Introduction
Colorectal cancer (CRC), the second leading cause of cancer-related deaths globally, has the third highest incidence among all types of cancer (1). Its association with thrombosis dates back to 1865, when Armand Trousseau identified superficial thrombophlebitis as an early indicator of underlying malignancy (2). Among all common types of cancer, CRC is characterized by significantly high incidence of thrombotic lesions (3). A hypercoagulable state, characterized by vascular endothelial cell damage, abnormalities in fibrinolytic and anticoagulant systems, and the presence of indicative markers, such as elevated D-dimer levels, is closely associated with the clinical progression and prognosis of patients with CRC (4).
Several factors, such as tumor size, depth and degree of differentiation, can affect the hypercoagulable state (5). Additionally, it has been reported that the presence of tumors can activate the immune system, which in turn releases several inflammatory factors that exacerbate inflammation and further enhance the risk of blood hypercoagulability (6). Combination chemotherapy and targeted therapies are the most significant treatment strategies for CRC. However, emerging evidence has suggested that they can significantly increase the likelihood of developing arteriovenous thromboembolism (7-9). KRAS mutations, found in ~30-50% of colorectal tumors, are involved in the aforementioned process (5,10-12). This mutation was associated with an increased risk of venous thromboembolism (VTE) in patients with metastatic CRC (13) and affected the secretion dynamics of D-dimers, thus promoting tumor metastasis and cancer cell proliferation (14).
However, the intrinsic procoagulant nature of cancer cells largely stems from their unique genetic profile. Particularly, previous studies demonstrated that mutations in oncogenes, such as KRAS, and the loss of p53 could upregulate tissue factor (TF), thus affecting the coagulation system (15,16). Elevated TF not only increased VTE risk, but it was also associated with tumor progression and metastasis.
The present study delved into the multifaceted factors affecting the hypercoagulable state in patients with CRC, further highlighting the pivotal role of KRAS. Therefore, the current study aimed to elucidate the association between this coagulation anomaly and clinical pathologies, thus providing novel insights for improving therapeutic outcomes and patient survival, and reducing mortality rates. The present study focused on patients with resectable CRC and analyzed preoperative D-dimer blood specimens to assess coagulation status.
Discussion
The association between malignancies and thromboembolic events is a well-established paradigm within oncology, which was also highlighted by the results of the present study, thus suggesting that the survival of patients with cancer, also suffering from thrombotic episodes, was notably reduced. Tumor-associated thrombosis, also known as cancer-associated thrombosis (CAT), can exacerbate patient morbidity, diminish survival rates and stand as a prominent cause of mortality among cancer cohorts (5). The disparity in the incidence of VTE among patients with different types of cancer can be attributed to their distinct interactions with the coagulation cascade, with several types of tumors promoting hypercoagulability to varying degrees (17). Hypercoagulability not only promotes VTE pathogenesis, but is also a harbinger of such vascular complications.
The current study meticulously explored the clinical conundrum of CAT via examining hypercoagulability, secondary to tumor pathology. The results revealed that the mean preoperative D-dimer levels were increased, exceeding the normal threshold by ~30%. Notably, a subset of patients was presented with D-dimer levels three times higher than the upper normal limit, underscoring the extent of the existing hypercoagulability. Nevertheless, the incidence of perioperative VTE was a modest 2.8%, a rate that differed from previous studies (18,19). The discrepancy in the prevalence of VTE could be attributed to the design of the present study, which focused on perioperative parameters, thus potentially mitigating the long-term recording of VTE incidents.
Previous studies indicated a temporal scope of VTE between six months prior the definitive clinical diagnosis of CRC and patient mortality, showing a considerable duration (20-22). However, the research design was structured to exclusively record VTE events in the perioperative phase, thus providing a diminished incidence rate. The present study aimed to delineate the effect of the neoplasm on the hypercoagulable state inherent in patients with CRC. Although longitudinal surveillance can mitigate the risk of missing VTE events, confounding effects of subsequent therapeutic interventions, such as chemotherapy, radiotherapy, immunotherapy and procedures involving deep vein access, cannot be ruled out. Fluorouracil-based chemotherapy has become the standard treatment approach for CRC (9). A previous study, including a large sample size, showed that postoperative chemotherapy for CRC predisposed to VTE, with a 1-year cumulative incidence of 13.7%. In addition, the administration of bevacizumab, a targeted therapy agent, could increase the likelihood of arterial and VTE (7,8).
In light of these considerations, it was hypothesized that the preoperative D-dimer levels in patients with resectable CRC could serve as a robust surrogate for assessing hypercoagulable state. The rationale for selecting this biomarker lies in its capacity to reflect thrombotic predisposition directly attributable to malignancy, independent of confounding variables introduced by postoperative treatments. Additionally, KRAS-driven tumors can induce a hypercoagulable state via upregulating prothrombotic factors and promoting vascular dysfunction, thus promoting the formation of blood clots. In turn, the aforementioned clots can then be broken down, thus releasing D-dimer fragments into the bloodstream (19). Therefore, elevated D-dimer levels serve as a biomarker reflecting both the presence of KRAS mutations and the associated prothrombotic environment in patients with cancer. By employing this approach, it was endeavored to provide a more isolated assessment of the contribution of cancer to coagulopathy, thereby yielding insights that are clinically relevant to the preoperative evaluation of thrombotic risk in patients with CRC. Focusing on preoperative D-dimer levels in patients with resectable CRC aimed to distill the effect of the tumor itself, without considering confounding therapeutic interventions.
D-dimer, a byproduct of fibrin degradation, serves as a versatile biomarker in various pathological conditions, including inflammation, malignancy and thrombosis (23). In CRC, enhanced D-dimer levels are indicative of the concomitant inflammatory response and prothrombotic milieu induced by malignancy progression (24). Herein, the stratified analysis revealed an association between enhanced hypercoagulability and KRAS mutations, distant metastasis and vascular invasion. However, no significant association with other demographic or tumor characteristics was obtained.
An intriguing facet of the current study was the association between KRAS mutations and hypercoagulability. The presence of mutations could enhance the risk of hypercoagulability, thus further verifying the findings from other cohort studies and shedding light on possible underlying molecular mechanisms (13). The interplay between KRAS mutations and hypercoagulability involves the effect of the oncogene in modulating key coagulation factors, such as TF expression, via intricate pathways, including the MEK/MAPK and PI3K pathways (25-27).
In the intricate association between malignancies and hemostatic processes, CRC cells are involved in inducing a hypercoagulable state, a phenomenon characterized by an increased tendency of blood to clot. This disorder in coagulation can be broadly classified into three distinct, but interrelated, mechanisms.
Firstly, tumor cells directly express procoagulant substances. A significant factor in this category is TF, also known as factor III, which stands at the forefront of the coagulation cascade under both physiological and pathological conditions (28). When TF forms a complex with activated factor VII, it catalyzes the activation of IX and X factors, thus promoting the activation of the exogenous coagulation pathway. Aberrant expression of TF is a hallmark of numerous solid tumors and hematologic malignancies, with its expression levels commonly serving as a barometer for tumor malignancy (29). Interestingly, a previous study demonstrated that TF expression was modulated by genetic alterations within cancer cells, including the activation of proto-oncogenes, such as KRAS and MET, or the inactivation of tumor suppressor genes, including TP53 and PTEN (30).
The second mechanism involves the procoagulant effects triggered by tumor cell-derived extracellular vesicles (EVs) (31,32). These vesicles not only reflect the surface proteins of their cells of origin, but can also assimilate proteins from other cells via fusion. In the context of thrombotic disorders, an increase in both the concentration and procoagulant activities of EVs has been associated with their pivotal role in the pathogenesis of thrombosis (33).
The third and final mechanism, by which CRC cells induce hypercoagulability, is through interactions between tumor and host cells. It has been reported that the interface of p-selectin proteins on platelet membranes and podoplanin proteins on particular tumor cells can facilitate the formation of tumor cell-platelet aggregates (34,35). In turn, the aforementioned aggregates can activate platelets, thus resulting in a hypercoagulable state. Furthermore, these platelet aggregates impart a form of ‘cloak’ over the tumor cells, which acts as a shield against the immune surveillance of circulating natural killer cells. This process not only aids in evading immunological detection, but also augments the possibility of hematogenous tumor metastasis (36).
In addition, cancer itself is a slow-moving inflammatory response. Therefore, it has been suggested that elevated C-reactive protein, IL-6, IL-8 and TNF-α levels are associated with an increased risk of VTE during systemic inflammatory response. Subsequent platelet activation could enhance the pre-thrombotic state, thus leading to the development of VTE (37-39). Identifying and elucidating inflammatory markers, associated with VTE, could provide novel targets for future therapy.
The aforementioned mechanisms, when considered collectively, could depict a multifaceted scheme through which CRC insidiously co-opts the body's coagulation system to its advantage, thus promoting both its survival and propagation. The implications of these findings are enormous, affecting therapeutic strategies and requiring a multifaceted approach to target the coagulation cascade at various junctures in the management of CRC. The results of the present study further emphasized the prognostic properties of CAT. Therefore, it was suggested that the KRAS mutational status could serve as a valuable marker to assess the risk of hypercoagulability and, by extension, could predict worse prognosis in patients with CRC.
Despite the robust findings, the present study has some limitations. Firstly, the current investigation was constrained only to the effect of a single gene, namely KRAS, on coagulation in patients with CRC. It is widely accepted that several oncogenes and tumor suppressor genes, through their aberrant expression or mutations, can regulate the production of coagulation factors by tumor cells (34,36,40-43). Therefore, comprehensive multigene studies are needed to unravel the differential effects of various genotypes on coagulation, thus potentially improving anticoagulant and anticancer therapeutic strategies. Additionally, the focus of the study on the perioperative period, without long-term follow-up, precluded further insights into the long-term effect of KRAS mutations on the survival of patients with CRC. Lastly, due to financial constraints, only a limited number of cases were assessed for KRAS mutations, introducing a degree of selection bias.
In summary, the results of the current study supported the association between cancer and thrombosis. Exploring the genetic factors associated with hypercoagulability holds promise for enhancing the management of patients with CRC.