Abstract Number: PB1785
Meeting: ISTH 2020 Congress
Background: Complement factor H (CFH) is the major inhibitor of the alternative pathway of the complement system and is structurally related to B2-GPI, which itself is known to bind to ligands including factor XI (FXI). We observed reduced complement activation when FXI activation was inhibited in a baboon model of sepsis, suggesting crosstalk between FXI and the complement cascade. While interaction of the complement system with other contact activation enzymes, FXIIa or kallikrein, has been demonstrated, it is unknown whether FXIa directly interacts with complement.
Aims: FXIa promotes complement activation by neutralizing CFH.
Methods: Recombinant CFH was incubated with FXIa for increasing times before being analyzed by Western blot and aminoterminal sequencing. CFH cofactor activity was evaluated by measuring the cleavage of C3b by factor I (FI) and the lysis of sheep red blood cells (RBCs). Binding of CFH to endothelial cells (ECs) was measured using a cell surface immunoassay. FXI activation by FXIIa or thrombin was evaluated using a FXIa chromogenic assay.
Results: Incubation of CFH with FXIa reduced the capacity of CFH to enhance the cleavage of C3b by FI. FXIa enhanced hemolysis in the presence of CFH. The binding of CFH to ECs was reduced after incubating CFH with FXIa. FXIa neutralized CFH by cleavage of the Arg341/Arg342 bonds at the end of complement control protein (CCP) 6 domain. The addition of polyP enhanced the capacity of FXIa to cleave CFH. FXIa cleaved CFH that was bound to the surface of ECs, and inhibited FXI activation by either thrombin or FXIIa.
Conclusions: Our study provides a novel molecular link between the contact pathway of coagulation and the complement system. These results suggest that FXIa generation enhances the efficiency of the complement system, thus, may support the immune system.
To cite this abstract in AMA style:Puy C, Keshari RS, Lorentz C, Tucker E, Morrissey J, Smith S, Gailani D, Gruber A, Lupu F, McCarty O. Activated Factor XI Promotes Complement Activation by Neutralizing Complement Factor H [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/activated-factor-xi-promotes-complement-activation-by-neutralizing-complement-factor-h/. Accessed January 26, 2022.
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