Fibrin exposure triggers αIIbβ3-independent platelet aggregate formation, ADAM10 activity and glycoprotein VI shedding in a charge-dependent manner.

Fibrin exposure triggers αIIbβ3-independent platelet aggregate formation, ADAM10 activity and glycoprotein VI shedding in a charge-dependent manner.
J Thromb Haemost. 2020 Mar 21;:
Authors: Montague SJ, Hicks SM, Lee CS, Coupland LA, Parish CR, Lee WM, Andrews RK, Gardiner EE
Abstract
Collagen and fibrin engagement and activation of glycoprotein (GP) VI induces proteolytic cleavage of the GPVI ectodomain generating shed soluble GPVI (sGPVI). Collagen-mediated GPVI shedding requires intracellular signalling to release the sGPVI, mediated by A Disintegrin And Metalloproteinase 10 (ADAM10), however the precise mechanism by which fibrin induces GPVI shedding remains elusive. Plasma sGPVI levels are elevated in patients with coagulopathies, sepsis or inflammation and can predict onset of sepsis and sepsis-related mortality, therefore it is clinically important to understand the mechanisms of GPVI shedding under conditions of minimal collagen exposure. Our aim was to characterize mechanisms by which fibrin-GPVI interactions trigger GPVI shedding. Platelet aggregometry, sGPVI enzyme-linked immunosorbent assay (ELISA) and an ADAM10 fluorescence resonance energy transfer (FRET) assay were used to measure fibrin-mediated platelet responses. Fibrin induced αIIbβ3-independent washed platelet aggregate formation, GPVI shedding and increased ADAM10 activity, all of which were insensitive to pre-treatment with inhibitors of Src family kinases b...

Source: Thrombosis and Haemostasis - March 20, 2020 Category: Hematology Authors: Montague SJ, Hicks SM, Lee CS, Coupland LA, Parish CR, Lee WM, Andrews RK, Gardiner EE Tags: J Thromb Haemost Source Type: research