title: Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development.
abstract: Expanding evidence indicates multiple interactions between the hemostatic system and innate immunity, and the coagulation and complement cascades. Here we show in a tissue factor (TF)-dependent model of flow restriction-induced venous thrombosis that complement factors make distinct contributions to platelet activation and fibrin deposition. Complement factor 3 (C3) deficiency causes prolonged bleeding, reduced thrombus incidence, thrombus size, fibrin and platelet deposition in the ligated inferior vena cava, and diminished platelet activation in vitro. Initial fibrin deposition at the vessel wall over 6 hours in this model was dependent on protein disulfide isomerase (PDI) and TF expression by myeloid cells, but did not require neutrophil extracellular trap formation involving peptidyl arginine deiminase 4. In contrast to C3-/-mice, C5-deficient mice had no apparent defect in platelet activation in vitro, and vessel wall platelet deposition and initial hemostasis in vivo. However, fibrin formation, the exposure of negatively charged phosphatidylserine (PS) on adherent leukocytes, and clot burden after 48 hours were significantly reduced in C5-/-mice compared with wild-type controls. These results delineate that C3 plays specific roles in platelet activation independent of formation of the terminal complement complex and provide in vivo evidence for contributions of complement-dependent membrane perturbations to prothrombotic TF activation on myeloid cells.
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Saravanan
authors.identifier: 0000-0002-0194-5044
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kerstin
authors.identifier: 0000-0001-5313-4035
authors.initials: K
authors.lastname: Jurk
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Lukas
authors.identifier: 0000-0002-4312-0366
authors.initials: L
authors.lastname: Hobohm
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Jäckel
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Saffarzadeh
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kathrin
authors.identifier: 0000-0002-5435-6382
authors.initials: K
authors.lastname: Schwierczek
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Philip
authors.identifier: 0000-0002-5397-2781
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: II. Medical Clinic and Polyclinic, University Medical Center Eppendorf, Hamburg, Germany; and.
authors.forename: Florian
authors.initials: F
authors.lastname: Langer
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Christoph
authors.identifier: 0000-0001-7002-8533
authors.initials: C
authors.lastname: Reinhardt
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.|Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA.
authors.forename: Wolfram
authors.identifier: 0000-0002-6064-2166
authors.initials: W
authors.lastname: Ruf
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics* / Q000378:metabolism; D003182:Complement C5 / Q000235:genetics* / Q000378:metabolism; D065206:Extracellular Traps / Q000235:genetics / Q000276:immunology; D005337:Fibrin / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006487:Hemostasis / Q000276:immunology*; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D010718:Phosphatidylserines / Q000378:metabolism; D015539:Platelet Activation / Q000276:immunology; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000276:immunology; D000080002:Protein-Arginine Deiminase Type 4; D013925:Thromboplastin / Q000235:genetics / Q000276:immunology; D013927:Thrombosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014682:Vena Cava, Inferior / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D003176:Complement C3; D003182:Complement C5; D010718:Phosphatidylserines; D005337:Fibrin; D013925:Thromboplastin; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse; D019704:Protein Disulfide-Isomerases