Platelet defects in patients and mice with Ehlers-Danlos syndrome

Ehlers-Danlos syndrome (EDS) is a group of connective tissue disorders characterized by joint hypermobility, skin hyperelasticity, perivascular tissue fragility, easy bruising, and increased bleeding risk. Abnormal bleeding in EDS ranges from mild ecchymoses to life-threatening hemorrhage. Platelet function abnormalities have been reported in people with EDS, but the broad nature and extent of these defects remain poorly defined. Herein, we evaluated blood samples from people with the hypermobile, classical, classical-like, and vascular types of EDS, and used a Col5a1+/- mouse model of classical EDS to characterize the extent of platelet dysfunction. Our findings suggest that platelet dysfunction in EDS is an outcome of reduced integrin αIIbβ3 activation resulting from decreased phosphorylation of talin-1, leading to defects in aggregation and spreading. The observed platelet dysfunction was associated with reduced expression of the platelet surface receptors glycoprotein VI (GPVI) and proteinase-activated receptor 1 (PAR1) and impaired downstream signaling. Col5a1+/- mice demonstrated increased tail bleeding time, reproduced the signaling defects observed in platelets from people with EDS, and exhibited decreased susceptibility to FeCl3-induced carotid artery thrombosis. Collectively, our data indicate that platelet dysfunction in EDS is likely contributing to hemorrhagic complications.