Patients with cancer are at high risk of venous thromboembolism (VTE). Fortunately, patient survival, diagnostic tools and the therapeutic armamentarium have all improved dramatically in recent years.
Still, the anticoagulant treatment remains challenging, and the burden of cancer-associated thrombosis (CAT) has been increasing in the last two decades [1].
Most of the clinical practice guidelines provide treatment recommendations for the management of CAT referring to the general cancer population. Limited indications are available for a specific subgroup of patients, such as those with thrombocytopenia, renal impairment, gastrointestinal cancer, primary or metastatic brain cancer, distal DVT of the lower extremities, catheter-related VTE, and many more.
A recent review overviews VTE treatment in these populations, discussing evidence and potential approaches [1]. In this article, we summarize the key findings. It is important to note that the available evidence on treatment is mainly indirect or derived from small observational studies. Still, they can provide some useful information.
Treatment of VTE in cancer patients with a high risk of bleeding
Cancer patients with thrombocytopenia
Cancer patients with thrombocytopenia are at high risk of both recurrent VTE and bleeding. Table 1 below summarizes some clinical management strategies [1].
Table 1: Clinical management strategies of VTE treatment in patients with thrombocytopenia.
| Platelet count | Comment | Recommendation | Reference |
| Above 50,000/μL | The risk of spontaneous bleeding is low | Full-dose anticoagulation | [1–4] |
| Between 25,000 and 50,000/μL | The therapeutic strategy needs to consider:
· Risks of bleeding · Recurrent VTE · The severity and the estimated duration of thrombocytopenia · The time since the occurrence of the VTE event |
Full-dose anticoagulation with periodic/repeated platelet transfusion or dose-adapted anticoagulation | [1,3] |
| Below 25,000/ μL and acute VTE at high risk of thrombus progression | Full-dose anticoagulation and periodic/repeated platelet transfusion support aimed at maintaining platelet count above 40–50,000/ μL may be considered | [1,3] | |
| Below 25,000/ μL and acute VTE and low risk of thrombus progression
or Below 25,000/ μL and subacute VTE |
Temporary discontinuation of anticoagulation is suggested while the platelet count is below 25,000/μL, with the plan of resuming full-dose anticoagulation upon resolution of severe thrombocytopenia | [1,3,5] | |
| Source: Becattini et al. 2021 [1] | |||
Cancer patients with renal impairment
Renal function might be impaired by anticancer medication, leading to an increased risk of VTE and major bleeding.
As the kidneys excrete direct oral anticoagulants (DOACs) in varying degrees, their use in patients with renal impairment requires surveillance for fluctuations in renal function and bleeding complications [1].
Table 2: Suggested treatment for cancer patients with VTE and renal impairment.
| Creatinine clearance | Suggested treatment | References |
| Above 30ml/min | LMWH or validated regimens of factor Xa inhibitors | [1,6,7] |
| Below 30ml/min | Consider treatment with
· Unfractionated heparin · LMWH with anti-Xa monitoring · Warfarin Dose reduction is allowed only for edoxaban with creatinine clearance lower than 50 ml/min |
[1] |
| LMWH= Low-molecular-weight heparin. | ||
| Source: Becattini et al. 2021 [1] | ||
Patients with gastrointestinal cancer
Caution in using DOACs in patients with gastrointestinal cancers is mandatory since a few studies reported a higher rate of major bleeding complications among these patients [8,9].
The National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) guidelines recommended DOACs as the treatment of choice for patients without gastric or gastroesophageal cancer [10,11].
In a previous article, we reported a post-hoc analysis of the AVERT trial assessing the efficacy and safety of apixaban in patients with gastrointestinal cancers [12].
Available evidence suggests using low molecular weight heparin (LMWH) or apixaban as the preferred treatment option for CAT in patients with gastrointestinal cancer [1].
Patients with primary brain tumors or secondary brain metastases
Patients with brain cancer have one the highest risks of VTE, and their treatment is complicated by the high rate of spontaneous intracranial hemorrhages. This is valid for both patients with brain tumors and metastatic cancer. Furthermore, no risk model today is validated for brain tumors [13].
You may be interested in our article “Risk assessment models for venous thromboembolism in ambulatory patients with cancer: A talk with Prof. Gerotziafas.”
A few studies indicate the relative safety of anticoagulant treatment in these patients with either LMWH or DOACs [14-16]. A meta-analysis suggests the use of anticoagulation therapy in patients with VTE and a brain tumor, and LMWH and DOACs may be considered [16]. A recent retrospective cohort study in 96 patients with brain metastases highlighted the comparable safety of LMWH or DOACs since any or major spontaneous intracranial hemorrhage (ICH) risk at 12 months did not differ statistically between 41 DOAC-treated and 55 LMWH-treated patients [15].
Catheter-related thrombosis
Central venous catheters (CVC) are often used in patients with cancer to allow easier access for laboratory tests and easier administration of chemotherapy, supportive care and parenteral nutrition. However, it is known that CVC can cause catheter-related thrombosis (CRT), which is mostly detected incidentally [1].
When CRT occurs, patients should start an anticoagulant treatment while deciding on the potential catheter removal to reduce the risk of thrombosis extension or recurrence.
Currently, treatment decisions are based on small cohort studies and indirect evidence. Since data on the use of DOACs are still limited, LMWH for a minimum of 3 months is the suggested anticoagulation treatment for symptomatic and incidental CRT. It is recommended to continue the treatment while the CVC is functional and required for ongoing therapy [1,17].
Incidental pulmonary embolism and deep vein thrombosis
A large percentage of diagnosed VTE is incidental, meaning that it is detected while performing exams for reasons other than suspected VTE.
A series of studies suggest that patients with cancer and both incidental and symptomatic VTE have the same risk of recurrent thrombosis.
A study based on the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) showed a substantial risk of recurrent VTE in patients with cancer who discontinued treatment for incidental VTE [18].
DOACs can provide great help in patients with incidental VTE, allowing better outpatient management.
International guidelines recommend the same anticoagulant treatment for patients with incidental and symptomatic VTE.
The American Society of Clinical Oncology, through an informal consensus, recommends the same treatment of incidental pulmonary embolism (PE) and DVT as symptomatic VTE, given their similar clinical outcomes [11].
The European Society of Cardiology’s formal recommendation suggests considering the same management for incidental PE and symptomatic PE if it involves segmental or more proximal branches, multiple subsegmental vessels, or a single subsegmental vessel in association with proven DVT [19].
The ISTH 2015 guidance statement recommends treating incidental VTE with standard anticoagulation in patients with symptoms compatible with VTE, or proximal DVT, or PE of the main, lobar, segmental, or multiple subsegmental pulmonary arteries, or isolated subsegmental PE with proximal DVT [20].
During the 10th ICTHIC, Prof. Marcello di Nisio and Prof. Marc Carrier discussed the management of incidental VTE. Is incidental VTE comparable to symptomatic events, or is it like mixing apples and oranges? Should incidental and symptomatic VTE be treated the same way?
Go deeper into the topic and read Incidental VTE: to treat or not to treat? – A debate from the 10th ICTHIC
References
1. Becattini C, Di Nisio M, Franco L, Lee A, Agnelli G, Mandalà M. Treatment of venous thromboembolism in cancer patients: The dark side of the moon. Cancer Treat Rev. 2021;96:102190. doi:10.1016/j.ctrv.2021.102190
2. Carrier M, Khorana AA, Zwicker J, Noble S, Lee AY; Subcommittee on Haemostasis and Malignancy for the SSC of the ISTH. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost. 2013;11(9):1760-1765. doi:10.1111/jth.12338
3. Samuelson Bannow BT, Lee A, Khorana AA, et al. Management of cancer-associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16(6):1246-1249. doi:10.1111/jth.14015
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5. Brunson A, Ho G, White R, Wun T. Inferior vena cava filters in patients with cancer and venous thromboembolism (VTE) does not improve clinical outcomes: A population-based study. Thromb Res. 2017;153:57-64. doi:10.1016/j.thromres.2017.03.012
6. Young AM, 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 Clin Oncol. 2018;36(20):2017-2023. doi:10.1200/JCO.2018.78.8034
7. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968-1975. doi:10.1182/blood-2014-04-571232
8. Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Cancer-Associated Venous Thromboembolic Disease. Version 1.2020. April 16, 2020. www.nccn.org/professionals/physician_gls/pdf/vte.pdf.
9. Kraaijpoel N, Di Nisio M, Mulder FI, et al. Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost. 2018;118(8):1439-1449
10. Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Cancer-Associated Venous Thromboembolic Disease. Version 1.2020. April 16, 2020. www.nccn.org/professionals/physician_gls/pdf/vte.pdf.
11. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020;38:496-520
12. Ladha D, Mallick R, Wang TF, Caiano L, Wells PS, Carrier M. Efficacy and safety of apixaban for primary prevention in gastrointestinal cancers: A post-hoc analysis of the AVERT trial. Thromb Res. 2021;202:151-154.
13. Riedl J, Ay C. Venous Thromboembolism in Brain Tumors: Risk Factors, Molecular Mechanisms, and Clinical Challenges. Semin Thromb Hemost. 2019;45(4):334-341.
14. Donato J, Campigotto F, Uhlmann EJ, et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood. 2015;126(4):494-499. doi:10.1182/blood-2015-02-626788
15. Leader A, Hamulyák EN, Carney BJ, et al. Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases. Blood Adv. 2020;4(24):6291-6297. doi:10.1182/bloodadvances.2020003238
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17. Zwicker JI, Connolly G, Carrier M, Kamphuisen PW, Lee AY. Catheter-associated deep vein thrombosis of the upper extremity in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2014;12(5):796-800. doi:10.1111/jth.12527
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20. Di Nisio M, Lee AY, Carrier M, Liebman HA, Khorana AA; Subcommittee on Haemostasis and Malignancy. Diagnosis and treatment of incidental venous thromboembolism in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(5):880-883. doi:10.1111/jth.12883