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Thromb Haemost 2022; 122(07): 1169-1176
DOI: 10.1055/a-1792-7720
Stroke, Systemic or Venous Thromboembolism

Growth Differentiation Factor-15, High-Sensitivity Cardiac Troponin T, and N-Terminal pro-B-type Natriuretic Peptide for Predicting Risk of Venous Thromboembolism in Ambulatory Cancer Patients Receiving Chemotherapy

Danielle Carole Roy 
1   School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
,
Tzu-Fei Wang
2   Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Ranjeeta Mallick
1   School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
2   Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Marc Carrier
2   Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Eisi Mollanji
3   Cardiac Function Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
,
Peter Liu
3   Cardiac Function Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
,
Liyong Zhang
3   Cardiac Function Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
,
Steven Hawken
1   School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
2   Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
,
Philip Wells
2   Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
› Author Affiliations Funding This study was supported by funding from Canadian Institute of Health Research (CIHR) and Bristol Myers Squibb/Pfizer (to P.W.).
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Abstract

Growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (hs-TnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with increased risk of venous thromboembolism (VTE) in noncancer patients. However, the performance of these biomarkers in cancer patients is unknown. Our objective was to assess performance of these biomarkers in predicting VTE in cancer patients at intermediate to high risk for VTE (Khorana Score ≥ 2). We used 1-month plasma samples from AVERT trial patients to determine if GDF-15, NT-proBNP, and hs-TnT levels are associated with VTE incidence between 1 and 7 months from the start of chemotherapy. The minimal Euclidean distance of the receiver operating characteristic curve was used to derive optimal cut-offs for GDF-15 and NT-proBNP given there was no evidence of a commonly used cut-off. Logistic and Fine and Gray competing risk regression analyses were used to calculate odds ratios (ORs) and subdistribution hazard ratios, respectively, while adjusting for age, sex, anticoagulation, and antiplatelet therapy. We tested in two groups: all patients (n = 476, Model 1) and all patients with nonprimary brain cancers (n = 454, Model 2). In models 1 and 2, GDF-15 ≥2,290.9 pg/mL had adjusted ORs for VTE of 1.65 (95% confidence interval [CI]: 0.89–3.08), and 2.28 (95% CI: 1.28–4.09), respectively. hs-TnT ≥14.0 pg/mL was associated with higher odds of VTE in models 1 and 2 (adjusted ORs: 2.26 [95% CI: 1.40–3.65] and 2.03 [95% CI: 1.07–3.84], respectively). For NT-proBNP, levels ≥183.5 pg/mL were not associated with VTE. Similar results were observed in the Fine and Gray analysis. Our results indicate that increased GDF-15 and hs-TnT levels predicted increased VTE risk.

Keywords

venous thromboembolism - cancer - prediction - biomarkers

Ethical Approval

No ethics approval was sought for this study. The AVERT trial did receive ethical approval for plasma and DNA blood banking for future thrombosis research, on the condition of patient consent.


Author Contributions

D.C.R. designed the research, performed statistical analysis, analyzed results, made the tables, and wrote the manuscript. L.Z. and P.L. designed the research, contributed laboratory tools, performed experiments, and proofread the manuscript. T-.F.W., M.C., and P.W. designed the research, collected the data, interpreted the data, and proofread the manuscript. R.M. designed the research, assisted with performing the statistical analysis, analyzing the results, and proofreading the manuscript. E.M. analyzed and interpreted the data and proofread the manuscript. S.H. aided with statistical analysis, analyzed results, and proofread the manuscript.




Publication History

Received: 03 November 2021

Accepted: 07 March 2022

Accepted Manuscript online:
09 March 2022

Article published online:
31 May 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

Comment to this article:

Growth Differentiation Factor-15: A Novel Biomarker for Predicting Risk of Venous Thromboembolism and Bleeding in Patients with CancerThromb Haemost 2022; 122(07): 1075-1075
DOI: 10.1055/a-1827-7328

 

  • References

  • 1 Mulder FI, Horváth-Puhó E, van Es N. et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021; 137 (14) 1959-1969
    CrossrefPubMedSearch in Google Scholar
  • 2 Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis - current understanding from an epidemiological point of view. Br J Haematol 2010; 149 (06) 824-833
    CrossrefPubMedSearch in Google Scholar
  • 3 Wun T, White RH. Venous thromboembolism (VTE) in patients with cancer: epidemiology and risk factors. Cancer Invest 2009; 27 (01, Suppl 1): 63-74
    CrossrefPubMedSearch in Google Scholar
  • 4 Kyriazi V, Theodoulou E. Assessing the risk and prognosis of thrombotic complications in cancer patients. Arch Pathol Lab Med 2013; 137 (09) 1286-1295
    CrossrefPubMedSearch in Google Scholar
  • 5 Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer 2010; 102 (01, Suppl 1): S2-S9
    CrossrefPubMedSearch in Google Scholar
  • 6 Lyman GH, Culakova E, Poniewierski MS, Kuderer NM. Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer. Thromb Res 2018; 164 (Suppl. 01) S112-S118
    CrossrefPubMedSearch in Google Scholar
  • 7 Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68 (06) 394-424
    Search in Google Scholar
  • 8 Khorana AA, Soff GA, Kakkar AK. et al; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019; 380 (08) 720-728
    CrossrefPubMedSearch in Google Scholar
  • 9 Carrier M, Abou-Nassar K, Mallick R. et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
    CrossrefPubMedSearch in Google Scholar
  • 10 Wang TF, Zwicker JI, Ay C. et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: Guidance from the SSC of the ISTH. J Thromb Haemost 2019; 17 (10) 1772-1778
    CrossrefPubMedSearch in Google Scholar
  • 11 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline update. J Clin Oncol 2020; 38 (05) 496-520
    CrossrefPubMedSearch in Google Scholar
  • 12 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
    CrossrefPubMedSearch in Google Scholar
  • 13 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
    CrossrefPubMedSearch in Google Scholar
  • 14 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
    CrossrefPubMedSearch in Google Scholar
  • 15 Pabinger I, van Es N, Heinze G. et al. A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol 2018; 5 (07) e289-e298
    CrossrefPubMedSearch in Google Scholar
  • 16 Hijazi Z, Oldgren J, Lindbäck J. et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
    Search in Google Scholar
  • 17 van Es N, Di Nisio M, Cesarman G. et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica 2017; 102 (09) 1494-1501
    CrossrefPubMedSearch in Google Scholar
  • 18 Khorana AA, Francis CW. Risk prediction of cancer-associated thrombosis: Appraising the first decade and developing the future. Thromb Res 2018; 164 (Suppl. 01) S70-S76
    CrossrefPubMedSearch in Google Scholar
  • 19 Zulkifly H, Lip GYH, Lane DA. Bleeding risk scores in atrial fibrillation and venous thromboembolism. Am J Cardiol 2017; 120 (07) 1139-1145
    CrossrefPubMedSearch in Google Scholar
  • 20 Mulder FI, Bosch FTM, van Es N. Primary thromboprophylaxis in ambulatory cancer patients: where do we stand?. Cancers (Basel) 2020; 12 (02) 367
    CrossrefPubMedSearch in Google Scholar
  • 21 Folsom AR, Lutsey PL, Nambi V. et al. Troponin T, NT-proBNP, and venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). Vasc Med 2014; 19 (01) 33-41
    CrossrefPubMedSearch in Google Scholar
  • 22 Hansen ES, Hindberg K, Latysheva N. et al; INVENT Consortium. Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism. Blood 2020; 136 (16) 1863-1870
    CrossrefPubMedSearch in Google Scholar
  • 23 Liang W, Wei F, Yang C. et al. GDF-15 is associated with thrombus burden in patients with deep venous thrombosis. Thromb Res 2020; 187: 148-153
    CrossrefPubMedSearch in Google Scholar
  • 24 Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol 2021; 17 (10) 592-607
    CrossrefPubMedSearch in Google Scholar
  • 25 Troponin T. High Sensitivity (hs-TnT). Cleveland HeartLab, Inc. Accessed September 15, 2021 at: https://www.clevelandheartlab.com/tests/troponin-t-cardiac/
    PubMed
  • 26 Demissei BG, Hubbard RA, Zhang L. et al. Changes in cardiovascular biomarkers with breast cancer therapy and associations with cardiac dysfunction. J Am Heart Assoc 2020; 9 (02) e014708
    CrossrefPubMedSearch in Google Scholar
  • 27 Lam E, Higgins V, Zhang L. et al. Normative values of high-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide in children and adolescents: a study from the CALIPER cohort. J Appl Lab Med 2021; 6 (02) 344-353
    CrossrefPubMedSearch in Google Scholar
  • 28 Amstad A, Coray M, Frick C. et al. Growth differentiation factor 15 is increased in stable MS. Neurol Neuroimmunol Neuroinflamm 2020; 7 (02) e675
    CrossrefPubMedSearch in Google Scholar
  • 29 Damman P, Kempf T, Windhausen F. et al; ICTUS investigators. Growth-differentiation factor 15 for long-term prognostication in patients with non-ST-elevation acute coronary syndrome: an Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy. Int J Cardiol 2014; 172 (02) 356-363
    CrossrefPubMedSearch in Google Scholar
  • 30 Puurunen MK, Enserro D, Xanthakis V. et al. Biomarkers for the prediction of venous thromboembolism in the community. Thromb Res 2016; 145: 34-39
    CrossrefPubMedSearch in Google Scholar
  • 31 Duran L, Kayhan S, Guzel A. et al. The prognostic values of GDF-15 in comparison with NT-proBNP in patients with normotensive acute pulmonary embolism. Clin Lab 2014; 60 (08) 1365-1371
    PubMedSearch in Google Scholar
  • 32 Lankeit M, Kempf T, Dellas C. et al. Growth differentiation factor-15 for prognostic assessment of patients with acute pulmonary embolism. Am J Respir Crit Care Med 2008; 177 (09) 1018-1025
    CrossrefPubMedSearch in Google Scholar
  • 33 Xiao F, Lv S, Zong Z. et al. Cerebrospinal fluid biomarkers for brain tumor detection: clinical roles and current progress. Am J Transl Res 2020; 12 (04) 1379-1396
    PubMedSearch in Google Scholar
  • 34 Lutsey PL, Nambi V, Cushman M. et al. Abstract 020: NT-proBNP, hs-troponin T and incident venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 2013; 127 (suppl_12): A020
    CrossrefPubMedSearch in Google Scholar
  • 35 Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem 2010; 56 (02) 254-261
    CrossrefPubMedSearch in Google Scholar
  • 36 Kaeberich A, Seeber V, Jiménez D. et al. Age-adjusted high-sensitivity troponin T cut-off value for risk stratification of pulmonary embolism. Eur Respir J 2015; 45 (05) 1323-1331
    CrossrefPubMedSearch in Google Scholar
  • 37 Xu RY, Zhu XF, Yang Y, Ye P. High-sensitive cardiac troponin T. J Geriatr Cardiol 2013; 10 (01) 102-109
    PubMedSearch in Google Scholar
  • 38 Folsom AR, Nambi V, Bell EJ. et al. Troponin T, N-terminal pro-B-type natriuretic peptide, and incidence of stroke: the atherosclerosis risk in communities study. Stroke 2013; 44 (04) 961-967
    CrossrefPubMedSearch in Google Scholar
  • 39 Reich LM, Folsom AR, Key NS. et al. Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism. J Thromb Haemost 2006; 4 (09) 1909-1913
    CrossrefPubMedSearch in Google Scholar
  • 40 Pavo N, Raderer M, Hülsmann M. et al. Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality. Heart 2015; 101 (23) 1874-1880
    CrossrefPubMedSearch in Google Scholar
  • 41 Tuñón J, Higueras J, Tarín N. et al. N-terminal pro-brain natriuretic peptide is associated with a future diagnosis of cancer in patients with coronary artery disease. PLoS One 2015; 10 (06) e0126741
    CrossrefPubMedSearch in Google Scholar
  • 42 Maisel AS, Krishnaswamy P, Nowak RM. et al; Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347 (03) 161-167
    CrossrefPubMedSearch in Google Scholar
  • 43 Sandri MT, Salvatici M, Cardinale D. et al. N-terminal pro-B-type natriuretic peptide after high-dose chemotherapy: a marker predictive of cardiac dysfunction?. Clin Chem 2005; 51 (08) 1405-1410
    CrossrefPubMedSearch in Google Scholar
  • 44 Ruggieri F, Noris A, Beretta L, Mortini P, Gemma M. Serum B-type natriuretic peptide is affected by neoplastic edema in patients with a brain tumor. World Neurosurg 2016; 85: 193-196
    CrossrefPubMedSearch in Google Scholar
  • 45 Kumar V, Shaw JR, Key NS. et al. D-dimer enhances risk-targeted thromboprophylaxis in ambulatory patients with cancer. Oncologist 2020; 25 (12) 1075-1083
    CrossrefPubMedSearch in Google Scholar
  • 46 Roy D, Modi A, Khokhar M. et al. Growth differentiation factor-15 as a candidate biomarker in gynecologic malignancies: a meta-analysis. medRxiv 2020. Doi: https://doi.org/10.1101/2020.07.07.20148221
    PubMed
  • 47 Spanopoulou A, Gkretsi V. Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients. Clin Exp Metastasis 2020; 37 (04) 451-464
    CrossrefPubMedSearch in Google Scholar
  • 48 Staff AC, Trovik J, Eriksson AG. et al. Elevated plasma growth differentiation factor-15 correlates with lymph node metastases and poor survival in endometrial cancer. Clin Cancer Res 2011; 17 (14) 4825-4833
    CrossrefPubMedSearch in Google Scholar
  • 49 Engerud H, Hope K, Berg HF. et al. Plasma growth differentiation factor-15 is an independent marker for aggressive disease in endometrial cancer. PLoS One 2019; 14 (01) e0210585
    CrossrefPubMedSearch in Google Scholar
  • 50 Bonita R, Pradhan R. Cardiovascular toxicities of cancer chemotherapy. Semin Oncol 2013; 40 (02) 156-167
    CrossrefPubMedSearch in Google Scholar