Cancer-associated venous thromboembolism: a comprehensive review

Abstract

It has been 200 years since the first case of cancer-associated thrombosis (CAT) was reported. Venous thromboembolism (VTE) remains a leading cause of morbidity and mortality in cancer patients. Malignant tumors interact with the coagulation system in complex ways. CAT continues to pose a significant challenge in clinical practice. The risk factors for CAT are complex and multifactorial, primarily including patient, cancer, and therapy-related factors. We have introduced assessment models for CAT and bleeding risk, but the performance of these models has been less than satisfactory. Currently, the main anticoagulant drugs for treating CAT include vitamin K antagonists (VKAs), low molecular weight heparin (LMWH), and direct oral anticoagulants (DOACs). We have provided a detailed overview of the advantages and disadvantages of these three types of drugs and suggestions on choosing the appropriate type of medication for different clinical scenarios. CAT incidence, pathophysiology, risk factors, risk prediction models, and recent advancements in treatment and management are summarized in this review.

Introduction

Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE). The estimated annual incidence rates of VTE among the general population range from 104 to 183 per 100,000 person-years (p-y) [1]. Nevertheless, compared with the general population, patients with cancer have an estimated ninefold increased VTE risk [2]. Cronin-Fenton et al. found that the overall VTE incidence in hospitalized cancer patients was 8.0 cases per 1000 person-years (p-y), with the highest incidence in the first year after cancer diagnosis (15.0 cases per 1000 p-y), decreasing to 6.3 cases per 1000 p-y in the second year, and 4.2 cases per 1000 p-y thereafter [3]. With longer follow-up, the overall incidence rate (IR) of VTE in patients with cancer decreased [3]. Mulder et al. reported that the cumulative incidence of cancer-associated thrombosis (CAT) increased from 1.0% in 1997 to 3.4% in 2017, with approximately 80% of all CAT cases occurring in ambulatory patients with cancer [4, 5]. Bouillaud first reported a cancer-associated thrombosis (CAT) case in 1823. Trousseau described an association between thrombosis and cancer in 1865. He noted that accident or migratory thrombophlebitis might be a precursor to occult visceral malignant tumor [6]. Although there is no standard definition, Trousseau syndrome most commonly represents unexplained thrombosis in patients with occult or recently diagnosed visceral malignancy [7]. Moreover, about 20 to 30% of all first venous thrombotic events are cancer-associated [8]. Thrombotic events have been reported as the second leading cause of death among patients with cancer [9]. A study by Sørensen and coworkers found that the one-year survival rate for the cancer group with VTE was 12%, compared with 36% in the control group without VTE [10]. Patients with cancer had a higher probability of PTE events, and PTE-related mortality was three times higher than in non-cancer individuals [11]. The burden of CAT is enormous. Optimal management strategies for CAT are an area of ongoing research. In this review, we will delve into new perspectives on CAT as well as highlight significant progress in its prevention and treatment.

Variations in VTE incidence among cancer types

Mulder and coworkers found that the overall cumulative incidence rate of VTE per 1000 p-y within six months after an oncologic diagnosis was 39.0 (95% CI 38.2–39.9) [2]. In recent years, an increase in the incidence of CAT has been observed. Mulder et al. found that the 1-year VTE incidence in patients with cancer rose from 1.0% (95% CI, 0.9% − 1.2%) in 1997, to 1.9% (95% CI, 1.7%—2.0%) in 2004, and further increased to 3.4% (95% CI, 2.9%—4.0%) in 2017 [2]. Within the initial 6 months following tumor diagnosis, individuals diagnosed with pancreatic, liver, biliary, and non–small cell lung carcinoma had the highest cumulative incidence rate of VTE per 1000 p-y (Fig. 1, data from reference [2]). The number of CAT cases in lung, breast, colon, and prostate carcinomas is higher in clinical practice, perhaps due to their higher incidence and longer survival times.

Fig. 1

Incidence rate of VTE in the first 6 months after cancer diagnosis by tumor type. Legends: NSCLC, non–small cell lung carcinoma; MM, multiple myeloma; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; SCLC, Small-cell lung carcinoma

Thrombosis location in patients with cancer

Amer found that in the population of cancer-related thrombosis studied, 45.2% presented with DVT, 11.7% with PTE, 27.4% with the coexistence of DVT and PTE, 10% with phlebitis, and 5.7% with intra-abdominal [12]. This study reported that in patients with cancer, 53.9% occurred in the lower limbs, 25.7% in the upper limbs, 17% at other sites, and 3.5% at multiple sites of all VTE events [12]. Lower extremity deep veins are most commonly involved in thrombotic events among patients with cancer. A higher incidence of upper extremities venous thrombosis might be associated with the increased use of central venous catheters (CVCs) [13].

Pathophysiology of CAT

The pathophysiology of CAT is multifactorial, affecting all aspects of Virchow's triad. Abnormal expression of tissue factor (TF) on tumor cells or tumor-derived particles can induce a hypercoagulable state; anticancer treatments such as chemotherapy and radiotherapy can damage endothelial cells; the tumor mass itself can compress veins and cause venous stasis; cancer-mediated inflammation and the secretion of pro-inflammatory cytokines can also promote coagulation activation and thrombosis [14]. In addition, platelets and neutrophils are considered to be key to the occurrence and development of thrombus. Khorana et al. recently summarized potential cancer-specific mechanisms of VTE. They noted that tumors may increase the number of circulating platelets and leukocytes, further elevating the risk of venous thrombosis through the formation of neutrophil extracellular traps (NETs) or the release of TF [15]. Tumors might also release extracellular vesicles (EVs) containing TF, polyphosphate, or podoplanin (PDPN), which can directly activate the clotting cascade or platelets [15]. Additionally, tumors might secrete plasminogen activator inhibitor- 1 (PAI1), thereby inhibiting fibrinolysis [15].

Hypercoagulability and tumor metastasis

Studies have found that TF expressed by tumor cells not only promotes hypercoagulability but also facilitates metastatic disease in experimental models [16]. Conversely, thrombin inhibitors and other coagulation factor inhibitors have been shown to reduce metastasis, highlighting the role of the coagulation cascade in tumor dissemination [17, 18]. Hypercoagulability is a complex process that not only increases the risk of thrombotic events but also contributes to tumor progression. Activation of the clotting cascade and platelet aggregation may protect cancer cells from degradation in the bloodstream and enhance their ability to disseminate to metastatic sites [19]. Platelets further support metastasis by helping cancer cells evade the immune system through the transfer of membrane proteins [20, 21]. Additionally, cancer-mediated modulation of platelet count and function contributes to tumor progression and metastasis. Platelets regulate the release of pro-angiogenic factors (including growth factors and signaling pathways), anti-angiogenic factors (such as angiostatin, endostatin, and thrombospondin- 1), and the activity of matrix metalloproteinases, all of which promote metastatic spread [22]. Moreover, cancer cells can induce neutrophils to adopt a pro-NETotic phenotype by expressing and releasing factors like granulocyte-colony-stimulating factor and interleukin- 8 [23]. These NETs, not only contribute to CAT but also facilitate tumor cell proliferation and metastasis [24, 25].

Risk factors for CAT

VTE risk factors in patients with cancer include patient, cancer, and therapy-related factors (Table 1, detailed information comes from reference [26]). Different malignancy types appear to have different risks of venous thrombosis. Patients with pancreas, liver, lung, ovarian, and brain cancers, as well as those with multiple myeloma, had higher VTE IR, whereas those with breast cancer and melanoma had lower VTE risk [3]. Active tumor therapy may also raise the incidence of VTE. Khorana and coworkers found that patients with cancer who received chemotherapy faced a nine-fold higher incidence of VTE compared to non-cancer controls [27]. Deitcher and colleagues found that when breast cancer was treated with hormonal therapy (such as tamoxifen or raloxifene), VTE risk was increased by two to three times [28]. It is also important to consider factors such as prolonged immobility, history of previous VTE, CVC placement, and inherited thrombophilia when evaluating thrombotic risk in cancer patients [29].

Table 1 Risk factors for venous thrombosis

Risk prediction models

To screen out cancer patients most likely to benefit from thromboprophylaxis, physicians can stratify CAT risk using several assessment models, in conjunction with bleeding risk scores. Khorana score (KS, Table 2) is the predominant model for assessing outpatient cancer patients’ VTE risk when starting chemotherapy [30]. The model demonstrated a negative predictive value of 98.5% (indicating the probability that low-risk patients did not develop VTE), a positive predictive value of 6.7% (the likelihood that high-risk patients experienced VTE), a sensitivity of 35.7% (the probability that patients who developed VTE were classified as high-risk), and a specificity of 89.6% (the probability that patients without VTE were at low risk) [30]. The sensitivity of this model was 35.7% in the derivation cohort, meaning that 64.3% of VTE patients were identified as low or intermediate risk [30]. A meta-analysis involving 45 studies and 34,555 cancer patients on the KS showed that among patients who developed VTE within the first six months (n = 2,386), only 23.4% (95% CI: 18.4–29.4) were identified as high risk (KS ≥ 3) [31]. The remaining 76.6% (95% CI: 70.6–81.6) of thromboembolic events occurred in patients classified as intermediate- or low-risk according to the KS [31]. A multicenter study conducted by Guman et al. reported that for the KS, the time-dependent c-index at 6 months of follow-up, which assesses discriminatory ability, was 0.57 (95% CI: 0.55–0.60), suggesting that the clinical KS performs poorly in predicting VTE [32]. Future models need to be refined to improve sensitivity. Several models were developed later, such as Vienna CATS [33], PROTECHT [34], COMPASS-CAT [35] and ONKOTEV [36], but most performed poorly [37]. Recently, Li et al. developed a parsimonious risk assessment model with improved performance and might replace the KS as the preferred thrombosis risk assessment model for patients with cancer [38]. Furthermore, van Es et al. discovered that the KS was ineffective in stratifying the VTE risk in patients with lung cancer [39]. Considering the varying incidence rates of VTE across different cancer types, developing a thrombosis risk assessment tool tailored to each specific cancer type may hold greater clinical significance. This approach can more effectively guide clinical decisions regarding the need for preventive anticoagulation therapy. In clinical practice, when cancer patients present with VTE or are identified as high-risk for VTE, it is crucial to assess their bleeding risk before initiating or adjusting anticoagulation therapy. Key moments for assessing bleeding risk include: 1. Initial Evaluation: Upon the diagnosis of VTE in a cancer patient and the initiation of treatment, it is essential to assess bleeding risk to determine the appropriateness of anticoagulation therapy. 2. During Therapy: As treatment progresses, bleeding risk should be routinely reassessed to guide necessary adjustments to anticoagulation therapy, particularly when there are changes in the patient’s clinical condition. 3. Post-Intervention Assessment: After major cancer treatments, including surgeries, chemotherapy, etc., bleeding risk must be re-evaluated to determine the continuation or modification of anticoagulation therapy. 4. Scheduled Follow-Up Evaluations: Regular reassessment of bleeding risk every 3 to 6 months is recommended to adjust anticoagulation management [40].

Table 2 Khorana score

Anticoagulant therapy

• (a) Vitamin K antagonists (VKAs)

  Before 2003, treatment with rapid-acting parenteral anticoagulation (such as heparin) for 7 days, followed by VKA for at least 3 months was the standard treatment for CAT [41]. However, VKA is not convenient to use. Its drug effect is susceptible to a variety of food and drugs, and frequent monitoring of the coagulation function is required during long-term anticoagulation therapy. Additionally, during anticancer treatment, hepatic dysfunction, renal dysfunction, drug interactions, nausea, vomiting, malnutrition, and other conditions may lead to unstable anticoagulation levels.

• (b) Low molecular weight heparin (LMWH)

  A significant change in anticoagulant therapy occurred in 2003. Using dalteparin as a treatment for cancer patients with VTE, Lee et al. reported lower rates of recurrent VTE than coumarin derivatives, without a prominent difference in bleeding rates [42]. In comparison to VKAs, LMWH has stable pharmacokinetics and drug interactions. Dosing is based on patient weight, and there is no need for frequent laboratory monitoring. Moreover, LMWH has a rapid onset of action and a predictable clearance rate. Since it is injected subcutaneously, it helps reduce interactions with certain anticancer drugs and avoid the reduced absorption of drug concentrations caused by chemotherapy-induced nausea and vomiting [43].

  One complication that needs to be noted when using LMWH is heparin-induced thrombocytopenia (HIT). The risk was estimated to be 2.2% with unfractionated heparin (UFH) and 0.5% with LMWH [44]. Platelet count decreases by 30–50% after heparin exposure, which is the most common manifestation of HIT [45]. HIT usually occurs 5–14 days following exposure, but platelet levels can plummet within hours in a minor proportion of individuals [46, 47]. During this period, the blood routine should be reviewed to observe whether there is a significant decrease in platelets. Additionally, the higher cost of LMWH and the inconvenience of daily subcutaneous injections may lead to decreased patient compliance.

• (c) Direct oral anticoagulants (DOACs)

  DOACs are drugs such as dabigatran, which inhibits thrombin, and rivaroxaban, edoxaban, and apixaban, which inhibit activated factor X. Frere et al. found that when treating cancer patients with acute VTE, compared to LMWH, the DOAC group had a lower risk of VTE recurrence (Risk Ratio, RR 0.67; 95%CI, 0.52–0.85) without an increased risk of major bleeding (RR 1.17; 95%CI, 0.82–1.67), whereas the risk of clinically relevant non-major bleeding (CRNMB) was increased (RR 1.66; 95%CI, 1.31–2.09) [48].

  Many guidelines exist on how anticoagulants should be chosen for CAT patients, including those from CHEST [49], Canadian Expert Consensus [50], and National Comprehensive Cancer Network (NCCN) [40]. The perspectives outlined in these guidelines are largely aligned, advocating for patients to opt for DOACs primarily, then LMWH as an alternative, and to only use VKAs if neither DOAC nor LMWH are deemed appropriate. In specific circumstances, it is advisable to utilize LMWH as an alternative to DOAC, including but not limited to cases where patients exhibit potential drug malabsorption (e.g., after gastrointestinal resection), have a high risk of hemorrhage (thrombocytopenia, liver insufficiency, kidney lesion, a history of bleeding, tumors located in the gastrointestinal tract, genitourinary tract, or intracranial region), or require concurrent medications that may lead to significant drug-drug interactions [51].

Complications of bleeding

In the course of anticoagulant therapy, adverse bleeding events are the part that requires the attention of clinicians. Major bleeding has been defined as any bleeding event that causes death, poses a significant threat to life, or results in chronic sequelae [52]. Bleeding events that do not meet the criteria for major bleeding but result in medical intervention, discomfort, or impairment in daily activities were defined as CRNMBs [53]. Additionally, existing bleeding risk scores (such as ACCP-VTE, Kuijer, Hokusai, Martinez, RIETE, etc.) did not perform well in patients with cancer, and the new CAT-BLEED model performed better slightly but still needed further verification [54]. Currently, no very reliable risk assessment model can accurately quantify the bleeding risk of patients with cancer. Clinicians can only rely on their own experience to provide individualized treatment to patients before anticoagulation treatment.

Numerous studies have revealed that individuals with gastrointestinal (GI) luminal tumors undergoing therapy with DOACs exhibit an elevated frequency of bleeding episodes, predominantly affecting the GI and genitourinary (GU) tracts. SELECT-D trial participants who had esophageal or gastroesophageal carcinoma experienced more major bleeding on rivaroxaban than on dalteparin- four (36%) of 11 cases compared to one (11%) of 19 cases, with most major bleeding events occurring in the GI tract [55]. Furthermore, the 6-month accumulation rate of CRNMB was 13% (95% CI, 9%—19%) in the rivaroxaban group, higher than the 4% (95% CI, 2%—9%) observed in the dalteparin group (hazard ratio, HR, 3.76; 95% CI, 1.63–8.69), with most CRNMBs occurring in the GI or urinary tract [55]. Their trial results demonstrated that, compared to LMWH, rivaroxaban reduced the recurrence rate of VTE but increased the risk of bleeding [55]. Special caution should be exercised when using rivaroxaban in patients with esophageal cancer. These findings provide strong evidence that oral rivaroxaban is a convenient and effective alternative to subcutaneous LMWH for the treatment of CAT. Similar results were observed in the Hokusai VTE cancer trial [56] and the Caravaggio trial [57]. In the Hokusai VTE cancer trial, Raskob et al. reported that the risk of major bleeding within six months was 5.6% (29 of 522 cases) in the edoxaban group and 3.2% (17 of 524 cases) in the dalteparin group (HR:1.74, 95%CI 0.95–3.18, P = 0.0707), and the incidence of CRNMB was 12.3% (64 of 522 cases) and 8.2% (43 of 524 cases), respectively (HR:1,55, 95%CI 1.05–2.28) [58, 59]. The risk of major bleeding between 6 and 12 months was 2.5% (7 of 294 cases) and 1.1%(3 of 273 cases), respectively (HR:2.23, 95%CI 0.59–8.46), and the incidence of CRNMB was 4.8% in both groups (14 of 294 cases vs. 13 of 273 cases, HR:1.02, 95%CI 0.48–2.16) [58, 59]. The incidence of major bleeding and CRNMB appeared slightly lower during the extended therapy period compared with the initial six months of anticoagulation. The findings of their study indicated that extended treatment with edoxaban demonstrated comparable efficacy and safety to dalteparin [59]. Edoxaban could offer a more practical option for the long-term management of CAT patients.

The potential role of anticoagulants in antitumor activity

Given the close relationship between CAT and tumor metastasis, anticoagulant therapies such as heparins have been explored for their potential to inhibit both thrombosis and metastatic spread. Anticoagulants possess potentially significant anti-cancer effects, and these effects are unrelated to their anticoagulant activity [60]. Kreisler first proposed the possible anti-tumor effects of heparin in 1952 [61], and recent studies have further elucidated its mechanisms. Numerous animal and in vitro studies have shown that anticoagulants exert antitumor effects by interfering with mechanisms such as tumor cell adhesion, invasion, metastasis formation, and angiogenesis [62,63,64,65,66]. For instance, Sarantis et al. reported that the combination of chemotherapeutic agents and tinzaparin (low-molecular-weight heparin) in a triple-drug regimen significantly attenuated tumor growth and progression through the modulation of multiple pathways, including cellular proliferation, apoptosis, and neoangiogenesis [67]. Whether heparin can serve as a potential anticancer treatment [68,69,70], as well as its antimetastatic activity [71, 72] and underlying molecular mechanisms [73] are under active investigation.

Managing CAT in certain special circumstances

• (a) Thrombocytopenia and anticoagulant treatment

  According to The International Initiative on Thrombosis and Cancer (ITAC) guidelines published in 2022, for individuals with CAT, when platelet levels fall below 80 × 10⁹/L, anticoagulant treatment should be used with great caution and require close monitoring [74]. The NCCN guidelines published in 2024 specified that contraindications for prophylactic anticoagulation included a platelet count < 50,000/µL and a history of or current HIT, which precluded the use of LMWH and UFH [75]. Relative contraindications for therapeutic anticoagulation included a platelet count < 30,000–50,000/µL, severe platelet dysfunction, and prolonged antiplatelet therapy [75]. In a prospective multicenter cohort study involving 121 CAT patients with thrombocytopenia, it was observed that among those administered with a full dosage anticoagulant therapy, the accumulated occurrence of total bleeding was 24% at 2 months, the accumulated occurrence of major bleeding was 12.8%, and in the lower-dose anticoagulation group, the accumulated occurrence of total bleeding at 2 months was 15.9%, and the accumulated occurrence of major bleeding was 6.6% [76].

• (b) Medication under conditions of impaired hepatic or renal function

  Patients with Child–Pugh class B or C hepatic function should not take drugs such as apixaban, edoxaban, and rivaroxaban that are highly dependent on hepatic metabolism [51]. American Society of Haematology guidelines suggested that VKAs might be superior to DOACs and LMWH for individuals suffering from severe renal insufficiency (creatinine clearance < 30 mL/min) [77].

Appropriate duration of anticoagulation

The VTE recurrence rate ranged from 1.1% to 12.0% after the index VTE event in a systematic review of 11 eligible studies involving 3019 CAT patients [78]. This systematic review observed that the recurrence rate of VTE after the index event within 6 months exceeded that between 6 to 12 months [78]. For example, VTE recurred in 4.5% of patients within the first 6 months and 1.1% between 6 to 12 months in the TiCAT trial [79].

American Society of Haematology Guidelines recommended anticoagulation for more than six months [77]. The 2024 NCCN guidelines recommended that the duration of anticoagulation therapy should be no less than 3 months or continue until the cancer is active or undergoing treatment [75]. For non-catheter-associated DVT or PTE, long-term anticoagulation was advised while the cancer was active, being treated, or if recurrence risk factors persisted [75]. Generally, decisions about long-term therapy should be regularly evaluated, balancing benefits against risks, including bleeding, cost, patient preference, recurrence risk, and expected survival [77].

Prevention strategies for CAT in outpatient patients receiving systemic anticancer therapy

Among outpatient patients with cancer, the 2022 ITAC guidelines did not recommend using anticoagulant therapy as a routine primary prevention strategy [74]. Customizing patient care involves conducting individual assessments to ascertain the necessity of anticoagulant prophylaxis, taking into account their unique risk scores for thrombosis and bleeding. In outpatient cancer patients with a KS of at least 2, compared with standard care or placebo, primary thromboprophylaxis (involving LMWH or DOACs) reduced VTE risk by 49% and did not increase major bleeding risk [80]. For cancer outpatients with a high VTE risk (KS ≥ 2) and who are receiving chemotherapy with a low bleeding risk, there is established evidence supporting the use of thromboprophylaxis with LMWHs or DOACs [81].

Managing recurrent VTE

Utilizing the Ottawa risk score, patients with cancer were stratified into two distinct categories regarding their risk of experiencing a recurrent VTE event: low-risk and high-risk [82]. However, a prospective multicenter cohort study conducted by Girard et al. involving cancer patients treated with LMWH for VTE demonstrated that the Ottawa score exhibited limited discriminatory power and was unable to reliably predict the recurrence of VTE [83]. VTE recurrence in patients with cancer may be influenced by various factors, including malignancy- and patient-specific risks, anticoagulant choice, dosage, duration, as well as additional variables. Poor compliance with anticoagulation therapy may be an important reason for the recurrence of thrombosis. Schaefer et al. found that CAT patients undergoing DOAC treatment typically experienced a median duration of 116 days (interquartile range [IQR]: 57–231) [84]. In contrast, those treated with LMWH had a median duration of 34 days (IQR: 30–92) [84]. The financial cost of drugs, the fear of hemorrhage, the burden of subcutaneous injections, and a lack of patient consciousness of CAT dangers may all contribute to decreased treatment compliance [85,86,87]. Furthermore, it is essential to consider potential drug interactions that could lower anticoagulant concentrations and thus affect their effectiveness.

If VTE recurrence occurred, the 2022 ITAC guidelines recommended considering alternative anticoagulants or increasing the LMWH dose [74]. This could include switching from VKAs to LMWH or DOACs, changing from DOACs to LMWH, increasing the LMWH dosage by 20–25%, or switching to DOACs [74]. Clinicians can also adjust LMWH dosage based on measurements of peak Anti-Xa levels. Sanfilippo et al. proposed a feasible strategy for managing recurrent CAT, which included a careful analysis of the recurrence causes, such as poor compliance, suspension of treatment, insufficient dosage, drug interactions, high bleeding risk, etc., and corresponding processing methods were provided [51].

Conclusions

There is an inextricable connection between tumor cells and coagulation. It is essential to identify patients with cancer who might benefit from prophylactic anticoagulant therapy, considering both pros and cons, and taking necessary measures to reduce VTE incidence.

In patients with cancer, commonly used thrombotic and bleeding risk scores perform poorly. Considering the considerable variation in VTE incidence rates among different cancer types, creating tailored thrombosis and bleeding risk assessment tools for prevalent cancer types can help pinpoint patients who would benefit from thromboprophylaxis.

Currently, the main anticoagulant drugs used in clinical practice include VKAs, LMWH, and DOACs. We have outlined the pros and cons of each type of medication in detail, along with recommendations for selecting the appropriate anticoagulant in various complex situations.

CAT has a particularly high morbidity and mortality rate among patients with cancer, making early identification, active treatment, and standardized management extremely important.