Figure 3 - uploaded by Fred P H T M Romijn
Content may be subject to copyright.
Representative pancreatic tumour tissue samples at  10 magnification. (A) Intermediate and (B) strong TF staining in moderately and poorly differentiated pancreatic adenocarcinoma, respectively, (C) MUC1 staining, (D) CD31 staining of endothelium, (E) CD68 staining of large clusters of macrophages and (F) corresponding very strongly TF þ macrophages.
Source publication
Background:
Cancer-related venous thromboembolism (VTE) heralds a poor prognosis, especially in pancreatic adenocarcinoma (PAC). Tissue factor (TF) is implicated as one of the main culprits in PAC-associated VTE and disease progression.
Methods:
In a prospective cohort study of 79 PAC patients, we measured plasma CA19-9 and microparticle-associa...
Similar publications
Surgery remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Therefore, a predictive score for resectability on diagnosis is needed. A total of 814 patients were included between 2014 and 2017 from 15 centers included in the BACAP (the national Anatomo-Clinical Database on Pancreatic Adenocarcinoma) prospective cohort. T...
Citations
... Numerous type of cancer modify the glycosylation of several mucins, which are crucial for cellular adherence, signalling, and differentiation [40,41] (Fig. 2). Elevated mucin and TF-MP levels are considered to be the two main markers for preventing VTE and increasing survival in pancreatic adenocarcinoma (PAC) [42]. ...
Opinion Statement
Cancer-associated thrombosis (CAT) has been identified as the second most prevalent cause of death after cancer itself. Moreover, the risk of thrombotic events in cancer patients increases due to anticancer drugs, such as tyrosine kinase inhibitors (TKIs). Venous thromboembolism (VTE) as well as arterial thromboembolic (ATE) events are present in CAT. Although VTE occurs more frequently, ATE events are very significant and in some cases are more dangerous than VTE. Guidelines for preventing thrombosis refer mainly VTE as well as the contribution of ATE events. Several factors are involved in thrombosis related to cancer, but the whole pathomechanism of thrombosis is not clear and may differ between patients. The activation of the coagulation system and the interaction of cancer cells with other cells including platelets, endothelial cells, monocytes, and neutrophils are promoted by a hypercoagulable state caused by cancer. We present an update on the pathomechanisms of CAT and the effect of anticancer drugs, mainly targeted therapies with a focus on TKIs. Considering the risk of bleeding associated with anticoagulation in each cancer patient, the anticoagulation strategy may involve the use of FXIa inhibitors, direct oral anticoagulants, and low-molecular-weight heparin. Further research would be valuable in developing strategies for reducing CAT.
... An elevated CA19-9 level was a significant risk factor for VTE and the occurrence of VTE was, overall, associated with poor prognosis in PDAC patients [80]. Another study showed that CA19-9 levels increase with the extent of VTE and are higher in PDAC patients with VTE compared to PDAC patients without VTE [81]. In patients being considered for the surgical resection of a pancreatic tumor, a preoperative high serum D-dimer level over 1.0 ug/mL is associated with metastasis and is an unfavorable prognostic marker of overall survival in PDAC patients [82]. ...
Citation: Prouse, T.; Mohammad, M.A.; Ghosh, S.; Kumar, N.; Duhaylungsod, M.L.; Majumder, R.; Majumder, S. Pancreatic Cancer and Venous Thromboembolism. Int. J. Mol. Sci. 2024, 25, 5661. https://doi.org/ 10.3390/ijms25115661 Academic Editors: Asfar S. Azmi and Cristiano Fava Abstract: Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing VTE. Hypoxia in a PDAC tumor microenvironment also elevates thrombotic risk. Direct oral anticoagulants (DOACs) or low-molecular-weight heparin (LMWH) are used only as thromboprophylaxis in PDAC. However, a precision medicine approach is recommended to determine the precise dose and duration of thromboprophylaxis in clinical setting.
... PC has numerous mechanisms which sustain the high rate of VTE incidence, such as high levels of tissular factor (TF), associated with microparticles or endosome vesicles derived from malignant cells, secretion of MUC1 protein or presence of CA19.9 antigen [4]. There are concerns about the rise of CAT cases, with Mahajan et al. stating that there is a significant increase of cumulative pulmonary embolism (PE) and deep vein thrombosis from 55.7% between 2005-2007 to 60.5% between 2014-2017 [5]. ...
... Elevated TF-MVs activity was linked with an unfavorable prognosis. However, TF expression in malignant cells was not correlated with plasma TF-MVs activity, suggesting that macrophages are another source of TF-MVs activity [4]. Clopidogrel was found to reduce the levels of TF-MVs in mice, suggesting a possible role of preventing VTE in cancer patients [10]. ...
... Pancreatic adenocarcinoma (PADC) is a mucinproducing tumors, which together with lung and gastrointestinal adenocarcinoma, have higher risk of association with VTE [12]. It was postulated that MUC1, a transmembrane glycoprotein, may also play an important role in the initiation and aggravation of thrombosis [4]. The structure of these factors can be modified by the action of CA19-9 or sialic Lewis antigen, another important factor associated with a worse prognosis [13]. ...
... To assess the link between UPR induction and clinical thrombosis, we explored the possibility that induction of UPR in cancer cells results in the release of prothrombotic material. We evaluated AGS gastric cancer cells and A549 lung adenocarcinoma cells as well as HPAF-II and BxPC13 pancreatic cells, since both UPR activation (9,63) and thrombosis (64,65) are associated with pancreatic cancer. ...
Thrombosis is a common complication of advanced cancer. Yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasmas from gastric and non-small cell lung cancer patients who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasmas of patients who developed clots compared to those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors IRE1α or PERK. Release of extracellular vesicles bearing tissue factor (EVTF) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase TF synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by Arf1 knockdown or GBF1 antagonism, confirming the role of vesicular trafficking. Our findings show that UPR activation results in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.
... Moreover, a pretreatment platelet count higher than 443 × 10 9 /mL was a significant predictor of VTE, with an OR of 5.63. Another study has shown that CA19.9 levels are higher in PDAC patients with VTE compared to patients without VTE and that CA19.9 levels increase with the extent of VTE [84]. Boone et al. showed a lower percentage decrease in CA19-9 levels in response to neoadjuvant therapy to be protective for VTE, which is likely due to low CA19.9 levels at baseline [83]. ...
Simple Summary
Historically, patients with pancreatic ductal adenoma carcinoma were subjected to immediate surgical resection of the pancreatic tumor. Nowadays, more and more patients are treated with chemo(radio)therapy before surgical resection. It is known that patients with pancreatic cancer have a high risk of developing thrombosis. However, as patients underwent immediate surgery before, the incidence of thrombosis in patients with pancreatic cancer during neoadjuvant chemotherapy is understudied. Few studies have investigated the VTE incidence in this population and it is unclear whether these patients should use perioperative thromboprophylaxis to prevent thrombosis. This narrative review summarizes the evidence that is currently available.
Abstract
Recent studies have shown that patients with pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemo(radio)therapy followed by surgery have an improved outcome compared to patients treated with upfront surgery. Hence, patients with PDAC are more and more frequently treated with chemotherapy in the neoadjuvant setting. PDAC patients are at a high risk of developing venous thromboembolism (VTE), which is associated with decreased survival rates. As patients with PDAC were historically offered immediate surgical resection, data on VTE incidence and associated preoperative risk factors are scarce. Current guidelines recommend primary prophylactic anticoagulation in selected groups of patients with advanced PDAC. However, recommendations for patients with (borderline) resectable PDAC treated with chemotherapy in the neoadjuvant setting are lacking. Nevertheless, the prevention of complications is crucial to maintain the best possible condition for surgery. This narrative review summarizes current literature on VTE incidence, associated risk factors, risk assessment tools, and primary thromboprophylaxis in PDAC patients treated with neoadjuvant chemo(radio)therapy.
... We and other investigators found that the patients with cancer have increased levels of EVTF activity compared with healthy controls [35,36,[43][44][45][46]. Of note, patients with adenocarcinoma have higher levels of EVTF activity compared with patients with other histological types of tumors [46]. ...
... Several studies have investigated if there is an association between levels of EVTF activity and VTE and survival in different types of cancer (Table 1). We and other found an association between EVTF activity and VTE in PDAC patients in both longitudinal and prospective studies [36,45,49,50]. In contrast, 1 study concluded that there was no association between EVTF activity and VTE in patients with PDAC [51]. ...
A State-of-the-Art lecture titled "Mechanisms of cancer-associated thrombosis" was presented at the ISTH Congress in 2022. Patients with cancer have a 4-fold to 9-fold increased risk of venous thromboembolism (VTE) compared with the general population, so-called cancer-associated thrombosis (CAT). Different rates of VTE are observed in different types of cancer, suggesting that there are cancer-type specific mechanisms of CAT. We will discuss 4 pathways of CAT: tissue factor, podoplanin, neutrophil extracellular traps, and plasminogen activator inhibitor-1. In addition, specific gene mutations may increase the rate of CAT in some cancer types. A better understanding of these pathways may lead to the identification of biomarkers that can identify patients at risk for VTE and allow the development of new treatments to prevent CAT. Finally, we summarize relevant new data on this topic presented at the 2022 ISTH Congress.
... Thrombin synthesis has also been reported in pancreatic tumors, with an increased plasma level in pancreatic cancer patients. 41 ADP and thrombin are platelet aggregation agonists which mediate primary hemostasis. This may, therefore, explain the enhancement of platelet activation and coagulation in cancer patients by these tumor-derived products, correlating with other studies on the effect of tumor-derived agonists on platelets. ...
Cancer-associated thrombosis (CAT) is a leading cause of mortality in cancer patients and its incidence varies in different parts of the world. Venous thromboembolism (VTE) is a prominent manifestation of CAT, and significantly impacts morbidity and survival compared to arterial thrombosis in cancer patients. Several risk factors for developing VTE such as chemotherapy and immobilization have also been found co-existing with cancer patients and contributing to the increased risk of VTE in cancer patients than in non-cancer patients. This review highlights recent mechanisms in the pathogenesis of hypercoagulable syndromes associated with cancer, multiple mechanisms implicated in promoting cancer-associated thrombosis and their diagnostic approaches. Cancer cells interact with every part of the hemostatic system; generating their own procoagulant factors, through stimulation of the prothrombotic properties of other blood cell components or the initiation of clotting by cancer therapies which can all directly activate the coagulation cascade and contribute to the VTE experienced in CAT. It is our hope that the multiple interconnections between the hemostatic system and cancer biology and the improved biomarkers reported in this study can be relevant in establishing a predictive model for VTE, optimize early detection of asymptomatic microthrombosis for more personalized prophylactic strategies and incorporate effective therapeutic options and patient management to reduce mortality and morbidity, and improve the quality of life of affected cancer patients.
... CA-19-9 is a well-established prognostic factor in patients with CC (Ali et al. 2007;Bergquist et al. 2016;Hahn et al. 2020;Li et al. 2017;Wang et al. 2013), but there are to the best of our knowledge no reports describing an association between CA 19-9 and the risk of TE in CC patients. It has been shown elsewhere that CA 19-9 correlated with the severity of VTE in patients with pancreatic cancer (Woei-A-Jin et al. 2016). CA 19-9 may serve as a surrogate marker to quantify mucins in blood as it binds to apomucins (Yue et al. 2011). ...
Background
Patients with cancer are at increased risk of thromboembolic events contributing significantly to cancer-related morbidity and mortality. Because cholangiocarcinoma is a rare type of cancer, the incidence of thromboembolism in this patient population is not well defined.
Methods
Patients with cholangiocarcinoma treated at the University Cancer Center Leipzig between January 2014 and December 2018 were analyzed retrospectively regarding the incidence of arterial and venous thromboembolism.
Results
A total of 133 newly and consecutively diagnosed patients were included, of whom 22% had stage IV disease. Thromboembolism was diagnosed in 39 (29.3%), with 48% of the events occurring between 60 days prior and 30 days after the initial diagnosis. Arterial thrombosis accounted for 19% and portal venous thrombosis for 33% of the events, while the rest of events occurred in the non-portal venous system. In multivariable analysis, an ONKOTEV score ≥ 2 was the only independent predictor for thromboembolism. Serum CA 19-9 was available in 87 patients (65.4%). In this subgroup, CA 19-9 above the median of 97.7 U/ml and vascular or lymphatic compression were independent predictors for thromboembolism in the first year and CA 19-9 alone remained a significant predictor over the whole observation period. An ONKOTEV score ≥ 2 and increasing age were predictors of survival.
Conclusions
A very high thromboembolic risk was observed in cholangiocarcinoma, comparable to the risk situation in pancreatic and gastric cancer. The ONKOTEV score and serum CA 19-9 are independent predictors of thromboembolic events. Prospective validation of our observations in this patient population is warranted.
... End-point/Zymuphen [39] Whole blood from healthy controls treated with LPS EVTF activity was increased by increasing centrifugation time Modified endpoint [33] Whole blood from healthy controls treated with LPS EVTF activity was increased in plasma from whole blood treated with LPS compared with plasma from nontreated whole blood Zymuphen [34] Whole blood from healthy controls treated with Escherichia coli EVTF activity was increased in plasma from whole blood treated with Escherichia coli compared with plasma from nontreated whole blood Zymuphen [60] Whole blood from healthy controls treated with Staphylococcus aureus EVTF activity was increased in plasma from whole blood treated with S. aureus compared with plasma from nontreated whole blood Zymuphen [61] Whole blood from healthy controls treated with Neisseria meningitidis EVTF activity was increased in plasma from whole blood treated with N. meningitidis compared with plasma from nontreated whole blood Zymuphen [45] Whole blood from healthy controls treated with cholesterol crystal ...
Purpose of review:
This review evaluates the different methods used to measure levels of tissue factor (TF) in plasma and on extracellular vesicles (EVs). Levels of TF-positive (TF+) EVs in blood are increased in a variety of diseases, such as cancer, sepsis, and viral infection, and are associated with thrombosis. Highly sensitive assays are required to measure the low levels of TF+ EVs in blood.
Recent findings:
TF antigen levels in plasma have been measured using standard ELISAs, SimpleStep ELISA technology, and solid-phase proximity ligation assay. Some studies reported the detection of TF+ EVs in plasma by flow cytometry. In addition, TF+ EVs can be captured onto beads and chips using anti-TF antibodies. Several assays have been developed to measure TF activity in EVs isolated from plasma. Importantly, activity-based assays are more sensitive than antigen-based assays as a single TF/FVIIa complex can generate large amounts of FXa.
Summary:
We recommend isolating EVs from plasma and measuring TF activity using a functional assay in the presence and absence of an anti-TF antibody. We do not recommend using antigen-based assays as these are not sensitive enough to detect the low levels of TF in plasma.
... The literature indicates that TF is prominently expressed in patients with glioma [2,3], pancreatic cancer [4,5], liver cancer [6,7], breast cance r [8,9], lung cancer [10,11] and ovarian cancer [12], and may contribute to the high risk of venous thromboembolism (VTE) [13][14][15]. Furthermore, tumor-derived TF-positive microvesicles (TF + MVs) release into circulatory system and cause clot generation in different types of tumors [13,[16][17][18][19]. Especially, TF + MVs activity directly causes VTE in pancreaticbiliary cancer patients [20,21].Moreover, TF + MVs are also secreted by endothelial cells, monocytes, platelets and neutrophils, which promote coagulation locally and formation of VTE [22,23]. ...
Tissue factor (TF), an initiator of extrinsic coagulation pathway, is positively correlated with venous thromboembolism (VTE) of tumor patients. Beyond thrombosis, TF plays a vital role in tumor progression. TF is highly expressed in cancer tissues and circulating tumor cell (CTC), and activates factor VIIa (FVIIa), which increases tumor cells proliferation, angiogenesis, epithelial-mesenchymal transition (EMT) and cancer stem cells(CSCs) activity. Furthermore, TF and TF-positive microvesicles (TF⁺MVs) activate the coagulation system to promote the clots formation with non-tumor cell components (e.g., platelets, leukocytes, fibrin), which makes tumor cells adhere to clots to form CTC clusters. Then, tumor cells utilize clots to cause its reducing fluid shear stress (FSS), anoikis resistance, immune escape, adhesion, extravasation and colonization. Herein, we review in detail that how TF signaling promotes tumor metastasis, and how TF-targeted therapeutic strategies are being in the preclinical and clinical trials.
