ENDOTHELIAL GAS6 Contributes to Thrombogenesis and Promotes TISSUE FACTOR Upregulation DURING Vessel Injury

Abstract 702

Gas6 is a vitamin K-dependent, secreted protein that amplifies platelet aggregation and secretion in response to platelet agonists. Gas6^−/− mice are protected from experimentally induced lethal venous and arterial thromboembolism. This protection has been attributed to defective aggregation in platelets from gas6^−/− mice. However, this platelet phenotype was only observed when platelets were challenged by only one agonist, ADP, and only at a concentrations of 5.0μM. This subtle platelet abnormality resulting in a rather dramatic clinical phenotype raise the possibility that gas6 from a source other than platelets contributes to thrombus formation. We hypothesize that gas6 derived from the endothelium plays a role in venous thrombus formation. Gas6^−/− mice are protected against venous thrombosis induced by 0.37 M FeCl₃ in the inferior vena cava (IVC). Bone marrow transplantation experiments generating mice with selective ablations of gas6 from either the hematopoietic or non-hematopoietic compartments demonstrate an approximately equal contribution by gas6 from both compartments to thrombus formation. Platelet depletion in wild type or gas6^−/− mice followed by reconstitution with platelets from either WT or gas6^−/− mice confirm that gas6 from compartments other than the platelet contribute to thrombosis development. Furthermore, gas6^−/− mice are hyporesponsive to FeCl₃ mediated tissue factor induction in venous endothelium, as observed by immunofluorescence staining and later validated by a functional assay. In addition, in vitro, gas6^−/− endothelial cells are hyporesponsive to thrombin mediated tissue factor mRNA induction. Taken together, these results suggest that non-hematopoietic gas6, possibly from the endothelium, contributes to thrombus formation in vivo and can be explained by the ability of gas6 to promote endothelial tissue factor induction. These findings support the notion that endothelial gas6 may play a pathophysiologic role in venous thromboembolism.