Kevin S Baker1,2, Anna K Kopec2,3, Asmita Pant3, Lauren G Poole3, Holly Cline-Fedewa3, Dora Ivkovich3, Mojtaba Olyaee4, Benjamin L Woolbright5, Adam Miszta6, Hartmut Jaeschke5, Alisa S Wolberg6, James P Luyendyk1,2,3. 1. From the Department of Pharmacology and Toxicology (K.S.B., J.P.L.), Michigan State University, East Lansing. 2. Institute for Integrative Toxicology (K.S.B., A.K.K., J.P.L.), Michigan State University, East Lansing. 3. Department of Pathobiology and Diagnostic Investigation (A.K.K., A.P. L.G.P., H.C.-F., D.I., J.P.L.), Michigan State University, East Lansing. 4. Division of Gastroenterology/Hepatology (M.O.), University of Kansas Medical Center, Kansas City. 5. Department of Pharmacology, Toxicology and Therapeutics (B.L.W., H.J.), University of Kansas Medical Center, Kansas City. 6. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (A.M., A.S.W.).
Abstract
OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestatic patients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acid glycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.
OBJECTIVE: Regulation of TF (tissue factor):FVIIa (coagulation factor VIIa) complex procoagulant activity is especially critical in tissues where plasma can contact TF-expressing cells. One example is the liver, where hepatocytes are routinely exposed to plasma because of the fenestrated sinusoidal endothelium. Although liver-associated TF contributes to coagulation, the mechanisms controlling the TF:FVIIa complex activity in this tissue are not known. Approach and Results: Common bile duct ligation in mice triggered rapid hepatocyte TF-dependent intrahepatic coagulation coincident with increased plasma bile acids, which occurred at a time before observable liver damage. Similarly, plasma TAT (thrombin-antithrombin) levels increased in cholestaticpatients without concurrent hepatocellular injury. Pathologically relevant concentrations of the bile acidglycochenodeoxycholic acid rapidly increased hepatocyte TF-dependent procoagulant activity in vitro, independent of de novo TF synthesis and necrotic or apoptotic cell death. Glycochenodeoxycholic acid increased hepatocyte TF activity even in the presence of the phosphatidylserine-blocking protein lactadherin. Interestingly, glycochenodeoxycholic acid and taurochenodeoxycholic acid increased the procoagulant activity of the TF:FVIIa complex relipidated in unilamellar phosphatidylcholine vesicles, which was linked to an apparent decrease in the Km for FX (coagulation factor X). Notably, the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate, a bile acid structural analog, did not increase relipidated TF:FVIIa activity. Bile acids directly enhanced factor X activation by recombinant soluble TF:FVIIa complex but had no effect on FVIIa alone. CONCLUSIONS: The results indicate that bile acids directly accelerate TF:FVIIa-driven coagulation reactions, suggesting a novel mechanism whereby elevation in a physiological mediator can directly increase TF:FVIIa procoagulant activity.
Authors: S M Wiener; R F Hoyt; J R Deleonardis; R R Clevenger; K R Jeffries; K Nagashima; M Mandel; J Owens; M Eckhaus; R J Lutz; B Safer Journal: Am J Physiol Gastrointest Liver Physiol Date: 2000-07 Impact factor: 4.052
Authors: Jasimuddin Ahamed; Henri H Versteeg; Marjolein Kerver; Vivien M Chen; Barbara M Mueller; Philip J Hogg; Wolfram Ruf Journal: Proc Natl Acad Sci U S A Date: 2006-09-07 Impact factor: 11.205
Authors: Martin Wagner; Peter Fickert; Gernot Zollner; Andrea Fuchsbichler; Dagmar Silbert; Oleksiy Tsybrovskyy; Kurt Zatloukal; Grace L Guo; John D Schuetz; Frank J Gonzalez; Hanns-Ulrich Marschall; Helmut Denk; Michael Trauner Journal: Gastroenterology Date: 2003-09 Impact factor: 22.682