Fibrinogen and D‐dimer levels elevate in advanced hepatocellular carcinoma: High pretreatment fibrinogen levels predict poor outcomes

Liu, Zhikun; Guo, Huimin; Gao, Feng; Shan, Qiaonan; Li, Jie; Xie, Haiyang; Zhou, Lin; Xu, Xiao

doi:10.1111/hepr.12848

Cited by 33 publications

(29 citation statements)

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“…In human patients, fibrinogen expression has been reported to be increased progressively with clinical tumor stage and higher plasma fibrinogen level has been associated with a poor prognosis [39] . Fibrinogen could also serve as a useful predictor of clinical HCC progression and recurrence [40] , [41] . In our study, we detected a progressive increase of fibrinogen level during the liver disease progression using liver tissue array slides with human liver disease.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish

2018

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Hepatocellular carcinoma (HCC) is one of the most common cancers and it usually develops from a background of liver fibrosis or inflammation. The crosstalk between tumor cells and stromal cells plays an important and stimulating role during tumor progression. Previously we found in a krasV12–induced zebrafish HCC model that oncogenic hepatocytes activate hepatic stellate cells (HSCs) by up-regulation of serotonin and activate neutrophils and macrophages by up-regulation of cortisol. In the present study, we found a novel signaling transduction mechanism between oncogenic hepatocytes and HSCs. After krasV12 induction, fibrinogen was up-regulated in oncogenic hepatocytes. We reasoned that fibrinogen may bind to integrin αvβ5 on HSCs to activate HSCs. Consistent with this notion, pharmaceutical treatment using an antagonist of integrin αvβ5, cilengitide, significantly blocked HSC activation and function, accompanied by attenuated proliferation of oncogenic hepatocytes and progression of liver fibrosis. On the contrary, adenosine 5’-diphosphate, an agonist of αvβ5, activated HSCs significantly that further stimulated the tumor progression and liver fibrosis. Interestingly, in human liver disease samples, we detected an increased level of fibrinogen during tumor progression which indicated the potential role of fibrinogen signaling in HCC progression. Thus, we concluded a novel interaction between oncogenic hepatocytes and HSCs through the fibrinogen related pathway in both the zebrafish HCC model and human liver disease samples.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish

2018

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“…D-dimer concentration was measure by either immunoturbidimetric assay (ITM) or Latex Test with various cut-off values among those studies. Of all eligible studies, Fifteen studies reported on lung cancer [2, 3, 19-31], followed by colorectal cancer (n = 9) [9, 21, 32-38], gastric cancer (n = 5) [21, 39-42], pancreatic cancer (n = 5) [21, 43-46], ovarian cancer (n = 3) [47-49], esophageal cancer (n = 3) [50-52], cervical cancer (n = 2) [6, 7], renal cancer (n = 2) [21, 53], sarcoma cancer (n = 2) [54, 55], brain cancer (n = 2) [21, 56], endometrial cancer (n = 2) [57, 58], breast cancer (n = 1) [21], nasopharyngeal cancer (n = 1) [59], prostate cancer (n = 1) [21], malignant melanoma (n = 1) [60], cholangiocarcinoma (n = 1) [61] and hepatobiliary cancer (n = 1) [62]. Thirteen studies only chose non-metastatic cancer patients as research subjects while six studies only enrolled cancer metastatic patients.…”

Section: Resultsmentioning

confidence: 99%

Prognostic Role of Pretreatment Plasma D-Dimer in Patients with Solid Tumors: a Systematic Review and Meta-Analysis

Tang²,

Song

et al. 2018

Cell Physiol Biochem

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Background/Aims: Elevated pretreatment plasma D-dimer level has been reported as an unfavorable prognostic indicator in several malignancies. The aim of this meta-analysis was to evaluate the prognostic value of elevated D-dimer level in solid tumors. Methods: A comprehensive search of electronic databases up to June 10, 2017 was carried out by two independent reviewers. We included studies exploring the association between pretreatment plasma D-dimer level and patients’ survival outcomes in solid tumors. Overall survival (OS) was regarded as primary outcome and progression-free survival (PFS), disease-free survival (DFS) as well as cancer-specific survival (CSS) were chosen as secondary outcomes. Hazard ratio and 95% confidence interval (CI) were extracted directly or indirectly from included studies. Results: 49 studies with 13001 patients were included in our meta-analysis. Elevated D-dimer was markedly associated with poor OS (pooled HR = 1.90, 95% CI = 1.63 - 2.20, P < 0.001). The effect was observed in all different tumor sites, disease stages, cut-off values and ethnicities. Meanwhile, patients with a high plasma D-dimer had a shorter PFS (HR = 1.46, 95% CI = 1.22–1.76; P < 0.001), DFS (HR = 2.02, 95% CI = 1.56–2.62) and CSS (HR = 2.04, 95% CI= 1.58 – 2.64). Conclusions: Analysis of the pretreatment plasma D-dimer might provide useful information to predict prognosis in patients with solid tumors.

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“…On the other hand, our prognostic value analyses, which included eight studies 18 , 19 , 24 , 32 – 36 with a total number of 1,961 patients with HCC, demonstrated that those patients with HCC and elevated fibrinogen levels are more likely to experience poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and recurrence (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Furthermore, TSA indicated that currently available studies are sufficient to validate the negative prognostic value of elevated plasma fibrinogen levels in patients with HCC.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies reported that HCC patients showed higher levels of pretreatment plasma fibrinogen compared to healthy controls or cirrhotic patients. 20 – 22 However, Basili et al 23 and Liu et al 24 found no significant difference in the plasma fibrinogen levels between HCC and control or cirrhotic groups, and Hessien et al 25 indicated lower levels of fibrinogen in HCC patients compared to that in control and cirrhotic patients. Therefore, our present study aims to summarize the currently available studies to examine 1) whether the pretreatment plasma fibrinogen levels were significantly different among HCC, cirrhotic, and healthy subjects; 2) the association between elevated plasma fibrinogen and prognosis in patients with HCC; and 3) the association between elevated fibrinogen levels and tumor progression in patients with HCC.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of plasma fibrinogen in hepatocellular carcinoma: a meta-analysis

Huang¹,

Jiang²,

Lin³

et al. 2018

CMAR

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BackgroundElevated plasma fibrinogen levels have been associated with tumor progression in several malignancies. Our study aims to characterize the clinical significance of elevated plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC).Materials and methodsRelevant published articles were systematically searched in electronic databases including PubMed, Embase, and Web of Science. The pooled differences in plasma fibrinogen levels among HCC, cirrhotic, and control groups were expressed as weighted mean differences (WMDs) and their corresponding 95% CIs. The associations between elevated fibrinogen and overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS) were expressed as HRs and their 95% CIs, whereas the associations between elevated fibrinogen and various types of clinical characteristic of patients with HCC were expressed as ORs and their corresponding 95% CIs.ResultsResults showed that the plasma fibrinogen levels in patients with HCC were not significantly different than that in healthy controls (WMD = 0.50, 95% CI = [−0.82, 1.82], P = 0.457) or patients with cirrhosis (WMD = −0.62, 95% CI = [−1.56, 0.33], P = 0.200). However, our results showed that compared to those with normal levels, patients with HCC and elevated plasma fibrinogen levels showed poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and DFS/RFS (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Results of trial sequential analysis of the OS indicated that currently available studies were sufficient to validate the negative prognostic value of elevated plasma fibrinogen in patients with HCC. Clinicopathological analyses showed that high plasma fibrinogen levels were associated with tumor progression as indicated by advanced tumor stage, larger tumor size, increased tumor number, and the presence of vascular invasion.ConclusionElevated plasma fibrinogen levels are associated with poor prognosis and advanced tumor progression. Plasma fibrinogen may serve as a negative prognostic biomarker in patients with HCC.

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Fibrinogen and D‐dimer levels elevate in advanced hepatocellular carcinoma: High pretreatment fibrinogen levels predict poor outcomes

Abstract: The fibrinogen and D-dimer levels, elevating after carcinogenesis, may serve as simple but effective predictors of adverse tumor profiles and outcomes in HCC.

Cited by 33 publications

References 33 publications

RETRACTED: Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish

RETRACTED: Activation of Hepatic Stellate Cells During Liver Carcinogenesis Requires Fibrinogen/Integrin αvβ5 in Zebrafish

Prognostic Role of Pretreatment Plasma D-Dimer in Patients with Solid Tumors: a Systematic Review and Meta-Analysis

Prognostic value of plasma fibrinogen in hepatocellular carcinoma: a meta-analysis

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