Dataset Information

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

ABSTRACT:

Introduction

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 (TFPI?), 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 TFPI?, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPI? by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin.

Methods and results

Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPI? proteolysis was analyzed by western blot. TFPI? activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPI? by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPI? by FXIa. TFPI? activity was not affected by SCP in recalcified FXI-depleted plasma.

Conclusions

Our data suggest that SCP is a cofactor for TFPI? inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP.

SUBMITTER: Puy C

PROVIDER: S-EPMC5072614 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

Puy Cristina C Tucker Erik I EI Ivanov Ivan S IS Gailani David D Smith Stephanie A SA Morrissey James H JH Gruber András A McCarty Owen J T OJ

PloS one 20161020 10

<h4>Introduction</h4>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. S ...[more]

PMID: 27764259

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Project description:High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR- 23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI. In the study presented here, we report arrays including 1,898 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 18.0) using total RNA extracted from a healthy human liver sample E122; a Caucasian donor that gave informed consent were provided by biobanc CIBERehd. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia. In the study presented here, we report arrays including 2,019 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 19.0) using total RNA extracted from 3 healthy human liver samples (662, 664, 771) from Caucasian donors that gave informed consent were provided by St. Jude Liver Resource at St. Distribution System and by cooperative Human Tissue Network. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia

Dataset Information

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

Introduction

Methods and results

Conclusions

Publications

Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI.

Similar Datasets

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