The role of Plasminogen Activator Inhibitor Type‐2 (PAI‐2) in modulating venous thrombus resolution

Abstract

Deep Vein Thrombosis (DVT) which can arise from vascular endothelial injury, venous stasis, and/or alterations in blood hypercoagulability, affects patients of increased age who have limited to no mobility, paralysis, cancer, surgery and/or trauma. DVT is characterized by thrombi that form on the surface of activated endothelium in both the vein valve pockets and dilated sinuses of the lower limbs and is a highly inflammatory process. Macrophages and neutrophils are known to play key roles, being major producers of inflammatory cytokines, chemokines, and proteases. However, the precise mechanisms and key players that modulate venous thrombosis and its resolution are poorly understood. Plasminogen activator inhibitor type‐2 (PAI‐2) or SerpinB2, a Clade B serine protease inhibitor (SERPIN) was originally identified as an inhibitor of the serine protease, urokinase‐plasminogen activator(uPA) and has also been found to possess unique properties associated with inflammation and cell survival. Utilizing a clinically relevant mouse model of DVT, we discovered that genetic deletion of PAI‐2 accelerates venous thrombus resolution in vivo. PAI‐2 deficiency leads to enhanced venous thrombus resolution, increased proteolytic activity of uPA, and modulation of inflammatory processes. Recent work in our lab has focused on the primary effector cells of thrombus formation and resolution, neutrophils and macrophages respectively. PAI‐2 expression can be found in both resident and activated, neutrophils and macrophages, and may modulate how these cells function on fibrin and collagen matrices found within the thrombus microenvironment. Clarifying the mechanism by which PAI‐2 contributes to venous thrombus resolution has potential to lead to new therapies that accelerate venous thrombus resolution.Support or Funding InformationDepartment of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine and VA Maryland Health Care System, Department of Veterans Affairs, Baltimore, MarylandThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.