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Thromb Haemost 2015; 114(06): 1251-1259
DOI: 10.1160/TH15-04-0357
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Fractal dimension (df ) as a new structural biomarker of clot microstructure in different stages of lung cancer

Nia Anne Davies
1   College of Medicine, Swansea University, Swansea, UK
2   NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
,
Nicholas Kim Harrison
1   College of Medicine, Swansea University, Swansea, UK
3   Respiratory Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
,
Roger H. Keith Morris
4   School of Applied Science, Cardiff Metropolitan University, Cardiff, UK
,
Simon Noble
5   School of Medicine, Cardiff University, Cardiff, UK
,
Matthew James Lawrence
1   College of Medicine, Swansea University, Swansea, UK
2   NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
,
Lindsay Antonio D’Silva
1   College of Medicine, Swansea University, Swansea, UK
2   NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
,
Laura Broome
1   College of Medicine, Swansea University, Swansea, UK
2   NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
,
Martin Rowan Brown
6   College of Engineering, Swansea University, Swansea, UK
,
Karl M. Hawkins
1   College of Medicine, Swansea University, Swansea, UK
,
Phylip Rhodri Williams
6   College of Engineering, Swansea University, Swansea, UK
,
Simon Davidson
7   Department of Haematology, Royal Brompton Hospital, Royal Brompton and Harefield NHS Foundation Trust, London, UK
,
Phillip Adrian Evans
1   College of Medicine, Swansea University, Swansea, UK
2   NISCHR Haemostasis Biomedical Research Unit, Morriston Hospital, ABMU Health Board, Swansea, UK
› Author Affiliations Financial support: This translational work was supported by the NISCHR Biomedical Research Unit (BRU) grant (BRO1).
Further Information

Publication History

Received: 29 April 2015

Accepted after major revision: 28 June 2015

Publication Date:
30 November 2017 (online)

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Summary

Venous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot micro-structure and greatest VTE risk.

Keywords

Lung cancer - venous thromboembolism - risk assessment - biomarker - fractal
 

  • References

  • 1 Silverstein MD, Heit JA, Mohr DN. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585-593.
    CrossrefPubMedSearch in Google Scholar
  • 2 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-8.
    PubMedSearch in Google Scholar
  • 3 Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer 2010; 102: S2-9.
    CrossrefPubMedSearch in Google Scholar
  • 4 Chew HK, Davies AM, Wun T. et al. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost 2008; 06: 601-608.
    CrossrefPubMedSearch in Google Scholar
  • 5 Khorana AA, Francis CW, Culakova E. et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 05: 632-634.
    CrossrefPubMedSearch in Google Scholar
  • 6 Blom JW, Doggen CJ, Osanto S. et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715-722.
    CrossrefPubMedSearch in Google Scholar
  • 7 Bick RL. Alterations of hemostasis associated with malignancy: etiology, patho-physiology, diagnosis and management. Semin Thromb Hemost 1978; 05: 1-26.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Zwicker JI. Tissue factor-bearing microparticles and cancer. Semin Thromb He-most 2008; 34: 195-198.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Vormittag R, Simanek R, Ay C. et al. High factor VIII levels independently predict venous thrombembolism in cancer patients. Arterioscler Thromb Vasc Biol 2009; 29: 2176-2181.
    CrossrefPubMedSearch in Google Scholar
  • 10 Geddings JE, Mackman N. Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013; 122: 1873-1880.
    CrossrefPubMedSearch in Google Scholar
  • 11 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow?. Lancet 2001; 357: 539-545.
    CrossrefPubMedSearch in Google Scholar
  • 12 Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860-867.
    CrossrefPubMedSearch in Google Scholar
  • 13 Rakoff-Nouham S. Why cancer and inflammation?. Yale J Biol Med 2006; 79: 123-130.
    PubMedSearch in Google Scholar
  • 14 Mills JD, Ariëns RAS, Mansfield MW. et al. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation 2002; 106: 1938-1942.
    CrossrefPubMedSearch in Google Scholar
  • 15 Undas A, Szuldrzynski K, Stepien E. et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress. Atherosclerosis 2008; 196: 551-557.
    CrossrefPubMedSearch in Google Scholar
  • 16 Undas A, Zawilska K, Ciesla-Dul M. et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114: 4272-4278.
    CrossrefPubMedSearch in Google Scholar
  • 17 Weisel JW. The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem 2004; 112: 267-276.
    CrossrefPubMedSearch in Google Scholar
  • 18 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood 2013; 121: 1712-1719.
    CrossrefPubMedSearch in Google Scholar
  • 19 Collet JP, Park D, Lesty C. et al. Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy. Arterioscler Thromb Vasc Biol 2000; 20: 1354-1361.
    CrossrefPubMedSearch in Google Scholar
  • 20 Martinez MR, Cuker A, Mills AM. et al. Enhanced lysis and accelerated establishment of viscoelastic properties of fibrin clots associated with pulmonary embolism. Am J Physiol Lung Cell Mol Physiol 2014; L397-404.
    PubMedSearch in Google Scholar
  • 21 Ustuner Z, Akay OM, Keskin M. et al. Evaluating coagulation disorders in the use of bevacizumab for metastatic colorectal cancer by thromboelastography. Med Oncol 2002; 29: 3125-3128.
    PubMedSearch in Google Scholar
  • 22 Toukh M, Siemens DR, Black A. et al. Thromboelastography identifies hypercoagulability and predicts thromboembolic complications in patients with prostate cancer. Thromb Res 2014; 133: 88-95.
    CrossrefPubMedSearch in Google Scholar
  • 23 Thorson CM, Van Haren RM, Ryan ML. et al. Persistence of hypercoagulable state after resection of intra-abdominal malignancies. J Am Coll Surgeons 2013; 216: 580-589.
    CrossrefPubMedSearch in Google Scholar
  • 24 Papa ML, Capasso F, Pudore L. et al. Thromboelastographic profiles as a tool for thrombotic risk in digestive tract cancer. Exp Oncol 2007; 29: 111-115.
    PubMedSearch in Google Scholar
  • 25 Akay OM, Ustuner Z, Canturk Z. et al. Laboratory investigation of hypercoagulability in cancer patients using rotation thromboelastography. Med Oncol 2009; 26: 258-364.
    PubMedSearch in Google Scholar
  • 26 Davies NA, Harrison NK, Sabra A. et al. Application of ROTEM to assess hyper-coagulability in patients with lung cancer. Thromb Res 2015; 135: 1075-1080.
    CrossrefPubMedSearch in Google Scholar
  • 27 Winter HH, Chambon F. Analysis of linear viscoelasticity of a cross-linking polymer at the Gel-Point. J Rheol 1986; 30: 367-382.
    CrossrefPubMedSearch in Google Scholar
  • 28 Muthukumar M, Winter HH. Fractal dimension of a crosslinking polymer at the gel point. Macromolecules 1986; 19: 1284-1285.
    CrossrefPubMedSearch in Google Scholar
  • 29 Evans PA, Hawkins K, Williams PR. et al. Rheometrical detection of incipient blood clot formation by Fourier transform mechanical spectroscopy. J Nonnewton Fluid Mech 2008; 148: 122-126.
    CrossrefPubMedSearch in Google Scholar
  • 30 Evans PA, Hawkins K, Morris RH. et al. Gel point and fractal microstructure of incipient clots are significant new markers of hemostasis for healthy and anticoagulated blood. Blood 2010; 116: 3341-3344.
    CrossrefPubMedSearch in Google Scholar
  • 31 Curtis DJ, Williams PR, Badiei N. et al. A study of microstructural templating in fibrin-thrombin gel networks by spectral and viscoelastic analysis. Soft Matter 2013; 09: 4883-4889.
    CrossrefPubMedSearch in Google Scholar
  • 32 Lawrence MJ, Kumar S, Hawkins K. et al. A new structural biomarker that quantifies and predicts changes in clot strength and quality in a model of progressive haemodilution. Thromb Res 2014; 134: 488-494.
    CrossrefPubMedSearch in Google Scholar
  • 33 Lawrence MJ, Sabra A, Mills G. et al. A new biomarker quantifies difference in clot microstructure in patients with venous thromboembolism. Br J Haematol 2014; 168: 571-575.
    PubMedSearch in Google Scholar
  • 34 Stanford SN, Sabra A, D’Silva LA. et al. The changes in clot microstructure in patients with ischaemic stroke and the effects of therapeutic intervention: a prospective observational study. BMC Neurology 2015; 15: 35.
    CrossrefPubMedSearch in Google Scholar
  • 35 Lawrence MJ, Sabra A, Thomas P. et al. Fractal dimension: A novel clot micro-structure use in ST elevation myocardial infarction patients. Atherosclerosis 2015; 240: 402-407.
    CrossrefPubMedSearch in Google Scholar
  • 36 Edge S, Byrd DR, Compton CC. et al. AJCC Cancer staging manual. 7th edition. Springer publications; 2010
    Search in Google Scholar
  • 37 Curtis DJ, Brown MR, Hawkins K. et al. Rheometrical and molecular dynamics simulation studies of incipient clot formation in fibrin-thrombin gels: An activation limited aggregation approach. J Nonnewton Fluid Mech 2011; 166: 932-928.
    CrossrefPubMedSearch in Google Scholar
  • 38 Brown MR, Curtis DJ, Rees P. et al. Fractal discrimination of random fractal aggregates and its application in biomarker analysis for blood coagulation. Chaos Solitons Fractals 2012; 45: 1025-1032.
    CrossrefPubMedSearch in Google Scholar
  • 39 Schneider C.A., Rasband W.S., Eliceiri K.W.. NIH Image to Image: 25 years of image analysis. Nat Methods 2012; 09: 671-675.
    CrossrefPubMedSearch in Google Scholar
  • 40 Ay C, Dunkler D, Pirker R, Thaler J. et al. High D Dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012; 97: 1158-1164.
    CrossrefPubMedSearch in Google Scholar
  • 41 Janicke F, Schmitt M, Pache L. et al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24: 195-208.
    CrossrefPubMedSearch in Google Scholar
  • 42 Kuhn W, Pache L, Schmalfeldt B. et al. Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FIGO III) after radical surgery and platinum-based chemotherapy. Gynecol Oncol 1993; 55: 401-409.
    PubMedSearch in Google Scholar
  • 43 Andreasen PA, Kjoller L, Christensen L. et al. The urokinase- type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1-22.
    CrossrefPubMedSearch in Google Scholar
  • 44 Schmitt M, Harbeck N, Thomssen C. et al. Clinical impact of the plasminogen activation system in tumour invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost 1997; 78: 285-296.
    Thieme ConnectPubMedSearch in Google Scholar
  • 45 Gronostaj K, Richter P, Nowak W. et al. Altered plasma fibrin clot properties in patients with digestive tract cancers: links with the increased thrombin generation. Thromb Res 2013; 131: 262-267.
    CrossrefPubMedSearch in Google Scholar
  • 46 Cheng Y, Liu Z, Yao F. et al. Current and former smoking and risk for venous thromboembolism: A systematic review and meta-analysis. PLOS Medicine 2013; 10: 1371.
    PubMedSearch in Google Scholar
  • 47 Tesselaar ME, Osanto S. Risk of venous thromboembolism in lung cancer. Curr opin pulm med 2007; 13: 362-367.
    CrossrefPubMedSearch in Google Scholar