Abstract:Platelet activation has been described in patients with chronic inflammation, however in type 2 diabetes mellitus it remains controversial. We compared levels of platelet leucocyte aggregates, monocyte and granulocyte activation across glucose tolerance statuses in mixed ancestry South Africans. Individuals (206) were recruited from Bellville-South, Cape Town, and included 66% with normal glucose tolerance, 18.7% pre-diabetes, 8.7% screen-detected diabetes and 6.3% known diabetes. Monocyte and neutrophil activ… Show more
“…Cluster 1 displayed an activated inflammatory phenotype with high co-expression of CD11c and HLA-DR ( Bernardo et al., 2018 ; Janols et al., 2014 ). In addition, we observed classical monocyte cell clusters (7, 9, and 10) with high CD226 and CD69 but low HLA-DR expression and thus signs of altered or alternative activation ( Davison et al., 2017 ; Reymond et al., 2004 ; Vo et al., 2016 ). Among the HLA-DR lo clusters, particularly cluster 7 showed high expression of CD34 indicative of a more immature phenotype.…”
Section: Resultsmentioning
confidence: 78%
“…Thus, an alternative activation pattern of classical monocytes appeared to be COVID-19-specific and was associated with severe disease. Besides activated lymphocytes, monocytes also upregulate CD69 expression ( Davison et al., 2017 ), which promotes tissue infiltration and retention ( Cibrián and Sánchez-Madrid, 2017 ). Similarly, CD226 expression on alternatively activated monocytes might also promote diapedesis and tissue infiltration ( Reymond et al., 2004 ).…”
Section: Resultsmentioning
confidence: 99%
“…CD14 + HLA-DR lo monocytes have also been implicated with immunosuppression in cancer patients ( Bronte et al., 2016 ; Mengos et al., 2019 ; Meyer et al., 2014 ). While exhibiting anti-inflammatory features, especially in the early stages of severe disease ( Figures S3 C–S3F), persistently high expression of CD226 and CD69 may promote tissue infiltration and organ dysfunction ( Davison et al., 2017 ; Reymond et al., 2004 ; Vo et al., 2016 ).…”
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DR
hi
CD11c
hi
inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and
HLA-DR
lo
monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
“…Cluster 1 displayed an activated inflammatory phenotype with high co-expression of CD11c and HLA-DR ( Bernardo et al., 2018 ; Janols et al., 2014 ). In addition, we observed classical monocyte cell clusters (7, 9, and 10) with high CD226 and CD69 but low HLA-DR expression and thus signs of altered or alternative activation ( Davison et al., 2017 ; Reymond et al., 2004 ; Vo et al., 2016 ). Among the HLA-DR lo clusters, particularly cluster 7 showed high expression of CD34 indicative of a more immature phenotype.…”
Section: Resultsmentioning
confidence: 78%
“…Thus, an alternative activation pattern of classical monocytes appeared to be COVID-19-specific and was associated with severe disease. Besides activated lymphocytes, monocytes also upregulate CD69 expression ( Davison et al., 2017 ), which promotes tissue infiltration and retention ( Cibrián and Sánchez-Madrid, 2017 ). Similarly, CD226 expression on alternatively activated monocytes might also promote diapedesis and tissue infiltration ( Reymond et al., 2004 ).…”
Section: Resultsmentioning
confidence: 99%
“…CD14 + HLA-DR lo monocytes have also been implicated with immunosuppression in cancer patients ( Bronte et al., 2016 ; Mengos et al., 2019 ; Meyer et al., 2014 ). While exhibiting anti-inflammatory features, especially in the early stages of severe disease ( Figures S3 C–S3F), persistently high expression of CD226 and CD69 may promote tissue infiltration and organ dysfunction ( Davison et al., 2017 ; Reymond et al., 2004 ; Vo et al., 2016 ).…”
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DR
hi
CD11c
hi
inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and
HLA-DR
lo
monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
“…The anti-TF blocking antibody (clone D3H44) was from Genentech (South San Francisco, CA), the anti-TF-PE antibody was from BioLegend, while the anti-TF-FITC was purchased from LSBio (Seattle, WA). All of the anti-TF antibodies used in our study have been previously validated for each experimental application by our lab and others (4,11,39). The direct thrombin inhibitor, hirudin, was obtained from CIBA-Geigy Pharmaceuticals (Horsham, UK).…”
Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.
“…The 30 studies were all published in English. These included 2 randomised control trial [ 21 , 22 ] and 28 non-randomised studies [ 6 – 9 , 11 , 12 , 22 – 44 ]. Fig.…”
Background
Antiretroviral therapy (ART) alters platelet reactivity, and as a consequence, patients living with HIV may be at an increased risk of cardiovascular disease (CVD). The current evidence on platelet activation levels in patients with HIV remains inconclusive. We therefore aimed to systematically synthesise evidence on the association of platelet activation in HIV-infected patients on successful treatment.
Methods
Electronic databases were searched from inception until November 2019. Studies were included if the primary or secondary outcome of the study was to assess platelet activation in HIV-infected patients on ART. The primary outcome of this review included the levels of platelet activation. The pooled effect estimates were calculated using a random-effects meta-analysis model.
Results
We identified 30 studies comprising of 2325 participants. The pooled estimates showed elevated levels of platelet activation in treatment-naïve HIV-infected patients compared to uninfected controls (Hedges’ g 2.00 [95%CI 1.05, 2.94]; z = 4.12, p < 0.0001). These remained elevated despite successful ART (Hedges’ g 2.05 [95%CI 0.58, 3.52]; z = 2.71, p = 0.0067).
Conclusion
The levels of platelet activation are elevated in treatment-naïve HIV-infected patients, and these persist during successful ART. Further studies should assess the clinical relevance of monitoring the levels of platelet activation in HIV-infected patients on ART.
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