Venous thrombosis (VT) is a national health concern, occurring at a constant rate over the past 20 years, with an annual incidence of at least 250,000 cases. It is estimated that deep venous thrombosis and pulmonary embolism are associated with approximately 300,000 to 600,000 hospitalizations and as many as 50,000 deaths per year. Chronic venous insufficiency, the sequela of venous thrombosis, affects approximately 400,000 to 500,000 patients with skin ulceration, 6 to 7 million patients with skin stasis changes, and up to 28 percent of patients with significant iliofemoral DVT over time will develop severe edema and skin changes which may lead to venous ulceration. VT in short costs the health system billions of dollars. Selectins are mucin like glycoprotein cell adhesion molecules that are expressed by activated endothelial cells and platelets and mediate leukocyte-platelet, leukocyte-endothelial cell, and leukocyte-leukocyte interactions. Preliminary data suggest that P-selectin is temporally related to the initiation and maintenance of the inflammatory and thrombotic response associated with VT. Our research hypotheses include: P-selectin is casually related to VT inflammation and thrombosis amplification; inhibition of P-selectin alone or augmented with other agents will decrease inflammation and thrombosis without systemic anticoagulant complications; and P-selectin inhibition will stimulate thrombolysis of thrombus that does form, augmenting other fibrinolytic agents. We will address these hypotheses with three specific aims:
Specific Aim 1 : To determine if the mechanism of inflammation associated with venous thrombosis involves P-selectin. This will be investigated using genetically altered mice which express high levels of circulating soluble P-selectin, and the effect of blocking the excess soluble P-selectin. They will then be contrasted to wild type mice administered soluble P-selectin, and mice genetically lacking P- selectin.
Specific Aim 2 : To assess P-selectin inhibition and to test the efficacy of other antithrombotic agents for VT treatment, agents with different mechanisms of action including inhibition of factor Xa and direct thrombin inhibition. Additionally, to combine agents to determine which agent or agents offer the best treatment for VT without anticoagulant activity.
Specific Aim 3 : To determine if direct P-selectin inhibition augments both spontaneous and pharmacologically induced thrombolysis and specifically to determine if P-selectin inhibition impairs fibrin deposition or increases fibrinolysis. These studies will define the role of P-selectin in VT pathogenesis, treatment and thrombolysis.
|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|
|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|
|Ramacciotti, Eduardo; Hawley, Angela E; Farris, Diana M et al. (2009) Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 101:748-54|
|Wakefield, Thomas W; Myers, Daniel D; Henke, Peter K (2009) Role of selectins and fibrinolysis in VTE. Thromb Res 123 Suppl 4:S35-40|
|Schmaier, Alvin H (2008) The elusive physiologic role of Factor XII. J Clin Invest 118:3006-9|
Showing the most recent 10 out of 16 publications