Abstract
Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy.
Highlights
Venous thromboembolism (VTE) is currently one of the largest sources of morbidity and mortality, comparable in scope to Alzheimer’s disease and diabetes. This disease encompasses both deep vein thrombosis (DVT) and its potential sequelae, including pulmonary embolism (PE) if the thrombus is dislodged from the vein wall and post thrombotic syndrome (PTS) whereby the thrombus and its resolution damage the vein wall and causes venous hypertension [1]
Neutropenia in toll-like receptor 9 (TLR9) mice impairs both figure illustrates a potential mechanism of immune cell influx into the developing thrombus: and fibrosis, resulting in an intermediate thrombus size because of instability alone. This figure neutrophils are first recruited by the chemoattractant IL8, these neutrophils trigger an influx of illustrates a potential mechanism of immune cell influx into the developing thrombus: neutrophils are monocyte-derived macrophages, partially through MCP-1 signaling
Homocysteine [164], phosphatase and tensin homolog (PTEN) [160], the tumor necrosis factor ligand FASLG, [161] SRC kinase signaling inhibitor 1 (SRCIN1) [162], and serum response factor (SRF) [163] delay re-endothelialization, which may have therapeutic utility by lengthening the window of opportunity for use of common anticoagulants, or thrombolytic agents. Another significant endothelial cell transformation in the context of DVT is the endothelialmesenchymal transition (EndMT), in which endothelial cells transdifferentiate into mesenchymal-like cells, an essential process in embryonic heart development [165]
Summary
Venous thromboembolism (VTE) is currently one of the largest sources of morbidity and mortality, comparable in scope to Alzheimer’s disease and diabetes. Across recent studies (with follow-up periods ending 2009–2013) of American and European populations, the age- and sex-adjusted incidence of VTE has been reported to be 1.22–2.39 per 1000 patient-years, rising to 5–11 per 1000 patient-years by the eighth decade of life [2,3,4,5,6,7] Of these VTE patients, 27–56% present with PE, putting them at imminent risk of death, while roughly another 20–50% of VTE patients later develop PTS, which reduces quality of life through loss in mobility, leg swelling, and skin ulcers [8]. Care to these later-stage patients, with less bleeding risk
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