Download PDF
Thromb Haemost 2017; 117(11): 2146-2155
DOI: 10.1160/TH17-05-0332
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH Stuttgart

Perivascular Perfusion on Contrast-Enhanced Ultrasound (CEUS) Is Associated with Inflammation in Patients with Acute Deep Vein Thrombosis

Mathias Kaspar
,
Stephan Imfeld
,
Sasan Partovi
,
Markus Aschwanden
,
Thomas Baldi
,
Alexander Dikkes
,
Deborah R. Vogt
,
Dimitrios A. Tsakiris
,
Daniel Staub
Further Information

Publication History

15 May 2017

08 July 2017

Publication Date:
30 November 2017 (online)

    Permissions and Reprints

Abstract

Background Inflammatory processes of the venous wall in acute deep vein thrombosis (DVT) play a role in thrombus formation and resolution. However, direct evaluation of the perivascular inflammation is currently not feasible.

Objective To assess perivascular perfusion in acute proximal DVT using contrast-enhanced ultrasound (CEUS) reflecting perivenous inflammation and its association with systemic inflammatory markers in a single-centre, prospective observational study.

Patients/Methods Twenty patients with proximal DVT underwent CEUS imaging in the thrombosed and contralateral popliteal vein at baseline and after 2 weeks and 3 months. Perfusion was quantified by measuring peak enhancement (PE) and wash-in rate (WiR) in a perivenous region after bolus injection of the contrast agent. High-sensitive C-reactive protein (hsCRP) and interleukin-6 (IL-6) were determined at the time of each CEUS imaging.

Results PE and WiR were significantly higher in the thrombosed compared with the unaffected leg at baseline (1,007 vs. 34 au and 103 vs. 4 au/s) and 2-week follow-up (903 vs. 35 au and 70 vs. 4 au/s). Compared with baseline, PE and WiR in the thrombosed leg significantly decreased to 217 au and 18 au/s at 3-month follow-up.

At baseline, hsCRP and IL-6 were elevated at 20.1 mg/mL and 8.2 pg/mL and decreased significantly to 2.8 mg/mL and 2.6 pg/mL at 2-week follow-up, remaining low after 3 months. There was a weak association between the level of inflammatory markers and the CEUS parameters at baseline on the thrombosed leg.

Conclusion Elevated perivascular perfusion assessed by CEUS imaging is associated with the inflammatory response in acute DVT.

Keywords

contrast agent - C-reactive protein - deep vein thrombosis - interleukin - ultrasound imaging

Funding Resources

This investigator-initiated prospective study was supported by a research grant to D. S. from the Swiss National Science Foundation (PZ00P3_142419), the University of Basel, the University Hospital of Basel and the Swiss Society of Phlebology. D. S. has also received an unrestricted research grant from Bracco SA. 3D measurement system for oedema measurement was provided by Bauerfeind AG.


 

  • References

  • 1 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
    CrossrefPubMedGoogle Scholar
  • 2 Kahn SR, Comerota AJ, Cushman M. , et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014; 130 (18) 1636-1661
    CrossrefPubMedGoogle Scholar
  • 3 Aschwanden M, Jeanneret C, Koller MT, Thalhammer C, Bucher HC, Jaeger KA. Effect of prolonged treatment with compression stockings to prevent post-thrombotic sequelae: a randomized controlled trial. J Vasc Surg 2008; 47 (05) 1015-1021
    CrossrefPubMedGoogle Scholar
  • 4 Kahn SR, Shrier I, Julian JA. , et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149 (10) 698-707
    CrossrefPubMedGoogle Scholar
  • 5 Galanaud JP, Monreal M, Kahn SR. Predictors of the post-thrombotic syndrome and their effect on the therapeutic management of deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2016; 4 (04) 531-534
    PubMedGoogle Scholar
  • 6 Rabinovich A, Cohen JM, Kahn SR. Predictive value of markers of inflammation in the postthrombotic syndrome: a systematic review: inflammatory biomarkers and PTS. Thromb Res 2015; 136 (02) 289-297
    CrossrefPubMedGoogle Scholar
  • 7 Deroo S, Deatrick KB, Henke PK. The vessel wall: a forgotten player in post thrombotic syndrome. Thromb Haemost 2010; 104 (04) 681-692
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
    CrossrefPubMedGoogle Scholar
  • 9 Saha P, Humphries J, Modarai B. , et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011; 31 (03) 506-512
    CrossrefPubMedGoogle Scholar
  • 10 Penn MS, Igwe C. Role of inflammation in modulating thrombotic-fibrinolytic balance in venous thrombosis. Circ Res 2016; 119 (12) 1256-1257
    CrossrefPubMedGoogle Scholar
  • 11 Luther N, Shahneh F, Brähler M. , et al. Innate effector-memory T-cell activation regulates post-thrombotic vein wall inflammation and thrombus resolution. Circ Res 2016; 119 (12) 1286-1295
    CrossrefPubMedGoogle Scholar
  • 12 Henke PK, Wakefield T. Thrombus resolution and vein wall injury: dependence on chemokines and leukocytes. Thromb Res 2009; 123 (Suppl. 04) S72-S78
    CrossrefPubMedGoogle Scholar
  • 13 Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost 2005; 94 (02) 362-365
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Reitsma PH, Rosendaal FR. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study. J Thromb Haemost 2004; 2 (04) 619-622
    CrossrefPubMedGoogle Scholar
  • 15 Rabinovich A, Cohen JM, Cushman M, Kahn SR. ; BioSOX Investigators. Association between inflammation biomarkers, anatomic extent of deep venous thrombosis, and venous symptoms after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2015; 3 (04) 347-53.e1
    PubMedGoogle Scholar
  • 16 Roumen-Klappe EM, den Heijer M, van Uum SH, van der Ven-Jongekrijg J, van der Graaf F, Wollersheim H. Inflammatory response in the acute phase of deep vein thrombosis. J Vasc Surg 2002; 35 (04) 701-706
    CrossrefPubMedGoogle Scholar
  • 17 Reiter M, Bucek RA, Koca N, Dirisamer A, Minar E. Deep vein thrombosis and systemic inflammatory response: a pilot trial. Wien Klin Wochenschr 2003; 115 (3–4): 111-114
    CrossrefPubMedGoogle Scholar
  • 18 Shbaklo H, Holcroft CA, Kahn SR. Levels of inflammatory markers and the development of the post-thrombotic syndrome. Thromb Haemost 2009; 101 (03) 505-512
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Bouman AC, Atalay S, Ten Cate H, Ten Wolde M, Ten Cate-Hoek AJ. Biomarkers for post-thrombotic syndrome. J Vasc Surg Venous Lymphat Disord 2014; 2 (01) 79-88.e3
    CrossrefPubMedGoogle Scholar
  • 20 Bouman AC, Cheung YW, Spronk HM. , et al. Biomarkers for post thrombotic syndrome: a case-control study. Thromb Res 2014; 134 (02) 369-375
    CrossrefPubMedGoogle Scholar
  • 21 Rabinovich A, Cohen JM, Cushman M. , et al. Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome. J Thromb Haemost 2015; 13 (03) 398-408
    CrossrefPubMedGoogle Scholar
  • 22 Roumen-Klappe EM, Janssen MC, Van Rossum J. , et al. Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study. J Thromb Haemost 2009; 7 (04) 582-587
    CrossrefPubMedGoogle Scholar
  • 23 Feinstein SB, Coll B, Staub D. , et al. Contrast enhanced ultrasound imaging. J Nucl Cardiol 2010; 17 (01) 106-115
    CrossrefPubMedGoogle Scholar
  • 24 Staub D, Schinkel AF, Coll B. , et al. Contrast-enhanced ultrasound imaging of the vasa vasorum: from early atherosclerosis to the identification of unstable plaques. JACC Cardiovasc Imaging 2010; 3 (07) 761-771
    CrossrefPubMedGoogle Scholar
  • 25 Staub D, Partovi S, Imfeld S. , et al. Novel applications of contrast-enhanced ultrasound imaging in vascular medicine. Vasa 2013; 42 (01) 17-31
    CrossrefPubMedGoogle Scholar
  • 26 Feinstein SB. The powerful microbubble: from bench to bedside, from intravascular indicator to therapeutic delivery system, and beyond. Am J Physiol Heart Circ Physiol 2004; 287 (02) H450-H457
    CrossrefPubMedGoogle Scholar
  • 27 Tranquart F, Mercier L, Frinking P, Gaud E, Arditi M. Perfusion quantification in contrast-enhanced ultrasound (CEUS)--ready for research projects and routine clinical use. Ultraschall Med 2012; 33 (Suppl. 01) S31-S38
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Burnham KP, Anderson DR. Model Selection and Multimodel Inference: A Practical Information-Theoretic Approach. 2nd ed. New York, NY: Springer; 2002
    Google Scholar
  • 29 Bouman AC, Smits JJ, Ten Cate H, Ten Cate-Hoek AJ. Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome. J Thromb Haemost 2012; 10 (08) 1532-1538
    CrossrefPubMedGoogle Scholar
  • 30 Dietrich CF, Averkiou MA, Correas JM, Lassau N, Leen E, Piscaglia F. An EFSUMB introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for quantification of tumour perfusion. Ultraschall Med 2012; 33 (04) 344-351
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Partovi S, Imfeld S, Aschwanden M, Bilecen D, Jaeger KA, Staub D. The use of contrast-enhanced ultrasound (CEUS) in chronic periaortitis. Ultraschall Med 2013; 34 (01) 3-6
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Fiocco U, Stramare R, Martini V. , et al. Quantitative imaging by pixel-based contrast-enhanced ultrasound reveals a linear relationship between synovial vascular perfusion and the recruitment of pathogenic IL-17A-F+IL-23+ CD161+ CD4+ T helper cells in psoriatic arthritis joints. Clin Rheumatol 2017; 36 (02) 391-399
    CrossrefPubMedGoogle Scholar
  • 33 Xu R, Yin X, Xu W, Jin L, Lu M, Wang Y. Assessment of carotid plaque neovascularization by contrast-enhanced ultrasound and high sensitivity C-reactive protein test in patients with acute cerebral infarction: a comparative study. Neurol Sci 2016; 37 (07) 1107-1112
    CrossrefPubMedGoogle Scholar
  • 34 Staub D. Atherosclerotic plaque neovascularization and inflammation - is there a link?. Vasa 2015; 44 (03) 163-165
    CrossrefPubMedGoogle Scholar
  • 35 Germanò G, Macchioni P, Possemato N. , et al. Contrast-enhanced ultrasound of the carotid artery in patients with large vessel vasculitis: correlation with positron emission tomography findings. Arthritis Care Res (Hoboken) 2017; 69 (01) 143-149
    CrossrefPubMedGoogle Scholar
  • 36 Le Roux PY, Robin P, Delluc A. , et al. Performance of 18F fluoro-2-désoxy-D-glucose positron emission tomography/computed tomography for the diagnosis of venous thromboembolism. Thromb Res 2015; 135 (01) 31-35
    CrossrefPubMedGoogle Scholar