Abstract
Neisseria meningitidis causes fulminant meningococcal sepsis with a massive activation of the coagulation and complement cascades. Bacterial cell envelope molecules from N. meningitidis, particularly lipopolysaccharide (LPS), induce tissue factor (TF) expression. In meningococcal sepsis, TF can be detected on circulating monocytes and microparticles (MPs) within the bloodstream. During infection, Nm activates C5 and C5a, which also is able to induce TF. We evaluated the effect of eculizumab, a C5-blocking monoclonal antibodies (mAb), on cell- and MP-associated TF. Using a lepirudin-anticoagulated whole blood model, we activated the coagulation and complement cascades by N. meningitidis, and investigated the interaction between the cascade systems with special focus on cell-associated TF-expression (mRNA and protein) and MP-associated TF-dependent thrombin and fibrin generation in platelet-free plasma. We also examined the ability of TF-positive MPs to support clot formation in whole blood. In addition, the effect of corn trypsin inhibitor and time-dependent changes on MP-associated functional TF activity was examined. Inhibition of C5 reduced cell-associated TF expression at both gene and protein level, and reduced MP-associated TF-dependent thrombin and fibrin generation in platelet-poor plasma, MP-induced TF-dependent clot formation in whole blood, implying that the complement and coagulation cascades are interplayers in N. meningitidis-mediated activation of these cascades.
Highlights
The Gram-negative bacterium Neisseria meningitidis causes fulminant meningococcal sepsis with a massive inflammatory response induced by activation of the ‘first line of defence’, including the coagulation and complement cascades
MPs released from whole blood exposed to 108/ml N. meningitidis gave a significant shortening of the clotting time (CT) compared with MPs obtained from unexposed whole blood [N. meningitidis-exposed: 74 s Æ 20 s, unexposed: 202 s Æ 22 s (P < 0.001)]
Our findings imply that complement activation plays an important role in N. meningitidis-induced tissue factor (TF) mRNA regulation, and it modulates N. meningitidisinduced TF expression on monocytes and TF activity associated with MPs
Summary
The Gram-negative bacterium Neisseria meningitidis causes fulminant meningococcal sepsis with a massive inflammatory response induced by activation of the ‘first line of defence’, including the coagulation and complement cascades. C5a may represent one of the many potential crosstalk links between the coagulation and the complement systems.[14,16,17] Blocking the C5a receptor in experimental sepsis in rodents significantly improved survival, indicating an important role of complement activation in sepsis.[18] The recombinant mAb eculizumab binds to C5, inhibiting its cleavage by the C5 convertase, thereby preventing the generation of C5a and TCC This Ab has been shown to reduce thrombotic complications in diseases such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.[19,20]
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