ABSTRACT
Background: Nuclei acid-based COVID-19 vaccines have proved highly effective in reducing the risk of hospitalisation and death. As they were distributed for the first time on a large-scale population, the adenovirus-based vaccines were linked to a very rare thrombosis with thrombocytopenia syndrome and the interplay between vaccination and platelet activation gained increasing attention. Aim(s): To compare the effect of mRNA-based and adenovirus-based vaccines on platelets of young healthy adults. Method(s): We prospectively enrolled 15 healthy volunteers (53% females) who received two doses of the mRNA-based vaccine BNT162b2, 21 days apart, and 25 healthy volunteers (64% females) that received one dose of the adenovirus-based vaccine, AZD1222, followed by one dose of BNT162b2 and we studied their platelet response before and after each dose of the vaccine (3 and 10 days post-injection). Result(s): Subjects receiving the AZD1222 vaccine experienced a transient but significant 20% decrease of the platelet count 3 days after the first injection, which was not detected after the first dose of BNT162b2. The BNT162b2, but not the AZD1222, vaccine was followed by increased plasmatic thrombopoietin concentration and mean platelet volume, indicative of higher platelet turnover. Three days after the AZD1222 injection, basal platelet integrin activation was elevated, but P-selectin exposure was unchanged. Conversely, the BNT162b2 vaccine induced a gradual increase in platelet P-selectin exposure and platelet-leukocyte aggregate formation, which correlated with the ability of the vaccines to evoke neutralizing antibodies against the Sars-COV- 2 spike protein. Moreover, three days after the AZD1222 injection we detected a transient 10-fold increase of the plasmatic concentration of IFN-gamma, while BNT vaccination induced a progressive increase of IL-1beta. Conclusion(s): Based on these observations we propose that the adenovirus-based vaccines, not the mRNA-based vaccines, transiently impair platelet count homeostasis. Future studies will investigate how these distinct vaccine vectors and inflammatory profiles affect platelet consumption and platelet production.
ABSTRACT
Background: Severe Coronavirus disease 2019 (COVID-19) has been associated with a dysregulated cytokine production, lymphocyte and monocyte exhaustion, and immunothrombotic complications that reduce gas exchange in the lungs and contribute to multiorgan failure. Aim(s): The objective of this study was to characterize the interplay between platelets and the dysregulated immune phenotype that drives disease severity. Method(s): To achieve this goal, we performed a high-throughput flow cytometric profiling of the phenotype and interactions of platelets circulating in the blood of Sars-COV2-positive subjects upon hospitalization. Patients were stratified into non-ICU (n = 35) and critically ill ICU (n = 25) patients and compared to sex-and age-matched Sars-COV2-negative patients (n = 15) and healthy volunteers (n = 20). All participants gave written informed consent. The study was approved by the Ethics Committee of our institution. Result(s): Platelets from ICU patients had dysfunctional mitochondria and a non-adhesive phenotype. Displayed significantly less glycoprotein (GP)Ibalpha and GPVI on the surface and failed to present active integrin alphaIIbbeta3 and P-selectin on the plasma membrane in response to exogenous stimuli. Platelet hypo-responsiveness positively correlated with the Horowitz index (PaO2/FiO2 ratio), a measure of lung function, and with the D-dimer concentration, a surrogate marker of ongoing thrombosis. Exposure of platelets from healthy volunteers to acute hypoxic conditions (1% O2) recapitulated this phenotype in vitro. Despite the low adhesiveness, platelets of ICU patients bound avidly to innate immune cells. Interactions with monocytes and NK cells increased with severity, even though these leukocytes subpopulations were reduced in the circulation of ICU patients. Platelet-T cell aggregates were doubled in non-ICU patients compared to controls but were not detectable among the ICU patients. Conclusion(s): In summary, platelets from COVID-19 patients who have reduced lung function present features of metabolic and functional exhaustion and bind primarily innate but not adaptive immune cells, thus promoting the dysregulated immune response that drives COVID19 severity.
ABSTRACT
Background : COVID-19 imposes a high burden of morbidity and mortality worldwide;since the beginning of this pandemic, several sex-related differences have been described in the pathogenesis and clinical course of the disease. Although the identification of biomarkers to stratify the severity of the disease is recognized as pivotal to identify patients with a higher risk of clinical deterioration, few studies investigated sex-related differences in the performance of these biomarkers. Aims : To evaluate sex differences in the serum concentrations of biomarkers of platelet activation and vascular inflammation in patients with COVID-19. Methods : We performed a retrospective, preliminary analysis of a single center study which is recruiting patients with COVID-19 at different stages of severity. Vascular inflammation and platelet activation markers were measured in batch in serum samples collected from the venous circulation by multiplex bead-based flow cytometry assay. Results : Among 74 COVID-19 patients (median age: 69 years;65% males;55% with clinically-diagnosed severe disease), data on individual biomarkers were available for 69 individuals (36% females). No significant differences were observed for age between males and females. Compared to SARS-Cov2-negative subjects, the serum concentration of soluble CD40L (sCD40L), Plasminogen Activator Inhibitor 1, Matrix Metalloproteinase-9, Myeloid-Related Protein 8/14, Myeloperoxidase, Osteopontin in SARS-Cov2-positive subjects increased significantly in relation to disease severity. Among these, men, compared to women, showed higher levels of sCD40L, an X-linked marker of platelet activation, (Median: 17892 pg/ml [Interquartile Range, IQR: 11197-34520] vs. 11225 pg/ml [IQR: 5625-22644], P = 0.019) and osteopontin, a sialoprotein implicated in estrogen-stimulated endothelial repair (Median: 151184 pg/ml [IQR: 82739-200141] vs. 74219 pg/ml [31602-144440], P = 0.011). Conclusions : In this preliminary analysis, we found that potentially relevant sex-based differences may exists in the levels of thromboinflammatory biomarkers which are currently investigated for the prognostic stratification of COVID-19 patients. Pre-specified analysis disaggregated by sex are needed to take into account differences in the performance of these biomarkers.