The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass (HIT) - RTDC 5801
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PROVIDER: PRJNA189554 | ENA |
REPOSITORIES: ENA
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Project description:The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass (HIT) - RTDC 5801
| PRJNA189555 | ENA
Project description:Pf4 is a filamentous bacteriophage integrated as a prophage into the genome of Pseudomonas aeruginosa PAO1. Pf4 virions can be produced without killing P. aeruginosa. Cell lysis can however occur during superinfection when Pf virions successfully infect a host lysogenized by a Pf superinfective variant. We have previously shown that infection of P. aeruginosa PAO1 with a superinfective Pf4 variant led to abolish twitching motility and to alter biofilm’s architecture. More precisely, the cells embedded into the biofilm were showing for most of them a filamentous morphology, that could be related to the activation of the cell envelope stress response involving both the AlgU and SigX extra cytoplasmic function sigma factors. Herein, we show that Pf4 variant-infection resulted also into a drastic dysregulation of 3,360 genes representing about 58% of P. aeruginosa’s genome, of which about 43% of the virulence factors encoding genes showing a down-regulation. Accordingly, Pf4 variant infection (termed Pf4*) causes in vivo reduction of P. aeruginosa virulence, decreased production of N-acyl-homoserine lactones and 2-alkyl-4-quinolones quorum sensing molecules, and related virulence factors, such as pyocyanin, elastase, and pyoverdine. In addition to virulence encoding genes, expression of genes involved in metabolism, including energy generation and iron homeostasis, was affected, suggesting further relationships between virulence and central metabolism. Altogether, these data suggest that Pf4 phage variant infection results in complex networks dysregulations, leading to reducing acute virulence in P. aeruginosa. This work contributes to the comprehension of the bacterial response to filamentous phage infection.
2022-07-05 | GSE201738 | GEO
Project description:Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to human youthful PF4 signaling, highlighting its potential in rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
2025-05-31 | GSE280042 | GEO
Project description:<p>The purpose of this study is to determine how often heart surgery patients who receive heparin develop an immune response (heparin-induced thrombocytopenia) that leads to clots forming in different parts of the body. These clots usually occur in the legs (deep venous thrombosis or DVT) or lungs (pulmonary embolism or PE) or cause heart attacks (myocardial infarction or MI) and strokes.</p>
| phs000606 | dbGaP
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy by intervening the M2-like TAM/Th1-Treg axis.
2024-11-07 | GSE251735 | GEO
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy.
2024-11-07 | GSE252052 | GEO
Project description:Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain.
2023-06-24 | GSE171929 | GEO
Project description:Srf is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. In order to test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to SrfF/F mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/SrfF/F (KO) mice are born with normal mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased numbers and percentages of CD41+ megakaryocytes (WT: 0.41+/-0.06%; KO: 1.92+/-0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by both FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are downregulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production, due at least in part, to regulation of cytoskeletal genes. C-kit+CD41+ megakaryocyte progenitors from PF4-Cre/SRF C57BL/6 SRF WT (3) and C57BL/6 SRF KO (3) mice were sorted by flow cytometry and cultured for three days in thrombopoietin.
2010-07-13 | E-GEOD-21859 | biostudies-arrayexpress
Project description:Background: The elevated risk on and health burden of thromboembolic events necessitates development of blood-based patient risk monitoring.Objective: We explored the potential of mass spectrometry-based plasma proteomics to provide insights into underlying plasma protein signatures with treatment and occurrence of thromboembolic events.Method: Utilizing a high-throughput, data-independent acquisition, discovery-based proteomics workflow we analysed 434 plasma proteomes from different groups of individuals with elevated risk of thromboembolic events, including individuals I) on vitamin K-antagonists (VKA), II) with a prior venous thromboembolism, III) with acute cerebral venous sinus thrombosis (CVST) and IV) with SARS-CoV-2 infection. Plasma protein levels measured with MS were correlated with international prothrombin time ratio (INR) and conventional clinical laboratory measurements. Plasma profile differences between different groups were assessed using principal component analysis, moderated t-test and clustering analysis.Results: Plasma protein levels were in agreement with conventional clinical laboratory parameters, including albumin and fibrinogen. In addition, levels of vitamin K-dependent proteins inversely correlated with INR. In the individual retrospective studies, we found decreased levels of vitamin K-dependent coagulation proteins in patients on VKAs, alterations in inflammatory signatures among CVST patients and a distinctive signature indicative of SARS-CoV-2 infection. However, no protein signature associated with a thromboembolic event could be identified neither in individual nor combined retrospective studies. Conclusion: Although VKA treatment- and disease-specific signatures were captured, our study highlights that the challenges of discovering biomarkers in patients at risk of thromboembolic events lie in the heterogeneity of individual plasma profiles in relation to treatment and etiology.
2025-05-06 | PXD044173 | Pride
Project description:Anti-protamine (PRT)/heparin antibodies are a newly described class of heparin-dependent antibodies occurring in patients exposed to PRT and heparin during cardiac surgery. To understand the biologic significance of anti-PRT/heparin antibodies, we developed a murine monoclonal antibody (ADA) specific for PRT/heparin complexes and compared it to patient-derived anti-PRT/heparin antibodies, as well as comparing polyclonal and monoclonal antibodies with anti-platelet factor 4 (PF4)/heparin. Using monoclonal antibodies and polyclonal patient-derived antibodies, we show distinctive binding patterns of anti-PRT/heparin antibodies as compared with PF4/heparin antibodies. Whereas heparin-induced thrombocytopenia (HIT) antibody binding to PF4/heparin is inhibited by relatively low doses of heparin (0-1 U/mL), anti-PRT/heparin antibodies, including ADA, retain binding to PRT/heparin over a broad range of heparin concentrations (0-50 U/mL). Unlike PF4/heparin antibodies, which recognize PF4 complexed to purified or cell-associated glycosaminoglycans (GAGs), anti-PRT/heparin antibodies show variable binding to cell-associated GAGs. Further, binding of anti-PRT/heparin antibodies to PRT/dextran complexes correlates closely with the ability of antibodies to bind to cell-surface PRT. These findings suggest that antibody binding to PRT/dextran may identify a subset of clinically relevant anti-PRT/heparin antibodies that can bind to cell-surface GAGs. Together, these findings show important serologic differences between HIT and anti-PRT/heparin antibodies, which may account for the variability in disease expression of the two classes of heparin-dependent antibodies.
| S-EPMC5727817 | biostudies-literature