Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases.

Abstract

Coagulation factor XII (FXII, Hageman factor) is a plasma protease that in its active form (FXIIa) initiates the procoagulant and proinflammatory contact system. This name arises from FXII's unique mechanism of activation that is induced by binding (contact) to negatively charged surfaces. Various substances have the capacity to trigger FXII contact-activation in vivo including mast cell-derived heparin, misfolded protein aggregates, collagen, nucleic acids, and polyphosphate. FXII deficiency is not associated with bleeding, and for decades, the factor was considered to be dispensable for coagulation in vivo. However, despite the fact that humans and animals with deficiency in FXII have a normal hemostatic capacity, animal models revealed a critical role of FXIIa-driven coagulation in thromboembolic diseases. In addition to its role in thrombosis, FXIIa contributes to inflammation through the activation of the inflammatory bradykinin-producing kallikrein-kinin system. Pharmacological inhibition of FXII/FXIIa interferes with thrombosis and inflammation in animal models. Thus, targeting the FXIIa-driven contact system seems to be a promising and safe therapeutic anticoagulation treatment strategy, with additional anti-inflammatory effects. Here, we discuss novel functions of FXIIa in cardiovascular thrombotic and inflammatory disorders.

• Authors: Katrin F Nickel, Andy T Long, Tobias A Fuchs, Lynn M Butler, Thomas Renné
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 37 Issue 1 Pg. 13-20 (01 2017) ISSN: 1524-4636 [Electronic] United States
• PMID: 27834692 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Heart Association, Inc.

Chemical References

• Anti-Inflammatory Agents
• Fibrinolytic Agents
• Inflammation Mediators
• Factor XII
• Factor XIIa

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Blood Coagulation (drug effects)
• Disease Models, Animal
• Factor XII (antagonists & inhibitors, genetics, metabolism)
• Factor XIIa (antagonists & inhibitors, metabolism)
• Fibrinolytic Agents (therapeutic use)
• Genetic Predisposition to Disease
• Humans
• Inflammation (blood, drug therapy, genetics, immunology)
• Inflammation Mediators (antagonists & inhibitors, blood)
• Kallikrein-Kinin System (drug effects)
• Mice, Knockout
• Molecular Targeted Therapy
• Thromboembolism (blood, drug therapy, genetics, immunology)