Structural biology of factor VIIa/tissue factor initiated coagulation

Abstract

Factor VII (FVII) consists of an N-terminal gamma-carboxyglutamic acid domain followed by two epidermal growth factor-like (EGF1 and EGF2) domains and the C-terminal protease domain. Activation of FVII results in a two-chain FVIIa molecule consisting of a light chain (Gla-EGF1-EGF2 domains) and a heavy chain (protease domain) held together by a single disulfide bond. During coagulation, the complex of tissue factor (TF, a transmembrane glycoprotein) and FVIIa activates factor IX (FIX) and factor X (FX). FVIIa is structurally “zymogen-like” and when bound to TF, it is more “active enzyme-like.” FIX and FX share structural homology with FVII. Three structural biology aspects of FVIIa/TF are presented in this review. One, regions in soluble TF (sTF) that interact with FVIIa as well as mapping of Ca2+, Mg2+, Na+ and Zn2+ sites in FVIIa and their functions; two, modeled interactive regions of Gla and EGF1 domains of FXa and FIXa with FVIIa/sTF; and three, incompletely formed oxyanion hole in FVIIa/sTF and its induction by substrate/inhibitor. Finally, an overview of the recognition elements in TF pathway inhibitor is provided.

Statins as Antithrombotic Drugs

“…Specifically, they demonstrated that fluvastatin dose-dependently inhibits activity of tissue factor (TF), a glycoprotein that converts factor X to factor Xa, 7 and suggested that downexpression of geranylgeranylated protein is implicated in TF lowering. These data were confirmed in patients affected by polygenic hypercholesterolemia 8 in whom simvastatin 20 mg/d for 8 weeks resulted in downregulation of TF antigen and activity and thrombin generation.…”

Pharmacology of Heparin and Related Drugs

“…It is the major inhibitor of the extrinsic pathway (Vadivel and Bajaj, 2012;Ellery and Adams, 2014) and is the subject of recent reviews (Adams, 2012;Ellery and Adams, 2014). The heparin-binding isoform TFPIa consists of an acidic N-terminal region, three Kunitz tandem domains, and a basic C-terminal end (Bajaj et al, 2001).…”

Tumor-derived tissue factor–positive microparticles and venous thrombosis in cancer patients

“…11 Tissue factor (TF) is a transmembrane receptor that binds plasma factor VII/VIIa and triggers blood coagulation after vascular injury and in various diseases. [12][13][14][15][16][17] TF is expressed by many cancer cells, particularly in cancers of epithelial origin. [18][19][20] Cancer cells also spontaneously release small membrane microparticles (MPs) bearing TF.…”