Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin
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
DOI:
10.1161/atvbaha.120.314301
Publication Date:
2020-07-23T09:01:01Z
AUTHORS (18)
ABSTRACT
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.
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