A Predictive Model for Cancer-Associated Thrombosis in Japanese Cancer Patients: Findings from the J-Khorana Registry

Abstract

Background Although the close relationship between cancer and venous thromboembolism (VTE) has been identified, risk stratification for VTE in Japanese patients with cancer remains unclear.

Objectives This study aimed to validate the Khorana VTE risk assessment score (KRS) for VTE diagnosis and establish an optimal predictive model for VTE in Japanese patients with cancer.

Methods A total of 7,955 Japanese patients with cancer were subdivided into low- (0), intermediate- (1–2), and high-score (3) groups according to the KRS. Using 37 explanatory variables, a total of 2,833 patients with cancer were divided into derivation and validation cohorts (5:5). A risk model for Japanese participants was developed using the derivation cohort data.

Results The prevalence of VTE in low-, intermediate-, and high-score patients was 1.2, 2.5, and 4.3%, respectively. Logistic regression analysis demonstrated that cancer stage (III–IV) and KRS ≥ 2 were independent and significant predictors of VTE onset. The risk model for VTE assigned 1 point to body mass index ≥25 kg/m² and 2 points each to the prevalence of osteochondral cancer and D-dimer level ≥1.47 µg/mL. The areas under the curve of the risk model were 0.763 and 0.656 in the derivation and validation cohorts, respectively.

Conclusion The KRS was useful in Japanese patients, and our new predictive model may be helpful for the diagnosis of VTE in Japanese patients with cancer.

Keywords

venous thromboembolism - cancer - predictive model

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The Khorana VTE risk assessment score was useful in Japanese patients, and our new predictive model, using BMI, cancer site, and D-dimer level, may aid the diagnosis of VTE in Japanese patients with cancer. #VTE#VenousThromboembolism#Cancer-AssociatedThrombosis

X (formerly Twitter): @daisukesueta

Trial Registration Number

The University Hospital Medical Information Network Clinical Trials Registry (UMIN000050391).

Publikationsverlauf

Eingereicht: 05. Oktober 2023

Angenommen: 07. November 2023

Accepted Manuscript online:
09. November 2023

Artikel online veröffentlicht:
08. Januar 2024

• References

• 1 Girardi L, Wang TF, Ageno W, Carrier M. Updates in the incidence, pathogenesis, and management of cancer and venous thromboembolism. Arterioscler Thromb Vasc Biol 2023; 43 (06) 824-831
• 2 Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 2012; 9 (07) e1001275
• 3 Gussoni G, Frasson S, La Regina M, Di Micco P, Monreal M. RIETE Investigators. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res 2013; 131 (01) 24-30
• 4 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
• 5 Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-Of-The-Art review. JACC Cardiooncol 2021; 3 (02) 173-190
• 6 Lyon AR, López-Fernández T, Couch LS. et al; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J 2022; 43 (41) 4229-4361
• 7 Ay C, Dunkler D, Marosi C. et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
• 8 Palumbo A, Rajkumar SV, Dimopoulos MA. et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22 (02) 414-423
• 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 Pelzer U, Opitz B, Deutschinoff G. et al. Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 Trial. J Clin Oncol 2015; 33 (18) 2028-2034
• 11 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
• 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 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
• 14 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
• 15 Prandoni P, Lensing AW, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125 (01) 1-7
• 16 Louzada ML, Carrier M, Lazo-Langner A. et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 2012; 126 (04) 448-454
• 17 Kim HK, Tantry US, Park HW. et al. Ethnic difference of thrombogenicity in patients with cardiovascular disease: a pandora box to explain prognostic differences. Korean Circ J 2021; 51 (03) 202-221
• 18 Kim HK, Tantry US, Smith Jr SC. et al. The East Asian paradox: an updated position statement on the challenges to the current antithrombotic strategy in patients with cardiovascular disease. Thromb Haemost 2021; 121 (04) 422-432
• 19 Kodama J, Seki N, Masahiro S. et al. D-dimer level as a risk factor for postoperative venous thromboembolism in Japanese women with gynecologic cancer. Ann Oncol 2010; 21 (08) 1651-1656
• 20 Chen JS, Hung CY, Chang H. et al. Venous thromboembolism in Asian patients with pancreatic cancer following palliative chemotherapy: low incidence but a negative prognosticator for those with early onset. Cancers (Basel) 2018; 10 (12) 501
• 21 Wang KL, Yap ES, Goto S, Zhang S, Siu CW, Chiang CE. The diagnosis and treatment of venous thromboembolism in Asian patients. Thromb J 2018; 16: 4
• 22 Hiraide M, Shiga T, Minowa Y. et al. Identification of risk factors for venous thromboembolism and evaluation of Khorana venous thromboembolism risk assessment in Japanese lung cancer patients. J Cardiol 2020; 75 (01) 110-114
• 23 Tsubata Y, Kawakado K, Hamai K. et al. Identification of risk factors for venous thromboembolism and validation of the Khorana score in patients with advanced lung cancer: based on the multicenter, prospective Rising-VTE/NEJ037 study data. Int J Clin Oncol 2023; 28 (01) 69-78
• 24 Akasaka-Kihara F, Sueta D, Ishii M. et al. Validation of the Khorana venous thromboembolism risk score in Japanese cancer patients. JACC Asia 2021; 1 (02) 259-270
• 25 WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004; 363 (9403) 157-163
• 26 Sueta D, Yamamoto E, Nishihara T. et al. H2FPEF score as a prognostic value in HFpEF patients. Am J Hypertens 2019; 32 (11) 1082-1090
• 27 Matsuo S, Imai E, Horio M. et al; Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53 (06) 982-992
• 28 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
• 29 Fluss R, Faraggi D, Reiser B. Estimation of the Youden Index and its associated cutoff point. Biom J 2005; 47 (04) 458-472
• 30 Perkins NJ, Schisterman EF. The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol 2006; 163 (07) 670-675
• 31 Lutsey PL, Wassel CL, Cushman M, Sale MM, Divers J, Folsom AR. Genetic admixture is associated with plasma hemostatic factor levels in self-identified African Americans and Hispanics: the multi-ethnic study of atherosclerosis. J Thromb Haemost 2012; 10 (04) 543-549
• 32 Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol 2014; 8: 129-137
• 33 Navi BB, Reiner AS, Kamel H. et al. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol 2017; 70 (08) 926-938
• 34 Itzhaki Ben Zadok O, Spectre G, Leader A. Cancer-associated non-bacterial thrombotic endocarditis. Thromb Res 2022; 213 (Suppl. 01) S127-S132
• 35 Galanaud JP, Sevestre MA, Pernod G. et al. Long-term outcomes of cancer-related isolated distal deep vein thrombosis: the OPTIMEV study. J Thromb Haemost 2017; 15 (05) 907-916
• 36 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
• 37 Gould MK, Garcia DA, Wren SM. et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) e227S-e277S
• 38 Kahn SR, Lim W, Dunn AS. et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) e195S-e226S
• 39 Hamamoto Y, Tokushige A, Toshinori Y. et al. A new pre-test probability score for diagnosis of deep vein thrombosis in patients before surgery. J Cardiol 2022; 79 (05) 664-670
• 40 Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013; 122 (10) 1712-1723
• 41 Walker AJ, Card TR, West J, Crooks C, Grainge MJ. Incidence of venous thromboembolism in patients with cancer - a cohort study using linked United Kingdom databases. Eur J Cancer 2013; 49 (06) 1404-1413
• 42 de Simone G, Devereux RB, Chien S, Alderman MH, Atlas SA, Laragh JH. Relation of blood viscosity to demographic and physiologic variables and to cardiovascular risk factors in apparently normal adults. Circulation 1990; 81 (01) 107-117