SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis. (15th May 2020)

• Record Type: Journal Article
• Authors: Tilburg, Julia; Coenen, Daniëlle M.; Zirka, Gaia; Dólleman, Sophie; van Oeveren‐Rietdijk, Annemarie M.; Karel, Mieke F. A.; de Boer, Hetty C.; Cosemans, Judith M. E. M.; Versteeg, Henri H.; Morange, Pierre E.; van Vlijmen, Bart J. M.; Maracle, Chrissta X.; Thomas, Grace M.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 18:Number 7(2020)
• Page Start: 1714
• Page End: 1727
• Publication Date: 2020-05-15
• Subjects: animal models of human disease -- basic science research -- thrombosis -- vascular biology -- vascular diseases; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14835
• Languages: English
• ISSNs: 1538-7933

Abstract

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.