Diagnosis, screening, and prevention of cancer-associated thrombosis

The tight association between malignancies and hypercoagulation was highlighted almost a century ago by the 19^th-century French physician Armand Trousseau, who experienced it himself. The most prevalent clinical phenotypes observed in malignancy-associated hypercoagulation are deep vein thrombosis (DVT) and pulmonary embolism (PE) [1].

DVT and PE diagnosis

Diagnosis of DVT and PE is not straightforward and involves a careful assessment by an experienced clinician and precise empirical evaluation based on objective testing.

Pain, swelling, and erythema in the limbs are common symptoms of DVT. Although these symptoms can occur in lower and bilateral limbs, their incidence in the upper limb is often associated with DVT. DVT can also occur in unusual anatomical places in cancer patients. Acute abdominal or pelvic pain, nausea, vomiting, and gastrointestinal bleeding in selected patients can signal splanchnic vein thrombosis (SVT). A significant frequency of SVT is often diagnosed incidentally [2].

On the other hand, PE manifests itself more ambiguously, as symptoms including dyspnea, chest pain, and hemoptysis can be mistaken for those induced by the tumor itself. Therefore, a PE diagnosis is often incidental, following a CT scan performed for reasons other than PE evaluation [2].

To improve the accuracy of DVT or PE diagnosis, pretest probability score (PTP) models can stratify the patients into low-, intermediate- and high-risk groups. In addition, PTP combines components of the patient’s history and physical examination and helps reduce the need for supplementary imaging [3].

These models include the simplified Wells scores for suspected DVT and PE, the Geneva score for suspected PE, and the Constants score for patients with suspected upper limb DVT [3].

The low risk of DVT or PE predicted by a PTP should be confirmed by performing a D-dimer test. In the general population, the likelihood of not having the disease when a patient has a low PTP, and a negative D-dimer result ranges from 99.1% to 99.6%. In addition, patients with a negative D-dimer result and a low PTP score at initial presentation can withhold anticoagulant therapy [4].

Unfortunately, the negative predicting value of a low PTP and D-dimer result in patients with cancer is less certain. In addition, D-dimer levels in patients with cancer are more frequently elevated than in patients without malignancy. For this reason, the clinical utility of this strategy is limited in patients with cancer because the combination of a low PTP and a negative D-dimer result occurs relatively uncommonly, excluding very few cancer patients [4].

Diagnostic imaging is recommended for cancer patients with suspected thromboembolism. Imaging examination for DVT diagnosis should include compression ultrasonography, while abdominal ultrasonography or CT angiography should be used to detect SVT. Diagnosis of PE should be made through multidetector CT pulmonary angiography [2].

 

Screening

Several risk factors are associated with cancer-associated thrombosis (CAT) and may be patient-, cancer-, and treatment-dependent.

In cancer patients aged above 65 years, sex (female), ethnicity (black), and comorbidities (obesity, anemia, pulmonary or renal diseases, infections, and prior thromboembolism) are increasing risk factors for venous thromboembolism (VTE) [5, 6].

Certain types of cancer (such as hematological malignancies, lung, pancreas, stomach, bowel, and brain cancers) carry a higher VTE risk compared to others; VTE is quite common in prostate and breast cancer due to their high prevalence [6].

In addition, reduced mobility (caused by hospitalization, therapies, or oncologic pain), cancer treatments, surgical procedures, and long-term catheters increase the risk of blood clots [6].

Despite these well-known risk factors, routine clinical and imaging screening for VTE is not recommended in patients at high risk of VTE. The VTE signs and symptoms are not specific, and diagnostics tests in asymptomatic patients have a limited accuracy [2].

Early identification of patients at high risk of VTE and who should receive thromboprophylaxis is of utmost importance, considering that thrombosis is the most frequent cause of death in cancer patients after cancer itself [7].

Risk assessment models have been developed to predict the risk of VTE in specific cancer populations.

The Khorana risk score is the first risk assessment model proposed in 2008 [8]. It relies on five simple clinical and laboratory variables: type of cancer, prechemotherapy platelet count (≥350 × 109/L), hemoglobin level (<10 mg/mL) or use of red cell growth factors, prechemotherapy leukocyte count (>11 × 109/L) and BMI (≥35 kg/m²). Patients with a score ≥3 are classified as at a high-risk level, although it has recently been proposed to set the cutoff at 2 for both outpatients and inpatients with cancer [9].

Over time, new scores were developed, such as Vienna, PROTECHT, ONKOTEV and Tic-Onco, Pabinger et al., IMPEDE, and SAVED. However, Pabinger et al., IMPEDE, and SAVED are the only scores that have been validated to date. [9]

Finally, a new class of risk scores evaluates VTE in outpatients receiving chemotherapy. They combine predictors related to the cancer characteristics (stage and diagnosis), the type of the treatment, and the patient’s characteristics.

The COMPASS-CAT score has been validated in outpatients with breast, ovarian, lung, and colorectal cancer who receive chemotherapy [10].

The ThroLy score is specific for lymphoma. It is composed of predictors related to the malignancy and the patients’ intrinsic risk factors for VTE, and it is applicable in outpatients after chemotherapy initiation [10]

Prevention

Thromboprophylaxis is long recommended in the postsurgical setting. The most recent recommendations suggest extending the postsurgical prophylaxis up to 4 weeks in patients undergoing high-risk abdominal or pelvic surgery [11].

Primary prophylaxis with low-molecular-weight heparin (LMWH) is recommended in hospitalized patients with cancer without VTE and should be discontinued at hospital discharge [11].

For cancer patients undergoing surgery, the use of LMWH or fondaparinux is recommended in the presence of low bleeding risk. In contrast, mechanical thromboprophylaxis is recommended in case of high bleeding risk. Therefore, a combination of mechanical and pharmacologic thromboprophylaxis should be used in patients with high thrombosis risk. Postoperative thromboprophylaxis should be preferred over preoperative thromboprophylaxis, and the pharmacological treatment should be continued after discharge [11].

In ambulatory patients with cancer receiving systemic therapy, pharmacologic prophylaxis with LMWH, apixaban, or rivaroxaban is recommended only for patients at high risk of thrombosis [11].

In addition, pharmacologic prophylaxis with low-dose acetylsalicylic acid, fixed low-dose vitamin K antagonists, or LMWH should be considered in patients with multiple myeloma receiving lenalidomide-, thalidomide-, or pomalidomide-based regimens [11].

In the outpatient setting, prophylaxis with rivaroxaban, apixaban, or LMWH should be considered in patients with cancer at intermediate to high risk of VTE with a Khorana score of ≥2 [2].

Moreover, together with pharmacological treatment, educating cancer patients about the risks, signs, and symptoms of thrombosis should be part of an effective prevention strategy.

Currently, patient information about the risks, signs, and symptoms of CAT is inadequate. Patients’ poor knowledge about CAT leads to delayed presentation, diagnosis, and treatment of VTE [12].

The EMPOWER study showed that a simple, easy-to-implement tool, such as a video highlighting the VTE risks from systemic anticancer therapy, could help reduce the time patients need to seek medical attention if they develop CAT symptoms [12].

Other ways to increase patients’ awareness about CAT include organizing listening and teaching moments in clinics and hospitals and sharing information about CAT’s reliable website and who to contact when experiencing symptoms.

In addition, it is important to share specific information about easy-to-implement prevention strategies that each patient can carry out to reduce the risk of developing VTE, such as walking (if possible) or performing simple exercises while lying in bed and staying hydrated.

 

References

1. Metharom P, Falasca M, Berndt MC. The history of Armand Trousseau and cancer-associated thrombosis. Cancers (Basel). 2019;11(2):158. doi:10.3390/cancers11020158.
2. Khorana AA, Mackman N, Falanga A, et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers. 2022;8(1):11. doi:10.1038/s41572-022-00336-y.
3. Kelly J, Hunt BJ. The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism. J Thromb Haemost. 2003;1(9):1888-1896. doi:10.1046/j.1538-7836.2003.00382.x.
4. Carrier M, Lee AY, Bates SM, Anderson DR, Wells PS. Accuracy and usefulness of a clinical prediction rule and D-dimer testing in excluding deep vein thrombosis in cancer patients. Thromb Res. 2008;123(1):177-183. doi:10.1016/j.thromres.2008.05.002.
5. Sevestre MA, Soudet S. Epidemiology and risk factors for cancer-associated thrombosis. J Med Vasc. 2020;45(6S):6S3-6S7.
6. Fernandes CJ, Morinaga LTK, Alves JL Jr, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28(151):180119.
7. Sheth RA, Niekamp A, Quencer KB, et al. thrombosis in cancer patients: etiology, incidence, and management. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S178-S185. doi:10.21037/cdt.2017.11.02.
8. 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.
9. Khorana AA, DeSancho MT, Liebman H, Rosovsky R, Connors JM, Zwicker J. Prediction and prevention of cancer-associated thromboembolism. Oncologist. 2021;26(1):e2-e7.
10. Gerotziafas GT, Mahé I, Lefkou E, et al. Overview of risk assessment models for venous thromboembolism in ambulatory patients with cancer. Thromb Res. 2020;191 Suppl 1:S50-S57.
11. 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(4):927-974. doi:10.1182/bloodadvances.2020003442.
12. Baddeley E, Torrens-Burton A, Newman A, et al. A mixed-methods study to evaluate a patient-designed tool to reduce harm from cancer-associated thrombosis: The EMPOWER study. Res Pract Thromb Haemost. 2021;5(5):e12545.
13. Falanga A, Girvalaki C, Monreal M, Easaw JC, Young A. How well do European patients understand cancer-associated thrombosis? A patient survey. Cancer Treat Res Commun. 2022;31:100557. doi:10.1016/j.ctarc.2022.100557.