Thromb Haemost 2024; 124(04): 324-336
DOI: 10.1055/a-2145-7238
Coagulation and Fibrinolysis

A Novel Risk Prediction Score for Clinically Significant Bleeding in Patients Anticoagulated for Venous Thromboembolism with Active Cancer

1   Department of Haematology, Guy's and St Thomas' Hospitals, NHS Foundation Trust, King's College London, London, United Kingdom
2   Institute for Epidemiology, Statistics and Informatics GmbH, Frankfurt, Germany
Satarupa Choudhuri
3   Northern Care Alliance NHS Foundation Trust, Manchester, United Kingdom
Ayman Nassar
4   Bristol Myers Squibb Pharmaceuticals Ltd., Uxbridge, Middlesex, United Kingdom
4   Bristol Myers Squibb Pharmaceuticals Ltd., Uxbridge, Middlesex, United Kingdom
2   Institute for Epidemiology, Statistics and Informatics GmbH, Frankfurt, Germany
› Author Affiliations
Funding This study was supported by Pfizer Ltd. and Bristol-Myers Squibb.


Background Cancer-associated venous thromboembolism (Ca-VTE) treatment with anticoagulation is associated with bleeding complications and there are limited data on risk factors. Current models do not provide accurate bleeding risk prediction.

Methods UK Clinical Practice Research Datalink data (2008–2020) were used to generate a cohort of patients with anticoagulant initiation for first Ca-VTE. Patients were observed up to 180 days for significant bleeding including major bleeding and clinically relevant nonmajor bleeding requiring hospitalization (CRNMB-H). A scoring scheme was developed from sub-distribution hazard ratios, and its discrimination (expressed by the C-statistic) estimated from cross-validation.

Results A total of 15,749 patients with Ca-VTE and anticoagulant treatment were included. In total, 537 significant bleeding events, 161 major bleeds, and 376 CRNMB-H were identified after adjudicated review in 4,914 person-years of observation. Incidence rates of 3.3 and 7.7 per 100 person-years were noted for major bleeding and CRNMB-H. Independent predictors of significant bleeding included cancer of the bladder, central nervous system, cervix, kidney, melanoma, prostate and upper gastrointestinal tract, metastases, minor surgery, minor trauma, and history of major bleeding or CRNMB (before or after the Ca-VTE diagnosis). Patients recognized as low, medium, and high risk (30.4, 56.8, and 1.7% of the population, respectively) had a 6-month significant bleeding incidence rate of 5.1, 19.0, and 56.5 per 100 person-years, respectively. Overall C-statistic for significant bleeding was 0.70 (95% confidence interval: 0.65–0.75), and 0.76 (0.68–0.84) and 0.67 (0.61–0.73) for major bleeding and for CRNMB-H, respectively.

Conclusion This risk score may identify patients at risk of significant bleeding, while also helping to determine treatment duration.

Data Availability Statement

All anonymized data and methodologies for analyses are available upon request provided the requestor becomes a CPRD client.

Authors' Contribution

A.T.C. and A.N. created the concept of the study. A.T.C., C.M., and S.C. adjudicated all relevant diagnoses. A.T.C., C.W., and C.M. performed all statistical analyses. All authors provided clinical interpretation and all authors co-wrote the draft and final versions of the manuscript. A.N. and K.G.P. sought final approvals for publication of the manuscript.

Supplementary Material

Publication History

Received: 02 February 2023

Accepted: 31 July 2023

Accepted Manuscript online:
01 August 2023

Article published online:
11 September 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017; 117 (01) 57-65
  • 2 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
  • 3 Weitz JI, Haas S, Ageno W. et al; GARFIELD-VTE investigators. Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE. J Thromb Thrombolysis 2020; 50 (02) 267-277
  • 4 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
  • 5 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152 (09) 578-589
  • 6 Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 (11) 2012-2020
  • 7 Lecumberri R, Alfonso A, Jiménez D. et al; RIETE investigators. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110 (04) 834-843
  • 8 Poénou G, Tolédano E, Helfer H. et al. In search of the appropriate anticoagulant-associated bleeding risk assessment model for cancer-associated thrombosis patients. Cancers (Basel) 2022; 14 (08) 1937
  • 9 de Winter MA, Dorresteijn JAN, Ageno W. et al. Estimating bleeding risk in patients with cancer-associated thrombosis: evaluation of existing risk scores and development of a new risk score. Thromb Haemost 2022; 122 (05) 818-829
  • 10 den Exter PL, Woller SC, Robert-Ebadi H. et al. Management of bleeding risk in patients who receive anticoagulant therapy for venous thromboembolism: communication from the ISTH SSC Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease. J Thromb Haemost 2022; 20 (08) 1910-1919
  • 11 Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159 (05) 457-460
  • 12 Ruíz-Giménez N, Suárez C, González R. et al; RIETE Investigators, Findings from the RIETE Registry. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Thromb Haemost 2008; 100 (01) 26-31
  • 13 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138 (05) 1093-1100
  • 14 Kooiman J, van Hagen N, Iglesias Del Sol A. et al. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLoS One 2015; 10 (04) e0122520
  • 15 Klok FA, Hösel V, Clemens A. et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J 2016; 48 (05) 1369-1376
  • 16 Di Nisio M, Ageno W, Rutjes AW, Pap AF, Büller HR. Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. Thromb Haemost 2016; 115 (02) 424-432
  • 17 Di Nisio M, Raskob G, Büller HR. et al. Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists. Thromb Haemost 2017; 117 (04) 784-793
  • 18 Martinez C, Katholing A, Wallenhorst C, Cohen AT. Prediction of significant bleeding during vitamin K antagonist treatment for venous thromboembolism in outpatients. Br J Haematol 2020; 189 (03) 524-533
  • 19 de Winter MA, van Es N, Büller HR, Visseren FLJ, Nijkeuter M. Prediction models for recurrence and bleeding in patients with venous thromboembolism: a systematic review and critical appraisal. Thromb Res 2021; 199: 85-96
  • 20 Kim K, Yamashita Y, Morimoto T. et al; COMMAND VTE Registry Investigators. Risk factors for major bleeding during prolonged anticoagulation therapy in patients with venous thromboembolism: from the COMMAND VTE registry. Thromb Haemost 2019; 119 (09) 1498-1507
  • 21 Menapace LA, McCrae KR, Khorana AA. Predictors of recurrent venous thromboembolism and bleeding on anticoagulation. Thromb Res 2016; 140 (Suppl. 01) S93-S98
  • 22 Trujillo-Santos J, Nieto JA, Tiberio G. et al; RIETE Registry, Findings from the RIETE Registry. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Thromb Haemost 2008; 100 (03) 435-439
  • 23 Nishimoto Y, Yamashita Y, Kim K. et al; COMMAND VTE Registry Investigators. Risk factors for major bleeding during anticoagulation therapy in cancer-associated venous thromboembolism. From the COMMAND VTE registry. Circ J 2020; 84 (11) 2006-2014
  • 24 Mahe I, Chidiac J, Bertoletti L. et al. RIETE investigators. The clinical course of venous thromboembolism may differ according to cancer site. Am J Med 2017; 130 (03) 337-347
  • 25 Prandoni P, Trujillo-Santos J, Surico T, Dalla Valle F, Piccioli A, Monreal M. RIETE Investigators. Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with solid cancer: findings from the RIETE registry. Haematologica 2008; 93 (09) 1432-1434
  • 26 Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014; 112 (02) 255-263
  • 27 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
  • 28 Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD. A note on competing risks in survival data analysis. Br J Cancer 2004; 91 (07) 1229-1235
  • 29 Arlot S, Celisse A. A survey of cross-validation procedures for model selection. Stat Surv 2010; 4: 40-79
  • 30 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
  • 31 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest 2021; 160 (06) e545-e608