biomarkers. Likewise, prior studies showing an association of aspirin use with improved COPD morbidity and mortality have been among prevalent users in observational cohorts susceptible to selection bias and confounding by indication. In order to understand the potential role of specific platelet activation pathways on respiratory morbidity in COPD, we propose directly measuring platelet activation and reactivity in a sample of 115 individuals with COPD without overt or subclinical CVD as determined by absence of coronary artery calcification on computed tomography scan. Specifically, we will measure membrane receptors uniquely expressed on activated platelets (CD62P/P-selectin, CD63, CD154/CD4L, and PAC1), platelet-leukocyte conjugates (platelet-monocyte and platelet-neutrophil conjugates), and platelet response (i.e. change in activation) to stimulation with three agonists (adenosine diphosphate, thromboxane, and serotonin). We hypothesize that higher proportion of baseline circulating activated platelets, higher proportion of platelet- leukocyte conjugates, and increased platelet reactivity in response to low doses of agonists will be associated with higher baseline respiratory symptoms, worse quality of life and higher rate of acute exacerbations of COPD over 1 year. Furthermore, we will conduct a randomized double-blinded sequential crossover study of three aspirin doses in 48 individuals with COPD without CVD to determine the most effective aspirin dose for suppression of platelet activation and reactivity in this population. Completion of the proposed aims will elucidate the role of platelet activation and reactivity pathways on respiratory outcomes in COPD and inform the design of a larger randomized controlled trial of antiplatelet therapy in COPD. We will recruit from the large pool of participants in ongoing and completed COPD studies at Johns Hopkins supplemented by leveraging the infrastructure of the Johns Hopkins COPD Precision Medicine Center of Excellence. My ultimate career goal is to be an independent translational researcher focusing on identifying novel targets for individualized therapy in COPD. My career development plan includes expert mentorship, formal coursework, and hands-on experience to develop new skills in COPD endotyping, translational research, platelet biology, and clinical trial design.