Abstract
Abstract 129: Bleeding Diathesis In Ehlers-danlos Syndrome Patients Is Caused By Impaired Platelet Inside-out Signaling And Integrin αIIbβ3 Activation
Arteriosclerosis, thrombosis, and vascular biology, Vol.43(Suppl_1)
05/2023
DOI: 10.1161/atvb.43.suppl_1.129
Abstract
Abstract only Background: Easy bruising is included as a major or minor criterion for the classification of multiple types of Ehlers-Danlos syndrome (EDS). Despite a longstanding recognition of the association between EDS and bleeding, we still lack a definitive understanding of the mechanisms that contribute to bleeding diathesis in EDS patients. Objective: To determine platelet function in a cohort of patients with defined EDS types and a murine EDS model. Methods: We analyzed a cohort of 52 patients with classical, classical-like, hypermobile, or vascular EDS and a matched group of 52 healthy-control subjects. The International Society of Thrombosis and Hemostasis bleeding assessment tool (ISTH-BAT) was used to differentiate the EDS group with a higher bleeding tendency. Platelet activation was evaluated using human and mouse samples in standardized agonist-induced in vitro assays. Results: The mean ISTH-BAT score was 0.1 for the healthy controls and 9.1 for the EDS subjects (P<0.0001). An abnormal ISTH-BAT score was observed in 32 out of 52 (61.5%) EDS subjects and 0 of 51 healthy controls (P<0.0001). Most frequent bleeding symptoms were bruising, muscle hematomas, menorrhagia, epistaxis, bleeding from the oral cavity, and bleeding after tooth extraction. Menorrhagia that was life-threatening or required surgery was reported in 7 of 52 (14%) EDS subjects. Platelets from EDS subjects exhibited reduced aggregation and αIIbβ3 activation (with normal αIIbβ3 surface exposure) in response to agonists, including collagen, collagen-related peptide, and thrombin receptor activator peptide-6. Platelet secretion (dense and α-granules) and annexin V exposure were comparable between EDS and healthy subjects. Analysis of GPVI downstream signaling showed defects in Syk, PLCγ, and talin phosphorylation in EDS subjects (P<0.05 vs. controls), suggesting a defect in platelet inside-out signaling. The Col5a1 +/- EDS mouse model recapitulated the platelet phenotype of human EDS subjects. Conclusions: Patients with multiple types of EDS exhibit a wide range of bleeding symptoms ranging from mild to life-threatening episodes. Our results suggest that bleeding diathesis in EDS patients is caused by impaired platelet inside-out signaling and integrin αIIbβ3 activation.
Details
- Title: Subtitle
- Abstract 129: Bleeding Diathesis In Ehlers-danlos Syndrome Patients Is Caused By Impaired Platelet Inside-out Signaling And Integrin αIIbβ3 Activation
- Creators
- Mariia Kumskova - University of IowaGagan D Flora - University of IowaManasa Nayak - University of IowaMadankumar Ghatge - University of IowaRakeshkumar Patel - University of IowaAditi Jain - University of IowaJanice Staber - University of IowaSteven R Lentz - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.43(Suppl_1)
- DOI
- 10.1161/atvb.43.suppl_1.129
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2023
- Academic Unit
- Internal Medicine; Stead Family Department of Pediatrics; Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Hematology/Oncology
- Record Identifier
- 9984473475102771
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