title: The role of activated coagulation factor XII in overall clot stability and fibrinolysis.
abstract: Activated coagulation factor XII (α-FXIIa) is able to bind to fibrin(ogen) and increases the density and stiffness of the fibrin clot. Conversely, proteins of the contact system and the fibrinolytic system show a high degree of homology and α-FXIIa can convert plasminogen into plasmin resulting in fibrin degradation. Therefore, we studied the contribution of α-FXIIa to overall clot stability and plasmin driven fibrinolysis in the absence and presence of tissue plasminogen activator (tPA). We observed that α-FXIIa directly converted plasminogen into plasmin and reduced clot lysis time at all tPA concentrations tested (15-1500 pM). Simultaneous assessment of plasmin generation (chromogenic substrate S-2251) and fibrin formation and degradation (absorbance at 405nm), showed an earlier onset of fibrinolysis and plasmin formation in the presence of α-FXIIa. Fibrinolysis of clots formed under flow conditions, revealed that incorporation of α-FXIIa accelerated clot breakdown (fluorescence release of labeled fibrin) by additional plasmin generation on top of formation by tPA. Scanning electron microscopy (SEM) revealed that the surface area pore size increased in the presence compared with the absence of α-FXIIa when fibrinolysis was initiated by the conversion of plasminogen with tPA during clot formation. α-FXIIa enhances fibrinolysis in the presence of plasminogen, irrespective of whether tPA was present during clot formation or was added afterwards to initiate fibrinolysis. We postulate that FXIIa first strengthens the clot structure during clot formation and thereafter contributes towards fibrinolysis.
authors.affiliation: Division of Clinical Thrombosis and Haemostasis, Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands; Departments of Biochemistry and Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
authors.forename: Joke
authors.initials: J
authors.lastname: Konings
authors.affiliation: Division of Clinical Thrombosis and Haemostasis, Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Hoving
authors.affiliation: Division of Cardiovascular and Diabetes Research, Theme Thrombosis, Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ariëns
authors.affiliation: Division of Cardiovascular and Diabetes Research, Theme Thrombosis, Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Hethershaw
authors.affiliation: Departments of Biochemistry and Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
authors.forename: Marisa
authors.initials: M
authors.lastname: Ninivaggi
authors.affiliation: Division of Cardiovascular and Diabetes Research, Theme Thrombosis, Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Hardy
authors.affiliation: Departments of Biochemistry and Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: de Laat
authors.affiliation: Division of Clinical Thrombosis and Haemostasis, Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.affiliation: Division of Cardiovascular and Diabetes Research, Theme Thrombosis, Faculty of Medicine and Health, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.affiliation: Division of Clinical Thrombosis and Haemostasis, Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address: j.govers@maastrichtuniversity.nl.
authors.forename: José W P
authors.initials: JW
authors.lastname: Govers-Riemslag
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D015956:Factor XIIa / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D014914:Whole Blood Coagulation Time
chemical_list: D015956:Factor XIIa; D005341:Fibrinolysin
keywords: Blood coagulation; Clot structure; Coagulation factor XII; Fibrin(ogen); Fibrinolysis; Tissue plasminogen activator (tPA)