Platelet function abnormalities underlying bleeding in a connective tissue disorder the Ehlers Danlos syndrome - Summary Ehlers-Danlos syndrome (EDS) is a heterogeneous group of hereditary connective tissue disorders characterized by disorganized extracellular matrix due to defects in collagen fibrillogenesis. Bleeding is a common problem in patients with EDS. Recently, we showed that EDS carries a high risk of hemorrhagic complications, including bleeding after surgery and tooth extraction, which were severe or life-threatening in nearly 42% of EDS patients. Currently, no approved protocols or guidelines exist to prevent or treat bleeding in EDS patients, which may result in treatment delays, especially in emergencies. The long-term objective of this proposal is to prevent hemorrhage and improve the outcome of the bleeding diathesis in patients with EDS. A few studies have identified platelet function abnormalities in EDS patients, but none have examined the mechanistic relationship between impaired platelet function and bleeding risk. In pilot studies, we found that platelets from EDS patients exhibit reduced baseline GPVI expression associated with decreased agonist-induced platelet aggregation and impaired integrin αIIbβ3 activation. We further found that a mouse model of the classical type of EDS recapitulates EDS patients' platelet and bleeding phenotypes. Using human samples and murine models, we propose to further define the underlying mechanisms linking impaired platelet function and the bleeding diathesis in EDS. In Aim 1, we will characterize the mechanism of impaired platelet function in vitro using patient and EDS mouse samples. In Aim 2, we will determine whether the impaired platelet function and hemostasis abnormalities are due to an intrinsic defect in platelets or an effect of the abnormal ECM environment. In Aim 3, we will test novel interventions to restore hemostasis in a murine model of EDS. A strength of the proposal is that we will use both clinical samples and preclinical models of EDS to define mechanisms in vitro and in vivo and to test interventions to restore hemostasis. Our team has extensive collaborative expertise, which will increase the feasibility and the likelihood of success. The overall impact of the proposed research is high because it will provide novel insights into platelet receptor characteristics and scientific knowledge regarding the underlying mechanisms of impaired platelet function and risk of bleeding in EDS. The study results are anticipated to raise awareness of the role of platelet function testing for appropriate evaluation and treatment of EDS patients with a high risk of bleeding, particularly prior to invasive procedures or surgery.
