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• W2014103672 abstract "Circulating endothelial cells (CECs) have been studied in cardiovascular disorders and as a marker of angiogenetic activity; clinical applications are limited by a lack of consensus on their phenotypic identification and quantification. We determined CECs in essential thrombocythemia (ET) patients, to investigate their possible pathogenetic role. We considered CECs as CD146+/CD45− nucleated cells, detected in peripheral blood from 21 healthy controls and 39 ET patients, performing a combination of pre-enrichment of CD146+ circulating cells and multiparametric flow cytometry measurement (FCM). Levels of CECs in ET patients were higher with respect to controls (median 2844 CECs/mL vs. 121.3 CECs/mL, P < 0.0001). Apparently hydroxyurea treatment did not influence the levels of CECs. As another established marker of endothelial activation, we also assessed soluble E-selectin (sE-selectin) levels in 31 of the ET patients and compared with 39 healthy volunteers: median sE-selectin level in ET patients was 35.3 ng/mL, higher with respect to controls (24.48 ng/mL), P = 0.0369. Our data suggest that endothelium in ET is activated, reflecting a significant role of angiogenesis in this disorder and suggesting an important endothelial contribution in the hypercoagulable state of ET patients. In recent years, CECs have emerged as a marker of endothelial damage in cardiovascular disorders and concurrently, as a marker of angiogenetic activity. Particularly, CECs are matured differentiated cells detached from the vessel wall, and they are present at very low levels in healthy subjects, representing physiological endothelial turnover, whereas elevated levels have been reported in pathologic situations. Elevation level of CECs is associated with vascular injury, and increased CECs have been demonstrated in several diseases including cardiovascular diseases, immune-mediated disorders, infectious diseases, and cancer [1]. The clinical and pathophysiological meaning of these cells has gained renewed attention, due to the importance of altered vascular endothelium function to the neoplastic disease process, largely dependent on abnormal angiogenesis [2]. In addition to its well-established role in solid tumors, angiogenesis plays an important role in the pathogenesis of hematological diseases, modifying bone marrow microvascular density and displaying an increase of endothelial progenitor cells (EPCs). This kind of phenomenon is still under investigation among chronic myeloproliferative neoplasms (MPNs; Ref.3), where angiogenesis may have a double concomitant role: first, taking part in the evolution of these diseases and concurrently, leading to an increased thrombotic risk, which may be partly related to endothelial activation. Although research studies of CECs and EPCs may have important clinical implications, they are often impeded by methodological issues and a lack of consensus on phenotypic identification, distinction, and quantification of these cells and particles [4]. CECs are phenotypically defined by the expression of endothelial markers such as von Willebrand factor (vWF), CD31 or CD146, and the lack of leukocyte and progenitor cell markers (CD45, CD133). Widemann et al. [5] developed a hybrid assay combining CD146+ cell enrichment and multiparametric FCM as an accurate alternative method for the detection of CECs. Performing this assay, we determined CECs in patients with ET, to investigate their possible role in the pathogenesis of this disease. CECs are defined in our study as CD146+/CD45− nucleated cells, determined in peripheral blood from 21 healthy volunteers (median age 47 years) and 39 ET patients (median age 54 years; median follow-up 5.35 years). At the time of sample collection, 32 ET patients were treated with hydroxyurea and aspirin, whereas 7 patients were receiving only disaggregation with aspirin. Collection of peripheral blood samples was performed after a median time from diagnosis of 3.53 years for ET patients; Hb level, Ht, white blood cell (WBC), and platelet (PLT) count at the time of collection were, respectively, 13.6 g/dL, 40.9%, 7,180/mm3, and 593,000/mm3. 20 ET patients were JAK2V617F positive, whereas 19 were wild type for the mutation. CECs in ET patients were significantly higher with respect to healthy controls (median 2844 CECs/mL vs. 121.3 CECs/mL, P < 0.0001), as shown in Fig. 1. Increased levels of CECs in ET patients (Mann–Whitney test). The detection of a second sample of CECs in 21 ET patients after a median time of 7.5 months was also performed, confirming the increased level of CECs with respect to controls, with no statistical differences with the previous sample. No significant differences were found in the levels of CECs between JAK2V617 positive and negative patients or in terms of correlations with gender, age, duration of disease, and hematology values at the time of detection. Considering thrombotic events, 7 patients (4 JAK2V617F positive and 3 JAK2V617F negative) presented a previous history of thrombosis (all arterial event). Comparing the levels of CECs in these patients and ET patients without a previous thrombotic event, no significant differences were found. Apparently, hydroxyurea treatment does not influence the levels of CECs in cytoreducted patients, with respect to patients receiving only disaggregation. As another established marker of endothelial activation, we also assessed sE-selectin levels from the collected serum of 31 of the ET patients and compared with 39 healthy volunteers (median age 51 years). ET patients displayed higher levels with respect to 39 healthy controls, with statistical significance (Fig. 2): median sE-selectin level in ET patients was 35.3 ng/mL, whereas median level detected in healthy controls was 24.48 ng/mL, P = 0.0369. Apparently, no differences in sE-selectin levels were found between JAK2V617F positive and wild-type patients. Increased sE-selectin levels in ET patients (Mann–Whitney test). Our study highlights that CECs in ET are significantly higher than in healthy controls. As reported recently in the literature, CECs and EPCs may represent a novel angiogenetic marker in hematological and nonhematological malignancies [6, 7]. Regarding MPN, only a few studies with different techniques investigated the role of CECs in this specific subgroup of patients. Alonci et al. [3] observed an increase in the level of CECs in MPN patients by flow cytometry detection, suggesting a role of vascular endothelial growth factor as an important angiogenic cytokine that may contribute to the pathogenesis of MPN. Performing the hybrid assay published from Widemann et al. [5], we demonstrated the higher detection of CECs in ET patients, confirming the validity of the proposed technique. Our data are in agreement with the results of the study by Treliński et al. [8], who found the increased levels of CECs in ET and polycythemia vera by flow cytometry assessment; according to this study, no differences in JAK2V617F positive and wild-type patients were observed in relation to CECs detected. It is known from the literature that established risk factors for thrombosis in ET are age older than 60 years and previous thrombosis, whereas leucocytosis and JAK2V167F allele burden have been hypothesized to represent additional risk factors and merit further validation in controlled trials [9]. The role of endothelium in the hypercoagulable state in ET has been investigated by Trappenburg et al. [10] who found elevated procoagulant microparticles expressing platelet and endothelial markers, suggesting ongoing endothelial activation; in fact, increased thrombin generation was associated with chronic endothelial activation given by an elevated level of mature vWF in the presence of a relatively low level of propeptide. Unlike this study, where apparently no differences in plasma levels of sE-selectin between ET patients and controls were found, we observed in our data a higher sE-selectin level with respect to healthy controls. This observation may reinforce the hypothesis of an important endothelial contribution in the hypercoagulable state of ET patients, even if an investigation on a higher number of patient is needed. From a different point of view, increased CECs could represent an additional risk factor for thrombosis in ET patients, particularly considering that hydroxyurea treatment does not influence the levels of CECs in our study; concerning this, a second sample detection after a median time of 7.5 months confirmed the increased levels of CECs, with no differences from the previous sample. Of note, this hypothesis needs further investigation extending our case study, to better estimate the impact on thrombotic incidence in ET patients. Moreover, the increased levels of CECs observed in ET patients, with respect to controls, may confirm a significant role of angiogenesis in the pathophysiology of MPN, regardless of JAK2V617F mutational status. CECs measurement was performed using a combination of pre-enrichment of CD146+ circulating cells and multiparametric FCM (CELL-QUANT FF CD146 kit, Biocytex). CD146+ cells were isolated using CD146-coated magnetic nanoparticles and labeled using CD45-fluorescein isothiocyanate and CD146-PE or isotype control antibody and propidium iodide before FCM. Quantitative detection of sE-selectin was performed with an enzyme-linked immunosorbent assay (human sE-selectin Platinum ELISA, eBioscience). Allele-specific polymerase chain reaction (PCR) for JAK2V617F mutational status was performed on genomic DNA from bone marrow cells or peripheral blood granulocytes [11]. Differences in the levels of CECs among ET patients and controls were evaluated by Mann–Whitney test; linear regression was performed to evaluate correlations between CECs and clinical variables (age, duration of disease, thrombosis, WBC, PLT, and Ht values). Similarly, differences in the sE-selectin levels between ET patients and healthy controls were evaluated by Mann–Whitney test. Comparison between the levels of CECs and sE-selectin in ET patients was performed with linear regression. Data were processed using the Graph Pad PRISM 5 Software. A P value of <0.05 was considered statistically significant. Angelo Belotti*, Elena Elli*, Tiziana Speranza*, Eraldo Lanzi*, Pietro Pioltelli*, Enrico Pogliani*, * Ospedale San Gerardo—Universita' Milano Bicocca, Clinica Ematologica, Monza, Italy." @default.
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• W2014103672 date "2011-12-21" @default.
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• W2014103672 title "Circulating endothelial cells and endothelial activation in essential thrombocythemia: Results from CD146+ immunomagnetic enrichment-flow cytometry and soluble E-selectin detection" @default.
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• W2014103672 doi "https://doi.org/10.1002/ajh.22264" @default.
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