Novel interaction of properdin and coagulation factor XI: Crosstalk between complement and coagulation

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.

The complement alternative pathway and hemostasis

“…They proposed that the positively charged protein properdin by interacting with surface polyanions may undergo conformational changes, making it more susceptible to cleavage by FXIa. Conversely, in the same study properdin modulated FXa generation downstream of FXI activation by interfering with FIXa cleavage of FX 55 . These findings, although preliminary, raise the possibility that FXIa and properdin may control each other to prevent clot spreading and to modulate inflammation.…”

“…Conversely, in the same study properdin modulated FXa generation downstream of FXI activation by interfering with FIXa cleavage of FX. 55 These findings, although preliminary, raise the possibility that FXIa and properdin may control each other to prevent clot spreading and to modulate inflammation. However, the latter hypothesis is questioned by results of in vivo studies that rather indicate an enhancing effect of FXIa on complement activity and inflammation.…”

“…Heal et al, 55 recently documented that FXI or FXIa binds to properdin with high affinity. FXI is a component of the contact pathway of coagulation, which is initiated when Factor XII is activated on negatively charge molecules.…”

Serum-integrated omics reveal the host response landscape for severe pediatric community-acquired pneumonia

“…Since ~ 50% of platelets are produced in the lungs [ 37 ], these platelets may help to aggravate lung injury and further induce cytokine storm. For example, C4BPB [ 18 ] and F11 [ 19 ] which are regulators of complement system were significantly decreased in S-CAP cases. PROC, which interacts with C4BP [ 20 ], was also downregulated in S-CAPs.…”

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

“…99 Another group recently demonstrated that FXI can also bind another regulator of the alternative complement pathway, properdin. 100…”