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J Immunol. 2019 Jul 3. pii: ji1900503. doi: 10.4049/jimmunol.1900503. [Epub ahead of print]

Cholesterol Crystals Induce Coagulation Activation through Complement-Dependent Expression of Monocytic Tissue Factor.

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Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, 0424 Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
K.G. Jebsen Inflammation Research Centre, University of Oslo, 0318 Oslo, Norway.
Research Laboratory, Nordland Hospital, 8092 Bodo, Norway.
Faculty of Health Sciences, K.G. Jebsen Thrombosis Research and Expertise Center, The Arctic University of Norway, 9037 Tromso, Norway.
Department of Neurology, Oslo University Hospital, 0424 Oslo, Norway.
Department of Neuroradiology, Oslo University Hospital, 0424 Oslo, Norway.
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4072, Australia.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Department of Immunology, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway; and.
Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway;
Centre for Obesity, Clinic of Surgery, St. Olav's University Hospital, 7006 Trondheim, Norway.


Cholesterol crystals (CC) are strong activators of complement and could potentially be involved in thromboinflammation through complement-coagulation cross-talk. To explore the coagulation-inducing potential of CC, we performed studies in lepirudin-based human whole blood and plasma models. In addition, immunohistological examinations of brain thrombi and vulnerable plaque material from patients with advanced carotid atherosclerosis were performed using polarization filter reflected light microscopy to identify CC. In whole blood, CC exposure induced a time- and concentration-dependent generation of prothrombin fragment 1+2 (PTF1.2), tissue factor (TF) mRNA synthesis, and monocyte TF expression. Blocking Abs against TF abolished CC-mediated coagulation, thus indicating involvement of the TF-dependent pathway. Blockade of FXII by corn trypsin inhibitor had a significant inhibitory effect on CC-induced PTF1.2 in platelet-free plasma, although the overall activation potential was low. CC exposure did not induce platelet aggregation, TF microparticle induction, or TF on granulocytes or eosinophils. Inhibition of complement C3 by CP40 (compstatin), C5 by eculizumab, or C5aR1 by PMX53 blocked CC-induced PTF1.2 by 90% and reduced TF+ monocytes from 18-20 to 1-2%. The physiologic relevance was supported by birefringent CC structures adjacent to monocytes (CD14), TF, and activated complement iC3b and C5b-9 in a human brain thrombus. Furthermore, monocyte influx and TF induction in close proximity to CC-rich regions with activated complement were found in a vulnerable plaque. In conclusion, CC could be active, releasable contributors to thrombosis by inducing monocyte TF secondary to complement C5aR1 signaling.


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