title: Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin.
abstract: In the contact activation pathway of the coagulation, zymogen factor XII (FXII) is converted to FXIIa, which triggers activation of FXI leading to the activation of FIX and subsequent thrombin generation and fibrin formation. Feedback activation of FXI by thrombin has been shown to promote thrombin generation in a FXII-independent manner and FXIIa can bypass FXI to directly activate FX and prothrombin in the presence of highly negatively charged molecules, such as long-chain polyphosphates (LC polyP). We sought to determine whether activation of FXII or FXI differentially regulate the physical biology of fibrin formation. Fibrin formation was initiated with tissue factor, ellagic acid (EA), or LC polyP in the presence of inhibitors of FXI and FXII. Our data demonstrated that inhibition of FXI decreased the rate of fibrin formation and fiber network density, and increased the fibrin network strength and rate of fibrinolysis when gelation was initiated via the contact activation pathway with EA. FXII inhibition decreased the fibrin formation and fibrin density, and increased the fibrinolysis rate only when fibrin formation was initiated via the contact activation pathway with LC polyP. Overall, we demonstrate that inhibition of FXI and FXII distinctly alter the biophysical properties of fibrin.
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA. jsylman@gmail.com.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Sylman
authors.affiliation: School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USA.
authors.forename: Uranbileg
authors.initials: U
authors.lastname: Daalkhaijav
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Gray
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Parsa A
authors.initials: PA
authors.lastname: Farhang
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Chu
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Jevgenia
authors.initials: J
authors.lastname: Zilberman-Rudenko
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Puy
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.|Aronora, Inc., Portland, OR, USA.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.affiliation: Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Morrissey
authors.affiliation: School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USA.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Walker
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Xiaolin L
authors.initials: XL
authors.lastname: Nan
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.|Aronora, Inc., Portland, OR, USA.
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Biomedical Engineering, School of Medicine, Oregon Health and Science University, 3303 SW Bond Ave, Portland, OR, 97239, USA.
authors.forename: Owen J T
authors.initials: OJT
authors.lastname: McCarty
mesh_terms: D019774:Blood Coagulation Factor Inhibitors / Q000737:chemistry*; D005172:Factor XI / Q000037:antagonists & inhibitors / Q000737:chemistry; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000737:chemistry; D005337:Fibrin / Q000737:chemistry*; D005342:Fibrinolysis; D006801:Humans; D011122:Polyphosphates / Q000737:chemistry
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D011122:Polyphosphates; D005174:Factor XII; D005337:Fibrin; D005172:Factor XI
keywords: Coagulation; FXI-deficiency; FXII-deficiency; Fibrin; Stability; Structure