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: Saravanan Subramaniam, Kerstin Jurk, Lukas Hobohm, Sven Jäckel, Mona Saffarzadeh, Kathrin Schwierczek, Philip Wenzel, Florian Langer, Christoph Reinhardt, Wolfram Ruf
• Journal: Blood (Blood) Vol. 129 Issue 16 Pg. 2291-2302 (04 20 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 28223279 (Publication Type: Journal Article)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• Complement C3
• Complement C5
• Phosphatidylserines
• Fibrin
• Thromboplastin
• Hydrolases
• Protein-Arginine Deiminase Type 4
• peptidylarginine deiminase 4, mouse
• Protein Disulfide-Isomerases

Topics

• Animals
• Blood Platelets (immunology, pathology)
• Complement Activation
• Complement C3 (genetics, metabolism)
• Complement C5 (genetics, metabolism)
• Extracellular Traps (genetics, immunology)
• Fibrin (genetics, immunology)
• Gene Expression
• Hemostasis (immunology)
• Humans
• Hydrolases (genetics, immunology)
• Immunity, Innate
• Leukocytes (immunology, pathology)
• Ligation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Cells (immunology, pathology)
• Phosphatidylserines (metabolism)
• Platelet Activation (immunology)
• Protein Disulfide-Isomerases (genetics, immunology)
• Protein-Arginine Deiminase Type 4
• Thromboplastin (genetics, immunology)
• Thrombosis (blood, genetics, immunology, pathology)
• Vena Cava, Inferior (immunology, metabolism, pathology)