Pulmonary origin and risk assessment of cancer-associated thrombosis.

Introduction

Cancer-associated thrombosis (CAT) poses a significant and potentially life-threatening risk to individuals with malignant tumors. Studies have shown that the incidence of CAT is 4–7 times higher in cancer patients compared to the general population [ 1 ]– [ 2 ]. Disseminated intravascular coagulation disease (DIC) is diagnosed in approximately 7–20% of patients with solid tumors, and autopsies have revealed that occult DIC is present in nearly all cancer patients [ 3 ]. The prevalence of thromboembolism varies depending on the type of cancer, with venous thromboembolism (VTE) occurring at different frequencies among various cancers. For instance, VTE affects approximately 7.4% of individuals diagnosed with pancreatic ductal adenocarcinoma within the first year, while the incidence ranges from 5% to 14% in non-small-cell lung carcinoma patients. However, the presence of anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusions can increase VTE risk to as high as 30%–48%. In patients with melanoma treated with immune checkpoint inhibitors, the incidence of VTE ranges from 2.6% to 5.2%. Higher rates of VTE have been observed in cancers such as ovarian, pancreatic, and brain cancer, with VTE occurring in 28.6% of ovarian cancer patients and 23.5% of pancreatic cancer patients, compared to only 1.2% in breast cancer and 1.5% in melanoma [ 4 – 7 ]. Notably, individuals with advanced cancer are at a greater risk of developing thrombosis, underscoring the close association between cancer progression and thrombotic events in these patients. The development of thrombosis significantly impacts the quality of life and prognosis of patients with cancer. While prophylactic anticoagulant therapy can be beneficial for those experiencing symptomatic thrombosis, the challenge lies in preventing thrombosis before it becomes clinically evident. However, the lack of accurate risk assessment tools and the potential risk of bleeding associated with anticoagulant treatment pose significant challenges in the diagnosis and prevention of subclinical DIC in clinical practice [ 8 , 9 ].

The conventional understanding of CAT has long focused on factors such as vascular wall damage, blood flow stasis, and a hypercoagulable state of blood, as outlined in Virchow’s Triad. While the connection between CAT and the hypercoagulable state of blood has been well-established, recent research has shed new light on the role of tumor cells in directly releasing procoagulants or indirectly activating the coagulation system through inflammatory factors [ 10 , 11 ]. However, a groundbreaking study published in February 2025 in the prestigious journal Cell challenges this paradigm. Led by a team of researchers from Weill Cornell Medical College, the study revealed that the lungs, rather than the tumors themselves or the blood vessel walls, serve as the “command center” for CAT. The findings suggest that thrombosis, a systemic complication of cancer, cannot be solely attributed to local interactions between tumors and platelets. Through a series of meticulously designed experiments, they have demonstrated that chemokines released by tumors have the ability to remotely influence the lung microenvironment, triggering a cascade of systemic thrombosis [ 3 ]. This discovery represents a paradigm shift in our understanding of CAT and offers a new perspective on its underlying mechanisms. By identifying the lungs as a key player in the development of CAT, this study opens avenues for the development of more precise diagnostic tools and targeted therapeutic interventions.

The CAT research field presents both clinical dilemmas and scientific opportunities. Currently available anticoagulants like low-molecular-weight heparin and direct oral anticoagulants are effective in preventing thrombosis, but their use in all cancer patients is limited by the risk of bleeding [ 12 ]. Additionally, the lack of reliable predictive markers for thrombus risk creates uncertainty in clinical decision-making [ 13 , 14 ]. Therefore, understanding the pulmonary origin mechanism of CAT and its molecular basis could help address these challenges. This review aims to comprehensively examine the latest research progress on the pulmonary origin mechanism of CAT, delve into its molecular mechanisms, and explore the clinical value of the related biomarkers. The potential for developing targeted intervention strategies is also discussed in this study. By bridging basic research findings with clinical translation, our goal is to generate fresh insights into the precise prevention and treatment of CAT, ultimately enhancing the quality of life and prognosis of patients with cancer.

Groundbreaking discovery of the pulmonary origin of CAT

A 2012 prospective study followed 186 patients with pancreatic, gastric, colorectal, or brain tumors and found that, among pancreatic-cancer patients, microparticle-associated tissue factor (MP-associated TF) activity correlated with VTE risk [ 15 ], when MP is now termed small extracellular vesicles (sEVs). In 2023, a study of 32 prostate cancer patients detected the sEV-specific RNA marker PCA3 in platelets of ~ 70% of cases, and levels were markedly reduced after prostatectomy. Mouse experiments showed that intravenous injections of cancer-sEVs accelerated thrombus formation, which was rescued by blocking CD63, which is the membrane protein of sEVs. The finding indicates that tumors communicate with platelets via sEVs, which deliver cancer markers and activate platelets in a CD63-dependent manner, thereby promoting thrombosis [ 16 ].

And in 2025, the Weill Cornell Medical College Research Team conducted a thorough and systematic experimental study using mouse models of pancreatic ductal adenocarcinoma, melanoma, and breast cancer. Their research focused on sEVs isolated from different organs, specifically examining their procoagulant activities. Surprisingly, only sEVs derived from the lungs induced severe respiratory distress, thrombocytopenia, and ultimately death in mice within five minutes of injection. Further investigations revealed that when lung sEVs obtained from tumor-bearing mice, with or without lung metastases, were introduced into normal mice, the recipients swiftly exhibited classical indications of systemic thrombosis. This condition is correlated with the presence of lung metastases, characterized by a rapid decline in platelet counts, increased D-dimer levels, and extensive fibrin deposition. Interstitial macrophages were identified as the principal source of prothrombotic sEVs. In the context of cancer, these macrophages undergo reprogramming induced by tumor-released C-X-C motif chemokine (CXCL13), triggering the abundant secretion of sEVs containing integrin β2 (sEV-β2). Notably, this alteration was not exclusive to lung metastatic models but was also observed in cancer-afflicted mice devoid of lung metastases. This indicates that the establishment of a prothrombotic environment in the lungs stems from the systemic repercussions of cancer rather than being directly linked to local metastasis [ 3 ]. It can be seen in Table 1 in detail.

Table 1 A comparison of traditional and new findings on the mechanism of CAT Characteristics Conventional views New findings Main parts Local or systemic vessels of the tumor Lung microenvironment Key cells Tumor cells, endothelial cells, platelets Pulmonary interstitial macrophages The core molecule Tissue factor Integrin β2 Signal transduction Direct cell contact or local spread Circulating chemokines and remote regulation of sEVs Time scale Relatively slow (hour level) Very fast (seconds) Clinical significance Interpretation of local thrombosis It explains systemic hypercoagulability.

Mechanisms of lung-originated CAT

Activation of pulmonary macrophages and release of sEVs

Macrophages are key players in the complex tumor microenvironment, demonstrating remarkable versatility as they respond to various signals by polarizing into different phenotypes. This ability has profound implications for tumor development, with two main phenotypes being the classically activated M1 (pro-inflammatory and anti-tumor) and the alternatively activated M2 (anti-inflammatory and pro-tumor) macrophages [ 17 ]. Within this microenvironment, tumor cells release the chemokine CXCL13, which does not directly cause thrombosis but instead circulates in the lungs [ 3 ]. The lung, uniquely positioned as a “receiving station” for systemic tumor signals, is a critical site where CXCL13 activates interstitial macrophages. These specialized macrophages respond by releasing sEV-β2. When these vesicles interact with platelet membrane glycoprotein IB (GPIb) through integrin β2 dimers and integrin αx, platelet activation and aggregation are induced. This activation leads to the exposure of phosphatidylserine (PS) on platelets, triggering the assembly of coagulation factors such as VIIa and XA on the platelet surface. This series of events ultimately initiates a coagulation cascade resulting in fibrin deposition and thrombus formation [ 3 ]. Furthermore, the sEVs released by macrophages also play a role in inducing endothelial cells to express adhesion molecules and inflammatory mediators, further exacerbating the process of thrombosis [ 18 , 19 ]. It can been seen in Fig. 1 in detail.

Fig. 1 Mechanisms underlying the pro-thrombotic effects of interstitial macrophage-derived sEVs

Activation of endothelium in the lungs

The mechanism of thrombosis in lung cancer involves four key points. First, tumor cells can secrete various procoagulant factors, such as TF and cancer procoagulant substances, which directly activate the coagulation system. This activation can lead to the expression of TF on endothelial cells, ultimately contributing to the promotion of thrombosis [ 20 ]. The study in lung cancer patients has shown a significant correlation between TF expression levels and the risk of thrombosis [ 21 ]. Second, inflammatory factors released by tumor cells, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), can trigger the activation of the lung endothelium. This activation not only upregulates TF expression on endothelial cells but also enhances the secretion of von Willebrand factor (vWF), which in turn facilitates platelet aggregation and promotes thrombosis [ 22 , 23 ]. Moreover, these inflammatory factors can suppress the release of anticoagulant substances like nitric oxide and prostaglandin I2 from endothelial cells, amplifying their procoagulant properties [ 24 – 26 ]. Third, direct interaction between tumor cells and the lung endothelium can activate endothelial cells, prompting them to release procoagulant factors. Additionally, the cytokines released by tumor cells, notably vascular endothelial growth factor, further intensify the procoagulant activities of the endothelial cells [ 27 , 28 ]. Fourth, tumor cells can stimulate neutrophils to release neutrophil extracellular traps (NETs), which act as scaffolds that trap platelets and activate the coagulation system. Histones within the NETs can activate endothelial cells, leading to an increased release of vWF and consequently, aggravating thrombosis [ 29 , 30 ].

Histological differences between different lung cancer subtypes (NSCLC vs. SCLC) and their association with thrombosis risk

There are many subtypes of lung cancer, including non-small-cell lung carcinoma (NSCLC) and small-cell carcinoma (SCLC). NSCLC accounts for about 85% of lung cancer, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is a malignant tumor originating from the glandular epithelium, commonly seen in the salivary gland, lung, and other organs, which belongs to the type of cancer with a higher malignant degree. There are significant differences in biological behavior, gene mutation spectrum, and clinical manifestations between NSCLC and SCLC. These differences also directly affect the risk level and mechanism path of concurrent VTE between NSCLC and SCLC, mainly including the following three points: (1) In NSCLC, adenocarcinoma is closely associated with VTE. The study found that thrombosis occurred at similar rates in patients with NSCLC and SCLC (10.8% and 10.5%, respectively). However, the incidence of thrombosis was higher in adenocarcinoma than in squamous-cell carcinoma (14.7% vs. 5.3%, respectively) [ 31 ], which may be related to the secretion of large amounts of mucin, platelet activation, and formation of microthrombi by adenocarcinoma cells. Adenocarcinomas are also more likely to metastasize early and promote thrombosis [ 32 ]. (2) TF is the core molecule linking tumor and thrombosis. It has been found that the TF expression level of SCLC is generally higher than that of NSCLC, which may be related to its stronger invasiveness and early metastatic ability. In addition, TF can directly activate the exogenous coagulation pathway and trigger the coagulation reaction. In NSCLC, mutations in specific driver genes are strongly associated with VTE risk and may be associated with the rearrangements of ALK and ROS1 and mutations of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) [ 33 ]. (3) Pre-treatment thrombocytosis (> 400 × 10 9 ·L⁻¹) was prevalent in all subtypes of lung cancer, and there was no significant difference in thrombocytosis rate and mean platelet count among subtypes. It is suggested that thrombocytosis is a common feature of lung cancer and not unique to a single subtype [ 34 ]. What ultimately tips the risk of thrombosis is the summation of platelet functional activation and TF expression. Adenocarcinomas combine micropapillary architecture with high TF output, synergistically elevating VTE risk. Although SCLC had similar platelet counts and the highest TF expression, the incidence of VTE did not increase further, which may be related to the short course of disease, intensive chemotherapy, and early death competition, which indicates that tumor behavior was not simply linearly related to thrombosis [ 35 , 36 ]. Therefore, the histological subtype should be considered above the platelet count when judging VTE risk in patients with cancer, and priority should be given to adenocarcinoma and any subtype with persistent thrombocytosis.

Other factors in the lung microenvironment

Association between pulmonary inflammatory response and thrombosis

Persistent low-grade inflammation in the lung cancer tissue microenvironment is not only the fuel for tumor progression but also the central driver of the significantly increased incidence of VTE. Malignant cells, immune cells, and the coagulation system form a positive feedback loop through a common signal axis, and its key nodes include: 1. TF and MPs: Lung cancer cells highly express TFs and their cancerous procoagulants, which are released into the blood in membrane-bound or soluble form. TF-positive MPs form a complex with activated factor VIIa (FVIIa) to activate factor X (FX), which directly triggers exogenous coagulation. TF-positive MPs can also bind to platelet p-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which are enriched in microvessels in situ, thus forming thrombosis [ 37 ].

2. Inflammatory cytokine storm: IL-6, IL-1β, TNF-α, and other proinflammatory cytokines upregulate endothelial TF, FVIII, and vWF and downregulate thrombomodulin (TM). What’s more, they promote NETs formation through the JAK-STAT3 pathway. Citrullinated histone H3 in NETs activates platelets and neutralizes TF pathway inhibitors, further amplifying coagulation signals [ 38 ].

3. Complement-coagulation cross-activation: in the lung tumor microenvironment, TF-induced coagulation activated the complement system and subsequently recruited myeloid-derived suppressor cells to promote tumor growth [ 39 ]. 4. The dual effects of immune checkpoint inhibitors (ICIs): lung cancer leads to an increased risk of thrombosis compared with other malignancies, and the use of ICIs may further increase the risk of CAT. It is speculated that ICIs enhance T cell effector function while also promoting the release of inflammatory factors and NETs [ 40 ]. However, a retrospective cohort reported a lower risk of VTE in the ICI-based group than in the chemotherapy-based group (26% lower risk), and it is suggested that the effect of immunotherapy on thrombus may depend on the “inflammation-immune” balance of the tumor microenvironment [ 41 ]. Furthermore, different regimens of ICIs modulate the “immune-inflammation-coagulation” axis in different directions, which may be an important reason for the heterogeneity of VTE [ 42 ].

Potential link between pulmonary microbiota and thrombosis

The lung microbiota is a diverse community primarily composed of bacteria, fungi, and viruses, all of which play crucial roles in maintaining the delicate balance of the lung microenvironment. Under normal circumstances, a dynamic equilibrium exists between the lung microbiota and host, ensuring efficient lung function. However, in certain pathological conditions, such as infections, inflammation, or tumors, this balance can be disrupted, leading to a condition known as dysbiosis. During dysbiosis, the composition and function of the microbiota are altered, potentially harming the host. One aspect of dysbiosis that has garnered attention is the production of microbial metabolites, such as trimethylamine n-oxide (TMAO), which has been linked to an increased risk of thrombosis. TMAO has been shown to play a role in the early stages of arteriosclerosis by increasing platelet reactivity and promoting the deposition of foam cells in blood vessels [ 43 ]. Furthermore, research has shown that the gut microbiota plays a key role in shaping the composition of the lung microbiota through the gut-lung axis. Gut microbiota dysbiosis can result in the translocation of pathogens and their associated molecular patterns to the lungs, triggering pulmonary inflammation and thrombosis. For instance, in patients with severe acute pancreatitis, intestinal barrier function may be compromised, allowing gut bacteria to migrate to the lung. This migration can activate an inflammatory response in the lungs and contribute to the development of thrombosis [ 44 ].

Clinical evidence of lung-originated mechanisms

Clinical research and observation

It can be seen in Table 2 in detail.

Table 2 Clinical evidence for pulmonary origin of cancer-related thrombus Year Findings 2015, [ 35 ] Plasma levels of Von Willebrand disease factor, IL-6 and extravesicular vesicles were significantly increased in patients with cancer-related pulmonary embolism. 2021, [ 45 ] A total of 9,571 cancer patients were enrolled in the study. Of these, death was considered pulmonary embolism-related in 642 patients (6.7%). 2021, [ 21 ] 1. Circulating tumor cells (CTCs) may form thrombi in pulmonary blood vessels, and the effect of CTCs on blood flow has been verified using computational modeling. Autopsy studies have also found that cancer cell clusters can be detected in most patients with pulmonary thrombosis, further supporting the role of lung cancer cells in thrombosis. 2. Lung cancer cells can release TF-positive microparticlesthat directly activate the coagulation cascade, leading to thrombosis. 2025, [ 3 ] 1. The tumor-released chemokine CXCL13 can activate interstitial macrophages in the lungs, prompting them to release sEv-β2, which is activated by binding to platelet surface glycoproteins, and to release sEv-β2, promoting the aggregation of platelets and thrombus formation. 2. Targeting integrin β2 effectively reduced thrombosis and unexpectedly reduced tumor metastasis in mice. 3.The lung acts as a“CXCL13 factory” that, even if not transferred to the lung, can remotely activate lung macrophages through circulating CXCL13 and induce thrombosis.

Changes in biomarkers related to CAT

Plasma biomarkers, including D-dimer, p-selectin, and TM, exhibit abnormal fluctuations in patients with CAT [ 46 ]. In addition, the sEV-β2 assay has emerged as a promising tool for predicting thrombus risk in clinical practice. Research has demonstrated that sEVs originating from the pulmonary prothrombotic niche play a role in platelet activation via integrin β2. This discovery holds potential for the development of new antithrombotic medications, indicating that sEV-β2 not only serves as an indicator of thrombosis but also offers predictive value for future thrombotic risks. This knowledge can enable early clinical intervention and offer a beacon of hope for preventing thrombosis in individuals with cancer [ 3 ]. Of particular note is the observation that changes in sEV-β2 levels follow a distinct temporal pattern: they tend to rise steadily until reaching a peak prior to thrombotic events and then decline post-event [ 3 , 47 , 48 ]. This pattern underscores the importance of timing in clinical testing and highlights the potential benefits of regular monitoring compared with individual assessments.

Furthermore, the chemokine CXCL13 secreted by the tumor not only stimulates pulmonary macrophages and facilitates the release of sEVs but also functions as a predictive biomarker for the risk of thrombosis [ 3 ]. Researches have revealed a notable correlation between elevated plasma CXCL13 levels and an increased risk of thrombosis in individuals with cancer. This not only contributes to the development of a prothrombotic environment in the lungs but can also indicate systemic inflammatory responses [ 49 – 51 ]. Numerous studies have indicated significant variances in the levels of CD151, CD171, and the transmembrane 4 superfamily within lung cancer tissues compared to healthy controls, highlighting the potential of specific proteins within plasma vesicles as biomarkers [ 52 – 55 ].

Application of biomarkers in diagnosis of CAT

D-dimer, a degradation product of fibrin, is frequently elevated in patients with cancer, and its levels are positively correlated with the risk of thrombosis [ 56 , 57 ]. Studies have shown that a D-dimer level of ≥ 1.44 µ g/mL can serve as a predictor for identifying high-risk patients and has been integrated into the Khorana score model [ 58 , 59 ]. Furthermore, increased levels of P-selectin, a marker of platelet activation, have been strongly linked to a 6-month VTE risk in individuals with cancer, showing a significant association (11.9% vs. 3.7%) [ 60 , 61 ]. Platelet count, particularly exceeding 350 × 10 9 /L, has been identified as an independent risk factor, particularly in pancreatic cancer, lung cancer, and other hypercoagulable tumor types [ 62 , 63 ]. Notably, the plasma levels of integrin β2, CXCL13, and other molecules have also been closely associated with thrombosis risk in cancer patients, potentially serving as predictive markers [ 3 ]. The emergence of a comprehensive four-point test for thrombus (TAT, PIC, t-PAIC, and TM) can indicate vascular endothelial damage and coagulation dysfunction at an early stage. In particular, elevated TM levels have been linked to the extent of tumor metastasis [ 64 , 65 ], suggesting that it may offer supplementary insight for assessing thrombosis risk in patients with lung cancer. These findings not only establish a multidimensional biomarker system for early CAT diagnosis but also lay the groundwork for developing antibody therapies targeting integrin β2. This innovation holds promise for enhancing anticoagulation in cancer patients, shaping a potential avenue for CAT treatment.

Clinical applications based on lung-originated mechanisms

Diagnostic strategies

Detection methods of pulmonary thrombus-related biomarkers

It can be seen in Table 3 in detail.

Table 3 The physiological function and detection methods of pulmonary thrombus-related biomarkers Names of biomarkers Physiological effects Detecting methods TM The elevation of TM indicates damage to the vascular endothelium, which is related to the degree of tumor metastasis. Chemiluminescence method Thrombin-antithrombin complex(TATIII) It is a marker of coagulation system activation. Plasmin-α2-plasmininhibitor complex(PIC) It reflects the activation of the fibrinolytic system and indicates the degree of activity of the fibrinolytic process. Tissue plasminogen activator-inhibitor complex(t-PAIC) It reflects the inhibition of the fibrinolytic system, suggesting inhibition of fibrinolysis. D-dimer D-dimer is a marker of activation of the fibrinolytic system, and its increased levels reflect an imbalance in the coagulation-fibrinolytic system. Immunoturbidimetric method Fibrinogen degradation products The product of secondary fibrinolytic activation indirectly reflects the presence of thrombus. Immunoturbidimetric method sEV-β2 It is released by lung macrophages, which promote platelet aggregation to form thrombi and may serve as a risk marker for cancer-related thrombosis. Flow cytometry

Table 4 Methods of lung imaging examination Detectingmethods Advantages Clinical applications Noting points CT angiography of pulmonary artery (CTPA) It is non-invasive, high specificity, and can directly show the pulmonary artery embolus Diagnosis of acute pulmonary embolism, assessment of Embolus location, number, and type It should be used with caution in patients with iodine allergies or renal insufficiency. Energy Spectrum CT Scan It can be used to separate iodine-based substances, quantitatively analyze iodine, and evaluate blood perfusion of lung tissue. To evaluate the changes of pulmonary blood flow perfusion after pulmonary embolism and to assist in the diagnosis of microembolism Image quality is affected by many factors because of the high requirements of equipment and technology. Radionuclide pulmonary ventilation/perfusion imaging (v/Q scan) It can evaluate pulmonary ventilation and perfusion and has a high diagnostic value for pulmonary embolism. The severity of pulmonary embolism was assessed in patients who were unable to undergo CTPA. The inspection time is longer and there is a need for professional equipment and technical personnel. Magnetic Resonance Imagin There is no need for ionizing radiation, iodinated contrast agents, or high-resolution soft tissues. Diagnosis of pulmonary embolism and assessment of right ventricular dysfunction The examination time is long for the patient to cooperate with the request and the expense is high. Echocardiography Right ventricular dysfunction can be assessed, and pulmonary embolism has auxiliary diagnostic value. To evaluate the effect of pulmonary embolism on cardiac function and to monitor the therapeutic effect The technical level of the operator must be high, and the results are affected by factors such as the body shape of the patient.

Application of pulmonary imaging in risk assessment of thrombosis

It can be seen in Table 4 in detail.

Preventive strategies

Measures to prevent CAT

The Khorana score is a widely used tool for assessing VTE risk in patients with cancer. This scoring system considers various factors, such as site of cancer, platelet count, and hemoglobin level. For patients who are considered to be at high risk, with a score of 3 or higher, prophylactic anticoagulation should be considered. However, it is important to carefully weigh the risk of developing thrombosis against the risk of bleeding in patients who are considered to be at low to intermediate risk [ 66 – 68 ]. But there are some limitations, including: (1) Low sensitivity and high rate of missed diagnosis (2) Time was static and could not be tracked dynamically: only the baseline status before chemotherapy was evaluated; however, the dynamic changes of hematological indicators, tumor progression, surgery, infection, and other acute events after chemotherapy could not be reflected. As a result, the prediction accuracy decreases with the extension of the treatment period. (3) Not applicable to in-hospital or perioperative patients: the model development cohort was limited to outpatient chemotherapy and did not include high-risk scenarios such as bed rest, immobilization, and perioperative periods; the ability to accurately discriminate VTE risk in most types of cancer patients either in inpatient or outpatient settings is poor, and direct use in hospitalized patients significantly underestimates the risk [ 66 ]. For the above reasons, the Khorana score should be used with caution. A study assessed VTE risk in patients with advanced lung cancer that modified the Khorana score and combined it with a multivariate logistic regression analysis, including lymphocyte count, platelet count, and prothrombin fragment 1 + 2 [ 69 ]. In addition, it has been found that using the Khorana score in combination with thromboelastography assessed coagulation in women cancer patients under chemotherapy [ 70 ].

The clinical approaches used to assess the risk of VTE in oncologic patients can be divided into five broad categories, as detailed in Table 5 . Here are some suggestions: (1) For outpatients with cancer who are not treated with chemotherapy, the Khorana score is preferred. And if the cancer type fits, the cancer type-specific model, such as COMPASS-CAT and IMPEDE, is preferred. (2) For hospitalized and perioperative patients: a CanClot score is appropriate. (3) For patients treated with ICIs, targeted, or antiangiogenic drugs: new models such as ICI-VTE or COVID-TE should be superimposed, and inflammatory-coagulation indicators such as D-dimer, platelets, and IL-6 should be dynamically monitored.

Table 5 Tools for assessing VTE risk in cancer patients Category Model Key Indicators Application Setting 1. General Chemotherapy Outpatient Models(No Biomarkers) Khorana Score Primary tumor site, platelet count, hemoglobin, leukocyte count, Body Mass Index (BMI) Pre-chemotherapy outpatients PROTECHT Score Khorana variables + cisplatin/gemcitabine/anti-angiogenic agents Pre-chemotherapy outpatients ONKOTEV Score Distant metastasis, vascular compression, VTE ±, Khorana > 2 Pre-chemotherapy outpatients 2. Cancer-Specific Models COMPASS-CAT Score Hormonal/anti-hormonal therapy, central venous catheter, VTE history, cardiovascular risk factors Breast, colorectal, lung, ovarian cancers ThroLY Score Histology, mediastinal involvement, BMI > 30, immobility, extranodal involvement Lymphoma IMPEDE Score Immunomodulatory drugs, dexamethasone dose, doxorubicin, central venous catheter Multiple myeloma SAVED Score VTE history, age ≥ 80, Asian race, surgery within 3 months, dexamethasone dose Multiple myeloma 3. Models Enhanced with Laboratory Biomarkers Pabinger Nomogram Tumor site + D-dimer Cancer outpatients TIC-ONCO Score 4 SNPs (e.g., FVL, PROCR) + BMI, family history of VTE, tumor site, stage Cancer outpatients 4. Perioperative/Inpatient Models CanClot Score Platelet count, leukocyte count, BMI, tumor stage, infection, central venous catheter Hospitalized cancer patients (medical) Postoperative Nomogram D-dimer, surgery duration, tumor size, pathological type Postoperative lung cancer patients 5. Special Situation/new treatment model COVID-TE Score Tumor site, VTE history, elevated D-dimer, recent systemic therapy, ICU admission, ethnicity Hospitalized cancer patients with COVID-19 ICI-VTE Risk Model Age, BMI, platelet count, cancer type, ICI regimen (dual vs. PD-1 monotherapy) Patients treated with ICIs

Several preventive measures can be taken to reduce VTE risk in cancer patients: (1) Patients should be encouraged to engage in appropriate physical activities, such as getting out of bed early and moving around. This helps to improve blood circulation and reduce the risk of thrombosis. (2) Maintaining adequate hydration by consuming 2000–2500 mL of water per day can help ensure proper blood volume and mobility, which can also reduce VTE risk. (3) For patients who are bedridden or have limited mobility, graded compression stockings or intermittent pneumatic compression devices can be used to promote venous return and reduce the likelihood of developing thrombosis. These devices work by applying physical pressure to the legs, which helps prevent blood from pooling and forming clots. (4) Drug prophylaxis may be necessary for some patients, particularly those who are at a high risk of developing VTE. Options for drug prophylaxis include low molecular weight heparin, unfractionated heparin, and new oral anticoagulants [ 71 – 73 ].

Prevention recommendations for special populations

It mainly includes the following three special populations: 1. Elderly patients: It is crucial to maintain a comfortable and consistent temperature in their living environment because sudden changes in temperature can be harmful. Ensuring that they are properly clothed and have access to heating sources, such as blankets or heaters, can help prevent issues related to vasoconstriction. Additionally, paying attention to their overall health and providing warm beverages or foods can assist in keeping them warm and comfortable. By taking these precautions, the risk of complications associated with cold stimulation can be reduced in elderly patients.

Obese patients: It is crucial for them to stay within the normal range to prevent the onset of various obesity-related health issues. Apart from focusing on weight management, it is also important to closely monitor blood lipids, blood glucose levels, and other relevant indicators. Regular checkups and consultations with healthcare providers can help obese patients keep track of their health status and make necessary adjustments to their lifestyle habits. By staying proactive and vigilant in managing weight and monitoring health metrics, obese patients can significantly reduce their risk of developing serious obesity-associated complications. It is vital for them to prioritize their health and well-being by making conscious efforts to improve their overall health and prevent potential health problems in the future. 3. Pregnant and postpartum patients: It is important to engage in appropriate exercise to promote good circulation and overall health. In some cases, prophylactic anticoagulant medications are recommended to prevent thrombosis. It is crucial for pregnant women to prioritize movement throughout the day, because long periods of sitting or standing can increase the risk of developing thrombosis. Simple exercises such as walking, stretching, and light aerobic activities can help improve circulation and reduce the risk of clot formation. Similarly, postpartum women should also be mindful of their activity levels and avoid being immobile for extended periods. Engaging in gentle exercises and staying active can aid in the recovery process and prevent complications such as thrombosis.

Treatment strategies

Anticoagulant therapy

There are four main points as follows: (1) Pharmacological treatment is essential in managing cancer-associated thrombi, with LMWH being the preferred choice for hospitalized patients and high-risk outpatients [ 74 , 75 ]. Studies have shown that LMWH effectively reduces VTE risk with manageable bleeding risks [ 61 , 76 ]. For high-risk outpatient chemotherapy patients, such as those with pancreatic, lung, and ovarian cancers, direct oral anticoagulants such as rivaroxaban or edoxaban may be considered. However, caution should be exercised in patients with gastrointestinal tumors because of the increased risk of bleeding [ 61 , 77 , 78 ]. In cases where patients have thrombocytopenia (≥ 50 × 10 9 · L − 1 ) but still require anticoagulation, LMWH can be used alongside platelet monitoring without immediate discontinuation. (2) Surgical interventions such as thrombectomy, stent placement, and inferior vena cava filter placement may also be options for treating CAT [ 79 , 80 ]. (3) Aggressive treatment of the primary cancer is also crucial in managing thrombotic complications [ 61 ]. (4) Incorporating regular exercise into the treatment plan can also be beneficial

The treatment of NETs

By releasing NETs, neutrophils can play a role in promoting thrombosis, stabilizing and growing thrombosis, and increasing the risk of thrombotic diseases. Several strategies can be employed to regulate neutrophil function and prevent the negative effects of NETs on thrombosis: (1) Regulation of neutrophil function: One approach to inhibit NET formation is to use DNase I, which can break down the DNA structures that make up NETs. Additionally, anti-inflammatory treatments with inhibitors of cytokines such as IL-1β or TNF-α can help reduce the inflammatory response that leads to NET formation [ 81 , 82 ]. (2) Targeting neutrophil-platelet interactions: Neutrophils and platelets interact through integrin signaling, and one way to modulate this interaction is to block the P-selectin/PSGL-1 pathway using inhibitors of P-selectin, such as crizanlizumab. By disrupting this pathway, the adhesion between neutrophils and platelets can be reduced, potentially lowering the risk of thrombosis [ 83 ]. (3) Immunomodulatory and anticoagulant combination therapy: Combining immunomodulatory treatment with anticoagulant therapy can effectively address the harmful effects of NETs on thrombosis. For example, drugs such as CSF3 and JAK inhibitors such as ruxolitinib can modulate the JAK-STAT pathway, which plays a role in the inflammatory response and clotting cascade [ 84 , 85 ]. (4) Nutritional support and metabolic intervention: Providing the body with key nutrients, such as vitamin C, zinc, and iron, as well as antioxidants like vitamin E, can help support overall health and reduce the risk of thrombosis [ 86 , 87 ]. Details of the measures to prevent and treat CAT are shown in Fig. 2 .

Fig. 2 Measures of preventingor treatingCAT

Discussion

CAT is a significant cause of mortality in patients with cancer, and the use of chemotherapy, immunotherapy, and targeted therapy can further elevate the risk of developing thrombosis. Understanding the varying levels of thrombosis risk during different stages of tumor progression, whether in early, advanced, or metastatic cancer, is crucial for developing precise prevention and treatment strategies [ 88 – 90 ]. In recent years, a major breakthrough in the field of tumor biology has been the discovery of the pulmonary origin of CAT. Recent studies have revealed that the lung microenvironment plays a critical role in CAT development. Studies have shown that tumors release a chemokine called CXCL13, which travels through the bloodstream to the lungs and activates the pulmonary interstitial macrophages. These macrophages then release sEV-β2. The sEV-β2 molecules bind to the platelet surface glycoprotein GPIb, initiating platelet aggregation and setting off a cascade of events that culminates in systemic thrombosis. This groundbreaking finding not only reshapes our understanding of CAT pathogenesis but also opens up new avenues for intervention in clinical practice [ 3 ]. Investigating the role of sEVs in thrombosis not only expands our comprehension of the systemic impact of cancer but also establishes a molecular framework for developing innovative antithrombotic approaches. The revelation of sEV-β2 provides insight into the origin and crucial effector molecules of thrombosis from a fresh perspective, moving beyond conventional understanding and offering significant theoretical and practical implications [ 3 , 91 – 93 ]. The multifunctional nature of macrophages implies that tailored intervention strategies may be necessary for macrophages in various locations and subpopulations. Furthermore, these findings underscore the importance of considering macrophage-mediated systemic effects, particularly the risks of thrombosis and distant metastasis, in cancer therapy, in addition to focusing solely on the tumor itself. What’s more, there are significant differences in the mechanism and risk of thrombosis between NSCLC and SCLC. Patients with adenocarcinoma are a high-risk group, and VTE screening and prevention should be strengthened. Although SCLC has high expression of TF, its VTE risk needs to be comprehensively evaluated according to clinical stage and treatment background [ 31 , 94 ]. Future studies should further explore the interaction mechanism between gene mutations and coagulation pathways and promote the establishment of individualized anticoagulation strategies [ 95 ]. Additionally, the link between pulmonary microbiota and thrombosis is of clinical significance. Monitoring changes in the composition and function of the lung microbiota could aid in the early identification of thrombosis risk. Therefore, options such as modulating the lung microbiota through probiotic or antibiotic intervention could present innovative strategies for preventing and treating thrombosis [ 96 – 98 ].

Nevertheless, the investigation of the pulmonary origin of thrombosis in cancer patients has three key challenges:1. Heterogeneity in thrombosis poses a significant obstacle. Different types of tumors have varying effects on thrombosis, with pancreatic cancer notably secreting large amounts of CXCL13, a chemokine that significantly increases the risk of systemic thrombosis. Conversely, breast cancer and melanoma produce low levels of CXCL13. When these tumors metastasize to the lungs, they can still induce thrombosis by locally affecting lung macrophages. This diversity in tumor behavior complicates the study and understanding of thrombosis in patients [ 99 ]. 2. There are challenges in predicting thrombus risk. While integrin β2 on CXCL13 and sEVs shows promise as potential biomarkers, the lack of reliable detection methods and standardized criteria for clinical application hinders their use. Moreover, the heterogeneity and individual variability of tumors make it difficult to develop accurate predictive models and personalized treatment strategies. This uncertainty in predicting thrombus risk adds another layer of complexity to the management of thrombosis in patients with cancer. 3. The exploration of therapeutic targets presents a set of difficulties. Current anticoagulant treatments, such as low-molecular-weight heparin, have the potential to increase the risk of bleeding. On the other hand, antibody therapies targeting integrin β2 have shown efficacy in animal models but have the drawback of increasing the risk of bleeding in clinical trials. The translation of these promising therapeutic approaches from preclinical studies to clinical settings requires further optimization to ensure their safety and suitability for a wider patient population.

There are a number of exciting directions for future research in the field of thrombosis and cancer: (1) Advanced Molecular Analysis: One promising avenue is the combination of single-cell sequencing and proteomics to conduct multi-omics analysis of the molecular characteristics of tumor-promoting neutrophils (PTN) in various cancer types. This approach could provide valuable insights into the role of PTN in CAT. (2) Immunometabolic Regulation: Another area of interest is the investigation of the relationship between macrophage polarization, specifically the M2 type, and thrombosis. For example, studies have shown that thrombospondin-2 can drive M2 polarization through fatty acid metabolism in lung adenocarcinoma, potentially influencing thrombotic events. Understanding this association could lead to new therapeutic strategies for preventing thrombosis [ 100 ]. (3) Clinical Translation: One important goal is the development of an early warning system that incorporates the detection of sEVs carrying integrin β2. By optimizing precise antithrombotic strategies targeting integrin β2, clinicians may be able to identify high-risk patients and intervene before thrombotic events occur. (4) Accurate Prediction Modeling: Researchers could focus on developing risk stratification models based on biomarkers such as integrin β2. By identifying patients at the highest risk for thrombosis, healthcare providers can tailor preventative measures and treatment plans accordingly. (5) Targeted Antithrombotic Agents: Efforts should also be made to identify specific subsets of prothrombotic neutrophils, such as antigen-presenting versus pro-inflammatory cells, using single-cell sequencing techniques. This knowledge could lead to the development of targeted antithrombotic agents tailored to an individual patient’s immune profile. Additionally, the use of microfluidic organ chips to simulate the interactions between neutrophils, endothelial cells, and platelets could be instrumental in screening novel antithrombotic compounds for future clinical use.

Conclusion

CAT is a significant consequence of how tumors affect the body as a whole, and the lungs are particularly crucial in this process, acting as the “command center” for thrombosis. Understanding the intricate mechanisms underlying the development of cancer-induced thrombosis in the lungs could not only lead to advancements in preventing and treating thrombosis but also spark innovative approaches to cancer therapy. It is imperative to focus on future research directions and potential breakthroughs in this field to inform clinical practice and improve patient outcomes.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Huan Sun and Qiaoli Zhai contributed equally to this work.

Change history

2/21/2026

The original publication was amended to correct the funding information.

Acknowledgements

We are very grateful to the Seventh People’s Hospital of Shanghai for its valuable guidance and support during the preparation of this review article.

Author contributions

Huan Sun: Conceptualization, Methodology, Validation, Formal analysis, Writing-Original draft. Qiaoli Zhai: Conceptualization, Methodology, Validation, Formal analysis, Data Curation. Beiwei Xin: Inverstigation, Resources, Writing-Review editing. Lingyu Zhong: Project administration, Funding acquistion, Supervision. Kourong Shi: Writing-Review editing, Funding acquistion, Supervision.

Funding

This work was funded by The Training Program for Academic Leaders in the Health System of Pudong New Area, Shanghai (Grant No. PWRd2023-14); Talents Training Program of the Seventh People’s Hospital, Shanghai Uiversity of Traditional Chinese Medicine (Grant No. JY2025-06); Talents Training Program of the Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine) (Grant No. BDX2022-01); Innovative Chinese Medicine Research Institute for the Pharmacy Department of Shanghai Seventh People’s Hospital (Grant No. 25-LCYJS-02); The 2024 Nantong University Clinical Medicine Special Research Fund Project(Grant No.2024LY057); The 2024 Research Project of the Nantong Municipal Health Commission (Grant No. QNZ2024069).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics and consent to participate declarations

Not applicable.

Consent to publish

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

Cancer-associated thrombosis

Disseminated intravascular coagulation

Tissue factor

Venous thromboembolism

ROS proto-Oncogene 1, receptor tyrosine kinase

Small extracellular vesicles

Small extracellular vesicles containing integrin β2

C-X-C motif chemokine 13

Tumor necrosis factor-alpha

Interleukin-1 beta

Glycoprotein IB

Phosphatidylserine

von Willebrand factor

Neutrophil extracellular traps

Trimethylamine n-oxide

Circulating tumor cells

Thrombomodulin

Thrombin-antithrombin complex

Plasmin-α2-plasmininhibitor complex

Tissue plasminogen activator-inhibitor complex

CT angiography of pulmonary artery

Radionuclide pulmonary ventilation/perfusion imaging

Low molecular weight heparin

P-selectin glycoprotein ligand-1

Activated factor VIIa

Factor X

Anaplastic lymphoma kinase

ROS proto-oncogene 1, receptor tyrosine kinase

Epidermal growth factor receptor

Kirsten rat sarcoma viral oncogene homolog

Body mass index

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