Imperial College London
Alternate

ProfessorJimCrawley

Faculty of Medicine, Department of Immunology and Inflammation

Professor of Haemostasis
 
 
 
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Contact

 

+44 (0)20 3313 2297j.crawley Website

 
 
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Location

 

5S5aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Santamaria:2017:10.1074/jbc.M116.769570,
author = {Santamaria, S and Regliska-Matveyev, N and Gierula, M and Camire, RM and Crawley, JTB and Lane, DA and Ahnström, J},
doi = {10.1074/jbc.M116.769570},
journal = {Journal of Biological Chemistry},
pages = {9335--9344},
title = {Factor V anticoagulant cofactor activity that targets the early phase of coagulation},
url = {http://dx.doi.org/10.1074/jbc.M116.769570},
volume = {292},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Tissue factor pathway inhibitor (TFPI), the main inhibitor of initiation of coagulation, exerts an important anticoagulant role through the factor Xa (FXa)-dependent inhibition of tissue factor/factor VIIa (FVIIa). Protein S is a TFPI cofactor, enhancing the efficiency of FXa inhibition. TFPI can also inhibit prothrombinase assembly by directly interacting with coagulation factor V (FV) which has been activated by FXa. Since full-length TFPI associates with FV in plasma, we hypothesized that FV may influence TFPI inhibitory function. Using pure component FXa inhibition assays, we found that while FV alone did not influence TFPI-mediated FXa inhibition, it further enhanced TFPI in the presence of protein S, resulting in an ~8-fold reduction in Ki compared with TFPI alone. A FV variant (R709Q/R1018Q/R1545Q, FVΔIIa) that cannot be cleaved/activated by thrombin or FXa, also enhanced TFPI-mediated inhibition of FXa ~12-fold in the presence of protein S. In contrast, neither activated FV (FVa) nor recombinant B-domain-deleted FV could enhance TFPI-mediated inhibition of FXa in the presence of protein S, suggesting a functional contribution of the B domain. Using TFPI and protein S variants we show further that the enhancement of TFPI-mediated FXa inhibition by protein S and FV depends on a direct protein S/TFPI interaction and that the TFPI C-terminal tail is not essential for this enhancement. In FXa-catalyzed prothrombin activation assays, both FV and FVΔIIa (but not FVa) enhanced TFPI function in the presence of protein S. These results demonstrate a new anticoagulant (cofactor) function of FV that targets the early phase of coagulation before prothrombinase assembly.
AU  - Santamaria,S
AU  - Regliska-Matveyev,N
AU  - Gierula,M
AU  - Camire,RM
AU  - Crawley,JTB
AU  - Lane,DA
AU  - Ahnström,J
DO  - 10.1074/jbc.M116.769570
EP  - 9344
PY  - 2017///
SN  - 0021-9258
SP  - 9335
TI  - Factor V anticoagulant cofactor activity that targets the early phase of coagulation
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1074/jbc.M116.769570
UR  - http://www.ncbi.nlm.nih.gov/pubmed/28420729
UR  - http://hdl.handle.net/10044/1/49754
VL  - 292
ER  -
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