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SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis

Abstract : Background Genome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot formation upon vascular injury. Objective To further investigate the role of SLC44A2 in VT by utilizing SLC44A2 deficient mice (Slc44a2(-)(/)(-)) in two representative disease models. Methods Mice were included in a hypercoagulability model driven by siRNA-mediated hepatic gene silencing of anticoagulants Serpinc1 (antithrombin) and Proc (protein C) and a flow restriction (stenosis) model induced by partial ligation of the inferior vena cava. Results In the hypercoagulability model, no effect in onset was observed in Slc44a2(-)(/)(-) animals; however, a drop in plasma fibrinogen and von Willebrand factor coinciding with an increase in blood neutrophils was recorded. In the neutrophil dependent stenosis model after 48 hours, Slc44a2(-)(/)(-) mice had significantly smaller thrombi both in length and weight with less platelet accumulation as a percentage of the total thrombus area. During the initiation of thrombosis at 6 hours post-stenosis, Slc44a2(-)(/)(-) mice also had smaller thrombi both in length and weight, with circulating platelets remaining elevated in Slc44a2(-)(/)(-) animals. Platelet activation and aggregation under both static- and venous and arterial shear conditions were normal for blood from Slc44a2(-)(/)(-) mice. Conclusions These studies corroborate the original GWAS findings and establish a contributing role for SLC44A2 during the initiation of VT, with indications that this may be related to platelet-neutrophil interaction. The precise mechanism however remains elusive and warrants further investigation.
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https://hal.inrae.fr/hal-03158414
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Submitted on : Wednesday, March 3, 2021 - 7:05:48 PM
Last modification on : Wednesday, April 14, 2021 - 8:41:30 AM

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Julia Tilburg, Daniëlle Coenen, Gaia Zirka, Sophie Dólleman, Annemarie Oeveren‐rietdijk, et al.. SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis. Journal of Thrombosis and Haemostasis, Wiley, 2020, 18 (7), pp.1714-1727. ⟨10.1111/jth.14835⟩. ⟨hal-03158414⟩

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