Lung cancer is recognized as one of the most thrombogenic cancer types, wherein venous thromboembolism (VTE) occurs in up to 14% of patients (1). The risk of VTE is particularly high in patients with advanced stages of lung cancer, such as those with adenocarcinoma, which has been associated with a higher incidence of thrombotic events compared with other histological types of lung cancer, such as squamous cell carcinoma or small cell lung cancer (1). The mechanisms underlying the increased risk of thrombogenesis include immobilization, the presence of central venous catheters and the direct activation of the coagulation system by cancer cells, which release procoagulant factors that stimulate platelet activation and coagulation pathways. Following vascular endothelial disruption, factor XII initiates the intrinsic coagulation pathway through contact activation with subendothelial collagen, thereby mediating hemostasis in deep tissue injuries. Concurrently, tissue factor (TF) exposure upon vascular rupture triggers the extrinsic pathway, enabling rapid thrombin generation via TF-factor VIIa complex formation. These two pathways synergistically regulate hemostasis and thrombosis through distinct yet complementary mechanism (2,3). Chemotherapy, a common treatment for lung cancer, further exacerbates the risk of thrombosis. Chemotherapy agents, such as cisplatin, carboplatin, gemcitabine and paclitaxel, have been demonstrated to elevate procoagulant activity in endothelial cells and other blood components such as fibrinogen, antithrombin III and tissue factor pathway inhibitor. The increase in procoagulant activity is primarily mediated through mechanisms that involve TF expression and disulfide bond formation, which contributes to a hypercoagulable state in patients with lung cancer (4). Furthermore, the presence of central venous catheters, which are often used for chemotherapy administration, further increases the risk of thrombosis. A previous study indicated that patients with lung cancer who had peripherally inserted central catheters experienced a high incidence of upper extremity venous thrombosis, particularly when treated with certain chemotherapeutic agents such as etoposide (5). The use of antiangiogenic agents, including bevacizumab, sorafenib, apatinib and amilorotinib, and immunotherapy has also been linked to an increased risk of thromboembolic events (2,3). In a previous study, which included 605 patients diagnosed with non-small cell lung cancer (NSCLC), the presence of EGFR mutations was associated with varying risks of VTE. Specifically, patients with EGFR wild-type status had a higher risk of developing VTE compared with patients with EGFR mutations. The probability of developing VTE was 8.3% in patients with EGFR mutations after 1 year, compared with 13.2% in patients without EGFR mutations. After 2 years, the probabilities of developing VTE differed significantly (9.7 and 15.5%, respectively; P=0.047) (6). Furthermore, another study highlighted that the mutation of EGFR was associated with a decreased risk of VTE. In a cohort of 310 patients with lung adenocarcinoma, patients with EGFR mutations had a hazard ratio (HR) of 0.46 for VTE, which suggested a protective effect against thrombosis compared with patients with wild-type EGFR with lung adenocarcinoma (7). This finding indicated that the presence of the EGFR-L858R mutation may not only be a driver of tumorigenesis but could also serve a role in modulating the risk of thrombotic events. Splenic infarction, a rare but clinically significant thromboembolic event, arises from the occlusion of the splenic artery or the splenic artery branches by emboli or thrombi. With an incidence of 0.016% in hospital admissions, VTE predominantly results from cardiogenic embolism (62.5%), most notably atrial fibrillation (1). Secondary etiologies include autoimmune disorders (12.5%), infections (12.5%) and hematologic malignancies (6%) (8). Clinically, sudden-onset left upper quadrant abdominal pain (84% of cases) constitutes the classic presentation, although asymptomatic cases (≤16%) and atypical manifestations such as fever and nausea may occur (9). Diagnostic delays are common due to nonspecific symptoms. The prognosis remains favorable with timely intervention (10,11). The median hospitalization duration is 6.5 days, and anticoagulation therapy is initiated in most cases to mitigate thromboembolic risks and promote recovery (12).

The clinical implications of multiple-site thrombosis in patients with lung cancer are notable (13,14). Patients with VTE often experience longer hospital stays, higher rates of inpatient mortality and increased healthcare costs compared with patients without VTE. Furthermore, the presence of thrombosis can complicate cancer treatment, as anticoagulation therapy may increase the risk of bleeding, particularly in patients undergoing chemotherapy or surgery (15). The present case illustrated the complex thrombotic evolution in EGFR-driven NSCLC, which emphasizes the need for precision anticoagulation strategies.

Patients with lung cancer are particularly susceptible to multi-site thrombosis due to a combination of factors that create a hypercoagulable state (23–25). Multi-site thrombosis is characterized by an increased tendency for blood clot formation, which can result in thromboembolic events in both the venous and arterial systems. A primary reason for this heightened risk is the presence of procoagulant factors associated with malignancy (26,27). Cancer cells, including those from lung cancer, can express various procoagulant substances such as TF, cancer procoagulant and heparanase. These factors serve a key role in the activation of the coagulation cascade, which leads to increased thrombin generation and subsequent clot formation (3,28). Additionally, tumor cells can secrete inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, which further stimulate the coagulation process and promote thrombosis. The presence of a tumor can disrupt normal blood flow, which leads to stasis, while chemotherapy and other cancer treatments may cause damage to the vascular endothelium and thereby increase the risk of clot formation. The hypercoagulable state observed in patients with cancer is also influenced by the inflammatory response associated with malignancy. Inflammation can lead to alterations in the balance between procoagulant and anticoagulant factors, which shifts the equilibrium towards increased clotting (29–31). This phenomenon is particularly relevant in lung cancer, where the inflammatory environment created by the tumor can heighten the risk of thromboembolic events (3,32). Additionally, elderly patients with lung cancer may have comorbid conditions, such as chronic obstructive pulmonary disease or cardiovascular disease, which can further elevate the risk of thrombosis (32,33). The interplay of these factors leads to a markedly increased incidence of VTE among patients with lung cancer, where previous studies (24,27) have shown that patients with lung cancer are four to seven times more likely to develop VTE than the general population (34). In summary, the elevated risk of multi-site thrombosis in patients with lung cancer is multifactorial and arises from the direct effects of tumor biology, the influence of cancer treatments and the presence of comorbid conditions. According to the Khorana scoring scale (17), which assesses the risk of VTE in patients with cancer, the current patient was classified as low risk on admission. The current case highlighted limitations of the Khorana risk assessment model in the prediction of VTE among patients with cancer. Despite being classified as low risk using this validated scoring system, the patient developed multi-site thrombosis, which highlighted the insufficient sensitivity of the model in certain clinical scenarios. This finding emphasizes the urgent need for the development of a novel VTE risk stratification tool that incorporates dynamic variables, including tumor histology (such as the association between lung cancer and hypercoagulability), treatment heterogeneity and biomarkers that reflect individual thrombotic potential. Further research is warranted to enhance predictive accuracy for high-risk populations such as patients with lung cancer, who exhibit high thrombotic event rates. Vigilant thromboprophylaxis monitoring is advised for patients with cancer, including patients stratified as low-risk, due to the life-threatening consequences of VTE.

The L858R mutation results in the continuous activation of EGFR, which in turn activates several downstream signaling pathways. These include the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways (35,36). The Ras pathway is particularly important as it regulates cell proliferation, survival and migration, which are key processes in cancer progression and metastasis (35,36). The activation of these pathways can lead to increased expression of pro-coagulant factors, which contribute to a hypercoagulable state.

Previous studies have suggested that the interaction between EGFR signaling and coagulation pathways can influence cancer progression. For example, the activation of EGFR can lead to the upregulation of ligands that promote TF expression and thereby enhance the pro-coagulant state in tumors (37,38). The crosstalk is particularly relevant in the context of KRAS mutations, where both mutations (KRAS and EGFR) can synergistically promote tumor growth and thrombosis (39). The presence of the EGFR-L858R mutation in patients with NSCLC may be associated with an increased risk of thromboembolic events. This association is particularly important for clinicians to consider when managing patients with the EGFR-L858R mutation, as the hypercoagulable state can complicate treatment and increase the risk of adverse outcomes. However, a previous study, which included 310 patients diagnosed with lung adenocarcinoma, reported that patients with EGFR mutations had a HR of 0.46 (95% CI, 0.23–0.94) for VTE, which suggests a protective effect against thrombosis compared with patients with wild-type EGFR. Additionally, treatment with TKIs further reduced the risk of VTE, with an HR of 0.42 (95% CI, 0.29–0.79) when compared with other treatment strategies that did not include TKIs. This finding suggested that the presence of the EGFR mutation was associated with a lower incidence of thrombosis and the therapeutic approach using TKIs may enhance this protective effect (7). The current patient was diagnosed with lung adenocarcinoma in October 2024, following the identification of lung adenocarcinoma cells in pleural effusion via immunohistochemistry. The patient exhibited pleural and lymph node metastases, which indicated advanced lung cancer. Subsequent genetic testing demonstrated the presence of the EGFR-L858R mutation, which prompted the initiation of targeted therapy with the TKI osimertinib. However, in October 2024, chest CT indicated tumor progression and the emergence of pericardial metastasis, which led to the conclusion that single-agent targeted therapy had failed. Consequently, the treatment plan was modified to include a combination of chemotherapy (carboplatin and pemetrexed) and targeted therapy (osimertinib). At this juncture, a venous color Doppler ultrasound of the lower limbs had already detected thrombosis, and rivaroxaban (10 mg twice daily) was prescribed for anticoagulation. The anticoagulation strategy proved ineffective, as novel thrombosis was identified when the patient was admitted to the First People's Hospital of Suining in November 2024. The role of the EGFR-L858R mutation in thrombosis among patients with lung cancer remains unclear. A previous study has suggested that the EGFR-L858R mutation may reduce the incidence of thrombotic events, while other studies have indicated an increased incidence associated with the EGFR-L858R mutation (40). Based on the observations in the current patient, we hypothesized that the EGFR-L858R mutation may exert a protective effect in thrombosis among patients with lung cancer. Notably, the patient did not experience thrombosis prior to the initiation of treatment with TKI inhibitors; however, following the commencement of TKI therapy, venous thrombosis developed in the lower extremities, despite treatment with anticoagulants. This phenomenon may arise from two potential factors: Firstly, the condition of the patient progressed during treatment, which led to pericardial metastasis and notable pericardial effusion. This prolonged state likely impaired systemic circulation, which resulted in slowed blood flow and increased coagulability. Secondly, the treatment approach for the patient was modified following the development of pericardial effusion. The patient was transitioned to a regimen that included chemotherapy (carboplatin and pemetrexed) combined with targeted therapy (osimertinib). Previous studies have indicated that platinum-based antitumor agents such as cisplatin, carboplatin, oxaliplatin and lopatin may elevate the risk of VTE in patients with lung cancer, particularly with regard to catheter-related thrombosis (41,42). In summary, the antithrombotic effect of the EGFR-L858R mutation appears to be counteracted by TKI-induced endothelial dysfunction and pharmacokinetic disturbances. Based on the observations from the present case, it is necessary to revise current guidelines (17) to include the following: i) EGFR mutation status in VTE risk models; ii) TKI-specific anticoagulation algorithms; and iii) protocolized cytokine monitoring during metastasis.

MPE markedly impacts hemodynamics and coagulation properties in patients with lung cancer. The presence of MPE can lead to alterations in blood flow dynamics due to the accumulation of fluid in the pericardial space, which can compress the heart and impede its ability to pump effectively (43–45). This condition can result in cardiac tamponade, where the pressure from the fluid prevents the heart chambers from filling properly, which leads to reduced cardiac output and compromised blood flow to vital organs (46). In terms of coagulation properties, patients with lung cancer and MPE often exhibit a hypercoagulable state. A hypercoagulable state is characterized by changes in plasma fibrin clot properties, which can include increased clot density and altered permeability (47–49). A single study has reported that patients with lung cancer undergoing chemotherapy exhibited higher levels of D-dimer, a marker of fibrin degradation, which indicated increased fibrinolytic activity (50). Additionally, chemotherapy has been associated with changes in clot structure, such as increased clot permeability and prolonged clot lysis time, which can contribute to thromboembolic complications (51). The presence of MPE can also influence the activity of TF, which is a key initiator of the coagulation cascade. In patients with lung cancer, the activity of microparticle-associated TF can be altered, which leads to an imbalance between coagulation activation and fibrinolytic potential. This imbalance may predispose patients to VTE, which is notably more common in patients with lung cancer compared with the general population (52). The hypercoagulable state is further exacerbated by the presence of tumor-derived factors that promote clot formation and inhibit fibrinolysis, which contributes to the overall risk of thrombotic events in patients with lung cancer (53). In November 2024, the patient developed chest pain, exertional dyspnea and fatigue. Pericardiocentesis and catheter drainage were performed following detection of a notable amount of pericardial effusion via chest CT. Lung adenocarcinoma cells were identified in the pericardial effusion. The pericardial metastasis of the patient resulted in a substantial accumulation of pericardial effusion. This process was gradual and continuous, which markedly impacted the systemic circulation of the patient, and exacerbated the hypercoagulable state commonly associated with lung cancer. Consequently, the process led to thrombosis in multiple locations, particularly arterial thrombosis, including splenic artery thrombosis. Although pericardiocentesis and catheter drainage were performed to alleviate the cardiac tamponade in the patient, the effects on the circulatory state are unlikely to improve in the short term.

In some cases, patients with lung cancer undergoing chemotherapy may experience acute complications such as splenic infarction due to embolic events, which can be precipitated by the underlying malignancy and the treatment (54). Furthermore, the anatomical and physiological characteristics of the spleen, along with the vascular supply, can make it susceptible to thrombotic events. The spleen is typically well-protected from non-hematological metastasis and splenic artery thrombosis is a rare occurrence (21,55). However, when splenic artery thrombosis does occur, it is often part of a broader pattern of vascular complications associated with malignancies, including lung cancer (56). In summary, lung cancer can cause splenic artery thrombosis primarily through the induction of a hypercoagulable state, either due to the malignancy itself or as a consequence of chemotherapy. This can lead to thrombus formation in the splenic artery, which results in complications such as splenic infarction. The splenic artery, which is a singular vessel, is particularly susceptible to thromboembolism, which can result in splenic infarction (10). The current patient experienced splenic artery thromboembolism and subsequent splenic infarction, a clinical occurrence that is extremely rare. Notably, splenic artery thromboembolism and splenic infarction occurred despite anticoagulation therapy. To the best of our knowledge, there is a lack of pertinent research reports on this phenomenon, which necessitates further research on the underlying causes. The causes of this phenomenon were analyzed and summarized as follows: i) Hypercoagulable state: Lung cancer may influence the coagulation status of patients through various mechanisms, which leads to a persistent hypercoagulable state; ii) cardiac embolism resulting from pericardial effusion: The patient had a notable history of MPE, which severely compromised blood circulation and contributed to thrombosis formation at multiple sites, including the splenic artery; and iii) treatment modalities: TKIs and platinum-based chemotherapy agents can elevate the risk of thrombosis in patients with lung cancer. Additionally, the use of deep vein catheterization for chemotherapy may lead to catheter-related thrombosis, as evidenced by the current patient undergoing internal jugular vein catheterization for chemotherapy. Subsequent cervical venous color ultrasound revealed thrombosis in the internal jugular vein.

Venous thrombosis was identified in the lower extremity and jugular veins in December 2024 via color ultrasound. In response, anticoagulation with rivaroxaban at a dosage of 10 mg twice a day was initiated; however, new thrombotic sites continued to emerge. Following an adjustment of the anticoagulant dosage to 15 mg rivaroxaban twice a day, marked dissolution and disappearance of the thrombus were observed, with no further occurrences of thrombosis. This observation led to the conclusion that the initial anticoagulant dosage was insufficient. Additionally, as the anticoagulant dosage was modified, the D-dimer levels of the patient gradually decreased to normal levels, which indicated a positive association between D-dimer levels and thrombosis, as well as a potential predictive value regarding anticoagulant efficacy. Nonetheless, further research is necessary to substantiate the findings of the present case report.

It is extremely rare for patients with lung adenocarcinoma and EGFR-L858R mutations to develop multiple thromboses that lead to splenic infarction. This phenomenon may be associated with hypercoagulability, cardiac tamponade and genetic mutations inherent to patients with lung cancer, exacerbated by factors such as chemotherapy, targeted therapy and insufficient anticoagulation dosing. The present case highlights the complex interplay between oncogenic drivers and hemostatic regulation. The authors propose three clinical practice modifications: i) Mandatory thrombophilia screening for patients with EGFR-mutant NSCLC initiating TKIs; ii) implementation of quantitative anti-factor Xa monitoring for patients with direct oral anticoagulants-treated cancer; and iii) development of EGFR mutation-specific VTE risk assessment tools. Further research is warranted to explore the role of PI3K inhibitors in mitigating TKI-associated thrombosis while preserving antitumor efficacy.

The present case underscored the paradoxical thrombotic risk in patients with EGFR-mutant NSCLC undergoing targeted therapy, highlighted the insufficiency of the Khorana score in molecularly defined cohorts, and established visceral thrombosis screening as a critical component of care in EGFR-mutant patients with pericardial effusion. It mandates revision of VTE risk stratification frameworks to incorporate oncogenic driver status, treatment-specific factors and dynamic biomarkers, while advocating for intensified anticoagulation protocols in this high-risk subgroup.