Presentation Abstract

Session: APS.709.03-Vascular Wall, Plasma Markers and Leukocytes Driving Thrombosis
Presentation: 14215 - A Novel Thrombin Interacting Partner Emerges in Heart Failure
Pres Time: Sunday, Nov 13, 2011, 9:30 AM -11:00 AM
Location: West Hall A1, Core 7, Poster Board: 7075
Pres. Time: Sunday, Nov 13, 2011, 9:30 AM -11:00 AM
Specialty: +709. Hemostasis, Thrombosis and Fibrinolysis
Keywords: Heart failure; Endothelium; Thrombin
Authors: Jill M. Gelow, Michael J. Hayes, Rachael M. Andrie, Wohaib Hasan, David J. Sahn, Oregon Health and Sciences Univ, Portland, OR; Charles T. Esmon, Oklahoma Medical Res Fndn, Oklahoma City, OK; Antony Y. Kim, Oregon Health and Sciences Univ, Portland, OR
Abstract: Introduction: Heart failure (HF) is a prothrombotic state that increases the risk for thromboembolic events. Thrombomodulin (TM) is an endothelial membrane protein that, in complex with thrombin, activates protein C, a potent anticoagulant. We previously demonstrated that left ventricular (LV) endocardial activated protein C (APC) generating capacity is increased in a murine model of HF, despite marked reduction of TM protein expression. Given the discrepancy between increased APC generation and decreased TM protein expression, we hypothesized that an alternate pathway for PC activation emerges in HF.
Methods: Using the CREBA133 murine model of chronic HF, we examined LV endocardial thromboresistance in mice with severe HF and non-transgenic littermate controls. CREB with severe HF were identified by phenotype and echocardiography. LV endocardial TM mRNA expression was analyzed using qPCR. APC generating capacity was measured directly on the surface of intact LV endocardium with an ex vivo chromogenic assay in the presence and absence of a direct thrombin inhibitor (PPACK-thrombin) and an anti-TM antibody.
Results: CREB with severe HF exhibit massive edema, labored breathing, lethargy, hepatic congestion, ventricular enlargement and markedly decreased LV function. TM gene expression was mildly increased in CREB with severe HF relative to controls (Fold change: 2.1±0.5 vs 0.8±0.1; p=0.1). The capacity of the LV endocardium to generate APC in CREB with severe HF was abrogated in the presence of PPACK-thrombin (398±57 vs 14±0.4 nM/cm2; p=0.001). As expected, APC activity was significantly decreased in the presence of anti-TM antibody in controls (165±26 vs 331±42 nM/cm2; p=0.04). However, in CREB with severe HF, APC activity was unchanged in the presence of an anti-TM antibody suggesting APC activation independent of TM.
Conclusions: HF augments the ability of the LV endocardium to generate APC despite marked reduction in TM protein expression. APC generation in HF is thrombin-dependent but TM-independent, suggesting the emergence of a novel thrombin interacting partner in HF. Improved understanding of the APC pathway and identification of a new thrombin partner in HF may translate to novel therapies that mitigate thromboembolic risk.
Disclosures:  J.M. Gelow: None. M.J. Hayes: None. R.M. Andrie: None. W. Hasan: None. D.J. Sahn: None. C.T. Esmon: None. A.Y. Kim: None.



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