Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions

Abstract

Observational studies have shown that inflammatory cells accumulate within the thrombus and surrounding vein wall during the natural history of venous thrombosis. More recent studies have begun to unravel the mechanisms that regulate this interaction and have confirmed that thrombosis and inflammation are intimately linked. This review outlines our current knowledge of the complex relationship between inflammatory cell activity and venous thrombosis and highlights new areas of research in this field. A better understanding of this relationship could lead to the development of novel therapeutic targets that inhibit thrombus formation or promote its resolution.

Fig 1. Inflammation in venous thrombogenesis

(i) Activation of the endothelium (EC - red cell) generates intravascular danger signals, which guide leukocytes to areas of inflammation and induces tissue factor (TF) production. (ii) Upregulation of adhesion molecules on endothelium mediate PMN recruitment while tissue factor generates thrombin, activating platelet (Plt) deposition and converting fibrinogen to cross-linked fibrin (Fb) that entraps the main red blood cell (RBC) mass. (iii) PMN accumulation in the subendothelial layer and subsequent exposure of collagen (Col) causes platelet aggregation and further PMN sequestration establishing a nidus for thrombus formation (iii). PMN apoptosis in response to inflammatory stimuli releases neutrophil extracellular traps (NETs, blue strands) that provide a scaffold for further RBC capture (iii). Reactive oxygen species (ROS), released from the vessel wall and leukocytes, oxidise haemoglobin (Hb) to methaemoglobin (MetHb, blue RBC). As trapped RBCs lyse, Fe3+ contained in metHb is released and induces further RBC lysis. This leads to a positive feedback loop with increased areas of endothelial dysfunction resulting in thrombus propagation (iv).

Fig 2. Putative functions of leukocytes in venous thrombus resolution

Leukocytes accumulate in the venous thrombus during its resolution. Polymorphonuclear neutrophils (PMN) predominate in the early stages of resolution with mononuclear phagocytes (M?) predominating later. The origin of these cells appears to be from the bone marrow (BM), however the contribution of tissue resident macrophages or cells derived from the ‘splenic reservoir’, remains unknown. Leukocytes signal through a TLR9 mechanism and may be stimulated by fibrin(ogen) and its degradation products. They are speculated to have a number of functions important for thrombus resolution.