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Immunomodulatory effects of therapeutic plasma exchange on monocytes in antiphospholipid syndrome.

ABSTRACT: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis and recurrent fetal loss, with the persistent presence of antiphospholipid antibodies (aPLs). aPLs exert their pathogenic effect via the overproduction of tissue factor and activation of complement and several cell types, including endothelial cells, platelets and notably monocytes. As a result, a hypercoagulable state develops leading to APS-associated obstetric complications and fetal loss. Despite being far from optimal, treatment of APS usually includes heparin and low dose aspirin. Recently, plasma exchange (PE) therapy was successfully used in patients with APS with obstetric complications who did not respond to the standard treatment. Therefore, the present study investigated the mechanism underlying PE action, and aimed to determine whether PE affects the functional activity of APS monocytes by examining the expression of 11 mRNA transcripts encoding cytokines, signaling molecules and transcription factors. Monocytes were collected prior to and following the PE treatment from women with APS who experienced recurrent pregnancy losses, as well as from healthy volunteers. Compared with control cells, APS monocytes showed deregulated expression of interleukin (IL)-1?, IL-6, IL-23, chemokine (C-C motif) ligand 2 (CCL2), C-X-C motif chemokine 10 (CXCL10), toll-like receptor 2, and signal transducer and activator of transcription 3. PE treatment resulted in increased IL-1?, IL-6, IL-23, CCL2, P2X7 and tumor necrosis factor-? mRNA transcripts in APS monocytes, restoring the mRNA expression levels to within normal ranges. Furthermore, PE therapy counterbalanced the expression levels of CCL2 and CXCL10, the levels of which are indicative of T helper cell 1/2 balance. The results of the present study indicate that the altered transcriptional profile in APS monocytes was restored by the immunomodulatory effect of plasmapheresis.

SUBMITTER: Martirosyan A

PROVIDER: S-EPMC4950391 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Immunomodulatory effects of therapeutic plasma exchange on monocytes in antiphospholipid syndrome.

Martirosyan Anush A Petrek Martin M Kishore Amit A Manukyan Gayane G

Experimental and therapeutic medicine 20160608 2

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombosis and recurrent fetal loss, with the persistent presence of antiphospholipid antibodies (aPLs). aPLs exert their pathogenic effect via the overproduction of tissue factor and activation of complement and several cell types, including endothelial cells, platelets and notably monocytes. As a result, a hypercoagulable state develops leading to APS-associated obstetric complications and fetal loss. Despite be ...[more]

PMID: 27446342

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Project description:BackgroundHELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome occurs in about 0.5%-0.9% of all pregnancies, but its prevalence is higher in patients with severe preeclampsia, accounting for a substantial maternal and perinatal morbidity and mortality. According to the latest American Society for Apheresis guidelines, Therapeutic plasma exchange (TPE) performed for postpartum cases and antepartum HELLP syndrome cases fall in Categories III and IV, respectively.Materials and methodsRetrospective analysis was done at our tertiary care center from January 2014 to June 2019 for patients diagnosed with HELLP syndrome. Clinical data for age, gestational age at the time of diagnosis, type of delivery, outcome of pregnancy, history of preeclampsia /eclampsia, hemoglobin levels, AST, ALT, LDH, platelet counts, prothrombin time, activated partial thromboplastin time, international normalised ratio, complete blood count, was obtained from patients' electronic medical records. The TPE was initiated within 24 hrs of diagnosis. All TPE was done on Spectra Optia apheresis system (Terumo BCT, Inc, USA). Statistical testing was conducted with the statistical package for the social science system version SPSS 20.0 and R-3.2.0. Continuous variables were expressed as mean±SD and were compared between Pre and Post TPE records of patients by using the paired T test.ResultsNine patients fulfilled the criteria of HELLP syndrome. Seven (77.8%) were diagnosed in the postpartum period and 2 (22.2%) during the second trimester. Out of the total nine patients, two patients (22.2%) recovered completely and were discharged on day 15 ± 7 days, whereas 4 (44.4%) patients were discharged on day 21 ± 7 days with the advice of hemodialysis. Two (22.2%) patients had an intrauterine death and were discharged 3-4 days after the demise. In all these patients (except one), the TPE was initiated within 24 h of the diagnosis. A significant increase in platelet count and decrease in the lactate dehydrogenase levels (P < 0.05) was observed post TPE.ConclusionOur data showed that TPE improved the treatment outcome in patients with HELLP syndrome despite being a Category III and IV indication among postpartum and antenatal females, respectively. However, a timely diagnosis and management are of paramount importance for a favorable outcome. TPE needs to be performed within 24 h of the diagnosis postdelivery when the patient is not responsive to the usual therapies, especially in class I HELLP syndrome.

Project description:BackgroundDisruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors.MethodsWe enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls.ResultsSDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8-18.6) vs. septic patients before TPE: 105.8 (30.8-143.4) μg/ml, p < 0.001; vs. after TPE: 70.7 (36.9-109.5) μg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2-21.2) vs. septic patients at inclusion: 2.9 (2.1-5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2-31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE.ConclusionsSeptic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020.

Project description:Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by thromboembolic events, pregnancy morbidity, and the presence of antiphospholipid (aPL) antibodies. There is sound evidence that aPL act as pathogenic autoantibodies being responsible for vascular clots and miscarriages. However, the exact mechanisms involved in the clinical manifestations of the syndrome are still a matter of investigation. In particular, while vascular thrombosis is apparently not associated with inflammation, the pathogenesis of miscarriages can be explained only in part by the aPL-mediated hypercoagulable state and additional non-thrombotic effects, including placental inflammation, have been described. Despite this difference, evidence obtained from animal models and studies in APS patients support the conclusion that complement activation is a common denominator in both vascular and obstetric APS. Tissue-bound aPL rather than circulating aPL-beta2 glycoprotein I immune complexes seem to be responsible for the activation of the classical and the alternative complement pathways. The critical role of complement is supported by the finding that complement-deficient animals are protected from the pathogenic effect of passively infused aPL and similar results have been obtained blocking complement activation. Moreover, elevated levels of complement activation products in the absence of abnormalities in regulatory molecules have been found in the plasma of APS patients, strongly suggesting that the activation of complement cascade is the result of aPL binding to the target antigen rather than of a defective regulation. Placental complement deposits represent a further marker of complement activation both in animals and in patients, and there is also some suggestive evidence that complement activation products are deposited in the affected vessels. The aim of this review is to analyze the state of the art of complement involvement in the pathogenesis of APS in order to provide insights into the role of this system as predictive biomarker for the clinical manifestations and as therapeutic target.

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Immunomodulatory effects of therapeutic plasma exchange on monocytes in antiphospholipid syndrome.

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Immunomodulatory effects of therapeutic plasma exchange on monocytes in antiphospholipid syndrome.

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