Summary Inflammatory bowel disease (IBD)-associated thromboembolic event often lacks precise aetiology. The aim of this study was to investigate the contribution of phosphatidylserine (PS) exposure and neutrophil extracellular traps (NETs) towards the hypercoagulable state in IBD. We demonstrated that the levels of PS exposed MPs and the sources of MP-origin, platelets, erythrocytes, leukocytes and cultured endothelial cells (ECs) were higher in IBD groups than in healthy controls using flow cytometry and confocal microscopy. Wright-Giemsa and immunofluorescence staining demonstrated that the elevated NETs were released by activated IBD neutrophils or by control neutrophils treated with IBD sera obtained from patients with the active disease. MPs and MP-origin cells in IBD groups, especially in active stage, markedly shortened coagulation time and had increased levels of fibrin, thrombin and FXa production as assessed by coagulation function assays. Importantly, we found that on stimulated ECs, PS rich membranes provided binding sites for FXa and FVa, promoting fibrin formation while TNF blockage or IgG depletion attenuated this effect. Treatment of control neutrophils with TNF and isolated IgG from PR3-ANCA-positive active IBD patients also resulted in the release of NETs. Blockade of PS with lactadherin prolonged coagulation time, decreased fibrin formation to control levels, and inhibited the procoagulant enzymes production in the MPs and MP-origin cells. NET cleavage by DNase I partly decreased PCA in IBD or stimulated neutrophils. Our study reveals a previously unrecognised link between hypercoagulable state and PS exposure or NETs, and may further explain the epidemiological association of thrombosis within IBD patients.
The SARS-CoV-2 virus is responsible for the human disease known as COVID-19. This virus is capable of generating a spectrum of infections ranging from moderate to severe. Serum apolipoprotein E (ApoE) inhibits inflammation by preserving immune regulatory function. Nonetheless, the relationship between serum ApoE and clinical prognosis in omicron remains elusive. A cohort of 231 patients was observed for 65 days, with death as the primary outcome. Based on their ApoE levels, the patients were categorized into patients with elevated ApoE levels and those with lower ApoE levels. To do statistical comparisons, the log-rank test was utilized, and the Kaplan-Meier method was utilized to estimate survival rates. Cox hazard models, both univariate and multivariate, were employed to examine the prognostic relevance. According to our research, omicron had significantly greater ApoE levels. In mild-to-moderate and severe cases, the study identified a statistically significant variation in ApoE levels. Additionally, there was a drop in overall survival that is statistically significant (OS, p < 0.0001) for patients with greater ApoE levels. Multiple Cox proportional hazards regression analysis indicates that an elevated ApoE level was determined to be an adverse and independent prognostic factor of OS in patients with omicron. Taken together, our study found that the level of serum ApoE at the time of initial diagnosis was substantially connected to the severity and prognosis of omicron. Consequently, we propose that ApoE might be a poor prognostic factor in individuals afflicted with the omicron variant.
The pathogenesis of hypercoagulability in retinal vein occlusion (RVO) is largely unknown. Whether the exposure of phosphatidylserine (PS) and microparticle (MPs) release will affect procoagulant activity (PCA) in RVO needs to be investigated. Objectives . To evaluate PS expression, circulating MPs, and the corresponding PCA in RVO patients. Twenty‐five RVO patients were compared with 25 controls. PS‐positive cells were detected by flow cytometry. Cell‐specific MPs were measured by lactadherin for PS and relevant CD antibody. We explored PCA with coagulation time, purified coagulation complex assays, and fibrin production assays. In RVO, MPs from platelets, erythrocytes, leukocyte, and endothelial cells were increased and the exposure of PS was elevated significantly when compared with controls. In addition, we showed that circulating MPs in RVO patients were mostly derived from platelets, representing about 60–70% of all MPs, followed by erythrocytes and leukocytes. Moreover, PS exposure, ECs, and MPs in RVO lead to shortened clotting time with upregulation of FXa and thrombin formation obviously. Importantly, ECs treated with RVO serum which bounded FVa and FXa explicitly suggested the damage of retinal vein endothelial cells. Furthermore, lactadherin can inhibit the combination between PS and coagulation factors by approximately 70% and then exert an anticoagulant effect. In summary, circulating MPs and exposed PS from different cells may contribute to the increased PCA in patients with RVO. Lactadherin can be used for PS detection and an anticoagulant agent.
Abstract Chemotherapy-induced myelosuppression is common and threatening, however, the effect of radiation on bone marrow activity especially leukocyte count has been underestimated in cervical cancer. Pelvic radiation-related intestinal toxicity is prevalent, and the relationship between leukopenia and intestinal toxicity is not clear. The clinical data of 59 patients who underwent conventional radiation alone for cervical cancer were retrospectively analyzed. The patients had normal leukocyte count on admission, and the blood cell count, GTV dose, intestinal toxicity were evaluated. During radiotherapy (RT), 47 patients (79.7%) developed into leukopenia with 38.3% mild and 61.7% moderate. The mean time for leucopenia was 9 days. Compared with leucopenia-negative patients, leucopenia-positive ones had lower baseline leukocyte count, while the neutrophil/lymphocyte (NLR) and monocyte/lymphocyte (MLR) showed no significance. Logistic regression analysis indicated that excluding the factors for age, BMI, TNM stage, surgery and GTV dose, baseline leukocyte count was an important independent predictor of leucopenia (OR=0.383). During RT, the significant reduction was found in leukocyte, neutrophil and lymphocyte count at week 2 while monocyte count after 2 weeks. Furthermore, NLR and MLR showed significant and sustained upward trend. About 54.2% patients had gastrointestinal symptoms, however, no significant difference was noted between leukocyte count as well as NLR/MLR and intestinal toxicity. Our results suggest a high prevalence of leucopenia in cervical cancer patients receiving RT, and those with low baseline leukocyte count are more likely for leucopenia, for whom early prevention of infection may be needed during RT.
Hypoxic microenvironment is immunosuppressive and protumorigenic, and elevated lactate is an intermediary in the modulation of immune responses. However, as critical lactate transporters, the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.
Summary Abundant senescent neutrophils traverse the vascular compartment and may contribute to pathologic conditions. For example, they become procoagulant when undergoing apoptosis and may contribute to thrombosis or inflammation. Our previous studies demonstrated a dominant clearance pathway in which the neutrophils can be phagocytosed by liver macrophages. The aim of this study was to explore an alternate pathway of neutrophil clearance by endothelial cells. Phagocytosis of the neutrophils by endothelial cells was performed using various experimental approaches including flow cytometry, confocal microscopy and electron microscopy assays in vitro and in vivo. Procoagulant activity of cultured neutrophils was evaluated by coagulation time, factor Xase and prothrombinase assays. Lactadherin functioned as a novel probe for the detection of phosphatidylserine on apoptotic cells, an opsonin (bridge) between apoptotic cell and phagocyte for promoting phagocytosis, and an efficient anticoagulant for inhibition of factor Xase and thrombin formation. When cultured, purified human neutrophils spontaneously entered apoptosis and developed procoagulant activity that was directly related to the degree of phosphatidylserine exposure. Co-culture of aged neutrophils and endothelial cells resulted in phagocytosis of the neutrophils and prolonged coagulation time. Lactadherin diminished the procoagulant activity and increased the rate of neutrophil clearance. In vivo, neutrophils were sequestered by endothelial cells after blockade of Kupffer cells, a process that was dependent upon both phosphatidylserine exposure and P-selectin expression. Thus, the ability of endothelial cells to clear senescent neutrophils may limit the procoagulant and/or inflammatory impact of these cells.
Acute promyelocytic leukemia (APL) cells exhibit disrupted regulation of cell death and differentiation, and therefore the fate of these leukemic cells is unclear. Here, we provide the first evidence that a small percentage of APL cells undergo a novel cell death pathway by releasing extracellular DNA traps (ETs) in untreated patients. Both APL and NB4 cells stimulated with APL serum had nuclear budding of vesicles filled with chromatin that leaked to the extracellular space when nuclear and cell membranes ruptured. Using immunofluorescence, we found that NB4 cells undergoing ETosis extruded lattice-like structures with a DNA-histone backbone. During all-trans retinoic acid (ATRA)-induced cell differentiation, a subset of NB4 cells underwent ETosis at days 1 and 3 of treatment. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly elevated at 3 days, and combined treatment with TNF-α and IL-6 stimulated NB4 cells to release ETs. Furthermore, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against Atg7 attenuated LC3 autophagy formation and significantly decreased ET generation. Our results identify a previously unrecognized mechanism for death in promyelocytes and suggest that ATRA may accelerate ET release through increased cytokines and autophagosome formation. Targeting this cellular death pathway in addition to conventional chemotherapy may provide new therapeutic modalities for APL.
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