title: Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor.
abstract: Activation of coagulation factor XI (FXI) may play a role in hemostasis. The primary substrate of activated FXI (FXIa) is FIX, leading to FX activation (FXa) and thrombin generation. However, recent studies suggest the hemostatic role of FXI may not be restricted to the activation of FIX. We explored whether FXI could interact with and inhibit the activity of tissue factor pathway inhibitor (TFPI). TFPI is an essential reversible inhibitor of activated factor X (FXa) and also inhibits the FVIIa-TF complex. We found that FXIa neutralized both endothelium- and platelet-derived TFPI by cleaving the protein between the Kunitz (K) 1 and K2 domains (Lys86/Thr87) and at the active sites of the K2 (Arg107/Gly108) and K3 (Arg199/Ala200) domains. Addition of FXIa to plasma was able to reverse the ability of TFPI to prolong TF-initiated clotting times in FXI- or FIX-deficient plasma, as well as FXa-initiated clotting times in FX-deficient plasma. Treatment of cultured endothelial cells with FXIa increased the generation of FXa and promoted TF-dependent fibrin formation in recalcified plasma. Together, these results suggest that the hemostatic role of FXIa may be attributed not only to activation of FIX but also to promoting the extrinsic pathway of thrombin generation through inactivation of TFPI.
authors.affiliation: Department of Biomedical Engineering and Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR;
authors.forename: Cristina
authors.initials: C
authors.lastname: Puy
authors.affiliation: Department of Biomedical Engineering and Aronora, Inc., Portland, OR;
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.affiliation: Department of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Anton
authors.initials: A
authors.lastname: Matafonov
authors.affiliation: Department of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Qiufang
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Research Department, Shriners Hospitals for Children, Portland, OR; and.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Zientek
authors.affiliation: Department of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, TN;
authors.forename: Dave
authors.initials: D
authors.lastname: Gailani
authors.affiliation: Department of Biomedical Engineering and Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR; Aronora, Inc., Portland, OR;
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Department of Biomedical Engineering and Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, OR; Cell & Developmental Biology, School of Medicine, Oregon Health & Science University, Portland, OR.
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D005164:Factor IX / Q000378:metabolism*; D015945:Factor XIa / Q000378:metabolism*; D015951:Factor Xa / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism*; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005164:Factor IX; D005337:Fibrin; D015945:Factor XIa; D015951:Factor Xa