Venous thromboembolism (DVT/PE) is a major healthcare problem causing significant morbidity and mortality. According to the AHA, up to two million Americans are affected annually by deep venous thrombosis (DVT) and 200,000 die annually from one of its complications, pulmonary embolism (PE), more than breast cancer and AIDs combined. We and others have demonstrated that a significant inflammatory response occurs with venous thromboembolism and that this inflammation, through the production of procoagulant microparticles, leads to thrombus amplification. Plasminogen Activator lnhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators in plasma. It is secreted in an active form from liver and endothelial cells and is stabilized by binding to vitronectin. It inactivats both tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). PAI-1 levels are elevated by hyperlipidemia, and PAI-1 elevation appears to synergize with Factor V Leiden genetic abnormalities, a thrombophilic mutation of Factor V (Leiden) which renders it resistent to proteolytic degradation. It is plausible that elevated PAI-1 could suppress fibrinolysis and increase thrombosis. Studies on the role of elevated levels of PAI-1 to venous thrombosis have been contradictory. The purpose of this proposal is to determine the role of PAI-1 in venous thrombogenesis in a murine complete IVC ligtion venous thrombosis model (aim 1a) and a murine IVC stenosis-induced venous thrombosis model (aim 1b). Mice with PAI-1 deletion and PAI-1 overexpression will be studied, as will vitronectin deficient mice, mice with combined PAI-1/vitronectin deficiency, and wild type mice. We will also use pharmacologic PAI-1 inhibition. Thrombogenesis, vein wall/thrombus inflammation, the production of procoagulant microparticles, and thrombus/vein wall fibrosis will be evaluated. Additionally, we will determine the efficacy of PAI-1 inhibition after thrombogenesis, the roles of plasmin generation, and the role of thrombin in venous thrombosis in both models (aim 1c). Finally, we will study levels of PAI-1 in Factor V Leiden heterozygous and homozygous mice, ApoE hyperlipidemic mice, Egr-1 null mice (the Egr-1 site in the PAI-1 promoter region is induced by hypoxia, a characteristic of venous stasis), and wild type mice in both models (aims 2a, 2b). These levels of PAI-1 will be correlated to thrombosis. The results of this proposal should better define the role of PAI-1 in venous thrombogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Obi, Andrea T; Andraska, Elizabeth; Kanthi, Yogendra et al. (2016) Gram-Negative Pneumonia Alters Large-Vein Cell-Adhesion Molecule Profile and Potentiates Experimental Stasis Venous Thrombosis. J Vasc Res 53:186-195
Wu, Jianbo; Strawn, Tammy L; Luo, Mao et al. (2015) Plasminogen activator inhibitor-1 inhibits angiogenic signaling by uncoupling vascular endothelial growth factor receptor-2-?V?3 integrin cross talk. Arterioscler Thromb Vasc Biol 35:111-20
Obi, A T; Diaz, J A; Ballard-Lipka, N L et al. (2014) Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J Thromb Haemost 12:1353-63
Obi, Andrea T; Diaz, Jose A; Ballard-Lipka, Nicole L et al. (2014) Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner. J Vasc Surg Venous Lymphat Disord 2:441-450.e1
Diaz, Jose A; Alvarado, Christine M; Wrobleski, Shirley K et al. (2013) The electrolytic inferior vena cava model (EIM) to study thrombogenesis and thrombus resolution with continuous blood flow in the mouse. Thromb Haemost 109:1158-69
Li, Shih-Hon; Reinke, Ashley A; Sanders, Karen L et al. (2013) Mechanistic characterization and crystal structure of a small molecule inactivator bound to plasminogen activator inhibitor-1. Proc Natl Acad Sci U S A 110:E4941-9
Patterson, K A; Zhang, X; Wrobleski, S K et al. (2013) Rosuvastatin reduced deep vein thrombosis in ApoE gene deleted mice with hyperlipidemia through non-lipid lowering effects. Thromb Res 131:268-76
Shuster, Katherine A; Wrobleski, Shirley K; Hawley, Angela E et al. (2013) Prothrombotic effects of thrombolytic therapy in a rat (Rattus norvegicus) model of venous thrombolysis. Comp Med 63:244-51
Osterholzer, John J; Christensen, Paul J; Lama, Vibha et al. (2012) PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury. J Pathol 228:170-80
Fredriksson, Linda; Nilsson, Ingrid; Su, Enming J et al. (2012) Platelet-derived growth factor C deficiency in C57BL/6 mice leads to abnormal cerebral vascularization, loss of neuroependymal integrity, and ventricular abnormalities. Am J Pathol 180:1136-44

Showing the most recent 10 out of 36 publications