Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases.
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.
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F., L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.). k.nickel@uke.de.
Katrin F
KF
Nickel
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F., L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.).
Andy T
AT
Long
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F., L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.).
Tobias A
TA
Fuchs
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F., L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.).
Lynn M
LM
Butler
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F., L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.).
Thomas
T
Renné
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004195:Disease Models, Animal; D005174:Factor XII / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015956:Factor XIIa / Q000037:antagonists & inhibitors / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000097:blood; D016234:Kallikrein-Kinin System / Q000187:drug effects*; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D013923:Thromboembolism / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology
D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D018836:Inflammation Mediators; D005174:Factor XII; D015956:Factor XIIa
blood coagulation; factor XII; inflammation; reperfusion injury; therapy; thrombosis