Thromb Haemost 2022; 122(07): 1198-1208
DOI: 10.1055/a-1695-8612
Stroke, Systemic or Venous Thromboembolism

Transient Bacteremia Promotes Catheter-Related Central Venous Thrombosis through Neutrophil Extracellular Traps

Jeng-Wei Chen
1   Division of Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
2   Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Chih-Chieh Hsu
3   Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan
4   Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
Chien-Chia Su
2   Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
5   Department of ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
Ron-Bin Hsu
1   Division of Cardiovascular Surgery, Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
Yen-Ling Chiu
2   Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
6   Division of Nephrology, Department of Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
7   Graduate Program in Biomedical Informatics, Department of Computer Science and Engineering, College of Informatics, Yuan Ze University, Taoyuan, Taiwan
8   Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Jean-San Chia*
2   Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
4   Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan
9   Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
› Author Affiliations
Funding This study was supported by the Ministry of Science and Technology of Taiwan (MOST 108–2314-B-002–088-MY3, MOST 108–2320-B-038–057-MY3, and MOST 110–2320-B-002-064).


Formation of intravenous catheter-related thrombosis leads to central venous stenosis in patients requiring renal replacement therapy or chemotherapy infusion, yet the triggers or mechanisms remain unclear, especially in patients without symptoms of infection. In this study, we found that neutrophil extracellular traps (NETs) could be detected in the fibrin sheaths from dialysis patients without clinical manifestations of infection. Confocal microscopy revealed bacteria imbedded in NETs in the fibrin sheaths. Thirty-nine of 50 (78%) fibrin sheath specimens contained bacteria detectable by 16S ribosomal RNA genome typing with a predominance of Staphylococcus aureus (69%). In rat models, transient bacteremia of S. aureus induced NETs in enlarged fibrin sheaths, and treatment with DNase I alone significantly reduced both NET and fibrin sheath formation surrounding the catheter. Therefore, transient bacteremia could be a silent trigger that induces NET-related immunothrombosis enhancing catheter-related central venous stenosis.

* Chiau-Jing Jung and Jean-San Chia contributed equally to this work.

Supplementary Material

Publication History

Received: 25 May 2021

Accepted: 10 November 2021

Accepted Manuscript online:
12 November 2021

Article published online:
21 January 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Jung CJ, Yeh CY, Shun CT. et al. Platelets enhance biofilm formation and resistance of endocarditis-inducing streptococci on the injured heart valve. J Infect Dis 2012; 205 (07) 1066-1075
  • 2 Hsu CC, Hsu RB, Ohniwa RL. et al. Neutrophil extracellular traps enhance Staphylococcus Aureus vegetation formation through interaction with platelets in infective endocarditis. Thromb Haemost 2019; 119 (05) 786-796
  • 3 Jung CJ, Yeh CY, Hsu RB, Lee CM, Shun CT, Chia JS. Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. Circulation 2015; 131 (06) 571-581
  • 4 Peters WR, Bush Jr WH, McIntyre RD, Hill LD. The development of fibrin sheath on indwelling venous catheters. Surg Gynecol Obstet 1973; 137 (01) 43-47
  • 5 Shanaah A, Brier M, Dwyer A. Fibrin sheath and its relation to subsequent events after tunneled dialysis catheter exchange. Semin Dial 2013; 26 (06) 733-737
  • 6 Hoshal Jr VL, Ause RG, Hoskins PA. Fibrin sleeve formation on indwelling subclavian central venous catheters. Arch Surg 1971; 102 (04) 353-358
  • 7 Damascelli B, Patelli G, Frigerio LF. et al. Placement of long-term central venous catheters in outpatients: study of 134 patients over 24,596 catheter days. AJR Am J Roentgenol 1997; 168 (05) 1235-1239
  • 8 Cardella JF, Lukens ML, Fox PS. Fibrin sheath entrapment of peripherally inserted central catheters. J Vasc Interv Radiol 1994; 5 (03) 439-442
  • 9 Faintuch S, Salazar GM. Malfunction of dialysis catheters: management of fibrin sheath and related problems. Tech Vasc Interv Radiol 2008; 11 (03) 195-200
  • 10 Agarwal AK. Central vein stenosis. Am J Kidney Dis 2013; 61 (06) 1001-1015
  • 11 Forauer AR, Theoharis C. Histologic changes in the human vein wall adjacent to indwelling central venous catheters. J Vasc Interv Radiol 2003; 14 (9, Pt 1): 1163-1168
  • 12 Forauer AR, Theoharis CG, Dasika NL. Jugular vein catheter placement: histologic features and development of catheter-related (fibrin) sheaths in a swine model. Radiology 2006; 240 (02) 427-434
  • 13 Kim S, Kim Y, Moon SB. Histological changes of the unligated vein wall adjacent to the central venous catheter after open cutdown in rats. J Pediatr Surg 2015; 50 (11) 1928-1932
  • 14 Xiang DZ, Verbeken EK, Van Lommel AT, Stas M, De Wever I. Composition and formation of the sleeve enveloping a central venous catheter. J Vasc Surg 1998; 28 (02) 260-271
  • 15 Shimohata T, Mawatari K, Uebanso T. et al. Bacterial contamination of hemodialysis devices in hospital dialysis wards. J Med Invest 2019; 66 (1.2): 148-152
  • 16 Mermel LA, Allon M, Bouza E. et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49 (01) 1-45
  • 17 Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res 2003; 60 (01) 26-39
  • 18 Kastrup CJ, Boedicker JQ, Pomerantsev AP. et al. Spatial localization of bacteria controls coagulation of human blood by ‘quorum acting’. Nat Chem Biol 2008; 4 (12) 742-750
  • 19 Pilsczek FH, Salina D, Poon KK. et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010; 185 (12) 7413-7425
  • 20 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663): 1532-1535
  • 21 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
  • 22 Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 2018; 18 (02) 134-147
  • 23 Frank JA, Reich CI, Sharma S, Weisbaum JS, Wilson BA, Olsen GJ. Critical evaluation of two primers commonly used for amplification of bacterial 16S rRNA genes. Appl Environ Microbiol 2008; 74 (08) 2461-2470
  • 24 Becerra SC, Roy DC, Sanchez CJ, Christy RJ, Burmeister DM. An optimized staining technique for the detection of Gram positive and Gram negative bacteria within tissue. BMC Res Notes 2016; 9: 216
  • 25 Chakravorty S, Helb D, Burday M, Connell N, Alland D. A detailed analysis of 16S ribosomal RNA gene segments for the diagnosis of pathogenic bacteria. J Microbiol Methods 2007; 69 (02) 330-339
  • 26 Hernández D, Díaz F, Rufino M. et al. Subclavian vascular access stenosis in dialysis patients: natural history and risk factors. J Am Soc Nephrol 1998; 9 (08) 1507-1510
  • 27 Bouza E, Cruces R, Pérez Granda MJ, Rodríguez-Sánchez B, Martín-Rabadán P, Guembe M. Use of MALDI-TOF to detect colonized vascular catheter tips after 6 and 12h of incubation. J Microbiol Methods 2016; 128: 10-12
  • 28 Beathard GA. Bacterial colonization of thrombosed dialysis arteriovenous grafts. Semin Dial 2015; 28 (04) 446-449
  • 29 Thammavongsa V, Kim HK, Missiakas D, Schneewind O. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 2015; 13 (09) 529-543
  • 30 Nanra JS, Buitrago SM, Crawford S. et al. Capsular polysaccharides are an important immune evasion mechanism for Staphylococcus aureus. Hum Vaccin Immunother 2013; 9 (03) 480-487
  • 31 Buchanan JT, Simpson AJ, Aziz RK. et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 2006; 16 (04) 396-400
  • 32 Grinberg N, Elazar S, Rosenshine I, Shpigel NY. Beta-hydroxybutyrate abrogates formation of bovine neutrophil extracellular traps and bactericidal activity against mammary pathogenic Escherichia coli. Infect Immun 2008; 76 (06) 2802-2807
  • 33 Young RL, Malcolm KC, Kret JE. et al. Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One 2011; 6 (09) e23637
  • 34 Hong W, Juneau RA, Pang B, Swords WE. Survival of bacterial biofilms within neutrophil extracellular traps promotes nontypeable Haemophilus influenzae persistence in the chinchilla model for otitis media. J Innate Immun 2009; 1 (03) 215-224
  • 35 Carestia A, Kaufman T, Rivadeneyra L. et al. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J Leukoc Biol 2016; 99 (01) 153-162
  • 36 Thomas S, Liu W, Arora S, Ganesh V, Ko YP, Höök M. The complex fibrinogen interactions of the Staphylococcus aureus coagulases. Front Cell Infect Microbiol 2019; 9: 106
  • 37 Foster TJ, Geoghegan JA, Ganesh VK, Höök M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 2014; 12 (01) 49-62
  • 38 McAdow M, Missiakas DM, Schneewind O. Staphylococcus aureus secretes coagulase and von Willebrand factor binding protein to modify the coagulation cascade and establish host infections. J Innate Immun 2012; 4 (02) 141-148
  • 39 Arrecubieta C, Asai T, Bayern M. et al. The role of Staphylococcus aureus adhesins in the pathogenesis of ventricular assist device-related infections. J Infect Dis 2006; 193 (08) 1109-1119
  • 40 Heying R, van de Gevel J, Que YA, Piroth L, Moreillon P, Beekhuizen H. Contribution of (sub)domains of Staphylococcus aureus fibronectin-binding protein to the proinflammatory and procoagulant response of human vascular endothelial cells. Thromb Haemost 2009; 101 (03) 495-504
  • 41 Que YA, Haefliger JA, Piroth L. et al. Fibrinogen and fibronectin binding cooperate for valve infection and invasion in Staphylococcus aureus experimental endocarditis. J Exp Med 2005; 201 (10) 1627-1635
  • 42 Katayama Y, Ito T, Hiramatsu K. A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 2000; 44 (06) 1549-1555
  • 43 Pozzi C, Waters EM, Rudkin JK. et al. Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. PLoS Pathog 2012; 8 (04) e1002626
  • 44 Rudkin JK, Edwards AM, Bowden MG. et al. Methicillin resistance reduces the virulence of healthcare-associated methicillin-resistant Staphylococcus aureus by interfering with the agr quorum sensing system. J Infect Dis 2012; 205 (05) 798-806
  • 45 McCarthy H, Rudkin JK, Black NS, Gallagher L, O'Neill E, O'Gara JP. Methicillin resistance and the biofilm phenotype in Staphylococcus aureus. Front Cell Infect Microbiol 2015; 5: 1
  • 46 Jhunjhunwala S, Aresta-DaSilva S, Tang K. et al. Neutrophil responses to sterile implant materials. PLoS One 2015; 10 (09) e0137550
  • 47 Selders GS, Fetz AE, Radic MZ, Bowlin GL. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater 2017; 4 (01) 55-68
  • 48 Agarwal AK, Haddad NJ, Vachharajani TJ, Asif A. Innovations in vascular access for hemodialysis. Kidney Int 2019; 95 (05) 1053-1063
  • 49 May RM, Magin CM, Mann EE. et al. An engineered micropattern to reduce bacterial colonization, platelet adhesion and fibrin sheath formation for improved biocompatibility of central venous catheters. Clin Transl Med 2015; 4: 9
  • 50 Folco EJ, Mawson TL, Vromman A. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler Thromb Vasc Biol 2018; 38 (08) 1901-1912
  • 51 Wang J. Neutrophils in tissue injury and repair. Cell Tissue Res 2018; 371 (03) 531-539
  • 52 Aldabbous L, Abdul-Salam V, McKinnon T. et al. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol 2016; 36 (10) 2078-2087
  • 53 Keller JE, Hindman JW, Mehall JR, Smith SD. Enoxaparin inhibits fibrin sheath formation and decreases central venous catheter colonization following bacteremic challenge. Crit Care Med 2006; 34 (05) 1450-1455
  • 54 Zhong L, Wang HL, Xu B. et al. Normal saline versus heparin for patency of central venous catheters in adult patients - a systematic review and meta-analysis. Crit Care 2017; 21 (01) 5
  • 55 Clase CM, Crowther MA, Ingram AJ, Cinà CS. Thrombolysis for restoration of patency to haemodialysis central venous catheters: a systematic review. J Thromb Thrombolysis 2001; 11 (02) 127-136
  • 56 Kim S, Kim Y, Hwang JW, Moon SB. Inhibitory effect of sustained perivascular delivery of paclitaxel on neointimal hyperplasia in the jugular vein after open cutdown central venous catheter placement in rats. Ann Surg Treat Res 2017; 92 (02) 97-104
  • 57 Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2018; 7 (24) e011245
  • 58 Alves D, Magalhães A, Grzywacz D, Neubauer D, Kamysz W, Pereira MO. Co-immobilization of palm and DNase I for the development of an effective anti-infective coating for catheter surfaces. Acta Biomater 2016; 44: 313-322