title: C-reactive protein enhances activation of coagulation system and inflammatory response through dissociating into monomeric form in antineutrophil cytoplasmic antibody-associated vasculitis.
abstract: BACKGROUND
  C-reactive protein (CRP) exerts prothrombotic effects through dissociating from pentameric CRP (pCRP) into modified or monomeric CRP (mCRP). However, although the high prevalence of venous thromboembolism (VTE) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has been identified, it remains unclear whether the high levels of circulating pCRP potentially contribute to this hypercoagulable state in AAV. ANCA can induce the generation of neutrophil extracellular traps (NETs). In this study, the NETs-dependent generation of mCRP from pCRP and the influences of mCRP on the activation of coagulation system and inflammatory response in AAV were investigated.
  
  
  RESULTS
  NETs were induced after TNF-α primed neutrophils were incubated with ANCA-containing IgG. After ANCA-induced netting neutrophils were incubated statically with platelet-rich plasma (PRP) containing mCRP (60 μg/mL), the proportion of platelets expressing CD62p increased significantly, while no increased CD62p expression of platelets was observed after static incubation with PRP containing pCRP (60 μg/mL). Under flow conditions, perfusing immobilized ANCA-induced netting neutrophils with pCRP-containing PRP caused platelets activation and mCRP deposition. The newly generated mCRP induced platelets activation on ANCA-induced netting neutrophils, enhanced D-dimer formation, and enhanced high mobility group box 1 secretion by platelets.
  
  
  CONCLUSIONS
  Under flow conditions, ANCA-induced netting neutrophils can activate platelets and then prompt the formation of mCRP on activated platelets. Then the newly generated mCRP can further enhance the activation of platelets, the process of thrombogenesis, and the inflammatory response. So the high level of circulating pCRP is not only a sensitive marker for judging the disease activity, but also a participant in the pathophysiology of AAV.
authors: Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, 300052, China. nkxpc@163.com.
authors: Peng-cheng
authors: PC
authors: Xu
authors: Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, 300052, China. shanlin_55@163.com.
authors: Shan
authors: S
authors: Lin
authors: Department of Nephrology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China. yangxw82@163.com.
authors: Xiao-wei
authors: XW
authors: Yang
authors: Department of Clinical Laboratory, Tianjin Medical University General Hospital, Tianjin, 300052, China. gudongmei1109@126.com.
authors: Dong-Mei
authors: DM
authors: Gu
authors: Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, 300052, China. tiekunyan@163.com.
authors: Tie-kun
authors: TK
authors: Yan
authors: Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, 300052, China. shokaku@163.com.
authors: Li
authors: L
authors: Wei
authors: Key Lab of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300070, China. baoliwang72@163.com.
authors: Bao-li
authors: BL
authors: Wang
mesh_terms: D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood*; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000378:metabolism*; D001777:Blood Coagulation / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D065206:Extracellular Traps; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D024002:HMGB Proteins / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D055503:Protein Multimerization; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054556:Venous Thromboembolism / Q000097:blood*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D005338:Fibrin Fibrinogen Degradation Products; D024002:HMGB Proteins; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; C036309:fibrin fragment D; D002097:C-Reactive Protein