Abstract 127: Aspirin Resistant Biomechanical Platelet Activation In Fibromuscular Dysplasia: Novel Mechanisms Of Platelet Activation & Stroke

Background: Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory disorder characterized by abnormal arterial morphology and turbulent blood flow. In regions of disturbed blood flow, circulating platelets may become activated. Cerebrovascular FMD is common and increases the risk of stroke in affected patients. Most FMD patients are treated with antiplatelet agents, however these medications target biochemical and not biomechanical pathways of platelet activation. Methods: Thrombotic outcomes were determined by multivariate regression analysis of 105,887 patients with FMD. Platelets were isolated from humans and activation was assessed by FACS and aggregometry following exposure to ex vivo steady laminar and disturbed flow (SF and DF, respectively) conditions using a cone and flow system. Single-cell phenotyping of control and FMD platelets with transcriptomics (RNAseq) and proteomics were performed. Cellular bioenergetics were evaluated by real-time metabolic analyses. Results: In patients with FMD, long-term aspirin therapy is paradoxically an independent risk factor for acute ischemic stroke (OR 1.64, 95% CI 1.29-1.94) but seems to protect against acute hemorrhagic stroke (OR 0.47, 95% CI 0.24-0.89). FMD platelet activation and aggregation were hyporeactive to biochemical agonists, but hyperreactive to ex vivo mechanical, disturbed blood flow conditions compared to age/gender-matched controls. FMD platelet activation in DF was attenuated by the mechanosensitive channel inhibitor, GsMTx4. Principle component analyses of RNAseq and proteomics identified markedly different platelet phenotypes with key differences in mitochondrial function/fission. Platelet imaging and metabolic analyses revealed abnormal mitochondrial architecture and respiration in FMD. Conclusions: FMD platelets display a divergent, dysregulated platelet phenotype with attenuated biochemical but augmented biomechanical activation. DF exposure of platelets in irregularly shaped arteries in FMD may alter the platelet phenotype and metabolic function. Therapeutics targeting biomechanical pathways of platelet activation may provide a superior mechanism for stroke prevention without unintended bleeding consequences.