Abstract Body: Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular condition primarily affecting women. Patients with FMD are prone to stroke through unclear mechanisms. Patients with FMD are given antiplatelet therapy for stroke prophylaxis without mechanistic data.
Hypothesis: Platelets are mediators of stroke in FMD patients.
Methods: Patients with FMD were evaluated from 2001 to 2022 for the impact of antiplatelet therapy on stroke outcomes. Platelets were analyzed via transcriptomics, metabolomics, and proteomics. Mitochondrial function was assessed using the Agilent Seahorse System. Platelet reactivity and ROS production were measured by flow cytometry. Mitochondrial DNA was sequenced, and morphology was examined by electron microscopy (EM). Plasma biomarkers were evaluated using ELISA.
Results: In 2083 FMD patients, 32% had ischemic stroke if antiplatelet therapy was not prescribed. After weighted analysis, antiplatelet drug therapy was associated with a significantly reduced risk of both stroke (odds ratio [OR] = 0.11; 95% confidence interval [CI], 0.08–0.15; P < 0.001) and transient ischemic attack (TIA) (OR = 0.26; 95% CI, 0.19–0.36; P < 0.001). Multi-omics fusion analysis (r=0.70) identified molecular pathways involved in dysregulated platelet function. FMD platelets showed mitofusin-2 deficiency and irregular mitochondria on EM. Mitochondrial dysfunction was noted in FMD platelets, with >4-fold reduction in oxygen consumption, 2-fold increase in mitochondrial reactive oxygen species (P=0.01), and 6-fold increase in mitochondrial permeability transition pore opening (P=0.0002) (Fig.1). Platelet-derived extracellular vesicles (PEVs) from FMD patients, but not from healthy women, were highly thrombogenic as compared to PEVs from healthy women and led to aggregation in healthy plasma (Fig. 2). These PEVs from FMD patients were procoagulant, which was measured as higher Annexin-V expression.
Conclusion: This study revealed that aspirin was twice as protective as clopidogrel in preventing stroke in FMD. Mechanistic data in isolated platelets, whole blood, platelet-deplete plasma, and platelet-rich plasma revealed that PEVs, not the adult platelet, are responsible for thrombosis and possibly stroke in FMD patients. Mitochondrial dysfunction in platelets of FMD patients leads to ROS production and potentially precedes vascular manifestations. PEVs from FMD patients are thrombogenic and procoagulant, promoting aggregation and thrombus formation.