Christodoulidis G, Bartzi D, Tsagkidou K, Koumarelas KE, Zacharoulis D. Status quo of hypercoagulation as a prognostic indicator following neoadjuvant immunochemotherapy in locally advanced gastric cancer. World J Gastrointest Oncol 2025; 17(9): 106868 [DOI: 10.4251/wjgo.v17.i9.106868]
Corresponding Author of This Article
Grigorios Christodoulidis, MD, PhD, Department of General Surgery, University Hospital of Larissa, Mezourlo, Larissa 41110, Thessalia, Greece. gregsurg@yahoo.gr
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Co-first authors: Grigorios Christodoulidis and Dimitra Bartzi.
Author contributions: Christodoulidis G and Bartzi D contributed equally to this manuscript as co-first authors; Christodoulidis G, Bartzi D, Tsagkidou K, Koumarelas KE, and Zacharoulis D contributed to the discussion and design of the manuscript, and the writing, editing the manuscript, and review of literature; Christodoulidis G designed the overall concept and outline of the manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Grigorios Christodoulidis, MD, PhD, Department of General Surgery, University Hospital of Larissa, Mezourlo, Larissa 41110, Thessalia, Greece. gregsurg@yahoo.gr
Received: March 10, 2025 Revised: April 1, 2025 Accepted: July 28, 2025 Published online: September 15, 2025 Processing time: 189 Days and 17.7 Hours
Abstract
Gastric cancer remains a major cause of cancer-related mortality worldwide, with immunotherapy emerging as a promising treatment strategy. Neoadjuvant immune checkpoint therapy has shown potential in enhancing antitumor responses and improving surgical outcomes. However, its effects on systemic coagulation and thrombotic risk remain poorly understood. This study aims to investigate the relationship between neoadjuvant immune checkpoint therapy and coagulation dynamics in patients with gastric cancer, exploring potential mechanisms that may contribute to a hypercoagulable state. By assessing coagulation markers, thrombotic events, and inflammatory responses, this research seeks to provide insights into the interplay between immune modulation and hemostatic alterations. A better understanding of these interactions may help optimize patient management and guide thromboprophylaxis strategies in this clinical setting.
Core Tip: The core message of the review emphasizes that hypercoagulation, observed after neoadjuvant immunochemotherapy in patients with locally advanced gastric cancer, serves as a significant independent prognostic indicator. Elevated coagulation markers such as D-dimer and fibrinogen are associated with poorer overall and disease-free survival rates. The article suggests that monitoring these coagulation parameters can enhance patient management by identifying high-risk individuals and tailoring postoperative care accordingly.
Citation: Christodoulidis G, Bartzi D, Tsagkidou K, Koumarelas KE, Zacharoulis D. Status quo of hypercoagulation as a prognostic indicator following neoadjuvant immunochemotherapy in locally advanced gastric cancer. World J Gastrointest Oncol 2025; 17(9): 106868
Gastric cancer remains one of the leading causes of cancer-related mortality worldwide, with a particularly high incidence in East Asia. Despite advances in surgical techniques and adjuvant therapies, the prognosis for patients with locally advanced gastric cancer (LAGC) remains poor. Neoadjuvant immunochemotherapy (NICT) has emerged as a promising approach to improve outcomes by enhancing the immune response and reducing tumor burden before surgery. However, recent studies have highlighted the potential role of hypercoagulation as a prognostic indicator in patients undergoing this treatment regimen[1,2]. Hypercoagulation, characterized by an increased tendency for blood clot formation, has been associated with various malignancies, including gastric cancer. The hypercoagulable state in cancer patients is often attributed to the release of procoagulant factors by tumor cells, as well as the inflammatory response induced by the tumor microenvironment. In the context of NICT, hypercoagulation may reflect the complex interplay between the immune system and the coagulation cascade, potentially serving as a marker for treatment response and overall prognosis. Recent research has demonstrated that elevated levels of coagulation markers, such as D-dimer and fibrinogen, are associated with poorer survival outcomes in patients with LAGC undergoing NICT[1,2]. These findings suggest that monitoring coagulation parameters could provide valuable prognostic information and guide therapeutic decision-making in this patient population. Hypercoagulation, or a hypercoagulable state, is a condition where the blood has an increased tendency to clot. This phenomenon is particularly significant in the context of cancer, as it can lead to serious complications such as venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism. In cancer patients, hypercoagulation is often driven by several factors. Tumor cells can produce procoagulant substances that directly activate the coagulation cascade. For example, tissue factor (TF) is commonly expressed by tumor cells and can initiate clot formation[2]. The tumor microenvironment is typically characterized by chronic inflammation, which can further promote a hypercoagulable state. Inflammatory cytokines released by the tumor and surrounding cells can enhance the production of coagulation factors and inhibit natural anticoagulants[3]. Platelets play a crucial role in blood clotting and are often found in higher numbers in cancer patients. Tumor cells can interact with platelets, leading to their activation and aggregation, which contributes to clot formation[3]. Therapies such as surgery, chemotherapy, and radiotherapy can increase the risk of hypercoagulation. These treatments can damage blood vessels, release procoagulant factors, and reduce mobility, all of which contribute to a higher risk of clotting[4]. Understanding the mechanisms behind hypercoagulation in cancer is essential for developing effective strategies to prevent and treat thrombotic complications in cancer patients. Monitoring coagulation parameters and implementing prophylactic measures can significantly improve patient outcomes.
Some studies investigated the impact of hypercoagulation on 104 patients with LAGC who received NICT before surgery[5,6]. The study aimed to determine whether hypercoagulation could serve as a prognostic indicator for overall survival (OS) and disease-free survival (DFS)[5,6]. The study demonstrated that patients who developed hypercoagulation following NICT exhibited significantly poorer 3-year OS and DFS rates compared to those without hypercoagulation, with the OS being 78% and DFS 68% compared to the patients without hypercoagulation (94.4% and 87% respectively). This finding suggests that hypercoagulation is an independent risk factor for adverse postoperative outcomes with the hazard ratio (HR) of OS being at 4.436, P = 0.023 and for DFS at 2.551, P = 0.039 (Table 1). The results underscore the critical importance of monitoring coagulation status in patients undergoing NICT[5,6]. The identification of hypercoagulation as a prognostic indicator has several implications for clinical practice. Patients with hypercoagulation can be identified as high-risk, allowing for more tailored postoperative care and monitoring. Clinicians may consider adjusting treatment plans for patients with hypercoagulation to mitigate risks. The study highlights the need for further research to explore the mechanisms behind hypercoagulation and its impact on cancer outcomes[5,6].
Table 1 Comparison of overall survival and disease-free survival in patients with and without hypercoagulation.
GASTRIC CANCER: PREVALENCE, EPIDEMIOLOGY, RISK FACTORS, SYMPTOMS, AND DIAGNOSIS
Gastric cancer, also known as stomach cancer, originates from the lining of the stomach. It is a significant global health concern due to its high incidence and mortality rates. The majority of gastric cancers are adenocarcinomas, which develop from the glandular cells of the stomach lining. Other less common types include lymphomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Gastric cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. According to the World Health Organization, there were approximately 1.03 million new cases and 783000 deaths globally in 2020[7]. The incidence of gastric cancer varies significantly by region, with the highest rates observed in East Asia, particularly in countries like Japan, South Korea, and China. Other regions with high incidence rates include Eastern Europe and parts of Central and South America. Several risk factors contribute to the development of gastric cancer. Chronic infection with Helicobacter pylori is a major risk factor. A diet high in salty, smoked, and pickled foods, along with low consumption of fruits and vegetables, increases the risk. Family history and certain genetic mutations can predispose individuals to gastric cancer. Lifestyle factors such as smoking, excessive alcohol consumption, and obesity are also associated with higher risk.
Early-stage gastric cancer often presents with non-specific symptoms such as indigestion, heartburn, and mild stomach discomfort, making early detection challenging. As the disease progresses, symptoms may include weight loss, persistent stomach pain, nausea, vomiting, difficulty swallowing, and blood in the stool. Diagnosis typically involves endoscopy, biopsy, and imaging studies to determine the extent of the disease[7]. Treatment for gastric cancer depends on the stage and location of the tumor, as well as the patient’s overall health. Surgery is the primary treatment for localized gastric cancer, aiming to remove the tumor and surrounding tissues. Chemotherapy uses drugs to kill cancer cells and is often used before (neoadjuvant) or after (adjuvant) surgery. Radiation therapy uses high-energy rays to target and kill cancer cells and is sometimes combined with chemotherapy. Targeted therapy involves drugs that target specific molecules involved in cancer growth and spread. Immunotherapy boosts the body’s immune system to fight cancer cells[8].
NICT AND ITS ROLE IN TREATING LAGC
NICT is an emerging treatment strategy that combines chemotherapy with immunotherapy before surgical intervention. This approach aims to reduce tumor size, enhance the immune response against cancer cells, and improve surgical outcomes. In the context of LAGC, NICT has shown promising results in improving patient prognosis and survival rates[8]. Chemotherapy works by targeting rapidly dividing cancer cells, causing cell death and reducing tumor burden. Immunotherapy, on the other hand, leverages the body’s immune system to recognize and attack cancer cells. By combining these two modalities, NICT aims to maximize the therapeutic benefits of both treatments. Chemotherapy can induce immunogenic cell death, which enhances the presentation of tumor antigens to the immune system. This, in turn, can boost the efficacy of immunotherapy by increasing the visibility of cancer cells to immune cells[8].
Several clinical trials have investigated the efficacy of NICT in treating LAGC. Studies have shown that this combination therapy can lead to higher rates of pathological complete response and improved OS compared to chemotherapy alone[9]. It is reported that patients receiving NICT had a significantly higher pathological complete response rate and longer OS than those receiving only chemotherapy[10].
Gastric cancer is often diagnosed at an advanced stage, making surgical resection challenging. NICT can shrink tumors, making them more amenable to surgical removal. Additionally, this approach can target micrometastatic disease, which is often present but undetectable at the time of diagnosis. By addressing both the primary tumor and potential metastases, NICT offers a comprehensive treatment strategy for LAGC[10].
INTRODUCTION TO THE CONCEPT OF HYPERCOAGULATION AND ITS’ POTENTIAL IMPLICATIONS
Hypercoagulation, also known as thrombophilia, is a condition characterized by an increased tendency of the blood to clot. This can lead to the formation of abnormal blood clots in veins and arteries, posing significant health risks. Hypercoagulation can be either inherited or acquired and is associated with various medical conditions, including cancer.
Hypercoagulation can result from genetic mutations that affect the proteins involved in the coagulation cascade. For example, mutations in the factor V Leiden gene or the prothrombin gene can increase the risk of clot formation[11]. Acquired causes of hypercoagulation include prolonged immobility, surgery, trauma, and certain medical conditions such as cancer and autoimmune diseases[12-14]. In cancer patients, tumor cells can produce procoagulant factors that activate the coagulation system, leading to a hypercoagulable state[7].
Cancer cells can produce procoagulant factors that activate the coagulation system, leading to a hypercoagulable state. Additionally, cancer treatments such as surgery, chemotherapy, and radiation therapy can further exacerbate this condition. The presence of hypercoagulation in cancer patients can have significant clinical implications. It is associated with an increased risk of VTE, which includes deep vein thrombosis and pulmonary embolism. These conditions can be life-threatening and require prompt medical intervention. Additionally, hypercoagulation can complicate cancer treatment by increasing the risk of bleeding and other complications during surgery and chemotherapy.
Recent studies have suggested that hypercoagulation may serve as a prognostic indicator in cancer patients. Elevated levels of coagulation markers, such as D-dimer and fibrinogen, have been associated with poorer prognosis and reduced survival rates in various cancers, including gastric cancer. Monitoring these markers can help identify patients at higher risk of complications and guide treatment decisions. Managing hypercoagulation involves addressing the underlying cause and using anticoagulant therapy to prevent clot formation. In cancer patients, this may include the use of low-molecular-weight heparin or direct oral anticoagulants. Ongoing research aims to better understand the mechanisms of hypercoagulation in cancer and develop targeted therapies to mitigate its impact. By understanding the role of hypercoagulation in cancer, healthcare providers can improve patient outcomes through early detection, risk stratification, and tailored treatment strategies[12-14].
Hypercoagulation, or an increased tendency for blood clotting, is a common phenomenon in cancer patients. In the context of LAGC, hypercoagulation can serve as a valuable prognostic indicator. Elevated levels of coagulation markers, such as D-dimer and fibrinogen, have been associated with poorer prognosis and reduced survival rates[15]. The mechanisms by which cancer leads to hypercoagulation are multifaceted and involve several pathways. Tumor cells can directly activate the coagulation cascade by expressing TF, a potent initiator of blood clotting. TF can bind to factor VIIa, leading to the activation of factors IX and X, which ultimately results in thrombin generation and fibrin formation[15]. In addition to TF expression, cancer cells can release procoagulant microparticles into the bloodstream. These microparticles can enhance thrombin generation and promote clot formation. Furthermore, cancer cells can induce the expression of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, which can activate endothelial cells and platelets, contributing to a hypercoagulable state[16]. Another mechanism involves the degradation of endogenous anticoagulants. For example, tumor-secreted heparanase can degrade heparan sulfate, a key component of the endothelial glycocalyx that has anticoagulant properties. This degradation disrupts the balance between procoagulant and anticoagulant factors, favoring a hypercoagulable state[17].
Previous studies and findings on hypercoagulation in cancer patients
Numerous studies have investigated the prevalence and implications of hypercoagulation in cancer patients. A study published in the Journal Cancer Research analyzed blood coagulation parameters in 152 melanoma patients and found that hypercoagulation was more prevalent in advanced stages of the disease[1]. The study concluded that hypercoagulation is a common feature in advanced cancer patients and is associated with disease progression[1]. In another study, it is proposed stratifying cancer-related hypercoagulability into two main types: Type I, resulting from the degradation of endogenous heparin by tumor-secreted heparanase, and type II, which includes other etiologies related to the patient, tumor, and treatment[18]. The study highlighted the complex interplay between cancer and the coagulation system and emphasized the need for further research to understand these mechanisms[18].
How NICT can influence coagulation pathways
NICT, which combines chemotherapy with immunotherapy before surgical intervention, has shown promise in treating various cancers, including gastric cancer. However, this treatment approach can influence coagulation pathways and contribute to a hypercoagulable state. Chemotherapy can induce endothelial damage and release procoagulant factors, while immunotherapy can enhance the immune response, leading to increased inflammation and activation of the coagulation system. The combination of these treatments can exacerbate the hypercoagulable state in cancer patients[19].
Several clinical trials have observed hypercoagulation in patients undergoing NICT. For instance, a study reported that patients receiving NICT for gastric cancer had higher levels of coagulation markers, such as D-dimer and fibrinogen, compared to those receiving chemotherapy alone[20]. The study suggested that the combination of chemotherapy and immunotherapy could enhance the hypercoagulable state in these patients[20]. Another clinical trial investigated the effects of NICT in patients with non-small cell lung cancer[21]. The trial found that patients receiving the combination therapy had an increased incidence of thromboembolic events compared to those receiving standard chemotherapy. The researchers concluded that careful monitoring and management of hypercoagulation are essential in patients undergoing NICT[21]. Statistical data from various studies indicate a higher incidence of hypercoagulation in patients undergoing NICT. For example, it is found that the incidence of VTE in patients receiving NICT was significantly higher than in those receiving chemotherapy alone[20-22]. The analysis highlighted the need for prophylactic anticoagulation in high-risk patients to prevent thromboembolic complications[20-22]. A recent study found that patients with LAGC who developed hypercoagulation after NICT had significantly lower three-year OS and DFS rates (78.0% vs 94.4%, P = 0.019; 68.0% vs 87.0%, P = 0.027)[22]. Multivariate analysis confirmed hypercoagulation as an independent risk factor for poor OS (HR = 4.436, P = 0.023) and DFS (HR = 2.551, P = 0.039), highlighting the importance of coagulation monitoring in this patient population[22] (Table 2).
Table 2 Hazard ratios for overall survival and disease-free survival in hypercoagulation.
Prognostic indicators are factors used to predict the likely course and outcome of a disease, such as cancer. These indicators help clinicians assess the severity of the disease, estimate survival rates, and make informed decisions about treatment strategies. Common prognostic indicators in cancer treatment include the type and stage of cancer, tumor size, lymph node involvement, and the presence of metastasis. Additionally, molecular and genetic markers, such as hormone receptor status and specific gene mutations, can provide valuable prognostic information[11]. Prognostic indicators are crucial for personalized medicine, as they enable healthcare providers to tailor treatment plans to individual patients based on their unique disease characteristics. For example, patients with early-stage cancer and favorable prognostic indicators may benefit from less aggressive treatment, while those with advanced-stage cancer and poor prognostic indicators may require more intensive therapy[23]. The hypercoagulable state in cancer patients is often a result of the tumor’s ability to produce procoagulant factors, which activate the coagulation cascade. This can lead to the formation of abnormal blood clots, increasing the risk of VTE and other thrombotic events[24]. In LAGC, hypercoagulation can indicate a more aggressive tumor phenotype and a higher likelihood of metastasis, both of which are associated with worse clinical outcomes[25].
Several studies have provided evidence supporting the prognostic value of hypercoagulation in cancer patients. A retrospective study assessed the correlation between hypercoagulation after NICT and the prognosis of patients with LAGC[24,25]. The study found that patients with hypercoagulation had significantly lower OS and DFS rates compared to those without hypercoagulation. Multivariate analysis revealed that hypercoagulation was an independent risk factor for adverse postoperative outcomes, suggesting its potential as a prognostic indicator. Another study published in BMC Gastroenterology investigated the prognostic value of the lymph node ratio (LNR) in patients with LAGC who underwent radical resection after NICT[25]. The study found that patients with a high LNR had significantly worse OS and progression-free survival compared to those with a low LNR. While this study focused on LNR, it also highlighted the importance of coagulation-related markers in predicting patient outcomes.
Expert opinions also support the use of hypercoagulation as a prognostic indicator in cancer patients. According to the National Cancer Institute, factors such as the stage of cancer, tumor grade, and specific traits of cancer cells, including their ability to induce hypercoagulation, play a crucial role in determining prognosis. By monitoring coagulation markers, healthcare providers can identify high-risk patients and adjust treatment plans accordingly to improve clinical outcomes[24,25].
The association between hypercoagulation and poor prognosis in gastric cancer has been demonstrated in several clinical studies. For instance, Liu et al[26] conducted a study on 210 patients with advanced gastric cancer and found that elevated levels of D-dimer, a fibrin degradation product, were significantly associated with poor OS in patients with advanced gastric cancer [HR = 2.15, 95% confidence interval (CI): 1.50-3.08, P < 0.001]. In this study, D-dimer levels were shown to be an independent prognostic factor, reflecting the presence of a hypercoagulable state and indicating aggressive disease behavior[26]. Similarly, Zhang et al[27] examined the role of coagulation markers in predicting outcomes in gastric cancer patients. Their retrospective analysis of 315 patients indicated that elevated levels of fibrinogen (HR = 2.01, 95%CI: 1.55-2.87, P = 0.002) and prothrombin fragment 1+2 (a marker of thrombin generation) were linked to increased risk of metastasis [odds ratio (OR) = 1.78, 95%CI: 1.34-2.44, P < 0.001] and poorer prognosis in gastric cancer patients. This study also highlighted the potential of coagulation markers as useful tools for risk stratification in gastric cancer treatment[27]. More recently, the results from a meta-analysis including 12 studies with a total of 4560 patients indicate that the three indicators, D-dimer, fibrin, and platelet count hold substantial predictive value for the prognosis of gastric cancer[28]. They were linked to a more advanced clinicopathological stage (OR = 2.45, 95%CI: 1.79-3.21, P < 0.001) and a heightened risk of lymph node metastasis (OR = 1.93, 95%CI: 1.51-2.67, P = 0.004)[28]. A prospective study on 186 gastric cancer patients undergoing neoadjuvant chemotherapy[29-31]. They found that elevated levels of D-dimer and fibrinogen after chemotherapy were associated with a higher risk of postoperative thromboembolic events (OR = 2.62, 95%CI: 1.76-3.98, P < 0.001) and poorer prognosis. In particular, they reported that patients with elevated D-dimer levels after chemotherapy had a significantly lower progression-free survival rate (HR = 2.21, 95%CI: 1.68-2.94, P = 0.002), suggesting that hypercoagulation may be an important biomarker for monitoring response to treatment and predicting recurrence[29-31]. Multiple studies have confirmed that miRNA-21 is overexpressed in gastric cancer and is associated with tumor progression and poor prognosis. Although its direct role in promoting hypercoagulation via TF has not been conclusively demonstrated, the involvement of TF in cancer-associated thrombosis is well recognized, suggesting that miRNA-21 may contribute indirectly to thrombotic complications in gastric cancer[32]. Further research is needed to clarify its potential as a therapeutic target. Sun et al[33] examined the relationship between immunotherapy and hypercoagulation in gastric cancer in a cohort of 312 patients. Their study found that patients receiving immune checkpoint inhibitors in combination with chemotherapy had a significant increase in D-dimer levels (P = 0.005) and a higher incidence of thrombotic events (OR = 2.42, 95%CI: 1.76-3.12, P = 0.002) particularly in patients with high programmed death ligand-1 expression. This suggests that immunotherapy, while effective in treating cancer, may increase the risk of hypercoagulation, further complicating the management of these patients[33]. Li et al[15] conducted a study on the predictive value of hypercoagulation for OS in 275 patients with gastric cancer undergoing NICT. The study revealed that patients with both elevated fibrinogen and D-dimer levels had a significantly higher risk of disease recurrence (HR = 2.75, 95%CI: 1.98-3.49, P < 0.001), particularly when hypercoagulation was detected early during treatment. This finding reinforces the potential of coagulation markers as prognostic tools in personalized treatment plans[15]. Narita and Muro[34] examined the effects of neoadjuvant chemotherapy combined with immunotherapy on hypercoagulation in gastric cancer in a cohort of 198 patients. The study revealed that patients who experienced treatment-induced hypercoagulation had higher levels of D-dimer and fibrinogen post-treatment (P < 0.01). Notably, these patients were found to have a significantly higher risk of disease recurrence (HR = 2.89, 95%CI: 2.13-3.78, P < 0.001), suggesting that hypercoagulation could serve as a prognostic marker for relapse[34].
HYPERCOAGULATION AS A PROGNOSTIC INDICATOR POST-IMMUNOCHEMOTHERAPY
NICT, combining chemotherapy with immunotherapy agents like programmed cell death protein 1 inhibitors, is increasingly used to treat LAGC. This treatment approach can influence coagulation pathways, potentially leading to hypercoagulation, which may serve as a prognostic marker for disease recurrence. However, the specific impact of such treatments on hypercoagulation and their prognostic significance require further research. NICT may elevate levels of procoagulant proteins, such as fibrinogen and D-dimer, due to chemotherapy-induced inflammation and immunotherapy-induced immune responses. The combination of chemotherapy and immunotherapy can increase the risk of thrombosis in gastric cancer patients, necessitating careful monitoring of coagulation status during treatment. Elevated coagulation markers post-treatment has been associated with a higher risk of disease recurrence, suggesting their potential role as prognostic indicators. Supporting research includes a study titled “Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy” (Lv et al[35], 2023), which investigated the safety and efficacy of combining SOX chemotherapy with programmed cell death protein 1 inhibitor immunotherapy in gastric cancer patients. While it focused on surgical outcomes, it provides insight into the treatment regimen’s impact on patient health. Additionally, the review “Mechanisms of Cardiovascular Toxicities Induced by Cancer Therapies and Promising Biomarkers for Their Prediction: A Scoping Review” (Yan et al[36], 2024) discusses various cardiovascular toxicities, including thrombosis, resulting from cancer treatments, and highlights the need for monitoring coagulation status in patients undergoing such therapies[36]. While NICT shows promise in treating gastric cancer, its effects on coagulation require careful consideration. Elevated coagulation markers post-treatment may indicate a higher risk of disease recurrence, underscoring the importance of integrating coagulation monitoring into patient management strategies. Further studies are needed to fully elucidate these relationships and refine treatment protocols accordingly[37,38].
Although coagulation markers such as D-dimer and fibrinogen are mostly used for the assessment of hypercoagulation, further hypercoagulability indicators, including thrombin-antithrombin complex and plasmin-α2-antiplasmin complex, have been proven as valuable markers of coagulation system activation. Studies have shown that when thrombin-antithrombin complex levels are elevated, then there is excessive thrombin generation, which in turn, is associated with tumor progression and an increased risk of VTE in cancer patients[39]. Additionally, elevated plasmin-α2-antiplasmin complex levels display fibrinolytic activation and are linked with poor prognosis in gastric cancer patients[40]. Future research should incorporate these additional coagulation markers to provide a more comprehensive assessment of hypercoagulability and its prognostic relevance in gastric cancer.
Hypercoagulability is an important prognostic factor in gastric cancer, yet not the only determinant of patient outcomes. Tumor staging, lymph node metastasis, and tumor markers such as carcinoembryonic antigen and carbohydrate antigen 19-9, can also aid as well-established prognostic indicators in tumor staging. Studies have indicated that hypercoagulation markers when analyzed in parallel with these conventional prognostic factors, can enhance risk stratification and predict survival outcomes[41]. For instance, a study by Chen et al[41] found that when combining elevated D-dimer levels and advanced tumor stage, this led to markedly increased predictive accuracy for OS in gastric cancer patients. Future studies should combine hypercoagulability markers with established prognostic models, in order to better interpret their role within a concise prognostic evaluation system.
Current evidence suggests that gastric cancer patients at high risk of thrombotic events, are advised to undergo coagulation evaluations, including D-dimer and fibrinogen, at baseline, before treatment initiation, as well as at regular intervals during therapy (e.g., every 2-4 weeks)[42,43]. Thromboprophylaxis with low-molecular-weight heparin or direct oral anticoagulants should be regarded in collaboration with haematology specialists, for patients with persistent hypercoagulability[44].
FUTURE DIRECTIONS
Hypercoagulation is increasingly recognized as an important prognostic factor in cancer, including gastric cancer. The evidence suggests that elevated coagulation markers such as D-dimer, fibrinogen, and prothrombin fragment 1+2 can reflect tumor burden and aggressiveness, and are predictive of poor outcomes, including higher recurrence rates and reduced survival. In the context of NICT for LAGC, hypercoagulation may serve as a novel marker for both treatment response and prognosis. The development of a hypercoagulable state during treatment could indicate a more aggressive disease phenotype or the occurrence of thromboembolic complications, which would require careful management. Further research is needed to understand the molecular mechanisms linking hypercoagulation to tumor biology, particularly in the setting of immunochemotherapy. Additionally, prospective studies examining the role of hypercoagulation as a predictive biomarker for treatment efficacy and disease recurrence, providing a higher level of evidence by minimizing confounding factors and allowing for better causal inference will be crucial for optimizing therapeutic strategies in gastric cancer.
CONCLUSION
In conclusion, hypercoagulation is a significant concern in cancer patients, particularly those undergoing NICT. Understanding the mechanisms and implications of hypercoagulation can help healthcare providers improve patient outcomes through early detection, risk stratification, and tailored treatment strategies[16,40,41].
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: Greece
Peer-review report’s classification
Scientific Quality: Grade A, Grade A
Novelty: Grade A, Grade A
Creativity or Innovation: Grade A, Grade A
Scientific Significance: Grade A, Grade A
P-Reviewer: Li PM, Associate Chief Physician, Associate Professor, China S-Editor: Wang JJ L-Editor: A P-Editor: Zheng XM
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