Microparticle-associated tissue factor activity is reduced by inhibition of the complement protein 5 in Neisseria meningitidis-exposed whole blood.
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.
Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway reidun.ovstebo@ous-hf.no.
Reidun
R
Øvstebø
Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway.
Marit
M
Hellum
Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Hans Christian D
HC
Aass
Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Anne M
AM
Trøseid
Department of Pediatrics, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway.
Petter
P
Brandtzaeg
Department of Immunology, Oslo University Hospital, Oslo, Norway Institute of Clinical Medicine, University of Oslo, Norway.
Tom E
TE
Mollnes
Blood Cell Research Group, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Carola E
CE
Henriksson
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000276:immunology; D055252:Cell-Derived Microparticles / Q000276:immunology*; D003167:Complement Activation / Q000187:drug effects; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000276:immunology*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D008589:Meningococcal Infections / Q000097:blood*; D009345:Neisseria meningitidis; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000276:immunology / Q000382:microbiology; D013925:Thromboplastin / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D000925:Anticoagulants; D003182:Complement C5; D006629:Hirudins; D011994:Recombinant Proteins; D013925:Thromboplastin; C481642:eculizumab; C083544:lepirudin
Neisseria meningitidis; TF activity; coagulation cascade; complement cascade; microparticles; monocytes