Venous thromboembolism (VTE;DVT/PE) is a national health concern, with an occurrence of over 900,000 cases per year and over 300,000 deaths per year, more than breast cancer and AIDs combined. The incidence of total cases of VTE exceeds the number of myocardial infarctions and strokes in this country yearly, while the incidence of VTE related deaths exceeds the number of myocardial infarction related deaths or stroke-related deaths. The incidence of VTE has been increasing with the aging of the population. Although the standard treatment of venous thromboembolism is anticaogulation (and in some cases thrombolytic therapy), such treatment has significant bleeding potential, is associated with thrombus progression in up to 30% of cases, and does not prevent the long-term sequelae of the postthrombotic syndrome, leg pain and swelling. Thus, current treatment for venous thromboembolism does not result in optimal outcomes. We and others have demonstrated that a significant inflammatory response occurs with venous thromboembolism and that this inflammation has great influence over both thrombosis and vein wall fibrosis. Specifically, P-selectin and its ligand receptor PSGL-1, 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 produce smaller thrombi. Although the role of VWF in venous thromboembolism is unclear, venous thrombogenesis is influenced both by platelet and leukocyte adhesion and interactions between these elements, interactions which are largely mediated by VWF. The current proposal addresses the role of VWF and P-selectin in basic studies in rodent models of venous thrombosis, evaluates new aptamer inhibitors to VWF and P-selectin in a well established primate model of iliac vein thrombosis, and evaluates biomarkers based on VWF and P- selectin for the diagnosis and follow-up of venous thrombosis in patients. This work will be the basis for eventual clinical application of such agents to the prophylaxis and treatment of venous thromboembolism. At the conclusion of this proposal, we will have defined the role of VWF in venous thrombosis, developed new aptamers to VWF and P-selectin, tested these aptamers in models of venous thrombosis, and determined the clinical value of new biomarkers.

Public Health Relevance

This proposal will determine the role of VWF and P-selectin in venous thrombosis in various animal models and in patients. We will also develop new agents to target these molecules for the prevention and treatment of venous thrombosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-W (S1))
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Link, Rebecca P
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Diaz, Jose A; Wrobleski, Shirley K; Alvarado, Christine M et al. (2015) P-selectin inhibition therapeutically promotes thrombus resolution and prevents vein wall fibrosis better than enoxaparin and an inhibitor to von Willebrand factor. Arterioscler Thromb Vasc Biol 35:829-37
Martinod, Kimberly; Wagner, Denisa D (2014) Thrombosis: tangled up in NETs. Blood 123:2768-76
Diaz, J A; Fuchs, T A; Jackson, T O et al. (2013) Plasma DNA is Elevated in Patients with Deep Vein Thrombosis. J Vasc Surg Venous Lymphat Disord 1:
Martinod, Kimberly; Demers, Melanie; Fuchs, Tobias A et al. (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci U S A 110:8674-9
Brill, A; Suidan, G L; Wagner, D D (2013) Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice. J Thromb Haemost 11:1773-5
Duerschmied, Daniel; Suidan, Georgette L; Demers, Melanie et al. (2013) Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 121:1008-15
Vandy, Frank C; Stabler, Cathy; Eliassen, Anna M et al. (2013) Soluble P-selectin for the diagnosis of lower extremity deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 1:117-1125
Brill, A; Fuchs, T A; Savchenko, A S et al. (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136-44
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
Fuchs, Tobias A; Brill, Alexander; Wagner, Denisa D (2012) Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol 32:1777-83

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