title: Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.
abstract: BACKGROUND
  Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin.
  
  
  RESULTS
  Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma.
  
  
  CONCLUSIONS
  Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.
authors.affiliation: Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.|Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Cristina
authors.initials: C
authors.lastname: Puy
authors.affiliation: Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.|Aronora, Inc, Portland, Oregon, United States of America.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.affiliation: Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Ivanov
authors.affiliation: Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Gailani
authors.affiliation: Biochemistry Department, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Biochemistry Department, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: James H
authors.initials: JH
authors.lastname: Morrissey
authors.affiliation: Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.|Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.|Aronora, Inc, Portland, Oregon, United States of America.
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.affiliation: Departments of Biomedical Engineering Oregon Health & Science University, Portland, Oregon, United States of America.|Division of Hematology and Medical Oncology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.|Department of Cell, Developmental and Cancer Biology Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D015942:Factor VIIa / Q000378:metabolism; D015945:Factor XIa / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011122:Polyphosphates / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D013925:Thromboplastin / Q000378:metabolism; D015032:Zinc / Q000737:chemistry
chemical_list: D008074:Lipoproteins; D011122:Polyphosphates; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D015942:Factor VIIa; D015945:Factor XIa; D015032:Zinc