The Coagulation Factors Fibrinogen, Thrombin, and Factor XII in Inflammatory Disorders-A Systematic Review

Abstract

Background: The interaction of coagulation factors has been shown to go beyond their traditional roles in hemostasis and to affect the development of inflammatory diseases. Key molecular players, such as fibrinogen, thrombin, or factor XII have been mechanistically and epidemiologically linked to inflammatory disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), and colitis.

Objectives: To systematically review the evidence for a role of coagulation factors, especially factor XII, fibrinogen, and thrombin in inflammatory disorders like MS, RA, and bowel disorders.

Methods: A systematic literature search was done in the PubMed database to identify studies about coagulation factors in inflammatory diseases. Original articles and reviews investigating the role of the kallikrein-kinin and the coagulation system in mouse and humans were included.

Results: We identified 43 animal studies dealing with inflammatory disorders and factors of the kallikrein-kinin or the coagulation system. Different immunological influences are described and novel molecular mechanisms linking coagulation and inflammation are reported.

Conclusion: A number of studies have highlighted coagulation factors to tip the balance between hemostasis and thrombosis and between protection from infection and extensive inflammation. To optimize the treatment of chronic inflammatory disorders by these factors, further studies are necessary.

Keywords: coagulation factors; contact system; factor XII; fibrinogen; neuroinflammation; thrombin.

Figure 1

Overview of the known pathways activated by factor XII (FXII) and the extrinsic coagulation system. Only factors that are involved in inflammation are shown. Activated FXII leads to the cleavage of factor XI, activates the intrinsic, the contact, and complement systems and can bind to CD87. Tissue factor finally leads to the release of thrombin (FIIa) that can directly bind several receptors and activates fibrinogen to fibrin. Deposition of fibrin is regulated by plasmin. Abbreviations: C1-INH, serine protease C1 inhibitor; CD87, urokinase-type plasminogen-activator receptor; tPA, tissue plasminogen activator; PAI-1, plasminogen-activator inhibitor 1; PAR, protease-activated receptor.

Figure 2

Overview of the contact system. Activation of factor XII (FXII) leads to the cleavage of plasma prekallikrein to kallikrein. Kallikrein can activate both the complement factors C3 and C5 and also high-molecular-weight kininogen (HMWK). Abbreviations: B1R, bradykinin 1 receptor; B2R, bradykinin 2 receptor; BK, bradykinin; CPK, creatinine phosphokinase.

Figure 3

Factor XII (FXII) as a mediator of inflammatory disease. FXII acts on dendritic cells through the urokinase-type plasminogen-activator receptor (CD87) to enhance the release of interleukin (IL)-6 and -23. This cytokine shift leads to increased amounts of IL-17A-producing CD4⁺ effector T helper cells (T_H17). Abbreviations: AC, adenylate cyclase; CD11b/CD18, leukocyte integrin adhesion molecule.

Figure 4

Fibrinogen as a mediator of inflammation. Fibrinogen acts on different cells through integrin and non-integrin receptors to induce specific inflammatory effects. Abbreviations: CD11b/CD18, leukocyte integrin adhesion molecule; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; NF-κB, nuclear factor κB; tPA, tissue plasminogen activator; PAI-1, plasminogen-activator inhibitor 1; TNF-α, tumor necrosis factor α.