Heal, SL, Hardy, LJ, Wilson, CL et al. (4 more authors) (2022) Novel interaction of properdin and coagulation factor XI: Crosstalk between complement and coagulation. Research and Practice in Thrombosis and Haemostasis, 6 (4). e12715. ISSN 2475-0379
Abstract
Background
Evidence of crosstalk between the complement and coagulation cascades exists, and dysregulation of either pathway can lead to serious thromboinflammatory events. Both the intrinsic pathway of coagulation and the alternative pathway of complement interact with anionic surfaces, such as glycosaminoglycans. Hitherto, there is no evidence for a direct interaction of properdin (factor P [FP]), the only known positive regulator of complement, with coagulation factor XI (FXI) or activated FXI (FXIa).
Objectives
The aim was to investigate crosstalk between FP and the intrinsic pathway and the potential downstream consequences.
Methods
Chromogenic assays were established to characterize autoactivation of FXI in the presence of dextran sulfate (DXS), enzyme kinetics of FXIa, and the downstream effects of FP on intrinsic pathway activity. Substrate specificity changes were investigated using SDS-PAGE and liquid chromatography–mass spectrometry (LC-MS). Surface plasmon resonance (SPR) was used to determine direct binding between FP and FXIa.
Results/Conclusions
We identified a novel interaction of FP with FXIa resulting in functional consequences. FP reduces activity of autoactivated FXIa toward S-2288. FXIa can cleave FP in the presence of DXS, demonstrated using SDS-PAGE, and confirmed by LC-MS. FXIa can cleave factor IX (FIX) and FP in the presence of DXS, determined by SDS-PAGE. DXS alone modulates FXIa activity, and this effect is further modulated by FP. We demonstrate that FXI and FXIa bind to FP with high affinity. Furthermore, FX activation downstream of FXIa cleavage of FIX is modulated by FP. These findings suggest a novel intercommunication between complement and coagulation pathways.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | coagulation factor, complement, complement system, enzyme kinetics, factor XI (FXI), polyanion, properdin (FP), substrate specificity, surface plasmon resonance (SPR) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation PG/16/6/31941 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Jun 2022 14:46 |
Last Modified: | 30 Jun 2022 14:46 |
Status: | Published |
Publisher: | Wiley Open Access |
Identification Number: | 10.1002/rth2.12715 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:188276 |