Venous thromboembolism (DVT) is a major healthcare problem causing significant morbidity and mortality. According to the AHA, up to two million Americans are affected annually by DVT and 200,000 die annually from one of its complications, pulmonary embolism, 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 likely has a great deal to do with the chronic vein wall changes associated with venous thromboembolism. Additionally, inflammation leads to thrombus amplification and the production of procoagulant microparticles, which augment thrombogenesis. Specifically, P-selectin and its ligand receptor PSGL-1, along with E-selectin appear to be strongly related to venous thrombogenesis, as animals with high circulating level of P-selectin produce large venous thrombi, while animals gene deleted for P-selectin/E- selectin produce small thrombi. It has been shown that when P-selectin binds to its receptor PSGL-1, procoagulant microparticles are produced, which can be taken up into developing thrombi. In preliminary studies, we have shown that microparticles are elevated in patients with documented DVT and that combining microparticle measurements with d-dimer and soluble P-selectin assays allows prediction of DVT with sensitivity/specificity improved over d-dimer alone. However, the natural history of microparticle production and their role in venous thrombogenesis is currently not known. The current proposal addresses the importance of microparticles to venous thrombogenesis. We will determine the natural history of microparticle formation in a mouse model of venousthrombosis (years 1 -3) and define their thrombogenic potential in-vitro and in-vivo (years 2-5). We will also validate a new means to determine the presence of microparticles using luminescence in our mouse model (years 1-3). We will then determine the ability of microparticles to augment the diagnosis of DVT in patients who have developed DVT (years 1-5). Microparticle analysis will be combined with soluble P-selectin, soluble E-selectin, d-dimer, interleukin-10, TNF-alpha, C-reactive protein, and clinical risk factor analysis. We will also determine the presence of prothrombotic proteins on the surface of microparticles (essentially for the first time) with a proteomics approach (years 1-2). These studies will more completely characterize the importance of microparticles to the process of venous thrombogenesis. Lay Summary: This proposal will determine the role of procoagulant elements termed microparticles in the etiology of venous thrombosis and their use as a diagnostic tool.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070766-09
Application #
7991812
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Link, Rebecca P
Project Start
2002-07-01
Project End
2012-02-29
Budget Start
2010-12-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$374,539
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Diaz, Jose A; Obi, Andrea T; Myers Jr, Daniel D et al. (2012) Critical review of mouse models of venous thrombosis. Arterioscler Thromb Vasc Biol 32:556-62
Ramacciotti, Eduardo; Blackburn, Susan; Hawley, Angela E et al. (2011) Evaluation of soluble P-selectin as a marker for the diagnosis of deep venous thrombosis. Clin Appl Thromb Hemost 17:425-31
Fuchs, Tobias A; Brill, Alexander; Duerschmied, Daniel et al. (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107:15880-5
Ramacciotti, Eduardo; Hawley, Angela E; Wrobleski, Shirley K et al. (2010) Proteomics of microparticles after deep venous thrombosis. Thromb Res 125:e269-74
Ramacciotti, Eduardo; Myers Jr, Daniel D; Wrobleski, Shirley K et al. (2010) P-selectin/ PSGL-1 inhibitors versus enoxaparin in the resolution of venous thrombosis: a meta-analysis. Thromb Res 125:e138-42
Diaz, Jose A; Ramacciotti, Eduardo; Wakefield, Thomas W (2010) Do galectins play a role in venous thrombosis? a review. Thromb Res 125:373-6
Wakefield, Thomas W; Myers, Daniel D; Henke, Peter K (2009) Role of selectins and fibrinolysis in VTE. Thromb Res 123 Suppl 4:S35-40
Abdullah, Newaj M; Kachman, Maureen; Walker, Angela et al. (2009) Microparticle surface protein are associated with experimental venous thrombosis: a preliminary study. Clin Appl Thromb Hemost 15:201-8
Schmaier, Alvin H (2008) The elusive physiologic role of Factor XII. J Clin Invest 118:3006-9
Wakefield, Thomas W; Myers, Daniel D; Henke, Peter K (2008) Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 28:387-91

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