Venous thromboembolic events (VTE) are a common complication of cancer and its therapy. Prognostic models and biomarkers are currently under investigation as a means to identify cancer patients who are at greatest risk for developing thromboembolic complications and thus are most likely to benefit from primary thromboprophylaxis. Elevations in circulating tissue factor bearing microparticles are associated with thrombosis in cancer patients. We initiated the MicroTEC study which is a randomized, multi-center trial to evaluate the benefit of low molecular weight heparin to prevent VTE in high risk cancer patients. This review details the evidence for tissue factor bearing microparticles in the malignant state and its association with thromboembolic phenomena.
"express or contain specific cellular proteins and nucleic acids that may mediate procoagulant activity . Elevated levels of circulating microparticles have been observed in several disorders including cardiovascular disease , venous thrombosis   , systemic lupus  , and cancer   , among others. Microparticles released in vitro in response to APLA-mediated endothelial activation, express prothrombotic properties . "
[Show abstract][Hide abstract] ABSTRACT: The antiphospholipid syndrome is characterized by venous or arterial thrombosis and/or recurrent fetal loss in the presence of circulating antiphospholipid antibodies. These antibodies cause activation of endothelial and other cell types leading to the release of microparticles with procoagulant and pro-inflammatory properties. The aims of this study were to characterize the levels of endothelial cell, monocyte, platelet derived, and tissue factor-bearing microparticles in patients with antiphospholipid antibodies, to determine the association of circulating microparticles with anticardiolipin and anti-β2-glycoprotein antibodies, and to define the cellular origin of microparticles that express tissue factor. Microparticle content within citrated blood from 47 patients with antiphospholipid antibodies and 144 healthy controls was analyzed within 2 hours of venipuncture. Levels of Annexin-V, CD105 and CD144 (endothelial derived), CD41 (platelet derived) and tissue factor positive microparticles were significantly higher in patients than controls. Though levels of CD14 (monocyte-derived) microparticles in patient plasma were not significantly increased, increased levels of CD14 and tissue factor positive microparticles were observed in patients. Levels of microparticles that stained for CD105 and CD144 showed a positive correlation with IgG (R = 0.60, p = 0.006) and IgM anti-beta2-glycoprotein I antibodies (R = 0.58, p = 0.006). The elevation of endothelial and platelet derived microparticles in patients with APS and their correlation with anti-β2-glycoprotein I antibodies suggests a chronic state of vascular cell activation in these individuals and an important role for β2-glycoprotein I in development of the pro-thrombotic state associated with antiphospholipid antibodies.
Thrombosis Research 11/2014; 135(1). DOI:10.1016/j.thromres.2014.11.011 · 2.45 Impact Factor
"In vivo the correlation between TF-MV and thrombosis may become more or less strong depending on the type of tumour/cancer present in a patient (6, 7, 10). Therefore, additional in vivo studies examining the relationship between tumour/cancer progression, thrombosis and TF-MV is critical. "
[Show abstract][Hide abstract] ABSTRACT: Patients with cancer have a 7- to 10-fold increased risk of developing venous thromboembolism. Circulating microvesicles could be a useful predictive biomarker for venous thromboembolism in cancer. Validated and standardised techniques that could be used to determine the complete microvesicle phenotype are required.
These were two-fold: a) to characterise tissue factor (TF)-bearing microvesicles released by cultured breast cancer cells MDA-MB-231 by flow cytometry (FCM), transmission electron microscopy (TEM) and thrombin generation assay (TGA); and b) to validate the sensitivity and variability intra/inter-assay of TGA as a useful method to study the procoagulant activity (PCA) of microvesicles.
Cultured breast cancer cells MDA-MB-231 were incubated for 45 minutes at 37°C. Samples were then centrifuged or not at 4,500 g for 15 minutes, and cells and MVs or MV-containing supernatants were used for TEM, FCM and TGA. In activity assays, microvesicles (i.e. cell-depleted supernatants) were incubated with anti-TF antibodies or with annexin V to assess the contribution of TF and phospholipids to the PCA. Alternatively, supernatants were filtered through 0.1, 0.22, 0.45 or 0.65 µm membranes and subjected to TGA.
The majority of the PCA was associated with microvesicles smaller than 0.1 µm, and the mean microvesicle size estimated by TEM after 10,000 g centrifugation was 121±54 nm with a majority of vesicles between 100 and 200 nm. Microvesicles derived from 5,000 MDA-MB-231cells/ml were sufficient to significantly increase the thrombin generation of normal pooled plasma.
TEM, FCM and filtration coupled to TGA represent a useful combination to study the PCA of TF-bearing microvesicles, whatever their size. And it will be interesting to implement these techniques in patients.
"Seminal studies of Dvorak and colleagues revealed extensive shedding of procoagulant TF-containing microvesicles from cancer cells (Dvorak et al., 1983). Numerous subsequent analyses interrogated the relevance of this process in cancer biology (Yu et al., 2005), progression (Tesselaar et al., 2007), and paraneoplastic (prothrombotic) syndromes (Burnier et al., 2009; Aharon and Brenner, 2010; Khorana, 2010; Zwicker, 2010). Production of exosomes by cancer cells has been frequently implicated in anticancer immunity (Wolfers et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: The brain is a frequent site of neoplastic growth, including both primary and metastatic tumors. The clinical intractability of many brain tumors and their distinct biology are implicitly linked to the unique microenvironment of the central nervous system (CNS) and cellular interactions within. Among the most intriguing forms of cellular interactions is that mediated by membrane-derived extracellular vesicles (EVs). Their biogenesis (vesiculation) and uptake by recipient cells serves as a unique mechanism of intercellular trafficking of complex biological messages including the exchange of molecules that cannot be released through classical secretory pathways, or that are prone to extracellular degradation. Tumor cells produce EVs containing molecular effectors of several cancer-related processes such as growth, invasion, drug resistance, angiogenesis, and coagulopathy. Notably, tumor-derived EVs (oncosomes) also contain oncogenic proteins, transcripts, DNA, and microRNA (miR). Uptake of this material may change properties of the recipient cells and impact the tumor microenvironment. Examples of transformation-related molecules found in the cargo of tumor-derived EVs include the oncogenic epidermal growth factor receptor (EGFRvIII), tumor suppressors (PTEN), and oncomirs (miR-520g). It is postulated that EVs circulating in blood or cerebrospinal fluid (CSF) of brain tumor patients may be used to decipher molecular features (mutations) of the underlying malignancy, reflect responses to therapy, or molecular subtypes of primary brain tumors [e.g., glioma or medulloblastoma (MB)]. It is possible that metastases to the brain may also emit EVs with clinically relevant oncogenic signatures. Thus, EVs emerge as a novel and functionally important vehicle of intercellular communication that can mediate multiple biological effects. In addition, they provide a unique platform to develop molecular biomarkers in brain malignancies.
Frontiers in Physiology 07/2012; 3:294. DOI:10.3389/fphys.2012.00294 · 3.53 Impact Factor
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