Monocyte/macrophage-mediated venous thrombus resolution

Abstract

Venous thromboembolism (VTE) poses a notable risk of morbidity and mortality. The natural resolution of the venous thrombus might be a potential alternative treatment strategy for VTE. Monocytes/macrophages merge as pivotal cell types in the gradual resolution of the thrombus. In this review, the vital role of macrophages in inducing inflammatory response, augmenting neovascularization, and facilitating the degradation of fibrin and collagen during thrombus resolution was described. The two phenotypes of macrophages involved in thrombus resolution and their dual functions were discussed. Macrophages expressing various factors, including cytokines and their receptors, adhesion molecules, chemokine receptors, vascular endothelial growth factor receptors, profibrinolytic- or antifibrinolytic-related enzymes, and other elements, are explored for their potential to promote or attenuate thrombus resolution. Furthermore, this review provides a comprehensive summary of new and promising therapeutic candidate drugs associated with monocytes/macrophages that have been demonstrated to promote or impair thrombus resolution. However, further clinical trials are essential to validate their efficacy in VTE therapy.

Keywords: inflammation; macrophages; monocytes; neovascularization; thrombus resolution; venous thromboembolism.

Figure 1

Monocytes/macrophages in the resolution of the venous thrombus. The period from day 1 to day 3 after modeling or thrombosis was considered the thrombus formation period. The early stage of thrombus resolution was considered from day 4 to day 7 after thrombosis. The middle and late stages of thrombus resolution were considered from day 8 after thrombosis. During thrombus resolution, macrophages transform from M1 type to M2 type and participate in thrombus resolution by clearing necrotic cells and matrix debris and promoting neovascularization, profibrinolysis, and collagenolysis. M1-type macrophages infiltrate into the thrombus during thrombus formation and play a major role in the early stage of thrombus resolution, while M2-type macrophages play a vital role in the middle and late stages of thrombus resolution. CCR2, C-C chemokine receptor 2; IL-6, interleukin-6; MMPs, matrix metalloproteinases; PAI-1, plasminogen activator inhibitor-1; PAI-2, plasminogen activator inhibitor-2; PECAM-1, platelet endothelial cell adhesion molecule 1; TNF-α, tumor necrosis factor-α; TNF-Rp55, tumor necrosis factor receptor p55; TLR4, Toll-like receptor 4; TLR9, Toll-like receptor 9; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor.