Our study focuses on exploring the connection between coagulation and the metastatic status of CRC. Our results indicate that a combination of multiple indicators is crucial in assessing tumor metastasis in CRC patients who have recently been diagnosed. These findings are particularly useful in clinical evaluations of tumor metastasis in CRC patients.
The metastasis of tumor cells is the primary cause of death, thus making the early detection of tumor metastasis especially crucial. Cancer spread is a complex process that involves multiple steps. Initially, tumor cells break away from the primary tumor and spontaneously metastasize. To accomplish effective metastasis, these cells must survive in blood vessels, overcome the mechanical flow of blood and immune system components, undergo trans-endothelial migration, and colonize within distant vascular beds. Establishment of a new supportive vasculature and growth are the main challenges that tumor cells must face[15]. The activation of coagulation is known to promote hematogenous tumor metastasis through several mechanisms. Specifically, a clot comprising of platelets, fibrinogen, and tumor cells can enhance adhesion to the endothelium[16], as well as assist tumor cells in avoiding immune surveillance, thus facilitating the spread of cancer[17]. Additionally, platelets can promote epithelial-mesenchymal transformation (EMT) in tumor cells by activating the TGFβ/SMAD and NF-κB pathways [18]. In metastasis, the coagulation process initiated by tissue factor, fibrinogen, and protease-activated receptor-4 (PAR4) signaling activates platelets, which in turn promote tumor cell survival in the bloodstream and facilitate distant metastasis[19]. Thrombin was found to promote colon cancer proliferation and tumor growth through PAR-1 and ECM protein fibrinogen. The study showed that tumor growth and proliferation decreased in mice deficient in PAR-1 and fibrinogen [20].
Anticoagulant or antithrombotic therapy can improve outcomes for cancer patients. Low molecular weight heparin (LMWH) can prolong survival in cancer patients with or without deep vein thrombosis[21]. Not only this, LMWH tinzaparin inhibits adhesion and invasion of human pancreatic tumor cells[22]. Furthermore, Hirudin functions as a highly specific thrombin inhibitor, effectively suppressing tumor metastasis and therefore prolonging survival [23].
A significant body of evidence suggests that the activation of coagulation plays a pivotal role in the promotion of tumor metastasis. Hence, it can be inferred that coagulation indicators hold the potential to serve as predictors for metastasis. In the case of gastric cancer patients, it has been observed that their plasma D-dimer levels were significantly higher when compared to healthy controls[24]. In NSCLC, with tumor formation and tumor metastasis, the level of D-dimer also gradually increased[11]. Fibrinogen is known to promote gallbladder cancer cell metastasis by inducing the expression of intercellular adhesion molecule 1 (ICAM1)[25]. Our previous studies have confirmed the value of D-dimer and FDP in predicting distant metastasis of gastric cancer[26]. APTT primarily reflects the body's endogenous coagulation function, and a reduced level indicates a state of hypercoagulation. This may lead to thrombotic diseases. D-dimer, on the other hand, reflects fibrinolytic function, and an increased level typically signifies hypercoagulability, secondary hyperfibrinolysis, disseminated intravascular coagulation, and other related diseases[27]. Based on our findings, significant differences in coagulation indexes were observed between the CRC metastasis group and the control group, leading us to hypothesize that CRC patients in a hypercoagulable state are more prone to developing distant metastases. Our results showed that patients with distant metastatic CRC have significantly elevated plasma D-dimer levels compared with primary CRC. We obtained the diagnostic parameters and cut-off values for each index through ROC analysis. Further, multivariate logistic regression confirmed that lower level of prealbumin and platelet, and higher level of glucose, CEA and D-dimer were independent risk factors for CRC distant metastasis. Combined ROC analysis confirmed that the combination of all risk factors had higher diagnostic efficiency than only combined CEA and CA199. This suggests that D-dimer may serve as novel tumor markers for predicting distant metastases in CRC, provided that other disorders that cause abnormally elevated coagulation indicators are excluded.
In our hospital, the level of D-dimer used to assess normal coagulation function was considered to be less than 1 mg/L. False-positives for D-dimer values are frequent in older patients, patients with cancer or systemic infection, pregnancy, recent surgery, or trauma[28]. It is essential to interpret the clotting indicators in conjunction with other clinical findings and imaging tests to avoid misdiagnosis and unnecessary treatment. The retrospective study conducted at a single center and the small sample size of participants somewhat limit the scope and generalizability of this study. In addition, the P value of platelets in multivariate analysis is closer to 0.05, and more data are needed to determine whether it is a risk factor for CRC metastasis.
To conclude, plasma D-dimer had higher diagnostic performance than traditional tumor markers in the evaluation of CRC metastasis. Combining D-dimer with CEA and CA199 provides a more accurate assessment of CRC metastatic status.