CC BY-NC-ND 4.0 · Thromb Haemost 2024; 124(05): 432-440
DOI: 10.1055/a-2195-3927
Blood Cells, Inflammation, and Infection

Proteomic Characterization of Plasma in Lemierre's Syndrome

David Nygren
1   Division of Infection Medicine, Lund University, Lund, Sweden
2   Department of Infectious Diseases, Skåne University Hospital, Lund/Malmö, Sweden
Gustav Torisson
2   Department of Infectious Diseases, Skåne University Hospital, Lund/Malmö, Sweden
3   Department of Translational Medicine, Clinical Infection Medicine, Lund University, Malmö, Sweden
Lotta Happonen
1   Division of Infection Medicine, Lund University, Lund, Sweden
Lisa Mellhammar
1   Division of Infection Medicine, Lund University, Lund, Sweden
2   Department of Infectious Diseases, Skåne University Hospital, Lund/Malmö, Sweden
Adam Linder
1   Division of Infection Medicine, Lund University, Lund, Sweden
2   Department of Infectious Diseases, Skåne University Hospital, Lund/Malmö, Sweden
Johan Elf
4   Center of Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden
Hong Yan
5   The Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Lund University, Lund, Sweden
Charlotte Welinder
5   The Swedish National Infrastructure for Biological Mass Spectrometry (BioMS), Lund University, Lund, Sweden
Karin Holm
1   Division of Infection Medicine, Lund University, Lund, Sweden
2   Department of Infectious Diseases, Skåne University Hospital, Lund/Malmö, Sweden
› Author Affiliations
Funding This work was supported by The Royal Physiographic Society in Lund, Region Skåne and the Swedish Government Funds for Clinical Research (ALF). In addition, support from the Swedish National Infrastructure for Biological Mass Spectrometry (BioMS) is gratefully acknowledged.


Background The underlying mechanisms of thrombosis in Lemierre's syndrome and other septic thrombophlebitis are incompletely understood. Therefore, in this case control study we aimed to generate hypotheses on its pathogenesis by studying the plasma proteome in patients with these conditions.

Methods All patients with Lemierre's syndrome in the Skåne Region, Sweden, were enrolled prospectively during 2017 to 2021 as cases. Age-matched patients with other severe infections were enrolled as controls. Patient plasma samples were analyzed using label-free data-independent acquisition liquid chromatography tandem mass spectrometry. Differentially expressed proteins in Lemierre's syndrome versus other severe infections were highlighted. Functions of differentially expressed proteins were defined based on a literature search focused on previous associations with thrombosis.

Results Eight patients with Lemierre's syndrome and 15 with other severe infections were compared. Here, 20/449 identified proteins were differentially expressed between the groups. Of these, 14/20 had functions previously associated with thrombosis. Twelve of 14 had a suggested prothrombotic effect in Lemierre's syndrome, whereas 2/14 had a suggested antithrombotic effect.

Conclusion Proteins involved in several thrombogenic pathways were differentially expressed in Lemierre's syndrome compared to other severe infections. Among identified proteins, several were associated with endothelial damage, platelet activation, and degranulation, and warrant further targeted studies.

Publication History

Received: 05 May 2023

Accepted: 18 October 2023

Accepted Manuscript online:
19 October 2023

Article published online:
07 February 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Riordan T. Human infection with Fusobacterium necrophorum (Necrobacillosis), with a focus on Lemierre's syndrome. Clin Microbiol Rev 2007; 20 (04) 622-659
  • 2 Nygren D, Holm K. Invasive infections with Fusobacterium necrophorum including Lemierre's syndrome: an 8-year Swedish nationwide retrospective study. Clin Microbiol Infect 2020; 26 (08) 1089.e7-1089.e12
  • 3 Lemierre A. On certain septicæmias due to anaerobic organisms. Lancet 1936; 227 (5874) 701-703
  • 4 Bank S, Jensen A, Nielsen HM, Kristensen LH, Voldstedlund M, Prag J. Fusobacterium necrophorum findings in Denmark from 2010 to 2014 using data from the Danish microbiology database. APMIS 2016; 124 (12) 1087-1092
  • 5 Hagelskjaer Kristensen L, Prag J. Lemierre's syndrome and other disseminated Fusobacterium necrophorum infections in Denmark: a prospective epidemiological and clinical survey. Eur J Clin Microbiol Infect Dis 2008; 27 (09) 779-789
  • 6 Brazier JS, Hall V, Yusuf E, Duerden BI. Fusobacterium necrophorum infections in England and Wales 1990-2000. J Med Microbiol 2002; 51 (03) 269-272
  • 7 Hagelskjaer LH, Prag J, Malczynski J, Kristensen JH. Incidence and clinical epidemiology of necrobacillosis, including Lemierre's syndrome, in Denmark 1990-1995. Eur J Clin Microbiol Infect Dis 1998; 17 (08) 561-565
  • 8 Tyrstrup M, Beckman A, Mölstad S. et al. Reduction in antibiotic prescribing for respiratory tract infections in Swedish primary care: a retrospective study of electronic patient records. BMC Infect Dis 2016; 16 (01) 709
  • 9 Nygren D, Brorson E, Musonda M, Wasserstrom L, Johansson Å, Holm K. Geographical differences in tonsillar carriage rates of Fusobacterium necrophorum: a cross-sectional study in Sweden and Zambia. Anaerobe 2021; 69: 102360
  • 10 Centor RM, Atkinson TP, Xiao L. Fusobacterium necrophorum oral infections: a need for guidance. Anaerobe 2022; 75: 102532
  • 11 Holm K, Bank S, Nielsen H, Kristensen LH, Prag J, Jensen A. The role of Fusobacterium necrophorum in pharyngotonsillitis: a review. Anaerobe 2016; 42 (42) 89-97
  • 12 Centor RM, Atkinson TP, Ratliff AE. et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study. Ann Intern Med 2015; 162 (04) 241-247
  • 13 Hedin K, Bieber L, Lindh M, Sundqvist M. The aetiology of pharyngotonsillitis in adolescents and adults: Fusobacterium necrophorum is commonly found. Clin Microbiol Infect 2015; 21 (03) 263.e1-263.e7
  • 14 Nygren D, Wasserstrom L, Holm K, Torisson G. Associations between findings of Fusobacterium necrophorum or β-hemolytic streptococci and complications in pharyngotonsillitis: a registry-based study in southern Sweden. Clin Infect Dis 2023; 76 (03) e1428-e1435
  • 15 Ehlers Klug T, Rusan M, Fuursted K, Ovesen T. Fusobacterium necrophorum: most prevalent pathogen in peritonsillar abscess in Denmark. Clin Infect Dis 2009; 49 (10) 1467-1472
  • 16 Wikstén JE, Laakso S, Mäki M, Mäkitie AA, Pitkäranta A, Blomgren K. Microarray identification of bacterial species in peritonsillar abscesses. Eur J Clin Microbiol Infect Dis 2015; 34 (05) 905-911
  • 17 Nygren D, Elf J, Torisson G, Holm K. Jugular vein thrombosis and anticoagulation therapy in Lemierre's syndrome-a post hoc observational and population-based study of 82 patients. Open Forum Infect Dis 2020; 8 (01) ofaa585
  • 18 Valerio L, Zane F, Sacco C. et al. Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases. J Intern Med 2021; 289 (03) 325-339
  • 19 Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367 (9516) 1075-1079
  • 20 Burn E, Duarte-Salles T, Fernandez-Bertolin S. et al. Venous or arterial thrombosis and deaths among COVID-19 cases: a European network cohort study. Lancet Infect Dis 2022; 22 (08) 1142-1152
  • 21 Beristain-Covarrubias N, Perez-Toledo M, Thomas MR, Henderson IR, Watson SP, Cunningham AF. Understanding infection-induced thrombosis: lessons learned from animal models. Front Immunol 2019; 10: 2569
  • 22 Charles K, Flinn WR, Neschis DG. Lemierre's syndrome: a potentially fatal complication that may require vascular surgical intervention. J Vasc Surg 2005; 42 (05) 1023-1025
  • 23 Beerens H. Procédé de différenciation entre Spherophorus necrophorus (Schmorl 1891) et Spherophorus funduliformis (Halle 1898). Ann Inst Pasteur (Paris) 1954; 86 (03) 384-386
  • 24 Forrester LJ, Campbell BJ, Berg JN, Barrett JT. Aggregation of platelets by Fusobacterium necrophorum . J Clin Microbiol 1985; 22 (02) 245-249
  • 25 Kanoe M, Yamanaka M, Inoue M. Effects of Fusobacterium necrophorum on the mesenteric microcirculation of guinea pigs. Med Microbiol Immunol (Berl) 1989; 178 (02) 99-104
  • 26 Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014; 58 (05) 515-523
  • 27 Holm K, Frick IM, Björck L, Rasmussen M. Activation of the contact system at the surface of Fusobacterium necrophorum represents a possible virulence mechanism in Lemièrre's syndrome. Infect Immun 2011; 79 (08) 3284-3290
  • 28 Rawish E, Sauter M, Sauter R, Nording H, Langer HF. Complement, inflammation and thrombosis. Br J Pharmacol 2021; 178 (14) 2892-2904
  • 29 Holm K, Rasmussen M. Binding and activation of plasminogen at the surface of Fusobacterium necrophorum . Microb Pathog 2013; 59–60: 29-32
  • 30 Betancourt LH, Sanchez A, Pla I. et al. Quantitative assessment of urea in-solution Lys-C/trypsin digestions reveals superior performance at room temperature over traditional proteolysis at 37°C. J Proteome Res 2018; 17 (07) 2556-2561
  • 31 UniProt Consortium. UniProt: the universal protein knowledgebase in 2023. Nucleic Acids Res 2023; 51 (D1): D523-D531
  • 32 Friberg N, Carlson P, Kentala E. et al. Factor H binding as a complement evasion mechanism for an anaerobic pathogen, Fusobacterium necrophorum . J Immunol 2008; 181 (12) 8624-8632
  • 33 Holm K, Collin M, Hagelskjær-Kristensen L, Jensen A, Rasmussen M. Three variants of the leukotoxin gene in human isolates of Fusobacterium necrophorum subspecies funduliforme. Anaerobe 2017; 45: 129-132
  • 34 Isogai N, Tanaka H, Asamura S. Thrombosis and altered expression of intercellular adhesion molecule-1 (ICAM-1) after avulsion injury in rat vessels. J Hand Surg [Br] 2004; 29 (03) 230-234
  • 35 Pierangeli SS, Espinola RG, Liu X, Harris EN. Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Circ Res 2001; 88 (02) 245-250
  • 36 Nagashima S, Mendes MC, Camargo Martins AP. et al. Endothelial dysfunction and thrombosis in patients with COVID-19-brief report. Arterioscler Thromb Vasc Biol 2020; 40 (10) 2404-2407
  • 37 Guo L, Bhatlekar S, Jacob SP. et al. Actin bundling protein L-plastin regulates megakaryocyte membrane rigidity and platelet spreading. Blood 2022; 140 (Suppl. 01) 5510-5511
  • 38 Jones WL, Ramos CR, Banerjee A. et al. Apolipoprotein A-I, elevated in trauma patients, inhibits platelet activation and decreases clot strength. Platelets 2022; 33 (08) 1119-1131
  • 39 Fiedel BA, Costello M, Gewurz H, Hussissian E. Effects of heparin and α 1-acid glycoprotein on thrombin or Activated Thrombofax Reagent-induced platelet aggregation and clot formation. Haemostasis 1983; 13 (02) 89-95
  • 40 Villard AV, Genna A, Lambert J. et al. Regulation of tissue factor by CD44 supports coagulant activity in breast tumor cells. Cancers (Basel) 2022; 14 (13) 3288
  • 41 Štok U, Blokar E, Lenassi M. et al. Characterization of plasma-derived small extracellular vesicles indicates ongoing endothelial and platelet activation in patients with thrombotic antiphospholipid syndrome. Cells 2020; 9 (05) 1211
  • 42 Healy LD, McCarty OJT. Contact system sends defensins to the rescue. Blood 2019; 133 (05) 385-386
  • 43 Abu-Fanne R, Stepanova V, Litvinov RI. et al. Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood 2019; 133 (05) 481-493
  • 44 Shi Y, Gauer JS, Baker SR, Philippou H, Connell SD, Ariëns RAS. Neutrophils can promote clotting via FXI and impact clot structure via neutrophil extracellular traps in a distinctive manner in vitro. Sci Rep 2021; 11 (01) 1718
  • 45 Nygren D, Oldberg K, Holm K. Short blood culture time-to-positivity in Fusobacterium necrophorum bacteremia is associated with Lemierre's syndrome. Anaerobe 2022; 73: 102474
  • 46 Markanday A. Acute phase reactants in infections: evidence-based review and a guide for clinicians. Open Forum Infect Dis 2015; 2 (03) ofv098
  • 47 McGurk KA, Dagliati A, Chiasserini D. et al. The use of missing values in proteomic data-independent acquisition mass spectrometry to enable disease activity discrimination. Bioinformatics 2020; 36 (07) 2217-2223
  • 48 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40 (05) 373-383
  • 49 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315 (08) 801-810