6533b7d0fe1ef96bd1259bca

RESEARCH PRODUCT

GAS6

subject

description

Venous thrombosis is determined by the recruitment of monocytes and neutrophils to the inflamed endothelium and is primarily influenced by the plasmatic coagulation system.1 Monocyte tissue factor (TF) was identified as the causative trigger for intraluminal fibrin formation and thrombus load in the inferior vena cava (IVC) stenosis model, resembling human deep vein thrombosis.1 Although monocyte TF is prothrombotic, the TF expressed by activated endothelial cells triggers proinflammatory protease-activated receptor signaling pathways.2,3 See accompanying article on page 1315 In the past years, GAS6 (growth arrest–specific gene-6) was described as a major regulatory protein of prothrombotic signaling (Table). Clinically, elevated plasma GAS6 levels were associated with venous thromboembolic disease.10 In previous work, the Blostein laboratory has identified GAS6, the major ligand of the TAM (Tyro3/Axl/Mer) receptor tyrosine kinase Axl, that protects endothelial cells from apoptosis via PI3K (phosphoinositide 3-kinase)-Akt–dependent inactivation of FOXO1a,7,9 as a stimulant of Akt-mediated endothelial TF expression.12 Mice deficient in GAS6 or the GAS6 receptors are protected against thrombosis.4,5 However, given that GAS6 derived from the hematopoietic and the nonhematopoietic vascular compartment contributes equally to thrombus formation,11 defective thrombus formation in mice deficient in GAS6 signaling4,5 may have several reasons. A platelet phenotype, characterized by impaired dense and α-granule release, impaired platelet aggregation, and retarded spreading on fibrinogen coatings, became apparent in these mice. The platelet defect was explained by the regulatory role of GAS6 receptors in platelet outside-in signaling via the …