Abstract Number: PB0410
Meeting: ISTH 2020 Congress
Background: A lack of understanding of the interactions between complement and coagulation means that existing mechanisms are often overlooked. Serious thrombo-inflammatory events can occur when these cascades become dysregulated. Components of the contact activation pathway of coagulation and the alternative pathway of complement both interact with polyanionic surfaces, thus we proposed that an interaction between the two pathways may exist.
Aims: To determine if a surface dependent interaction may occur between coagulation factor (F)XI and its activated form, FXIa, and the positive regulator of complement, properdin.
Methods: Surface plasmon resonance (SPR) was employed to determine binding characteristics between immobilised properdin, and injected FXI(a). Chromogenic assays were optimised to investigate several mechanisms: autoactivation of FXI in the presence of properdin, the effect of properdin on the catalytic activity of FXIa, and the inhibition profile of the serpin C1 esterase inhibitor (C1-INH) on FXIa with and without properdin, all in the in the presence and absence of high-molecular weight (500 kDa) dextran sulfate (DXS500kDa). SDS-PAGE was used to analyse substrate specificity assays and mass spectrometry (MS) was utilised for band analysis.
Results: Properdin binds to FXI and FXIa with high affinity and properdin appears to inhibit the autoactivation of FXI by DXS500kDa. DXS500kDa inhibits FXIa through an uncompetitive mechanism and this study has shown that this is partially reversed by properdin. Incubation of FXIa, DXS500kDa and properdin revealed unknown bands assessed by SDS-PAGE and were identified as properdin cleavage products by MS, suggesting FXIa was able to cleave properdin in the presence of DXS500kDa, indicating a substrate specificity change of FXIa. Inhibition of FXIa by C1-INH in the presence of DXS500kDa is reversed by properdin.
Conclusions: These findings suggest a novel regulatory mechanism of the alternative pathway of complement and the contact pathway of the coagulation cascade, influenced by the presence of a polyanionic surface.
To cite this abstract in AMA style:Heal SL, Hardy LJ, Wilson C, Ali M, Ariëns R, Foster R, Philippou H. A novel Interaction between Coagulation Factor XI and its Activated Form, FXIa, with the Complement Protein Properdin [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/a-novel-interaction-between-coagulation-factor-xi-and-its-activated-form-fxia-with-the-complement-protein-properdin/. Accessed March 3, 2021.
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