The Clinical Significance of Preoperative Plasma Fibrinogen Levels and Platelet Count in Resectable Colon Cancer

doi:10.21203/rs.3.rs-132738/v1

Background and aims: There is still much unknown about the relationship between colon cancer and markers of hemostasis. İn these study, whether or not preoperative platelet (PLT) counts, plasma fibrinogen levels were associated with postoperative lymph node involvement and venous invasion was evaluated in patients of colon cancer.

Methods: Eighty patients (mean age: 58.09 years, 37% females, 63% male) were retrospectively included in this study.

Results: PLT and fibrinogen values in patients with lymph node and venous invasion negative colon cancer; were significantly lower than patients with positive lymph node (p<0.001, all of them) and venous invasion (p<0.001, all of them). A positive correlation was found between the venous invasion and lymphatic involvement with PLT count and plasma fibrinogen levels (r=0.640, p<0.001; r=0.810, p<0.001, respectively).

Conclusion: It was concluded that preoperative PLT count and plasma fibrinogen levels may be useful marker for monitoring postoperative lymph node involvement and venous invasion in patients with colon cancer.

Surgery

Oncology

Colon cancer

platelet count

fibrinogen

lymph node

venous invasion

Recently, the incidence of gastrointestinal cancer has increased as standards of living have improved. Colon cancer is one of the most common malignancies of the digestive track in humans. Recent evidence indicates that fibrinogen a major protein in the blood clotting process. Elevated fibrinogen levels and thrombocytosis have been correlated with tumor progression, invasiveness and node metastasis. However the role of elevated fibrinogen and platelet (PLT) count in colon cancer remains unclear. Thrombocytosis and activation of the coagulation system are observed in patients with various malignancies including colon cancer [1–11]. PLT function in hemostasis and thrombosis in its simplest form can be represented as a temporal sequence of events involving adhesion, activation, and aggregation to a damaged vascular surface. Major ligand supporting the adhesion and aggregation include collagen, von Willebrand factor (vWF) and fibrinogen [12].

Activated PLTs play multiple roles in the progression of tumor metastasis including facilitation of tumor cell epithelial–mesenchymal transition (EMT), degradation of surrounding extracellular matrix (ECM), increasing vascular permeability, and aiding in the establishment of malignancies in distant tissues. PLTs also influence tumor metastasis and invasion by enhancing tumor cell expression of tissue factor, a primary initiator of the coagulation cascade. Thrombocytosis in patients with cancer has been reported to be associated with increase expression of angiogenic factors and with a poor prognosis in colon cancer [13].

The major ligand of integrin αIIbβ3 (GP IIb-IIIa) is the most abundant receptor on the PLT surface that fibrinogen is also implicated in metastasis. As a central ligand supporting platelet/ platelet interactions and as a key cleavage substrate for thrombin in coagulation fibrinogen is essential in the well characterized paradigm of hemostasis and thrombosis. In the realm of tumor biology, fibrinogen supports the formation of PLT-fibrinogen tumor cell emboli as tumor cells intrastate [14].

Hyperfibrinogenemia can modify the stromal constituents in the primary tumor which may possibly lead to augmentation of lymphatic metastasis. Fibrinogen can augment fibrin deposition in the tumor stroma since fibrin is well known to facilitate tumor progression by various mechanism hyperfibrinogenemia can enhance fibrin deposition in the primary tumor, which might be a preferable circumstance for the metastasis through the lymphatic system [15].

The protocol of the current study was approved by the ethics committee of Cerrahpaşa Medical Faculty (No: 8304 5809- 604.01.02). This was a retrospective study that conducted in the İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Department of Medical Oncology, from January 2019 to February 2020, 80 patients (mean age: 58,09 years; 30% female, 50% male) with colon cancer were enrolled in the study. There was no distant organ metastasis in all patients.

The patient’s age, sex, medical history, in preoperative blood routine examination as PLTs and fibrinogen levels were obtained from the patient’s medical record. All patients were of Turkish descent. Postoperative histopathological reports regarding tumor, lymph node involvement (negative or positive), and venous invasion (negative or positive) were obtained. The patient potentially curative surgery was defined. None of the patients received preoperative chemotherapy, radiotherapy or immunotherapy.

Patients with incomplete follow-up data or active concurrent infection were excluded. Patients were confirmed to have no distant organ metastasis. A hematologic disease or other infectious which could influence fibrinogen levels; liver disease, kidney disease, myocardial infarction, hypertension, use of procoagulant or anticoagulant drugs, the enrollment and a history of blood transfusion were also excluded from the study. The colon cancer patients were evaluated findings of physical tests, routine laboratory tests, diagnostic imaging (computed tomography, positron emission tomography), puncture biopsies and postoperative pathology reports.

Blood samples were obtained before surgery, blood samples were taken into standardized tubes containing ethylenediaminetetraacetic acid (EDTA) for complete blood count (CBC) parameters [platelet (PLT) (× 10³/µL)] were obtained with automatic hematology analyzer (Beckman Coulter Brea CA, USA) plasma fibrinogen was measured by using Clauss method using Fibrintimer II coagulometer and Multifibren U kit (Siemens Health Care Diagnostics, Germany) İn preoperative blood routine examination and PLTs were obtained from the patient’s medical record. The manufacturer recommended normal ranges for plasma fibrinogen concentrations and PLT counts were 180–350 mg/dL and 15.6–34.8 × 10⁴/µL, respectively.

Statistical analysis

Statistical analyses were performed using SPSS 20.0 (SPSS Inc; Chicago, IL, USA). All data were first checked for normally. Normally distributed continious variables are presented as mean ± standard deviasyon (SD) and were analyzed by one- way analysis of variance (ANOVA) followed by Tukey’s multiple comparison tests Pearson and Spearman’s correlations were used for numerical and nominal data respectively.

The characteristic of colon cancer patients are shown (Table 1). The mean and standard deviations of the clinicopathologic parameters of the patient are shown in (Table 2).

The operated colon cancer; whose lymph node is negative and positive; venous invasion negative or positive are compared. PLT count and fibrinogen values in patients with negative lymph node and negative venous invasion were significantly lower than patients with positive lymph node (p < 0.001, all of them) and venous invasion (p < 0.001, all of them) (Table 2).

There was a positive correlation between PLT count and fibrinogen levels in patients with negative lymph node and venous invasion (r = 0.640, p < 0.001; r = 0.810, p < 0.001, respectively).

Increased plasma fibrinogen levels and PLT counts have been found in different cancer such as gastric, colorectal, pancreatic, prostate, lung, and esophageal squamous cell carcinoma [3–7, 11, 15–17]. In the current study, we found that PLT count and fibrinogen values in patients with negative lymph node were significantly lower than patients with positive lymph node. It was concluded that pre-operative PLT counts and plasma fibrinogen levels may be useful marker for monitoring postoperative lymph node involvement.

It has been observed in the last decades that thrombocytosis may prognosticate worse survival in patients with solid tumors. There are several studies evaluating the prognostic significance of thrombocytosis in colon cancer [18–25]. The association between thrombocytosis, hyper-fibrinogenemia and malignancy has been well demonstrated. Sasaki et al. [22] investigated associated of thrombocytosis with survival of 636 patients with colorectal cancer. They reported that the preoperative thrombocytosis is a potential predictive factor of poor survival factor in patients with colorectal cancer. There are several reports that demonstrated that the associated of thrombocytosis with survival in colorectal cancer [20, 22]. Lin et al. [4] reported that increased PLT count might play some role in the progress of colorectal cancer and preoperative PLT count might be a prognostic indicator in the colorectal cancer patients. Navarro et al. [26] showed that a colorectal cancer predictive character exists in blood which can be quantified by an interaction index of several blood parameters including PLT counts, fibrinogen, total leukocytes, neutrophils, and hemoglobin, hematocrit and eosinophil levels. In our study, PLT count in patients with negative lymph node and venous invasion was significantly lower than patients with positive lymph node and venous invasion. In a recent study, PLT count was significantly associated with 5-year overall and cancer-related survival after stratification of patients according to TNM stage. This is also reasonable since PLTs may contribute to cancer development by promoting neoangiogenesis, increasing both microvessel permeability and extravasation of cancer cells, producing growth factors (e.g. VEGF, PDGF and TGF-β) and facilitating the interaction between cancer cells and endothelia at metastatic sites [27]. Preoperative PLT count represents a simply available tool for assuming the likelihood to undergo an incomplete tumor resection [28].

Cancer progression has been associated with the host hemostasis system. It is quite interesting whether preoperative plasma hemostasis factors can predict survival in colon cancer. Thromboembolic complications are considered the second cause of mortality due to malignant disease [29, 30]. Son et al. [31] found that we found that preoperative hyperfibrinogenemia was significantly associated with shorter survival in patients with colon cancer. Fibrinogen as one of inflammatory markers may be considered a possible prognostic marker in colon cancer. A previous study found that the formations of PLT–fibrin–tumor cell aggregates are associated with endothelial adhesion and metastatic potential [32]. Sun et al. [33] reported that fibrinogen is closely associated with several clinicopathological features and 5-year survival rates of colon cancer patients. Preoperative fibrinogen is a promising prognostic marker for colon cancer patients receiving radical surgery. In our study, fibrinogen values in patients with negative lymph node were significantly lower than patients with positive lymph node. The high levels of fibrinogen and PLT, observed in patients with colon cancer indicate that these patients have an increased tendency to clotting. In addition, these parameters in particular rise more clearly with lymph node (+). Yamashita et al. [34] showed that hyperfibrinogenemia is clinically relevant in tumor recurrence before a systemic inflammatory response and thus can be a useful predictor of recurrence in the preinflammatory stage of colon cancer. Their other results might support the idea that hyperfibrinogenemia can augment lymphatic and hematogeneous metastasis of advanced gastric cancer, which is major determinant of the prognosis in T2 gastric cancer. Therefore, in the situation without peritoneal involvement, hyperfibrinogenemia is a useful biomarker to predict the possible metastasis and worse clinical outcome in T2 gastric cancer. Hyperfibrinogenemia may also provide favorable circumstances for cancer cells to metastasize via the lymphatic system [35]. Preoperative plasma fibrinogen level is a useful predictor of lymphatic metastasis in intestinal-type gastric cancer [36]. Our results have confirmed that plasma fibrinogen is an inflammatory marker and is considered a prognostic marker in colon cancer [34, 37, 38].

Our results show that higher levels of circulating fibrinogen and PLT count are associated with an increased risk of developing lymph node and venous invasion positive colon cancer. The mechanism of thrombosis formation in patients with colon cancer has not been fully elucidated. Preoperative plasma fibrinogen and PLT count is a prognostic factor once validation studies have been conducted at other laboratory in colon cancer patients without distant organ metastasis. Further studies using larger sample size are more precisely warranted to establish the role of thrombocytosis and hyper-fibrinogenemia in colon cancer patients.

PLT: Platelet; EMT: Epithelial–mesenchymal transition; ECM: Extracellular matrix; vWF: von Willebrand factor; CBC: Complete blood count.

Authors’ contributions

BPK and CP designed the study, wrote the manuscript, revised it critically for important intellectual content, and approved its content; BPK and CP created the study materials and recruited patients. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

The data sets during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The protocol of the current study was approved by the ethics committee of Cerrahpaşa Medical Faculty (No: 8304 5809- 604.01.02). This was a retrospective study that conducted in the İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Department of Medical Oncology, from January 2019 to February 2020 were enrolled in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

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TABLE 1. Characteristics of patients with colon cancer.

Characteristics n (%)

Total number of patients 80

Gender

Female 30 (37)

Male 50 (63)

Age (Year) 58.09 ± 6.06

BMI (kg/m²) 27.41±2.95

Platelet counts (×104/μL) 30.95±8.52

Fibrinogen (mg/dL) 316.00±97.68

_____________________________________________________________

BMI; Body mass index

TABLE 2. Clinicopathological parameters of patients without distant metastatic colon cancer.

Characteristics n (%)

Total number of patients 80

Venous invasion

Positivity 45 (56)

Age (Year) 57.62±5.69

BMI (kg/m²) 27.56±3.22

Platelet counts (×104/μL) 36.00±7.49

Fibrinogen (mg/dL) 388.78±59.39

Negativity 35 (44)

Age (Year) 58.69±6.54

BMI (kg/m²) 27.21±2.59

Platelet counts (×104/μL) 24.46±4.35^a,*

Fibrinogen (mg/dL) 222.43±39.79^a,*

Lymph Node Status

Positivity 45 (56)

Age (Year) 57.62±5.69

BMI (kg/m²) 27.56±3.22

Platelet counts (×104/μL) 36.00±7.49

Fibrinogen (mg/dL) 388.78±59.39

Negativity 35 (44)

Age (Year) 58.69±6.54

BMI (kg/m²) 27.21±2.59

Platelet counts (×104/μL) 24.46±4.35^b,*

Fibrinogen (mg/dL) 222.43±39.79^b,*

______________________________________________________________

BMI; Body mass index

a: vs Venous invasion (positivity); b: vs Lymph node status (positivity); *p<0.001.

The Clinical Significance of Preoperative Plasma Fibrinogen Levels and Platelet Count in Resectable Colon Cancer

Status:

Version 1

Abstract

Introduction

Materİals And Methods

Statistical analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Status:

Version 1