The physicochemical properties of lipopolysaccharide chemotypes regulate activation of the contact pathway of blood coagulation.

Abstract

Lipopolysaccharide (LPS) is the primary pathogenic factor in Gram-negative sepsis. While the presence of LPS in the bloodstream during infection is associated with disseminated intravascular coagulation, the mechanistic link between LPS and blood coagulation activation remains ill-defined. The contact pathway of coagulation-a series of biochemical reactions that initiates blood clotting when plasma factors XII (FXII) and XI (FXI), prekallikrein (PK) and high molecular weight kininogen (HK) interact with anionic surfaces-has been shown to be activated in Gram-negative septic patients. In this study, using an in vivo baboon model of Gram-negative Escherichia coli sepsis, we observed activation of the contact pathway including FXII, FXI and PK. We examined whether E.coli LPS molecules could binding and activate contact pathway members by quantifying the interaction and activation of either FXII, FXI, or PK with each of three chemotypes of LPS: O111:B4, O26:B6, or Rd2. The LPS chemotypes exhibited distinct physicochemical properties as aggregates and formed complexes with FXII, FXI and PK. The LPS chemotype O26:B6 uniquely promoted the autoactivation of FXII to FXIIa, and in complex with FXIIa, promoted the cleavage of FXI and prekallikrein to generate FXIa and plasma kallikrein, respectively. Furthermore, in complex with the active forms of FXI or prekallikrein, LPS chemotypes were able to regulate the catalytic activity of FXIa and plasma kallikrein, respectively, despite the inability to promote the autoactivation of either zymogen. These data suggest that the procoagulant phenotype of E.coli is influenced by bacterial strain and the physicochemical properties of the LPS chemotypes.