专家论坛

肿瘤相关静脉血栓栓塞症的防治新认识

展开
  • 上海交通大学医学院附属瑞金医院呼吸与危重症医学科,上海 200025

收稿日期: 2023-05-10

  网络出版日期: 2023-12-18

基金资助

上海市科委课题(22015830600);上海市科委课题(21Y11901500);国家自然科学基金(82200041)

New knowledge of prophylaxis and treatment about cancer-associated thrombosis

Expand
  • Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received date: 2023-05-10

  Online published: 2023-12-18

摘要

肿瘤相关血栓(cancer-associated thrombosis,CAT)是肿瘤患者的第二大死亡原因,仅次于肿瘤自身进展,并可导致患者住院时间延长和再住院,造成严重的社会医疗负担。JAK2、ALK、KRAS突变等肿瘤特异性基因突变与实体肿瘤患者的CAT风险密切相关。接受免疫检查点抑制剂治疗的患者有很高的CAT风险,1年的累计发病率为10.86%。因此,准确的风险评估至关重要。Khorana评分(Khorana risk score,KRS)是首个评估CAT风险的模型,并已在多项研究中得到验证。新一代模型是基于KRS的升级改良,如Vienna CAT模型、PROTECHT模型、CONKO模型,但尚未经过大规模的外部验证。由于肿瘤与CAT密切相关,国内外制定了多个CAT相关预防指南,均建议肿瘤术后患者接受预防性抗凝治疗。低分子肝素(low molecular weight heparin,LMWH)是最广泛用于预防CAT的抗凝药物,新型口服抗凝药物(new oral anticoagulants,NOAC)亦被用于CAT预防。预防性抗凝治疗虽有导致大出血发生率增加的风险,但患者总体获益大于风险。治疗CAT的策略复杂,NOAC可作为非消化道肿瘤患者的一线药物,而胃肠道肿瘤患者抗凝首选LMWH。由于CAT患者同时接受抗凝治疗与抗肿瘤治疗,故需考虑药物间的相互作用,注意避免药物所致的出血,尤其是联合用药对NOAC药代动力学的影响。目前尚不明确CAT抗凝治疗的最佳持续时间,指南均建议CAT初发患者完成3~6个月抗凝治疗后,应继续接受无限期的抗凝。医师在确定肿瘤患者的抗凝疗程时,应评估血栓复发风险、出血风险,优化治疗方案。

本文引用格式

丁永杰, 张柳, 李庆云 . 肿瘤相关静脉血栓栓塞症的防治新认识[J]. 诊断学理论与实践, 2023 , 22(04) : 323 -331 . DOI: 10.16150/j.1671-2870.2023.04.001

Abstract

Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients, second only to the progression of the tumor. It leads to extended hospitalization and re-hospitalization, resulting in a serious social medical burden. Tumor-specific gene mutations such as JAK2, ALK, and KRAS mutations are closely related to the risk of CAT in patients with solid tumors. Patients treated with immune checkpoint inhibitors have a high risk of CAT, with a 1-year cumulative incidence rate of 10.86%. Therefore, accurate risk assessment is important. The Khorana risk score (KRS) is the first model to assess CAT risk and has been validated in several studies. The new generation models are based on the improvement of KRS, but they have not yet undergone large-scale external verification, such as the Vienna CAT model, PROTECHT model, and CONKO model. Due to the strong correlation between tumors and CAT, several CAT-related prevention guidelines have been established domestically and abroad. All of these guidelines recommend that patients undergo preventive anticoagulation therapy after tumor surgery. Low molecular weight heparin (LMWH) is the most widely used anticoagulant drug to prevent CAT. New oral anticoagulants (NOAC) are also used to prevent CAT, despite the incidence of hemorrhaging increases, the overall benefits to patients outweigh the risks. The strategy for treating CAT is complex. For patients with non-gastrointestinal tumors, NOAC can be used as a first-line drug, while LMWH is recommended for anticoagulation in patients with gastrointestinal tumors. Since CAT patients receive anticoagulation and anti-tumor therapy at the same time, drug interactions need to be considered to avoid drug-induced bleeding, especially the impact of combined medication on NOAC pharmacokinetics. The ideal length of anticoagulation therapy for CAT remains unclear. Guidelines recommend that patients with CAT should indefinitely continue the anticoagulation therapy after completing 3 to 6 months of initial anticoagulation therapy. Therefore, when determining the course of anticoagulation therapy for cancer patients, physicians should evaluate the risk of recurrence of thrombosis and bleeding, and optimize the treatment plan.

参考文献

[1] RASKOB G E, ANGCHAISUKSIRI P, BLANCO A N, et al. Thrombosis: a major contributor to global disease burden[J]. Arterioscler Thromb Vasc Biol, 2014, 34(11):2363-2371.
[2] MULDER F I, HORVáTH-PUHó E, VAN ES N, et al. Venous thromboembolism in cancer patients: a population-based cohort study[J]. Blood, 2021; 137(14):1959-1969.
[3] GEROTZIAFAS G T, MAHé I, LEFKOU E, et al. Overview of risk assessment models for venous thromboembolism in ambulatory patients with cancer[J]. Thromb Res, 2020, 191(Suppl 1): 50-57.
[4] WALKER A J, WEST J, CARD T R, et al. When are breast cancer patients at highest risk of venous thromboembolism? A cohort study using English health care data[J]. Blood, 2016, 127(7): 849-857,953.
[5] KHORANA A A, KUDERER N M, CULAKOVA E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis[J]. Blood, 2008, 111(10): 4902-4907.
[6] KHORANA A A, MACKMAN N, FALANGA A, et al. Cancer-associated venous thromboembolism[J]. Nat Rev Dis Primers, 2022, 8(1):11.
[7] MOIK F, AY C, PABINGER I. Risk prediction for cancer-associated thrombosis in ambulatory patients with cancer: past, present and future[J]. Thromb Res, 2020, 191(Suppl 1):S3-S11.
[8] ROOPKUMAR J, SWAIDANI S, KIM A S, et al. Increased incidence of venous thromboembolism with cancer immunotherapy[J]. Med, 2021, 2(4):423-434.
[9] ROTUNNO G, MANNARELLI C, GUGLIELMELLI P, et al. Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Impact ofcalreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia[J]. Blood, 2014, 123(10):1552-1555.
[10] DUNBAR A, BOLTON K L, DEVLIN S M, et al. Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors[J]. Blood, 2021, 137(15):2103-2113.
[11] STREIFF M B, HOLMSTROM B, ANGELINI D, et al. Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw. 2021, 19(10):1181-1201.
[12] M VERSO, G AGNELLI, S BARNI, et al. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score[J]. Intern Emerg Med, 2012, 7(3): 291-292.
[13] AY C, DUNKLER D, MAROSI C, et al. Prediction of venous thromboembolism in cancer patients[J]. Blood, 2010, 116(24):5377-5382.
[14] GEROTZIAFAS G T, TAHER A, ABDEL-RAZEQ H, et al. A predictive score for throm- bosis associated with breast, colorectal, lung or ovarian cancer. The prospective COMPASS-Cancer Associated Thrombosis study[J]. Oncologist, 2017, 22(10): 1222-1231.
[15] RUPA-MATYSEK J, LEMBICZ M, ROGOWSKA E K, et al. Evaluation of risk factors and assessment models for predicting venous thromboembolism in lung cancer patients[J]. Med Oncol, 2018, 35(5):63.
[16] XIONG W, ZHAO Y, DU H, et al. Optimal authoritative risk assessment score of Cancer-associated venous thromboembolism for hospitalized medical patients with lung Cancer. Thromb J, 2021, 19(1):95.
[17] YMAN G H, CARRIER M, AY C, et al. American Socie-ty of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer[J]. Blood Adv, 2021, 5(4):927-974.
[18] KEY N S, KHORANA A A, KUDERER N M, et al. Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update[J]. J Clin Oncol, 2020, 38(5):496-520.
[19] KHORANA A A, DESANCHO M T, LIEBMAN H, et al. Prediction and Prevention of Cancer-Associated Thromboembolism[J]. Oncologist, 2021, 26(1):e2-e7.
[20] BEN-AHARON I, STEMMER S M, LEIBOVICI L, et al. Low molecular weight heparin (LMWH) for primary thrombo-prophylaxis in patients with solid malignancies - systematic review and meta-analysis[J]. Acta Oncol, 2014, 53(9):1230-1237.
[21] DI NISIO M, PORRECA E, CANDELORO M, et al. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy[J]. 2016, 12(12):CD008500.
[22] CARRIER M, ABOU-NASSAR K, MALLICK R, et al. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer[J]. N Engl J Med, 2019, 380(8):711-719.
[23] KHORANA A A, SOFF G A, KAKKAR A K, et al. Riva-roxaban for thromboprophylaxis in high-risk ambulatory patients with cancer[J]. N Engl J Med, 2019, 380(8):720-728.
[24] LI A, CARLSON J J, KUDERER N M, et al. Cost-effectiveness analysis of low-dose direct oral anticoagulant (DOAC) for the prevention of cancer-associated thrombosis in the United States[J]. Cancer, 2020, 126(8):1736-1748.
[25] PRANDONI P, LENSING A W, 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.
[26] LEE A Y, LEVINE M N, BAKER R I, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer[J]. N Engl J Med, 2003, 349(2):146-153.
[27] CARRIER M, CAMERON C, DELLUC A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis[J]. Thromb Res, 2014, 134(6):1214-1219.
[28] YOUNG A M, MARSHALL A, THIRLWALL J, et al. Comparison of an oral factor xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D)[J]. J Clin Oncol, 2018, 36(20):2017-2023.
[29] KRAAIJPOEL N, DI NISIO M, MULDER F I, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE Cancer Study[J]. Thromb Haemost, 2018, 118(8):1439-1449.
[30] FRERE C, FARGE D, SCHRAG D, et al. Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials[J]. J Hematol Oncol, 2022 15(1):69.
[31] STEVENS S M, WOLLER S C, KREUZIGER L B, et al. Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report[J]. Chest, 2021, 160(6):e545-e608.
[32] GIUSTOZZI M, PROIETTI G, BECATTINI C, et al. ICH in primary or metastatic brain cancer patients with or without anticoagulant treatment: a systematic review and meta-analysis[J]. Blood Adv, 2022, 6(16):4873-4883.
[33] CARNEY BJ, UHLMANN EJ, PULIGANDLA M, et al. Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors[J]. J Thromb Haemost, 2019, 17(1):72-76.
[34] SWARTZ AW, DRAPPATZ J. Safety of direct oral anticoagulants in central nervous system malignancies[J]. Oncologist. 2021; 26(5):427-432.
[35] FALANGA A, LEADER A, AMBAGLIO C, et al. EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer[J]. Hemasphere, 2022, 6(8):e750.
[36] HSU C, PATELL R, ZWICKER J I. The prevalence of thrombocytopenia in patients with acute cancer-associa-ted thrombosis[J]. Blood Adv, 2023, 7(17):4721-4727.
[37] YEOMANS N D, GRAHAM D Y, HUSNI M E, et al. Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial[J]. Aliment Pharmacol Ther, 2018, 47(11):1453-1463.
[38] SCALLY B, EMBERSON J R, SPATA E, et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials[J]. Lancet Gastroenterol Hepatol, 2018, 3(4):231-241.
[39] STEFFEL J, VERHAMME P, POTPARA T S, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoa-gulants in patients with atrial fibrillation[J]. Eur Heart J. 2018, 39(16):1330-1393.
[40] KANURI S H, KREUTZ R P. Pharmacogenomics of novel direct oral anticoagulants: newly identified genes and genetic variants[J]. J Pers Med, 2019, 9(1):7.
[41] LAPéBIE F X, BURA-RIVIèRE A, ESPITIA O, et al. Predictors of recurrence of cancer-associated venous thromboembolism after discontinuation of anticoagulant therapy: a multicenter cohort study[J]. J Thromb Haemost, 2023, 21(8):2189-2201.
[42] LOUZADA M L, 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[J]. Circulation, 2012, 126(4):448-454.
[43] NISHIMOTO Y, YAMASHITA Y, MORIMOTO T, et al. Predictive ability of modified Ottawa score for recurrence in patients with cancer-associated venous thromboembolism: From the COMMAND VTE Registry[J]. Thromb Res, 2020, 191:66-75.
[44] FRERE C, CRICHI B, WAHL C, et al. The ottawa score performs poorly to identify cancer patients at high risk of recurrent venous thromboembolism: insights from the TROPIQUE study and updated meta-analysis[J]. J Clin Med, 2022, 11(13):3729.
[45] JARA-PALOMARES L, SOLIER-LOPEZ A, ELIAS-HERNANDEZ T, et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study[J]. Thromb Res. 2017, 157:90-96.
[46] FRANCIS C W, KESSLER C M, GOLDHABER S Z, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study[J]. J Thromb Haemost, 2015, 13(6):1028-1035.
文章导航

/