Circulating Platelets Play a Pivotal Role in Thrombus Maturation and Vessel Wall Remodeling During Venous Thrombus Resolution

Abstract

Purpose: Platelets are known to play an important role in venous thrombogenesis, but their role in thrombus maturation, resolution, and post-thrombotic vein wall remodeling is unclear. The purpose of this study was to determine the role that circulating platelets play in the later phases of venous thrombosis. Methods: We utilized a murine inferior vena cava (IVC) stenosis model. Baseline studies in untreated mice were performed to determine an optimal post-thrombotic time point for tissue harvest that would capture both thrombus maturation and post-thrombotic vein wall remodeling. This time point was found to be post-operative day 10. After undergoing IVC ultrasound on day 2 to confirm venous thrombosis (VT), mice were treated with a daily injection of platelet depleting antibody (anti-GP1bα) to maintain thrombocytopenia or control IgG until post-operative day 10. IVC and thrombi were harvested at on post-operative day 10. Thrombus length, volume, fibrosis, neovascularization, and smooth muscle cell invasion were analyzed. Vein wall fibrosis and intimal thickening were also analyzed. Results: Mice that were made thrombocytopenic after venous thrombogenesis had thrombi that were significantly less fibrotic, with significantly fewer invading smooth muscle cells. Furthermore, thrombocytopenia in the setting of venous thrombosis resulted in significantly less post-thrombotic vein wall intimal thickening. Thrombus volume failed to significantly differ in thrombocytopenic mice compared to their control peers. Conclusions: This work suggests that circulating platelets contribute significantly to venous thrombus maturation, fibrosis, and adverse vein wall remodeling. We can speculate that pro-fibrotic and smooth muscle cell-directing cytokines within platelets, such as TGF-β, bFGF, PDGF, and VWF may be responsible for driving thrombus fibrosis and vein wall intimal thickening. P-selectin, which is shed from activated platelets and mediates platelet-leukocyte binding during thrombosis, may also play an important pro-thrombotic role in the later stages of thrombosis. These cytokines and cell adhesion molecules may be potential targets for future therapies aimed at decreasing thrombus fibrosis without altering the normal rate of thrombus resolution, and decreasing adverse post-thrombotic vein wall remodeling.