ORIGINAL PAPERS

 

Influence of type 2 diabetes mellitus on Khorana venous thromboembolism risk in colorectal cancer patients

 

 

Ruyao Wang^1,2, Rui Liu², Lijie Zhao², Dandan Xu² and Liling Hu²

¹Graduate School of Tianjin Medical University. Tianjin, People's Republic of China.
²Department of Clinical Laboratory Tianjin Union Medical Center. Tianjin, People's Republic of China.

The study was supported financially by a Key Project of the Tianjin Bureau of Public Health (No. 12KG104).

Correspondence

 

 

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ABSTRACT

Background: Many studies have documented the association between venous thromboembolism (VTE) and colorectal cancer (CRC). The Khorana model is a VTE risk assessment model for predicting cancer-associated thrombosis. Type 2 diabetes (T2DM) has also been reported to increase the risk of VTE.
Purpose: The aim of this study was to investigate the influence of T2DM on Khorana VTE risk in CRC patients and to explore the relationship between Khorana VTE category and CRC clinicopathological factors.
Methods: This analysis included 615 CRC patients (205 with T2DM). Fibrinogen and D-dimer levels were compared within each group. A comparison was made of the proportion of patients in different Khorana VTE risk categories in CRC patients with and without T2DM. The association between Khorana VTE risk category and clinicopathological factors among all the CRC patients was evaluated.
Results: Fibrinogen levels of CRC patients with T2DM were significantly higher than those of non-diabetes patients (4.13 ± 1.06 vs 3.94 ± 0.98, p < 0.001). A higher proportion of CRC patients with T2DM were in the Khorana intermediate-to-high risk category (H = 4.749, p = 0.029). Female sex, diabetes, colon location (compared with rectum), larger tumor size, advanced pT stage and pN stage were correlated with the intermediate-to-high Khorana VTE risk category, with odd ratios (95% confidence intervals [CI]) of 1.537 (1.064-2.220), 1.499 (1.027-2.186), 2.313 (1.588-3.370), 2.284 (1.542-3.383), 4.429 (2.088-9.396) and 1.822 (1.230-2.698), respectively.
Conclusion: T2DM increases Khorana VTE risk in CRC patients. Female sex, diabetes, colon location, large tumor size and poor stage are associated with the intermediate-to-high Khorana VTE risk category.

Key words: Venous thromboembolism. Colorectal cancer. Type 2 diabetes mellitus. Khorana risk.

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Introduction

In 1865, Trousseau (1,2) first reported the association between venous thromboembolism (VTE) and visceral cancer, and since then many other studies have reported on cancer-associated coagulation disorders. Patients without any apparent signs of cancer who develop symptomatic idiopathic thromboembolism have a 10% probability of subsequently being diagnosed with cancer (3). In cancer patients without perioperative prophylactic anticoagulation, the incidence of VTE occurring within 30 days after surgery is 1.4% (4), and the cumulative incidence is 3.1% during a 2-year follow-up period (5). Moreover, VTE is among the leading causes of death in cancer patients (6). Thus, the identification of cancer patients with an increased risk of VTE and the implementation of effective thromboprophylaxis has important implications (7).

In addition, diabetes has been regarded as a prothrombotic condition and is expected to increase the risk of VTE (8,9). Causative mechanisms relating diabetes to VTE include changes in circulating levels of the pro- and anti-coagulant components. It has been reported that diabetes patients exhibit higher levels of pro-coagulant factors such as the Von Willebrand factor, fibrinogen (FIB) and factor VII (10). Thrombin is also significantly increased in type 2 diabetes mellitus (T2DM), especially in patients with poor metabolic control, and improvement of glycemic control is associated with a reduction of thrombin generation (11). Apart from these procoagulant changes, T2DM is also characterized by the reduction of several anticoagulant proteins such as protein C and antithrombin III (12). Therefore, hypercoagulability in patients with T2DM should also be taken into consideration.

This study used a VTE risk assessment model proposed by Khorana et al. (13) incorporating five clinical and laboratory variables. These included the site of cancer, prechemotherapy platelet count, hemoglobin and/or use of erythropoiesis stimulating agents, leukocyte count and body mass index to predict cancer-associated thrombosis. The cohort included colorectal cancer (CRC) patients with T2DM, and the influence of T2DM on Khorana VTE risk in CRC patients was examined. The relationship between the Khorana VTE risk category and the clinicopathological factors of all CRC patients included in the study was also explored.

 

Material and methods

Patients

This study cohort included 615 patients comprised of 205 CRC patients with T2DM (male:female ratio 133:72) aged between 39 and 87 years and 410 matched CRC patients without T2DM (male:female ratio 231:179) aged between 34 and 88 years. All patients consecutively treated in the Tianjin Union Medical Center from March 2011 to December 2014 with a histologically proven diagnosis either from a surgical specimen or with enteroscope biopsy were included in the study. Staging was carried out according to the American Joint Committee on Cancer TNM staging system for the classification of carcinoma of the colon and rectum (7^th edition). T2DM was defined according to the most recent clinical practice recommendations by the American Diabetes Association. The following exclusion criteria were applied: thromboembolic event within three months, anticoagulant treatment within three months, congenital thrombophilia, severe acute infectious disease, inflammatory bowel disease, active peptic ulcer and severe untreated hypertension. Patients were divided into a high risk category (three points, six patients), intermediate risk category (one to two points, 148 patients) and low risk category (zero points, 461 patients) according to the Khorama risk model (Table I).

 

 

Blood samples and clinical data

Patient gender, age, tumor location, size of tumor, general type, pathological differentiation and pathological tumor, node, and metastasis (TNM) stage data were collected. Blood samples were collected during the early morning after hospitalization after 8-hours of fasting and before surgery. Three milliliter blood samples were collected using coagulant for the glucose (GLU) test. Three milliliter blood samples were collected using citrate anticoagulation for the FIB and D-dimer test. Two milliliter blood samples were collected using ethylenediaminetetraacetic acid disodium salt anticoagulation for complete blood analysis. GLU was measured by the glucose oxidase method using an automatic biochemical analyzer ARCHITECT CI16000 (Abbott, USA) and a reagent kit provided by Roche (Switzerland). The FIB levels were quantified by the coagulation method, and D-dimer levels by the immunoturbidimetry method using an auto coagulation analyzer from StagoR (France) and the corresponding reagent kit. We used a SYSMEX/XE-5000 automated hematology analyzer (Japan) for complete blood analysis.

Statistical analysis

Categorical variables were analyzed using the Chi-squared or non-parametric test. For intergroup comparisons, continuous normal distribution variables were analyzed by the independent samples ANOVA test and expressed as mean ± standard deviations. Continuous non-normal distribution variables were analyzed by the Kruskal-Wallis H test and expressed as a median with percentiles (25%, 75%). We used the median as a cut-off value for age. Odd ratios (ORs) and 95% CI for intermediate and high risk of VTE were estimated using logistic regression for all clinical characteristic. All statistical analyses were performed using the SPSS19.0 software. Graphical plots were produced using GraphPad Prism X6. A two-side p < 0.05 was considered as statistically significant.

Ethics

The protocol for this study was compatible with the local ethical guidelines. The study was approved by the Academic Committees in the Tianjin Union Medical Center. Informed consent was obtained from all patients.

 

Results

Demography and clinicopathological factors

The study included 205 CRC patients with T2DM and 410 CRC patients without T2DM. The comparisons of demography and clinicopathological factors are shown in table II. The proportion of males is higher in the CRC with T2DM group than in the CRC without T2DM group (64.9% vs 56.3%, χ² = 4.123, p = 0.046). The proportion of patients with a tumor diameter ≥ 5 cm in the CRC with T2DM group was significantly higher than in the CRC without T2DM group (53.2% vs 38.8%, χ² = 10.181, p = 0.001). There were no significant differences between the two groups (p > 0.05) with regard to other factors analyzed.

 

 

Comparison of intergroup GLU, FIB and D-dimer levels

The comparison of GLU, FIB and D-dimer level is shown in table III. GLU levels in the CRC with T2DM group were significantly higher than those of the CRC without T2DM group (7.60 ± 2.50 vs 5.61 ± 1.07, t = -10.904, p < 0.001). FIB levels in the CRC with T2DM group were significantly higher than those of the CRC without T2DM group (4.13 ± 1.06 vs 3.94 ± 0.98, t = -2.028, p = 0.043). The intergroup comparison of D-dimer levels showed no significant difference (0.36 [0.26, 0.63] vs 0.38 [0.24, 0.62], Z = 0.240, p = 0.081).

 

 

Relationship between Khorana VTE category and clinicopathological factors

We explored the relationship between the Khorana VTE risk category and the clinicopathological factors (Table IV). The Khorana VTE risk category of CRC patients was associated with gender, diabetes, tumor location, tumor diameter, pT stage and pN stage. There were more females than males in the Khorana intermediate-to-high VTE risk category. A higher proportion of patients with T2DM were in the Khorana intermediate-to-high VTE risk category compared to patients without T2DM. There was also a higher proportion of colon cancer patients in the Khorana intermediate-to-high VTE risk category than rectal cancer patients. Similarly, there were more patients with a tumor diameter ≥ 5 cm in the Khorana intermediate-to-high VTE risk category than with a tumor of < 5 cm. There was a higher proportion of patients with a pT3-4 tumor in the Khorana intermediate-to-high VTE risk category as compared to those with a pT1-2 tumor; this was also true for the comparison of pN1-2 and pN0 patients. The differences were statistically significant (p < 0.05, respectively). However, age, general type and pathological differentiation had no relationship with Khorana VTE risk category. In addition, the ORs (95% CI) for Khorana intermediate-to-high VTE risk category were statistically significant for the following comparisons: female vs male, 1.537 (1.064-2.220); diabetes patients vs non-diabetes patients, 1.499 (1.027-2.186); colon vs rectum location, 2.313 (1.588-3.370); tumor size ≥ 5 cm vs < 5 cm, 2.284 (1.542-3.383); pT3-4 vs pT1-2, 4.429 (2.088-9.396); and pN1-2 vs pN0, 1.822 (1.230-2.698). Other estimated ORs were non-significant (Table IV and Fig. 1).

 

 

 

Discussion

VTE is a potentially life-threatening condition with a significant morbidity (14). Thrombosis and cancer are linked by numerous pathophysiological mechanisms. It is reported that approximately 50% of non-metastatic cancer patients and 90% metastatic cancer patients present with abnormal activation of coagulation and fibrinolysis (15). A positive association has also been reported between diabetes and risk of VTE. Thus, we explored the influence of T2DM on Khorana VTE risk in CRC patients and the relationship between Khorana VTE risk category and clinicopathological factors in CRC patients.

FIB is a glycoprotein synthesized in the liver. As a hemostatic agent, FIB promotes adhesion and the aggregation of platelets and acts as a substrate for coagulation factor XIII and plasmin. D-dimer is an end-product of FIB and cross-linked fibrin degradation. It appears in the blood as a small peptide fragment after the activation of the fibrinolytic system and also signals the activation of coagulation (16). Tumor growth produces large amounts of inflammatory cytokines and inflammation can cause elevated levels of FIB (17,18). Tumor cells can also release FIB by binding with the fibroblast growth factor (19). In addition, tumor stroma cells can produce urokinase-type plasminogen activator (u-PA). Binding of u-PA activates plasminogen and acts as a protease to disintegrate the matrix of the tumor-host interface and elevate the D-dimer levels (20). All these lead to the elevation of FIB and D-dimer levels in cancer patients. In this study, higher FIB levels were observed in CRC patients with T2DM compared to CRC patients without T2DM. Thus, we further compared the proportion of patients with an intermediate-to-high risk of VTE according to the Khorana score in CRC patients with and without T2DM and observed that CRC patients with T2DM are more frequently classified into the intermediate- and high-risk Khorana categories. The logistic regression also suggested that T2DM increased the Khorana VTE risk by 1.499 fold. Several meta-analyses have documented that diabetes is associated with increased risk of VTE (21,22). This association may be caused by factors such as hyperglycemia, hyperinsulinemia, inflammation, and shared factors such as age, obesity, dyslipidemia, etc. (22,23). Chronic hyperglycemia can cause glycosylation of a variety of body proteins (24,25) stimulating the secretion of tumor necrosis factor and interleukin 1 of macrophages, which can promote the generation of thrombin and the activation of blood coagulation factor X (26). In addition, a high blood sugar level is correlated with shortened clotting time, reflecting the association between hyperglycemia and hypercoagulability (23). All these consequently increased the Khorana VTE risk of CRC patients with T2DM.

Accordingly, we explored the relationship between Khorana VTE risk category and the clinicopathological factors of CRC patients and observed that the Khorana VTE risk category was associated with gender, tumor location, tumor size and pathological stage. We found a higher proportion of patients in the Khorana intermediate-to-high VTE risk category were female. This observation is in accordance with a previous meta-analysis that evaluated gender differences with regard to VTE risk after total hip and knee arthroplasty, revealing that female patients had higher risk of VTE than male patients (27). This study also demonstrated that a higher proportion of colon cancer patients were in the Khorana intermediate-to-high VTE risk category compared to rectal cancer patients. This was also true for patients with larger tumors and patients with tumors of an advanced pathological stage. These findings closely mirror those of other studies. Rectosigmoid cancer is associated with a lower incidence of VTE compared with cancers in the colon (5), and tumor size was independently correlated with thrombocytosis (OR = 3.79; p = 0.006) (28). In addition, a cohort study of 747 patients with solid tumors showed that patients with high-grade tumors had a significantly higher risk of VTE compared with those with low-grade tumors (HR = 2.0; 95% CI 1.1-3.5) (29). Similarly, a retrospective analysis of 68,142 CRC patients demonstrated that a 2-year cumulative incidence of VTE increased significantly with age, female sex, advancing stage or patients with metastatic disease (5).

We acknowledge that our study was limited by the inherent biases of a transversal study design. Our results should be validated with studies that include a sufficient number of patients and our hypothesis must be confirmed by molecular evidence. In addition, there are only six patients with a high Khorana VTE risk. This might be explained by the fact that patients with a history of thromboembolic events or anticoagulant treatment were excluded from the study. This may to some extent decrease the risk multiplier reported in this study.

The increase of FIB concentration is often considered as a risk factor for cardiovascular disease and thrombosis (30). Besides, a number of studies have confirmed the predictive value of D-dimer levels for venous thromboembolism (16). This study found that FIB levels were increased in CRC patients, especially in those with T2DM. This suggests that preoperative FIB and D-dimer levels should be closely monitored in CRC patients with T2DM in order to accurately assess thrombosis and secondary cardiovascular disease risk. The use of anticoagulants for the prevention of postoperative thromboembolism should be rational and safe. In addition, this study found that females had a higher Khorana VTE risk and, therefore, should be carefully monitored for blood coagulation.

In addition, the study found that colon location, large tumor size and poor pathological stage was correlated with a higher Khorana VTE risk. An effective and safe thromboprophylaxis should be applied in these patients, especially in those with T2DM.

In conclusion, our study suggests T2DM might increase Khorana VTE risk in CRC patients. There is a positive correlation between female sex, diabetes, colon location, large tumor size, poor pathological stage and intermediate-to-high Khorana VTE risk in CRC patients. Identification of CRC patients who are at increased VTE risk needs further investigation and should enable effective and safe thromboprophylaxis.

 

Aknowledgements

We would like to sincerely thank the patients and healthy blood donors for providing blood samples.

 

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Correspondence:
Rui Liu.
Department of Clinical Laboratory Tianjin Union Medical Center.
190 Jieyuan Street.
Hongqiao District.
300121 Tianjin,
People's Republic of China
e-mail: lr3596@163.com

Received: 18-03-2016
Accepted: 09-03-2017