Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin

• DOI: 10.1161/atvbaha.120.314301
• Publication Date: 2020-07-23T09:01:01Z
• Authors: Muhammad Usman Ahmed; Valeria Kaneva; Stéphane Loyau; Dmitry Nechipurenko; Nicolas Receveur; Marion Le Bris; Emily Janus-Bell; Mélusine Didelot; Antoine Rauch; Sophie Susen; Nabil Chakfé; François Lanza; Elizabeth E. Gard...; Robert K. Andrews; Mikhail Panteleev; Christian Gachet; Martine Jandrot-P...; Pierre H. Mangin
• Keywords: Blood Platelets; 2. Zero hunger; Microscopy, Video; Platelet Aggregation; [SDV]Life Sciences [q-bio]; Thrombin; 610; Fibrinogen; Thrombosis; Platelet Membrane Glycoproteins; Afibrinogenemia; Models, Biological; [SDV] Life Sciences [q-bio]; Immunoglobulin Fab Fragments; Kinetics; Fibrinolytic Agents; Humans; Computer Simulation; Stress, Mechanical; Platelet Aggregation Inhibitors; Signal Transduction

Objective: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation a mural thrombus. Computational fluid dynamics numerical models indicated that mechanical stress applied thrombus increases dramatically as grows, strong inter-platelet interactions are essential maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps stability by using real-time video-microscopy. Approach Results: showed blockade with 2 distinct Fab fragments promoted efficient disaggregation human thrombi preformed on collagen or material in absence thrombin. ACT017-induced was achieved under arterial blood flow conditions, effect increased wall shear rate. regulated within growing evidenced loss contraction when blocked, disaggregating anti-GPVI agent were fully activated soluble agonists. The GPVI-dependent stabilizing further supported fact inhibition any 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kβ, phospholipase C, resulted kinetics similar ACT017. from afibrinogenemic patients suggests role requires interaction fibrinogen. Finally, fibrin-rich also ACT017 combination r-tPA (recombinant tissue plasminogen activator). Conclusions: This work identifies unrecognized for maintaining targeting could dissolve aggregates poor fibrin content.