Thrombin Generation Markers as Predictors of Cancer-Associated Venous Thromboembolism: A Systematic Review

Abstract

Venous thromboembolism (VTE) is a main contributor to morbidity and mortality in cancer patients. Biomarkers with the potential to predict cancer-associated VTE are continually sought. Of these, markers of thrombin generation present a likely option. The present systematic review examines the ability of three widely used biomarkers of thrombin generation: prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and ex vivo thrombin generation, to predict VTE in both solid and hematologic adult cancer patients. Relevant studies were identified in the PubMed and Embase databases, and the review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Each study was evaluated using the quality assessment tool from the National Heart, Lung, and Blood Institute. The review protocol was published on PROSPERO with identifier CRD42022362339. In total, 24 papers were included in the review: 11 reporting data on F1.2, 9 on TAT, and 12 on ex vivo thrombin generation. The quality ratings of the included studies varied from good (n = 13), fair (n = 8), to poor (n = 3) with a high heterogenicity. However, F1.2, TAT complex, and ex vivo thrombin generation were all found to be associated with the development of VTE. This association was most pronounced for F1.2. Furthermore, the determination of F1.2 was able to improve the precision of several established risk assessment scores. In conclusion, markers of thrombin generation were found to be elevated in cancer patients with VTE, and particularly, F1.2 was found to be a promising predictor of cancer-associated VTE.

Keywords

prothrombin fragment 1.2 - antithrombin III-protease complex - thrombin generation - cancer-associated thrombosis - embolism and thrombosis - neoplasms

Publikationsverlauf

Artikel online veröffentlicht:
09. Oktober 2023

• References

• 1 Van Haren RM, Valle EJ, Thorson CM. et al. Long-term coagulation changes after resection of thoracoabdominal malignancies. J Am Coll Surg 2014; 218 (04) 846-854
• 2 Fernandes CJ, Morinaga LTK, Alves Jr JL. et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev 2019; 28 (151) 180119
• 3 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5 (03) 632-634
• 4 Costamagna G, Navi BB, Beyeler M, Hottinger AF, Alberio L, Michel P. Ischemic stroke in cancer: mechanisms, biomarkers, and implications for treatment. Semin Thromb Hemost 2023; 50 (03) 342-359
• 5 Khorana AA, Francis CW, Kuderer NM. et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res 2017; 151: 89-95
• 6 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122 (10) 1712-1723
• 7 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
• 8 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
• 9 Verso M, Agnelli G, Barni S, Gasparini G, LaBianca R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the PROTECHT score. Intern Emerg Med 2012; 7 (03) 291-292
• 10 Cella CA, Di Minno G, Carlomagno C. et al. Preventing venous thromboembolism in ambulatory cancer patients: the ONKOTEV study. Oncologist 2017; 22 (05) 601-608
• 11 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
• 12 Gerotziafas GT, Taher A, Abdel-Razeq H. et al; COMPASS–CAT Working Group. A predictive score for thrombosis associated with breast, colorectal, lung, or ovarian cancer: the prospective COMPASS-cancer-associated thrombosis study. Oncologist 2017; 22 (10) 1222-1231
• 13 Schorling RM, Pfrepper C, Golombek T. et al. Evaluation of biomarkers for the prediction of venous thromboembolism in ambulatory cancer patients. Oncol Res Treat 2020; 43 (09) 414-427
• 14 Guman NAM, van Geffen RJ, Mulder FI. et al. Evaluation of the Khorana, PROTECHT, and 5-SNP scores for prediction of venous thromboembolism in patients with cancer. J Thromb Haemost 2021; 19 (12) 2974-2983
• 15 Pépin M, Kleinjan A, Hajage D. et al. ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. J Thromb Haemost 2016; 14 (02) 306-315
• 16 Larsen JB, Hvas AM. Thrombin: a pivotal player in hemostasis and beyond. Semin Thromb Hemost 2021; 47 (07) 759-774
• 17 Zwicker JI, Furie BC, Furie B. Cancer-associated thrombosis. Crit Rev Oncol Hematol 2007; 62 (02) 126-136
• 18 Reddel CJ, Tan CW, Chen VM. Thrombin generation and cancer: contributors and consequences. Cancers (Basel) 2019; 11 (01) 100
• 19 Ay C, Vormittag R, Dunkler D. et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27 (25) 4124-4129
• 20 Chen Q, Shou W, Wu W, Wang G, Cui W. Performance evaluation of thrombomodulin, thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, and t-PA: PAI-1 complex. J Clin Lab Anal 2019; 33 (06) e22913
• 21 Ay C, Dunkler D, Simanek R. et al. Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2011; 29 (15) 2099-2103
• 22 Tripodi A. Thrombin generation assay and its application in the clinical laboratory. Clin Chem 2016; 62 (05) 699-707
• 23 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372 (71) n71
• 24 National Heart L, and Blood Institute. Study quality assessment tools. Accessed 14.04. at: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
• 25 Falanga A, Ofosu FA, Cortelazzo S. et al. Preliminary study to identify cancer patients at high risk of venous thrombosis following major surgery. Br J Haematol 1993; 85 (04) 745-750
• 26 Iversen LH, Okholm M, Thorlacius-Ussing O. Pre- and postoperative state of coagulation and fibrinolysis in plasma of patients with benign and malignant colorectal disease—a preliminary study. Thromb Haemost 1996; 76 (04) 523-528
• 27 Iversen LH, Thorlacius-Ussing O. Relationship of coagulation test abnormalities to tumour burden and postoperative DVT in resected colorectal cancer. Thromb Haemost 2002; 87 (03) 402-408
• 28 Posch F, Thaler J, Zlabinger GJ. et al. Soluble vascular endothelial growth factor (sVEGF) and the risk of venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study (CATS). Clin Cancer Res 2016; 22 (01) 200-206
• 29 Reitter EM, Kaider A, Ay C. et al. Longitudinal analysis of hemostasis biomarkers in cancer patients during antitumor treatment. J Thromb Haemost 2016; 14 (02) 294-305
• 30 Sallah S, Husain A, Sigounas V. et al. Plasma coagulation markers in patients with solid tumors and venous thromboembolic disease receiving oral anticoagulation therapy. Clin Cancer Res 2004; 10 (21) 7238-7243
• 31 Thaler J, Ay C, Kaider A. et al. Biomarkers predictive of venous thromboembolism in patients with newly diagnosed high-grade gliomas. Neuro-oncol 2014; 16 (12) 1645-1651
• 32 Tsubata Y, Hotta T, Hamai K. et al. A new risk-assessment tool for venous thromboembolism in advanced lung cancer: a prospective, observational study. J Hematol Oncol 2022; 15 (01) 40
• 33 van Doormaal F, Kleinjan A, Berckmans RJ. et al. Coagulation activation and microparticle-associated coagulant activity in cancer patients. An exploratory prospective study. Thromb Haemost 2012; 108 (01) 160-165
• 34 Kirwan CC, McDowell G, McCollum CN, Kumar S, Byrne GJ. Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer. Br J Cancer 2008; 99 (07) 1000-1006
• 35 Liang H, Guo X, Li Y. Cervical cancer associated biomarkers of identify high risk of venous thrombosis. Clin Lab 2020; 66 (05)
• 36 Qi Y, Hu X, Chen J, Ying X, Shi Y. The risk factors of VTE and survival prognosis of patients with malignant cancer: implication for nursing and treatment. Clin Appl Thromb Hemost 2020; 26 (e-pub ahed of print)
• 37 Takata H, Hirakata A, Ueda J. et al. Prediction of portal vein thrombosis after hepatectomy for hepatocellular carcinoma. Langenbecks Arch Surg 2021; 406 (03) 781-789
• 38 Abu Saadeh F, Langhe R, Galvin DM. et al. Procoagulant activity in gynaecological cancer patients; the effect of surgery and chemotherapy. Thromb Res 2016; 139: 135-141
• 39 Chalayer E, Tardy-Poncet B, Karlin L. et al. Thrombin generation in newly diagnosed multiple myeloma during the first three cycles of treatment: an observational cohort study. Res Pract Thromb Haemost 2018; 3 (01) 89-98
• 40 Gezelius E, Flou Kristensen A, Bendahl PO. et al. Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: a sub-study of RASTEN—-a randomized trial with low molecular weight heparin. PLoS One 2018; 13 (11) e0207387
• 41 Leiba M, Malkiel S, Budnik I. et al. Thrombin generation as a predictor of thromboembolic events in multiple myeloma patients. Blood Cells Mol Dis 2017; 65: 1-7
• 42 Syrigos K, Grapsa D, Sangare R. et al. Prospective assessment of clinical risk factors and biomarkers of hypercoagulability for the identification of patients with lung adenocarcinoma at risk for cancer-associated thrombosis: the observational ROADMAP-CAT study. Oncologist 2018; 23 (11) 1372-1381
• 43 Undas A, Zubkiewicz-Usnarska L, Helbig G. et al. Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications. Blood Coagul Fibrinolysis 2015; 26 (06) 621-627
• 44 Yerrabothala S, Gourley BL, Ford JC. et al. Systemic coagulation is activated in patients with meningioma and glioblastoma. J Neurooncol 2021; 155 (02) 173-180
• 45 Gezelius E, Belting M. Biomarkers of venous thromboembolism in cancer: a silent echo from local events?. Biomarkers Med 2019; 13 (07) 507-509
• 46 Mrozinska S, Cieslik J, Broniatowska E, Malinowski KP, Undas A. Prothrombotic fibrin clot properties associated with increased endogenous thrombin potential and soluble P-selectin predict occult cancer after unprovoked venous thromboembolism. J Thromb Haemost 2019; 17 (11) 1912-1922