Fibrinolysis and Inflammation in Venous Thrombus Resolution

Abstract

Clinical observations and accumulating laboratory evidence support a complex interplay between coagulation, inflammation, innate immunity and fibrinolysis in venous thromboembolism (VTE). VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), and the subsequent complications of post-thrombotic syndrome (PTS), are significant causes of morbidity and mortality in patients. Clinical risk factors for VTE include cancer, major trauma, surgery, sepsis, inflammatory bowel disease, paralysis, prolonged periods of immobility, and aging. Abnormalities in venous blood flow or stasis initiates the activation of endothelial cells, and in concert with platelets, neutrophils and monocytes, propagates VTE in an intact vein. In addition, inflammatory cells play crucial roles in thrombus recanalization and restoration of blood flow via fibrinolysis and vascular remodeling. Faster resolution of the thrombus is key for improved disease prognosis. While in the clinical setting, anticoagulation therapy is successful in preventing propagation of venous thrombi, current therapies are not designed to inhibit inflammation, which can lead to the development of PTS. Animal models of DVT have provided many insights into the molecular and cellular mechanisms involved in the formation, propagation, and resolution of venous thrombi as well as the roles of key components of the fibrinolytic system in these processes. Here, we review the recent advances in our understanding of fibrinolysis and inflammation in the resolution of VTE.

Keywords: DVT; PE; fibrinolysis; inflammation; innate immunity; plasminogen; venous thromboembolism; venous thrombus resolution.

Figure 1

Innate immune cells in DVT. Venous thrombosis can be initiated by venous stasis, increased blood hypercoagulability or endothelial damage. Innate immune cells, neutrophils, and monocytes, bind to the activated vascular endothelium and along with platelets, initiate thrombus formation and fibrin deposition. The thrombus grows by deposition of more fibrin, accumulation of red blood cells and immune cells. Thrombus infiltrating neutrophils and macrophages (differentiated from monocytes) modulate generation of plasmin and matrix metalloproteinases (MMPs), and thus set the stage for fibrinolysis and the collagen remodeling required for the resolution of the thrombus. In the early phase of thrombus resolution, fibrinolysis occurs at a high rate generating fibrin degradation products (FDPs), intrathrombus collagen fibrils start to appear, and thrombus-associated immune cells are induced to produce inflammatory cytokines and various proteases. As the thrombus matures, the rate of fibrinolysis slows down, intrathrombus collagen deposition increases, matrix remodeling via macrophage secreted MMPs occurs and eventually blood flow through the thrombus is restored. Resolution of inflammation and acceleration of this process is believed to be beneficial for restoring vein wall patency and reducing the pathology associated with PTS.

Figure 2

Histochemical analysis of thrombus sections from a stasis induced mouse model of DVT. In this model, thrombus formation occurs maximally at day 4 and resolves naturally thereafter with day 12 serving as a measure of thrombus resolution. (A) Hematoxylin and Eosin (HandE) stain showing overall tissue morphology; (Original magnification x100, Scale bar 500 μm) and (B) cell infiltrates. The nucleated cellular population at day 4 comprises mostly of neutrophils and few macrophages, whereas both macrophages and neutrophils can be seen at day 12 (Original magnification x400, Scale bar 100 μm). (C) Martius Scarlet Blue (MSB) stain showing fibrin content in red (Original magnification x100, Scale bar 500 μm). (D) Picrosirius Red stain showing collagen content in red (Original magnification x100, Scale bar 500 μm). As the thrombus resolves, it becomes smaller in size, fibrin content is decreased via fibrinolysis and there is an increase in intrathrombus collagen content.