P- and E- selectin in venous thrombosis and non-venous pathologies

Abstract

Venous thromboembolism is a very common and costly health problem worldwide. Anticoagulant treatment for VTE is imperfect: all have the potential for significant bleeding, and none prevent the development of post thrombotic syndrome after deep vein thrombosis or chronic thromboembolic pulmonary hypertension after pulmonary embolism. For these reasons, alternate forms of therapy with improved efficacy and decreased bleeding are needed. Selectins are a family (P-selectin, E-selectin, L-selectin) of glycoproteins that facilitate and augment thrombosis, modulating neutrophil, monocyte, and platelet activity. P- and E-selectin have been investigated as potential biomarkers for thrombosis. Inhibition of P-selectin and E-selectin decrease thrombosis and vein wall fibrosis, with no increase in bleeding. Selectin inhibition is a promising avenue of future study as either a stand-alone treatment for VTE or as an adjunct to standard anticoagulation therapies.

Keywords: inflammation; pulmonary embolism; selectins; venous thromboembolism; venous thrombosis.

FIGURE 1

E‐selectin and P‐selectin involvement in thrombosis and inflammation. Upon activation of the endothelium or platelets, P‐selectin becomes exposed and E‐selectin becomes upregulated. These selectin glycoproteins, located on inflammatory cells (P‐ and E‐selectin) and platelets (P‐selectin) allow for leukocyte‐endothelial, leukocyte‐platelet, and leukocyte‐leukocyte interactions, the release of tissue factor rich microparticles from neutrophils, the upregulation of tissue factor on monocytes, and thus the facilitation of thrombosis and thrombosis amplification. At the same time, other inflammatory cells hone into the area of thrombosis. These include neutrophils which become activated to produce procoagulant neutrophil extracellular traps. These inflammatory cells bind to other receptors such as the MAC‐1 receptor, facilitating the production of fibrin, the accumulation of red blood cells, and the ultimate development of a very cellular thrombus. Additionally, inflammatory cell entrance into the vein wall and surrounding tissue contributes to vein wall inflammation and eventually vein wall and valve fibrosis. Note circulating sP‐selectin (s). The location of the primary mechanism of action for the inhibitors of P‐selectin (including inhibitors to the PSGL‐1 ligand) and E‐selectin are included