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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(10): 1653-1661
DOI: 10.1055/a-1816-8347
Coagulation and Fibrinolysis

Do Antiangiogenics Promote Clot Instability? Data from the TESEO Prospective Registry and Caravaggio Clinical Trial

Alberto Carmona-Bayonas
1   Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, University of Murcia, IMIB, Murcia, Spain
,
Melina Verso
2   Medicina Vascolare e d'Urgenza, Ospedale S. Maria della Misericordia, Università di Perugia, Perugia, Italy
,
Manuel Sánchez Cánovas
1   Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, University of Murcia, IMIB, Murcia, Spain
,
Jaime Rubio Pérez
3   Medical Oncology Department, Hospital Fundación Jiménez Diaz, Madrid, Spain
,
Marta García de Herreros
4   Medical Oncology Department, Hospital Clinic, Barcelona, Spain
,
Purificación Martínez del Prado
5   Medical Oncology Department, Hospital Universitario de Basurto, Bilbao, Spain
,
Isaura Fernández Pérez
6   Medical Oncology Department, Hospital Álvaro Cunqueiro/Complejo Hospitalario Universitario de Vigo, Vigo, Spain
,
Teresa Quintanar Verduguez
7   Medical Oncology Department, Hospital General Universitario de Elche, Elche, Spain
,
Berta Obispo Portero
8   Medical Oncology Department, Hospital Universitario Infanta Leonor, Madrid, Spain
,
Vanessa Pachón Olmos
9   Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
,
David Gómez
10   Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
,
Laura Ortega
11   Medical Oncology Department, Hospital Universitario Gregorio Marañon, Madrid, Spain
,
Marta Serrano Moyano
12   Medical Oncology Department, Hospital de Especialidades de Jerez de la Frontera, Jerez de la Frontera, Spain
,
Elena M. Brozos
13   Medical Oncology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain
,
Mercedes Biosca
14   Medical Oncology Department, Hospital Universitario Vall d́Hebron, Barcelona, Spain
,
Maite Antonio Rebollo
15   Medical Oncology Department, Instituto Catalán de Oncología (ICO), L'Hospitalet de Llobregat, Llobregat, Spain
,
Lucía Teijeira Sanchez
16   Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain
,
Carolina Hernández Pérez
17   Medical Oncology Department, Hospital Universitario Nuestra Señora de la Candelaria, Tenerife, Spain
,
José David Cumplido Burón
18   Medical Oncology Department, Hospital Universitario de Torrevieja, Torrevieja, Spain
,
Nieves Martínez Lago
19   Medical Oncology Department, Hospital Clínico Universitario A Coruña, La Coruña, Spain
,
Estefanía García Pérez
20   Medical Oncology Department, Hospital de Barcelona, Barcelona, Spain
,
Jose Muñoz Langa
21   Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
,
Pedro Pérez Segura
22   Medical Oncology Department and IdISSC, Hospital Universitario Clínico San Carlos, Madrid, Spain
,
Eva Martínez de Castro
23   Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
,
Paula Jimenez-Fonseca
10   Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
,
Giancarlo Agnelli
24   Internal Vascular and Emergency Medicine-Stroke Unit, University of Perugia, Perugia, Italy
,
Andrés Muñoz
10   Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
› Author Affiliations Funding This study was supported by unrestricted grants from Sanofi, Leo Pharma Rovi, and BMS-Pfizer. The sponsors of this research have not participated in data collection, analysis, or interpretation, in writing the report, or in the decision to submit the article for publication.
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Abstract

Background Venous thromboembolism (VTE) is a common complication in cancer patients. Much of its morbidity stems from the development of fatal pulmonary embolisms (PE). Little is known about the factors involved in clot stability, with angiogenesis possibly being implicated.

Methods The database is from the TESEO prospective registry that recruits cancer patients with VTE from 41 Spanish hospitals. Independent validation was conducted in a cohort from the Caravaggio trial. The objective is to evaluate the association between exposure to antiangiogenic therapies and the PE/VTE proportion in oncological patients.

Results In total, 1,536 subjects were evaluated; 58.4% (n = 894) had a PE and 7% (n = 108) received antiangiogenic therapy (bevacizumab in 75%). The PE/VTE proportion among antiangiogenic-treated individuals was 77/108 (71.3%) versus 817/1,428 (57.2%) among those receiving other alternative therapies (p = 0.004). The effect of the antiangiogenics on the PE/VTE proportion held up across all subgroups except for active smokers or those with chronic obstructive pulmonary disease. Exposure to antiangiogenics was associated with increased PEs, odds ratio (OR) 2.27 (95% CI, 1.42–3.63). In the Caravaggio trial, PE was present in 67% of the individuals treated with antiangiogenics, 50% of those who received chemotherapy without antiangiogenic treatment, and 60% without active therapy (p = 0.0016).

Conclusion Antiangiogenics are associated with increased proportion of PE in oncological patients with VTE. If an effect on clot stability is confirmed, the concept of thrombotic risk in cancer patients should be reconsidered in qualitative terms.

Keywords

antiangiogenic therapy - cancer - clot stability - pulmonary embolism - venous thromboembolism

Ethical Approval

This study was performed in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments. This observational, non-interventional trial was approved by the Research Ethics Committees of all centres, and by the Spanish Agency of Medicines and Medical Devices (AEMPS). Signed informed consent was obtained from all patients. Informed consent and approval by the competent national authorities includes permission for publication and dissemination of the data.


Supplementary Material



Publication History

Received: 10 January 2022

Accepted: 22 March 2022

Accepted Manuscript online:
05 April 2022

Article published online:
18 June 2022

© 2022. 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. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160 (06) 809-815
    CrossrefPubMedGoogle Scholar
  • 2 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch Intern Med 1999; 159 (05) 445-453
    CrossrefPubMedGoogle Scholar
  • 3 Carmona-Bayonas A, Jiménez-Fonseca P, Font C. et al. Predicting serious complications in patients with cancer and pulmonary embolism using decision tree modelling: the EPIPHANY Index. Br J Cancer 2017; 116 (08) 994-1001
    CrossrefPubMedGoogle Scholar
  • 4 Tutwiler V, Singh J, Litvinov RI, Bassani JL, Purohit PK, Weisel JW. Rupture of blood clots: mechanics and pathophysiology. Sci Adv 2020; 6 (35) c0496
    CrossrefPubMedGoogle Scholar
  • 5 Shaya SA, Saldanha LJ, Vaezzadeh N, Zhou J, Ni R, Gross PL. Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism. J Thromb Haemost 2016; 14 (01) 143-152
    CrossrefPubMedGoogle Scholar
  • 6 Carmona-Bayonas A, Gómez D, Martínez de Castro E. et al. A snapshot of cancer-associated thromboembolic disease in 2018-2019: first data from the TESEO prospective registry. Eur J Intern Med 2020; 78: 41-49
    CrossrefPubMedGoogle Scholar
  • 7 van der Hulle T, den Exter PL, Planquette B. et al. Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients. J Thromb Haemost 2016; 14 (01) 105-113
    CrossrefPubMedGoogle Scholar
  • 8 Plasencia-Martínez JM, Carmona-Bayonas A, Calvo-Temprano D. et al. Prognostic value of computed tomography pulmonary angiography indices in patients with cancer-related pulmonary embolism: data from a multicenter cohort study. Eur J Radiol 2017; 87: 66-75
    CrossrefPubMedGoogle Scholar
  • 9 Carmona-Bayonas A, Jiménez-Fonseca P, Garrido M. et al. Multistate models: accurate and dynamic methods to improve predictions of thrombotic risk in patients with cancer. Thromb Haemost 2019; 119 (11) 1849-1859
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Pabinger I, Thaler J, Ay C. Biomarkers for prediction of venous thromboembolism in cancer. Blood 2013; 122 (12) 2011-2018
    CrossrefPubMedGoogle Scholar
  • 11 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
    CrossrefPubMedGoogle Scholar
  • 12 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis. J Biol Chem 2000; 275 (03) 1521-1524
    CrossrefPubMedGoogle Scholar
  • 13 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144 (05) 646-674
    CrossrefPubMedGoogle Scholar
  • 14 Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis. J Thromb Haemost 2006; 4 (01) 19-25
    CrossrefPubMedGoogle Scholar
  • 15 Al-Husein B, Abdalla M, Trepte M, Deremer DL, Somanath PR. Antiangiogenic therapy for cancer: an update. Pharmacotherapy 2012; 32 (12) 1095-1111
    CrossrefPubMedGoogle Scholar
  • 16 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
    CrossrefPubMedGoogle Scholar
  • 17 Harrell F. Regression Modeling Strategies: with Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis. 2nd ed.. New York: Springer; 2015
    CrossrefGoogle Scholar
  • 18 R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R. Foundation for Statistical Computing; 2014
    Google Scholar
  • 19 Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300 (19) 2277-2285
    CrossrefPubMedGoogle Scholar
  • 20 Hurwitz HI, Saltz LB, Van Cutsem E. et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 2011; 29 (13) 1757-1764
    CrossrefPubMedGoogle Scholar
  • 21 Abdel-Qadir H, Ethier J-L, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: a systematic review and meta-analysis. Cancer Treat Rev 2017; 53: 120-127
    CrossrefPubMedGoogle Scholar
  • 22 Liu M, Zheng Y, Chen Z. et al. Risk of severe pulmonary embolism in cancer patients receiving bevacizumab: results from a meta-analysis of published and unpublished data. Tumor Biol 2017; 39: 1010428317714897
    CrossrefPubMedGoogle Scholar
  • 23 Kotlowska MP, Cabezón L, Custodio-Cabello S. Thrombosis incidence in cancer patients treated with antiangiogenic therapy. Ann Oncol 2020; S1052
    CrossrefPubMedGoogle Scholar
  • 24 Corral J, Roldán V, Vicente V. Deep venous thrombosis or pulmonary embolism and factor V Leiden: enigma or paradox. Haematologica 2010; 95 (06) 863-866
    CrossrefPubMedGoogle Scholar
  • 25 Mäkelburg ABU, Veeger NJGM, Middeldorp S. et al. Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study. Haematologica 2010; 95 (06) 1030-1033
    CrossrefPubMedGoogle Scholar
  • 26 Dardik R, Loscalzo J, Eskaraev R, Inbal A. Molecular mechanisms underlying the proangiogenic effect of factor XIII. Arterioscler Thromb Vasc Biol 2005; 25 (03) 526-532
    CrossrefPubMedGoogle Scholar
  • 27 Verheul HMW, Jorna AS, Hoekman K, Broxterman HJ, Gebbink MF, Pinedo HM. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 2000; 96 (13) 4216-4221
    CrossrefPubMedGoogle Scholar
  • 28 Chen N, Ren M, Li R. et al. Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma. Mol Cancer 2015; 14: 140
    CrossrefPubMedGoogle Scholar
  • 29 Mitchell P, Mok T, Barraclough H, Strizek A, Lew R, van Kooten M. Smoking history as a predictive factor of treatment response in advanced non-small-cell lung cancer: a systematic review. Clin Lung Cancer 2012; 13 (04) 239-251
    CrossrefPubMedGoogle Scholar
  • 30 Ząbczyk M, Królczyk G, Czyżewicz G. et al. Altered fibrin clot properties in advanced lung cancer: strong impact of cigarette smoking. Med Oncol 2019; 36 (04) 37
    CrossrefPubMedGoogle Scholar
  • 31 Tritschler T, Kraaijpoel N, Girard P. et al; Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease. Definition of pulmonary embolism-related death and classification of the cause of death in venous thromboembolism studies: Communication from the SSC of the ISTH. J Thromb Haemost 2020; 18 (06) 1495-1500
    CrossrefPubMedGoogle Scholar
  • 32 Maraveyas A, Waters J, Roy R. et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48 (09) 1283-1292
    CrossrefPubMedGoogle Scholar