Abstract
Objective
To comprehend the effects of diverse therapeutic interventions on thromboelastography (TEG) and conventional coagulation parameters among individuals diagnosed with colorectal cancer, this study aims to explore the clinical relevance of both thromboelastography and conventional coagulation metrics in evaluating coagulation function and predicting the incidence of thrombotic and hemorrhagic events in patients with colorectal cancer.
Methods
A cohort of 122 patients with colorectal cancer retrospectively recruited and divided into 2 groups: those undergoing surgical intervention (operation group) and those not subjected to surgery (non-operation group). According to the different types of treatment they received, the operation group was divided into chemotherapy-only group and a group receiving a combination of targeted therapy and chemotherapy. Blood samples were collected on admission and subjected to coagulation parameter assessment, including conventional coagulation tests and thromboelastography (TEG) assessment. Receiver operating characteristic (ROC) analysis was performed to predict the occurrence of complications in patients with colorectal cancer.
Results
Compared with the operation group, the non-operation group showed significant reductions in reaction time(R-time) and kinetics time (K-time), and significant elevation in angle, maximum amplitude (MA), fibrinogen and platelets. Patients receiving targeted therapy and chemotherapy had lower angle and maximum amplitude and higher R-time and K-time, activated partial thromboplastin time and fibrinogen. The area under the curve for TEG in patients without treatment was 0.802. The area under the curve for TEG and conventional coagulation parameters were 0.654 and 0.660 respectively.
Conclusion
Diverse treatments distinctly impact on the coagulation indicators of individuals diagnosed with colorectal cancer. The coagulation parameters observed in patients prior to operation suggest a hypercoagulable state. Nevertheless, following postoperative chemotherapy and targeted therapy, this hypercoagulable state demonstrates a notable improvement, occasionally leading to a propensity for hypocoagulation. The findings of this investigation underscore the unique clinical importance of thromboelastography (TEG) alongside traditional coagulation parameters, demonstrating that these diagnostic tools possess complementary value and cannot be substituted interchangeably.
Keywords: Colorectal cancer, Chemotherapy, Targeted therapy, Thromboelastography, Conventional coagulation parameters
Introduction
Colorectal cancer (CRC) a globally prevalent digestive malignancy, with the majority of patients being diagnosed at an advanced stage [1]. In recent years, the incidence and mortality rates of colorectal cancer have both shown an upward trend in China. As indicated in the Chinese Cancer Statistics Report 2020, colorectal cancer ranks second in incidence and fifth in mortality, among all malignant tumors [2]. The therapeutic strategies for colorectal cancer encompass operation, chemotherapy, targeted therapy, immunotherapy, traditional Chinese medicine, and combination therapies [3, 4]. The targeted therapy includes bevacizumab, cetuximab and fruquintinib. Bevacizumab is a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF) and fruquintinib is a potent and highly selective small molecule inhibitor of vascular endothelial growth factor receptor (VEGFR). These two pharmacological strategies were tumor angiogenesis inhibitors (TAIs) and belong to vascular-targeted therapy [5, 6]. Cetuximab, a chimerized monoclonal antibody to EGFR, blocks ligand-induced EGFR tyrosine kinase activation and leads to cancer cell proliferation [7].
Study suggests that anomalies in coagulation function are commonly observed among patients with colorectal cancer [8]. Compared with conventional coagulation tests, Thromboelastography (TEG) is a laboratory-based method that provides graphical representations of the dynamics of whole blood fibrin polymerization, measuring the dynamic coagulation process from clot formation to thrombolysis [9]. However, the influence of treatment on the conventional indicators primarily focusing on coagulation parameters in colorectal cancer patients have not been widely investigated. In the present study, we describe the impact of different treatments on thromboelastography and other conventional parameters in patients with colorectal cancer retrospectively.
Material and methods
Patients
We reviewed the clinical and laboratory data of 122 colorectal cancer patients admitted to Affiliated Hospital of Nanjing University of Chinese Medicine from October 2022 to October 2023. The cohort comprised75 males and 47 females, with an age range of 33 to 81 years (mean age: 63.37 years), with no complications except for burns. There were 14 patients with stage I and II tumors compared with 108 patients with stage III and IV tumors. The study inclusion criteria included (1) Patients of any gender, aged ≥ 18 years; (2) Patients with colorectal cancer diagnosed through clinical, radiological imaging, and histopathological diagnosis; (3) TEG and conventional parameters tests performed within the first 24 h of hospitalization; (4) no patient in the study had thrombosis or hemorrhagic disease, or took any anticoagulant medications within 2 weeks; (5) no operated patients were received the prevention of VTE during the treatment. The study exclusion criteria encompassed: (1) history of epilepsy or other central nervous system diseases; (2) pregnancy or lactation; (3) uncontrolled comorbid conditions. This study and all methods was approved by the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine in accordance with the provisions of the “The Measures for Ethical Review of Life Science and Medical Research Involving Human Being” (2023) issued by the National Health Commission, China. The informed consent was waived by the Ethics Committee of Affiliated Hospital of Nanjing University of Chinese Medicine.
Laboratory tests
Peripheral venous blood samples from patients in non-operation group were collected before their operations, while in operation group were collected at least one month after their operations and after at least one treatment cycle. All blood samples were collected from patients in the morning. TEG was performed within 2 h of sample collection, according to the manufacturer’s recommendations (TEG 5000 Hemostasis Analyzer System; Haemonetics Corporation, Boston, MA, USA). TEG parameters included reaction time (R-time; minutes), kinetics time (K-time; minutes), alpha angle (Angle; degrees), and maximum amplitude (MA; mm). Activated prothrombin time (APTT; seconds), fibrinogen (FIB; g/L), and D-dimer(DD; mg/L) were analyzed using the STAR-R EVOLUTION automatic coagulation analyzer (Stago Diagnostica, Paris, France). Complete blood count, including red blood cell (RBC) count, platelet (PLT) count, and hemoglobin (Hb) level, were measured using the SYSMEX XN-10[B3] hematology analyzer (Sysmex Corporation, Kobe, Japan).
Statistical analysis
Categorical variables were analyzed via Pearson chi-squared tests. Continuous variables were analyzed via a t-test. Data analysis was conducted in SPSS version 27.0 (IBM). For all statistical comparisons, P < 0.05 was considered statistically significant. A receiver operating characteristic (ROC) curve was generated and the area under the ROC curve (AUC) was computed with 95% confidence intervals to evaluate the predictive performance of TEG and conventional coagulation tests. All analysis were performed by Graph Pad Prism Version 10.1.0.
Results
Patient population
We enrolled 122 patients and divided them into two primary groups: the operation group and the non-operation group. 89 samples were collected post-operation, while 32 samples were obtained prior to any surgical or therapeutic intervention. In the operation group, 47 samples were attributed to chemotherapy-only group and 42 samples were from targeted therapy combined with chemotherapy group separately. The chemotherapy regimens include xelox, folfox, folfiri, folfirinox and capecitabine only. Targeted therapy regimens were primarily based on bevacizumab and fruquintinib, with bevacizumab being the predominant agent. An overview of the demographic and clinical characteristics of the study population is shown in Tables 1 and 2.
Table 1.
Baseline characteristics and parameters of non-operation group and operation group
| Characteristics | Non-operation group (n = 33) | Operation group (n = 89) | P |
|---|---|---|---|
| Age (years) | 51.31 ± 9.91 | 47.83 ± 14.98 | 0.122 |
| Sex, n (%) | 0.473 | ||
| Male | 22 (66.67%) | 53 (59.55%) | |
| Female | 11 (33.33%) | 36 (40.45%) | |
| TNM stage, n (%) | 0.112 | ||
| I–II | 6 (18.18%) | 8 (8.99%) | |
| III–IV | 27 (81.82%) | 81 (91.01%) | |
| APTT (s) | 37.25 ± 5.55 | 37.14 ± 5.46 | 0.921 |
| FIB (g/L) | 4.01 ± 1.30 | 3.51 ± 1.09 | 0.039 |
| DD (ug/L) | 1.60 ± 2.41 | 1.09 ± 1.55 | 0.178 |
| Platelet (× 109/L) | 261.16 ± 79.52 | 164.60 ± 64.24 | 0 |
| RBC (× 1012/L) | 3.84 ± 0.66 | 3.84 ± 0.54 | 0.994 |
| Hb (g/L) | 106.88 ± 23.73 | 114.30 ± 17.37 | 0.063 |
| R-time (min) | 4.79 ± 1.60 | 6.04 ± 1.54 | 0 |
| K-time (min) | 1.55 ± 1.06 | 2.88 ± 1.66 | 0 |
| Angle (degree) | 69.29 ± 10.54 | 56.45 ± 13.01 | 0 |
| MA (mm) | 65.13 ± 8.76 | 54.32 ± 9.25 | 0 |
Table 2.
Baseline characteristics and parameters of chemotherapy alone group and Targeted therapy combined with chemotherapy group
| Characteristics | Chemotherapy alone group (n = 47) | Targeted therapy combined with chemotherapy group (n = 42) | P |
|---|---|---|---|
| Age (years) | 58.98 ± 17.03 | 47.83 ± 14.98 | 0.799 |
| Sex, n (%) | 0.662 | ||
| Male | 29 (61.70%) | 24 (57.14%) | |
| Female | 18 (38.30%) | 18 (42.86%) | |
| TNM stage, n (%) | 0.156 | ||
| I–II | 7 (14.89%) | 1 (2.38%) | |
| III–IV | 40 (85.11%) | 41 (97.62%) | |
| APTT (s) | 35.97 ± 4.20 | 38.50 ± 6.36 | 0.027 |
| FIB (g/L) | 3.26 ± 0.88 | 3.81 ± 1.23 | 0.019 |
| DD (ug/L) | 1.02 ± 1.35 | 1.17 ± 1.77 | 0.638 |
| Platelet (× 109/L) | 175.55 ± 64.49 | 150.68 ± 62.99 | 0.07 |
| RBC (× 1012/L) | 3.86 ± 0.52 | 3.82 ± 0.57 | 0.676 |
| Hb (g/L) | 112.74 ± 18.21 | 116.05 ± 16.42 | 0.374 |
| R-time (min) | 5.71 ± 1.55 | 6.41 ± 1.59 | 0.038 |
| K-time (min) | 2.42 ± 1.15 | 3.39 ± 1.98 | 0.006 |
| Angle (degree) | 60.07 ± 10.74 | 52.41 ± 14.22 | 0.005 |
| MA (mm) | 56.14 ± 8.43 | 52.28 ± 9.78 | 0.049 |
| Fecal occult blood, n (%) | 0.122 | ||
| Negative | 39 (82.98%) | 29 (69.05%) | |
| Positive | 8 (17.02%) | 13 (30.95%) | |
Coagulation and blood count parameters: operation vs. non-operation groups
Patients undergoing operation had higher FIB, DD and PLT and lower APTT, RBC and Hb compared to their non-surgical counterparts (Table 1, Fig. 1).
Fig. 1.
Conventional coagulation parameters and blood count parameters of operation group and non-operation group. A Activated prothrombin time. B Fibrinogen. C D-dimer. D Red blood cell. E Platelet. F Hemoglobin
Comparison of TEG parameters between the operation group and the non-operation group
Patients undergoing operation had significantly longer R-time and K-time and lower angle and maximum amplitude compared with non-surgical group (P < 0.05) (Table 1, Fig. 2). These changes represented hypercoagulability in patients with no treatment.
Fig. 2.
TEG parameters of operation group and non-operation group. A R-time. B K-time. C Alpha angle. D Maximum amplitude
Comparison of conventional coagulation parameters and blood count parameters between chemotherapy-only group and targeted therapy combined with chemotherapy group
Patients with targeted therapy combined with chemotherapy had higher APTT, FIB, DD and Hb and lower PLT and RBC compared with patients with chemotherapy (P < 0.05) (Table 2, Fig. 3).
Fig. 3.
Conventional coagulation parameters and blood count parameters of chemotherapy alone group and targeted therapy combined with chemotherapy group. A Activated prothrombin time. B Fibrinogen. C D-dimer. D Red blood cell. E Platelet. F Hemoglobin
Comparison of TEG parameters between chemotherapy-only group and targeted therapy combined with chemotherapy group
Patients with targeted therapy combined with chemotherapy had significantly longer R-time and K-time and lower angle and maximum amplitude compared with patients with chemotherapy (P < 0.05) (Table 2, Fig. 4). These changes indicated a tendency of hypocoagulation in patients with targeted therapy combined with chemotherapy.
Fig. 4.
TEG parameters of chemotherapy alone group and targeted therapy combined with chemotherapy group. A R-time. B K-time. C Alpha angle. D Maximum amplitude
Comparison of fecal occult blood indicator between chemotherapy alone group and targeted therapy combined with chemotherapy group
The positive rate of targeted therapy combined with chemotherapy group was higher than chemotherapy alone group in fecal occult blood indicator, while the difference was not statistically significant (P > 0.05) (Table 2).
TEG and conventional coagulation parameters to predict hypercoagulable state
The sensitivity and specificity of TEG parameters and conventional coagulation parameters for predicting hypercoagulable state in patients with no treatment were determined by analyzing receiver operating characteristic (ROC) curves (Fig. 5, for TEG, AUC = 0.802, sensitivity: 74.2%, specificity: 81.8%;for conventional coagulation parameters, AUC = 0.634, sensitivity: 62.9%, specificity: 69.7%).
Fig. 5.
TEG and conventional coagulation parameters to predict hypercoagulable state in colorectal cancer patients with no treatment
TEG and conventional coagulation parameters to predict hypocoagulation tendency
The sensitivity and specificity of TEG parameters and conventional coagulation parameters for predicting hypocoagulation tendency in patients with targeted therapy combined with chemotherapy were determined by analyzing receiver operating characteristic (ROC) curves (Fig. 6, for TEG, AUC = 0.654, sensitivity:54.8%, specificity:72.3%;for conventional coagulation parameters, AUC = 0.660, sensitivity:40.5%, specificity: 93.6%).
Fig. 6.
TEG and conventional coagulation parameters to predict hypocoagulation tendency in colorectal cancer patients with targeted therapy combined with chemotherapy
Discussion
It is known that 20 to 30% of first-time diagnoses of venous thrombotic events are cancer-related, significantly impacting prognosis and survival rates [10, 11]. Cancer is known to enhance coagulability, facilitating tumor stromal growth, angiogenesis, and the recruitment of inflammatory cells [12], these processes collectively contribute to the promotion of tumor cell growth, proliferation, and metastatic dissemination, thereby posing a threat to the overall prognosis of patients [13]. It also carries the risk of triggering venous thromboembolism, disseminated intravascular coagulation, and even both high-morbidity and high-mortality complications such as pulmonary thromboembolism by releasing procoagulant microparticles into the circulation [14]. However, in early-stage colorectal cancer, hypercoagulable states may not manifest with significant clinical symptoms, emphasizing the importance of regular coagulation parameter monitoring for early detection and intervention.
Bevacizumab used the vascular-targeted therapy primarily in this study is the first anti-angiogenic drug used in the treatment of malignant solid tumors. Bevacizumab is a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF) that inhibits tumor growth by inhibiting angiogenesis [15]. It has shown antitumor effects in several cancer types, especially in colorectal cancer [16]. Colorectal cancer patients who received combination chemotherapy with bevacizumab has been reported to prolong both overall survival and progression-free survival [17]. Nonetheless, bevacizumab is associated with increased risks of hypertension and hemorrhage, likely due to VEGF inhibition impacting fibrinogen expression and tissue plasminogen activity, which can compromise coagulation and vascular integrity. The hemorrhage caused by bevacizumab can be categorized into two types. One is mucocutaneous hemorrhage, commonly observed in the nose, oral mucosa, and gingiva, the other one is tumor-related hemorrhage, such as rectal or gastrointestinal bleeding in patients with colorectal cancer. Therefore, equally high-sensitive and specific indicators are required to monitor patients' coagulation parameters, preventing the occurrence of hypocoagulability, and even severe bleeding events induced by anti-angiogenic targeted drugs.
Unlike conventional coagulation tests, thromboelastography (TEG) is a test that evaluates clot formation and fibrinolysis in real-time [18]. R-time reflects coagulation factor activity, K-time and angle both represent the propagation phase of enzymatic factors resulting in clot strengthening; which in this phase of clotting is mostly achieved by fibrinogen cleavage and fibrin polymerization, and MA assesses the combination of platelet count and function as well as fibrinogen activity [19]. Low R-time and K-time, high angle and MA values indicate hypercoagulation and vice versa show hypocoagulation. Compared with TEG, conventional coagulation tests include APTT, FIB and DD only reflect a small amount of thrombin formed in the acute stage of coagulation [20], limiting their application in the treatment of patients with colorectal cancer. According to the study, R-time and K-time increased significantly, while angle and MA decreased significantly with patients who received cancer treatments. The results suggest that the hypercoagulable state in colorectal cancer patients can be reversed after cancer treatments. When compared with patients who received chemotherapy only, significant higher R-time, K-time, APTT and FIB in parallel to lower angle and MA can be observed in patients who received combination chemotherapy with targeted therapy. While targeted therapy reverses the hypercoagulable state in patients with colorectal cancer, it also poses a risk of inducing a hypocoagulable tendency. Simultaneously, the positive rate of fecal occult blood in patients receiving who received combination chemotherapy with targeted therapy is indeed higher than that who received chemotherapy only. The ROC curves conveyed that TEG values could be a predictive marker for hypercoagulable risk at high sensitivity and specificity values in colorectal cancer patients with no treatment.
Current guidelines have not recommended thromboprophylaxis for patients with colorectal cancer unless they have at intermediate risk of thrombosis or bleeding [21]. However the hypercoagulable state of the colorectal cancer patients and the hypocoagulation tendency of patients who received vascular-targeted therapy are both significant in our study. We propose those patients may have possibility to benefit from thromboprophylaxis. Thus, TEG is more proficient in depicting the hypercoagulable state [22, 23]. In addition, when evaluating the efficacy of the hypocoagulable tendency in patients with colorectal cancer receiving combination chemotherapy with targeted therapy, the AUC and specificity of conventional coagulation parameters are superior to TEG. It suggests that in the assessment of coagulation in colorectal cancer patients under various treatments, TEG and conventional coagulation indicators have their specific and distinct clinical values and cannot be mutually replaced.
However, this study still has its limitations: (1) the sample size is relatively small. (2) No grouping analysis was for patients undergoing different chemotherapy regimens or targeted therapy regimens. (3) No complete records regarding nose, oral mucosa, and gingiva bleeding after targeted therapy. The analysis of fecal occult blood alone has certain limitations in assessing bleeding. In the later stages, the sample size will be expanded, and follow-up data will be recorded to explore the prospective application of TEG and conventional coagulation parameters.
Conclusion
The coagulation parameters observed in colorectal cancer patients with no treatment suggest a hypercoagulable state, which can be reversed by cancer treatments including operation, chemotherapy and combination chemotherapy with targeted therapy. TEG, with its superior sensitivity and specificity, is instrumental in early hypercoagulation detection and monitoring, aiding in the timely initiation of anticoagulant therapy. In assessing the hypocoagulable tendency induced by bevacizumab-based targeted therapy, a combined approach using both conventional coagulation tests and TEG provides a comprehensive analysis, each method offering unique advantages in bleeding prevention.
Author contributions
Peng Shu designed the whole study. Wenqin Ren performed the analysis and wrote the paper. Hao Chen participated in the conception and collected the data. Yujie Huang and Jiaqian Zuo contributed to drafting the article. Xinyan Shu revised and polished the article. All authors have read and approved the final submitted manuscript.
Data availability
Data is provided within the manuscript or supplementary information files.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Wenqin Ren and Hao Chen are co-first athors
Change history
7/1/2025
This article has been updated to correct the co-first author statement.
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Associated Data
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Data Availability Statement
Data is provided within the manuscript or supplementary information files.