823 migraine in pfo patients: characterization of a platelet-associated pathophysiological mechanism before and after pfo closure: the learner study

Abstract Background A strong relationship links migraine with aura (MHA) and patent foramen ovale (PFO). Increased platelet aggregation and oxidative stress were documented in migraineurs. To date, no mechanisms connecting MHA to PFO have been demonstrated. Objectives To perform a comprehensive analysis of platelet activation, inflammation, and oxidative stress status in 78 aspirin-treated MHA-patients before (T0) and 6-months after (T1) PFO closure (LEARNER Study-NCT03521193-clinicaltrials.gov). The primary endpoint was migraine regression rate in relation to these parameters. Methods P-selectinpos-, activated-glycoprotein IIbIIIa (aGPIIbIIIa)pos-, Tissue Factor (TF)pos-, reactive oxygen species (ROS)pos-platelets, platelet-leukocyte aggregates (PLA) and microvesicles (MVs) were evaluated by flow cytometry; thrombin generation (TG) by Calibrated Automated Thrombogram (CAT) assay; oxidative stress status by mass spectrometry; serotonin and cytokines by ELISA. 12 aspirin-treated-healthy subjects (HS) were enrolled for comparison. Results Migraine resolution occurred in 69.7%, a significant reduction in 27%, while no effect was observed in 2 patients (3.2%). Only ROSpos-platelets, and TFpos-platelets and -MVs were significantly higher at T0, sustaining a TG capacity that was associated with an altered blood GSSG/GSH (Oxidized/Reduced Glutathione). This phenotype reverted to HS levels at T1. MHA-PFO plasma, added to HS blood, mirrored the in vivo platelet activation and N-acetylcysteine blunted it. GSSG in vitro reproduced the in vivo condition. Aspirin had little effect on the platelet prothrombotic phenotype which was effectively inhibited by a P2Y12-antagonist. Conclusion This study suggests a pathophysiological mechanism linking PFO, or its right-to-left shunt, with MHA. MHA-PFO patients show a platelet-associated prothrombotic phenotype, sustained by altered oxidative stress status. This phenotype, not fully controlled by aspirin but by P2Y12-antagonism, could play a primary role in producing the prodromal symptoms of migraine, and it is reverted after PFO closure together with a complete migraine remission