Title: Direct Amplification of Tissue Factor:Factor VIIa Procoagulant Activity by Bile Acids Drives Intrahepatic Coagulation.

Authors: Baker, Kevin S; Kopec, Anna K; Pant, Asmita; Poole, Lauren G; Cline-Fedewa, Holly; Ivkovich, Dora; Olyaee, Mojtaba; Woolbright, Benjamin L; Miszta, Adam; Jaeschke, Hartmut; Wolberg, Alisa S; Luyendyk, James P

Published In Arterioscler Thromb Vasc Biol, (2019 10)

Abstract: 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.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.

PubMed ID: 31412737

MeSH Terms: Animals; Bile Acids and Salts/metabolism; Bile Ducts/surgery*; Blood Coagulation Disorders/physiopathology; Blood Coagulation Tests; Blood Coagulation/physiology; Cells, Cultured; Cholestasis, Intrahepatic/metabolism*; Cholestasis, Intrahepatic/physiopathology*; Disease Models, Animal; Factor VIIa/metabolism*; Factor X/metabolism*; Hepatocytes/metabolism; Humans; Kinetics; Ligation/methods; Mice; Mice, Inbred C57BL; Phosphatidylserines/metabolism; Random Allocation