Background: Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arterial disorder with distorted arterial architecture and turbulent blood flow.  FMD patients are empirically treated with an antiplatelet drug to prevent stroke, however current antiplatelet medications target biochemical and not biomechanical pathways of activation.

Aims: Characterize the platelet phenotype in FMD and responses to ex vivo disturbed blood flow to identify surface proteins that mediate mechanical platelet activation and mechanisms of thrombosis.

Methods: Thrombotic outcomes were determined by multivariate regression analysis in 105,887 patients with FMD.  Isolated human platelets were assessed for activation by FACS and aggremometry following exposure to ex vivo steady laminar and disturbed flow (S-Flow and D-Flow, respectively) conditions using a cone and flow system. Changes in protein expression of mechanically-sensitive glycoprotein VI (GPVI) was evaluated by FACS and Western blotting. RNA sequencing (seq) of FMD platelets was compared to matched controls. 

Results: In FMD, long-term aspirin is paradoxically an independent risk factor for ischemic stroke (OR 1.64 95% CI 1.29-1.64) yet protects against hemorrhagic stroke (OR 0.47 95% CI 0.24-0.89). FMD platelets are hyporeactive vs. controls to TRAP, ADP, and Convulxin (Figure 1). However in the presence of D-Flow, FMD platelets exhibit time-dependent augmentation of platelet activation greater than controls (Figure 2). FMD platelet activation in D-Flow was attenuated by the mechanosensitive channel inhibitor, GsMTx4. Expression of GPVI was decreased in FMD vs control at baseline and with D-Flow. RNA-seq revealed several downregulated mitochondrial proteins in FMD platelets and evaluation of FMD platelet bioenergetics suggests the possibility of mitochondrial dysfunction.
 Biochemical activation of FMD platelets

Biomechanical Activation of FMD platelets

Conclusions: FMD platelets are dysregulated, with attenuated biochemical activation pathways but augmented to biomechanical stimuli. D-flow exposure of platelets in irregularly shaped arteries of patients with FMD may alter the platelet phenotype and metabolic function. Therapeutics targeting biomechanical pathways of platelet activation may be superior for stroke prevention in FMD.
 

« Back to ISTH 2021 Congress

ISTH Congress Abstracts - https://abstracts.isth.org/abstract/features-of-aspirin-resistant-biomechanical-platelet-activation-in-fibromuscular-dysplasia/