@article{65410a1a458e4e26b74c59a5714ec1f9,
title = "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.",
keywords = "animal models of human disease, basic science research, thrombosis, vascular biology, vascular diseases, VON-WILLEBRAND-FACTOR, DEEP-VEIN THROMBOSIS, TRANSPORTER-LIKE PROTEIN-2, FACTOR-BINDING, NEUTROPHILS, GLYCOPROTEIN, INDIVIDUALS, INITIATE, LOCI, LUNG",
author = "Julia Tilburg and Coenen, {Danielle M.} and Gaia Zirka and Sophie Dolleman and {van Oeveren-Rietdijk}, {Annemarie M.} and Karel, {Mieke F. A.} and {de Boer}, {Hetty C.} and Cosemans, {Judith M. E. M.} and Versteeg, {Henri H.} and Morange, {Pierre E.} and {van Vlijmen}, {Bart J. M.} and Maracle, {Chrissta X.} and Thomas, {Grace M.}",
note = "Funding Information: This work was supported by Trombosestichting Nederland (#2015-4), the Landsteiner Foundation for Blood Transfusion Research (#1503), the Dutch Heart Foundation (2015T79), the Netherlands Organization for Scientific Research (NWO Vidi 91716421), a European Molecular Biology Organization Short-Term Fellowship (EMBO #7468), a European Society of Cardiology First Contact Initiative grant, and by a French ANR grant (ANR-17-CE14-0003-01). The authors thank Dr Pavan K. Kommareddi, Thankam S. Nair, and Dr Thomas E. Carey (Kresge Hearing Research Institute, Department of Otolaryngology/Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA) for the floxed Slc44a2 mouse embryos used to generate the mice on a C57BL/6J background and Dr Charles Esmon (University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA) for providing the 59D8 fibrin antibody. Also, we thank Lieke van den Heijkant for assisting with the hypercoagulability model. Funding Information: This work was supported by Trombosestichting Nederland (#2015‐4), the Landsteiner Foundation for Blood Transfusion Research (#1503), the Dutch Heart Foundation (2015T79), the Netherlands Organization for Scientific Research (NWO Vidi 91716421), a European Molecular Biology Organization Short‐Term Fellowship (EMBO #7468), a European Society of Cardiology First Contact Initiative grant, and by a French ANR grant (ANR‐17‐CE14‐0003‐01). Publisher Copyright: {\textcopyright} 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis",
year = "2020",
month = jul,
doi = "10.1111/jth.14835",
language = "English",
volume = "18",
pages = "1714--1727",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Elsevier B.V.",
number = "7",
}