SARS-CoV-2 Lysate Stimulation Impairs the Release of Platelet-like Particles and Megakaryopoiesis in the MEG-01 Cell Line.

SARS-CoV-2 infection causes a considerable inflammatory response coupled with impaired platelet reactivity, which can lead to platelet disorders recognized as negative prognostic factors in COVID-19 patients. The virus may cause thrombocytopenia or thrombocytosis during the different disease stages by destroying or activating platelets and influencing platelet production. While it is known that several viruses can impair megakaryopoiesis by generating an improper production and activation of platelets, the potential involvement of SARS-CoV-2 in affecting megakaryopoiesis is poorly understood. To this purpose, we explored, in vitro, the impact of SARS-CoV-2 stimulation in the MEG-01 cell line, a human megakaryoblastic leukemia cell line, considering its spontaneous capacity of releasing platelet-like particles (PLPs). We interrogated the effect of heat-inactivated SARS-CoV-2 lysate in the release of PLPs and activation from MEG-01, the signaling pathway influenced by SARS-CoV-2, and the functional effect on macrophagic skewing. The results highlight the potential influence of SARS-CoV-2 in the early stages of megakaryopoiesis by enhancing the production and activation of platelets, very likely due to the impairment of STATs signaling and AMPK activity. Overall, these findings provide new insight into the role of SARS-CoV-2 in affecting megakaryocyte-platelet compartment, possibly unlocking another avenue by which SARS-CoV-2 moves.

What can the plasma proteome tell us about platelets and (vice versa)?

Multi-omics approaches are being used increasingly to study physiological and pathophysiologic processes. Proteomics specifically focuses on the study of proteins as functional elements and key contributors to, and markers of the phenotype, as well as targets for diagnostic and therapeutic approaches. Depending on the condition, the plasma proteome can mirror the platelet proteome, and hence play an important role in elucidating both physiologic and pathologic processes. In fact, both plasma and platelet protein signatures have been shown to be important in the setting of thrombosis-prone disease states such as atherosclerosis and cancer. Plasma and platelet proteomes are increasingly being studied as a part of a single entity, as is the case with patient-centric sample collection approaches such as capillary blood. Future studies should cut across the plasma and platelet proteome silos, taking advantage of the vast knowledge available when they are considered as part of the same studies, rather than studied as distinct entities.

Platelets are key cellular elements of blood with plasma constituting the liquid component. Both platelets and proteins found in plasma rapidly work in unity to prevent/limit blood loss in response to blood vessel damage. Proteomics is the analysis of the entire protein complement of a cell, tissue, or organism under a specific, defined set of conditions. Of note, research to date has shown that platelet and plasma proteomes share many common proteins. In some disease scenarios, plasma proteomes can be used to identify platelet function or dysfunction, while in other scenarios, platelet-specific proteins are needed for physiological assessment. Thus, it may be beneficial to simultaneously study the plasma and platelet proteomes, thereby exploiting the considerable wealth of information provided under such circumstances.

Review on the Biogenesis of Platelets in Lungs and Its Alterations in SARS-CoV-2 Infection Patients.

Thrombocytes (platelets) are the type of blood cells that are involved in hemostasis, thrombosis, etc. For the conversion of megakaryocytes into thrombocytes, the thrombopoietin (TPO) protein is essential which is encoded by the TPO gene. TPO gene is present in the long arm of chromosome number 3 (3q26). This TPO protein interacts with the c-Mpl receptor, which is present on the outer surface of megakaryocytes. As a result, megakaryocyte breaks into the production of functional thrombocytes. Some of the evidence shows that the megakaryocytes, the precursor of thrombocytes, are seen in the lung's interstitium. This review focuses on the involvement of the lungs in the production of thrombocytes and their mechanism. A lot of findings show that viral diseases, which affect the lungs, cause thrombocytopenia in human beings. One of the notable viral diseases is COVID-19 or severe acute respiratory syndrome caused by SARS-associated coronavirus 2 (SARS-CoV-2). SARS-CoV-2 caused a worldwide alarm in 2019 and a lot of people suffered because of this disease. It mainly targets the lung cells for its replication. To enter the cells, these virus targets the angiotensin-converting enzyme-2 (ACE-2) receptors that are abundantly seen on the surface of the lung cells. Recent reports of COVID-19-affected patients reveal the important fact that these peoples develop thrombocytopenia as a post-COVID condition. This review elaborates on the biogenesis of platelets in the lungs and the alterations of thrombocytes during the COVID-19 infection.

Increased platelet activation and lower platelet-monocyte aggregates in COVID-19 patients with severe pneumonia.

BACKGROUND: The increased procoagulant platelets and platelet activation are associated with thrombosis in COVID-19. In this study, we investigated platelet activation in COVID-19 patients and their association with other disease markers. METHODS: COVID-19 patients were classified into three severity groups: no pneumonia, mild-to-moderate pneumonia, and severe pneumonia. The expression of P-selectin and activated glycoprotein (aGP) IIb/IIIa on the platelet surface and platelet-leukocyte aggregates were measured prospectively on admission days 1, 7, and 10 by flow cytometry. RESULTS: P-selectin expression, platelet-neutrophil, platelet-lymphocyte, and platelet-monocyte aggregates were higher in COVID-19 patients than in uninfected control individuals. In contrast, aGPIIb/IIIa expression was not different between patients and controls. Severe pneumonia patients had lower platelet-monocyte aggregates than patients without pneumonia and patients with mild-to-moderate pneumonia. Platelet-neutrophil and platelet-lymphocyte aggregates were not different among groups. There was no change in platelet-leukocyte aggregates and P-selectin expression on days 1, 7, and 10. aGPIIb/IIIa expression was not different among patient groups. Still, adenosine diphosphate (ADP)-induced aGPIIb/IIIa expression was lower in severe pneumonia than in patients without and with mild-to-moderate pneumonia. Platelet-monocyte aggregates exhibited a weak positive correlation with lymphocyte count and weak negative correlations with interleukin-6, D-dimer, lactate dehydrogenase, and nitrite. CONCLUSION: COVID-19 patients have higher platelet-leukocyte aggregates and P-selectin expression than controls, indicating increased platelet activation. Compared within patient groups, platelet-monocyte aggregates were lower in severe pneumonia patients.

Effect of Defecation Delay in Patients After Tricuspid Valve Replacement: A Retrospective Study.

BACKGROUND: Defecation delay is a common symptom in patients after tricuspid valve replacement (TVR). Previous studies have demonstrated that defecation delay was associated with worse clinical outcomes of critically ill patients. Our study aimed to investigate the incidence and risk factors of defecation delay in patients after TVR and its adverse clinical outcomes. METHODS: A retrospective study was conducted in 206 patients undergoing TVR under cardiopulmonary bypass from May 2005 to July 2021. According to the first postoperative defecation time after surgery, patients were divided into the delayed group (>3 days) and control group (≤3 days). Baseline characteristics and preoperative, intraoperative, and postoperative data were collected to investigate the clinical outcomes of defecation delay. RESULTS: Among the 206 patients, 51.9% (107/206) cases were classified into the defecation delay group. Univariate analysis showed that age (P = 0.043), preoperative platelets (PLT) (P < 0.001), cardiopulmonary bypass (CPB) time (P = 0.013), minimum rectal temperature (P = 0.042), and the use of prokinetic drugs (P = 0.015) were significantly different in the two groups. In addition, the perioperative adverse events in the defecation delay group were significantly higher than that of the control group. Logistic regression analysis indicated that the mortality of patients was associated with postoperative renal dysfunction (P = 0.047) and postoperative respiratory failure (P = 0.004) but was not associated with defecation delay (P > 0.05). CONCLUSION: Patients with defecation delay after TVR were more likely to appear adverse events, however, defecation delay was not associated with mortality after TVR.

Meta-analysis of the characteristic expression of circulating microRNA in type 2 diabetes mellitus with acute ischemic cerebrovascular disease.

Objective: To comprehensively evaluate the characteristics of the circulating microRNA expression profile in type 2 diabetic patients with acute ischemic cerebrovascular disease by systematic evaluation and meta-analysis. Methods: The literatures up to March 2022 related to circulating microRNA and acute ischemic cerebrovascular disease in type 2 diabetes mellitus were searched and screened from multiple databases. The NOS quality assessment scale was used to evaluate methodological quality. Heterogeneity tests and statistical analyses of all data were performed by Stata 16.0. The differences in microRNA levels between groups were illustrated by the standardized mean difference (SMD) and 95% confidence interval (95% CI). Results: A total of 49 studies on 12 circulating miRNAs were included in this study, including 486 cases of type 2 diabetes complicated with acute ischemic cerebrovascular disease and 855 controls. Compared with the control group (T2DM group), miR-200a, miR-144, and miR-503 were upregulated and positively correlated with acute ischemic cerebrovascular disease in type 2 diabetes mellitus patients. Their comprehensive SMD and 95% CI were 2.71 (1.64~3.77), 5.77 (4.28~7.26) and 0.73 (0.27~1.19), respectively. MiR-126 was downregulated and negatively correlated with acute ischemic cerebrovascular disease in type 2 diabetes mellitus patients, its comprehensive SMD and 95% CI were -3.64 (-5.56~-1.72). Conclusion: In type 2 diabetes mellitus patients with acute ischemic cerebrovascular disease, the expression of serum miR-200a, miR-503, plasma and platelet miR-144 was upregulated and the expression of serum miR-126 was downregulated. It may have diagnostic value in the early identification of type 2 diabetes mellitus with acute ischemic cerebrovascular disease.

Immature platelets in COVID-19.

Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters including thrombocytopenia, and at the same time the proportion of immature platelets increases. In this study, the platelet count and the immature platelet fraction (IPF) of hospitalized patients with different oxygenation requirements was investigated daily over a course of 40 days. In addition, the platelet function of COVID-19 patients was analyzed. It was found that the number of platelets in patients with the most severe course (intubation and extracorporeal membrane oxygenation (ECMO)) was significantly lower (111.5 ∙ 106 /mL) than in the other groups (mild (no intubation, no ECMO): 203.5 ∙ 106 /mL, p < .0001, moderate (intubation, no ECMO): 208.0 ∙ 106 /mL, p < .0001). IPF tended to be elevated (10.9%). Platelet function was reduced. Differentiation by outcome revealed that the deceased patients had a highly significant lower platelet count and higher IPF (97.3 ∙ 106 /mL, p < .0001, 12.2%, p = .0003).

What is the context? Pathological coagulation is a feature of severe cases of COVID-19, with both bleeding complications and thrombosis. Patients with severe COVID-19 are frequently treated with extracorporeal membrane oxygenation (ECMO), which is often associated with bleeding complications. Platelets play an important role in blood clotting. The proportion of immature platelets has been characterized as hyperreactive and associated with high prothrombotic activity. In addition, they are discussed as predictors of COVID-19 disease severity.What is new? In grading the severity of disease in our patient cohort, we consider the required oxygenation measures. Thus, the focus is on severe cases requiring intubation and ECMO compared to moderate (intubation, no ECMO) and mild (no intubation, no ECMO) cases.What is the impact? This study focuses on severely ill patients who require ECMO treatment. Therefore, this study provides further evidence to use immature platelet fraction to predict the outcome of severe COVID-19 courses.

The association between systemic immune-inflammation index and rheumatoid arthritis: evidence from NHANES 1999-2018.

PURPOSE: We aimed to explore the relationship between the systemic immune-inflammation index (SII) and rheumatoid arthritis (RA) using NHANES from 1999 to 2018. METHODS: We collected data from the NHANES database from 1999 to 2018. The SII is calculated from the counts of lymphocytes (LC), neutrophils (NC), and platelets (PC). The RA patients were derived from questionnaire data. We used weighted multivariate regression analysis and subgroup analysis to explore the relationship between SII and RA. Furthermore, the restricted cubic splines were used to explore the non-linear relationships. RESULT: Our study included a total of 37,604 patients, of which 2642 (7.03%) had rheumatoid arthritis. After adjusting for all covariates, the multivariate logistic regression analysis showed that high SII (In-transform) levels were associated with an increased likelihood of rheumatoid arthritis (OR=1.167, 95% CI=1.025-1.328, P=0.020). The interaction test revealed no significant effect on this connection. In the restricted cubic spline regression model, the relationship between ln-SII and RA was non-linear. The cutoff value of SII for RA was 578.25. The risk of rheumatoid arthritis increases rapidly when SII exceeds the cutoff value. CONCLUSION: In general, there is a positive correlation between SII and rheumatoid arthritis. Our study shows that SII is a novel, valuable, and convenient inflammatory marker that can be used to predict the risk of rheumatoid arthritis in US adults.

Combinatorial Blood Platelets-Derived circRNA and mRNA Signature for Early-Stage Lung Cancer Detection.

Despite the diversity of liquid biopsy transcriptomic repertoire, numerous studies often exploit only a single RNA type signature for diagnostic biomarker potential. This frequently results in insufficient sensitivity and specificity necessary to reach diagnostic utility. Combinatorial biomarker approaches may offer a more reliable diagnosis. Here, we investigated the synergistic contributions of circRNA and mRNA signatures derived from blood platelets as biomarkers for lung cancer detection. We developed a comprehensive bioinformatics pipeline permitting an analysis of platelet-circRNA and mRNA derived from non-cancer individuals and lung cancer patients. An optimal selected signature is then used to generate the predictive classification model using machine learning algorithm. Using an individual signature of 21 circRNA and 28 mRNA, the predictive models reached an area under the curve (AUC) of 0.88 and 0.81, respectively. Importantly, combinatorial analysis including both types of RNAs resulted in an 8-target signature (6 mRNA and 2 circRNA), enhancing the differentiation of lung cancer from controls (AUC of 0.92). Additionally, we identified five biomarkers potentially specific for early-stage detection of lung cancer. Our proof-of-concept study presents the first multi-analyte-based approach for the analysis of platelets-derived biomarkers, providing a potential combinatorial diagnostic signature for lung cancer detection.

Correlation between neutrophil/lymphocyte ratio, platelet/lymphocyte ratio and postoperative cognitive dysfunction in elderly patients with esophageal cancer.

The present study intends to investigate the correlation between neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and postoperative cognitive dysfunction (POCD) in elderly patients with esophageal cancer. Elderly patients >65 years old with esophageal cancer in our department from October 2017 to June 2021 were included in the study. The cognitive function of the patients was assessed by the mini-mental state examination (MMSE) Scale at 1day, 3 days, and 7days after surgery. POCD was considered when the scores were <27 points, and the remaining patients were included in the control group. A total of 104 elderly patients with esophageal cancer were included in this study, and 24 patients developed POCD, with an incidence of 23.1%. The expression of NLR and PLR in both 2 groups was increased on the 1st postoperative day compared with that before surgery. There was no significant difference in the expression of NLR and PLR between the 2 groups before operation, but the expression of both in the POCD group was significantly higher than that in the control group after operation (P < .05). Logistic regression analysis showed that smoking, postoperative NLR and postoperative PLR were independent risk factors for POCD. Spearman test showed that NLR was negatively correlated with MMSE scores at postoperative 1 day and 3 days (P < .05), while PLR was negatively correlated with MMSE scores at postoperative 1 day, 3 days and 7 days (P < .05). The Area Under receiver operating characteristic curve (AUC) of postoperative NLR for predicting POCD in elderly patients with esophageal cancer was 0.656, and the AUC of postoperative PLR was 0.722. After combination of NLR and PLR, the AUC increased to 0.803 with the sensitivity of 66.7% and specificity of 82.5%. The expression level of postoperative NLR and PLR in elderly patients with esophageal cancer combined with POCD is significantly increased, which is associated with postoperative cognitive impairment. Moreover, the combination of NLR and PLR has a good predictive ability for POCD, which could be used as a potential biomarker for early diagnosis of POCD.

Designing a Resilient-Sustainable Supply Chain Network of Age-Differentiated Blood Platelets Using Vertical-Horizontal Transshipment and Grey Wolf Optimizer.

Blood platelets are a typical instance of perishable age-differentiated products with a shelf life of five days (on average), which may lead to significant wastage of some collected samples. At the same time, a shortage of platelets may also be observed because of emergency demands and the limited number of donors, especially during disasters such as wars and the COVID-19 pandemic. Therefore, developing an efficient blood platelet supply chain management model is highly necessary to reduce shortage and wastage. In this research, an integrated resilient-sustainable supply chain network of perishable age-differentiated platelets considering vertical and horizontal transshipment is designed. In order to achieve sustainability, economic cost, social cost (shortage), and environmental cost (wastage) are taken into account. A reactive resilient strategy utilizing lateral transshipment between hospitals is adopted to make the blood platelet supply chain powerful against shortage and disruption risks. The presented model is solved using a metaheuristic based on a local search-empowered grey wolf optimizer. The obtained results demonstrate the efficiency of the proposed vertical-horizontal transshipment model in reducing total economic cost, shortage, and wastage by 3.61%, 30.1%, and 18.8%, respectively.

Novel Biomarkers for Diagnosis and Monitoring of Immune Thrombocytopenia.

Lower-than-normal platelet counts are a hallmark of the acquired autoimmune illness known as immune thrombocytopenia, which can affect both adults and children. Immune thrombocytopenia patients' care has evolved significantly in recent years, but the disease's diagnosis has not, and it is still only clinically achievable with the elimination of other causes of thrombocytopenia. The lack of a valid biomarker or gold-standard diagnostic test, despite ongoing efforts to find one, adds to the high rate of disease misdiagnosis. However, in recent years, several studies have helped to elucidate a number of features of the disease's etiology, highlighting how the platelet loss is not only caused by an increase in peripheral platelet destruction but also involves a number of humoral and cellular immune system effectors. This made it possible to identify the role of immune-activating substances such cytokines and chemokines, complement, non-coding genetic material, the microbiome, and gene mutations. Furthermore, platelet and megakaryocyte immaturity indices have been emphasized as new disease markers, and prognostic signs and responses to particular types of therapy have been suggested. Our review's goal was to compile information from the literature on novel immune thrombocytopenia biomarkers, markers that will help us improve the management of these patients.

Platelets, Protean Cells with All-Around Functions and Multifaceted Pharmacological Applications.

Platelets, traditionally known for their roles in hemostasis and coagulation, are the most prevalent blood component after erythrocytes (150,000-400,000 platelets/µL in healthy humans). However, only 10,000 platelets/µL are needed for vessel wall repair and wound healing. Increased knowledge of the platelet's role in hemostasis has led to many advances in understanding that they are crucial mediators in many other physiological processes, such as innate and adaptive immunity. Due to their multiple functions, platelet dysfunction is involved not only in thrombosis, mediating myocardial infarction, stroke, and venous thromboembolism, but also in several other disorders, such as tumors, autoimmune diseases, and neurodegenerative diseases. On the other hand, thanks to their multiple functions, nowadays platelets are therapeutic targets in different pathologies, in addition to atherothrombotic diseases; they can be used as an innovative drug delivery system, and their derivatives, such as platelet lysates and platelet extracellular vesicles (pEVs), can be useful in regenerative medicine and many other fields. The protean role of platelets, from the name of Proteus, a Greek mythological divinity who could take on different shapes or aspects, is precisely the focus of this review.

Calculated inflammatory markers derived from complete blood count results, along with routine laboratory and clinical data, predict treatment failure of acute peritonitis in chronic peritoneal dialysis patients.

BACKGROUND & AIMS: Complete blood count (CBC)-derived inflammatory markers are predictive biomarkers for the prognosis of many diseases. However, there was no study on patients with peritoneal dialysis-associated peritonitis (PDAP). We aimed to investigate the value of these markers in predicting treatment failure of acute peritonitis in chronic PD patients. METHODS: The records of 138 peritonitis episodes were reviewed and divided into treatment success or failure groups in a single center for 10 years. CBC-derived markers and other routine data were recorded before peritonitis treatment was initiated. Univariate and multivariate regression analyses and the receiver operating characteristic (ROC) curve about the predictors of treatment outcomes were performed. RESULTS: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and derived NLR were significantly higher in the failure group. Univariate logistic regression results showed that NLR and PLR were risk factors of treatment outcomes. The backward stepwise multivariate logistic regression results demonstrated that NLR [adjusted odds ratio (aOR), 1.376; 95% confidence intervals (CI), 1.105-1.713; p = .004], PLR (aOR, 1.010; 95%CI, 1.004-1.017; p = .002) were risk factors, but hemoglobin-to-lymphocyte ratio (HLR) (aOR, 0.977; 95%CI, 0.963-0.991; p = .001), and SII (aOR, 0.999; 95%CI, 0.998-1.000; p = .040) were protective factors. A combination of age, PD vintage, Gram-positive peritonitis, staphylococcus aureus, culture-negative, NLR, PLR, HLR, and SII would improve prognostic performance. The area under this ROC curve was 0.85, higher than other factors. CONCLUSIONS: NLR, PLR, HLR, and SII were associated with PDAP outcomes. Age, PD vintage, NLR, and PLR were significant risk factors in PDAP patients.

Antimicrobial 405 nm violet-blue light treatment of ex vivo human platelets leads to mitochondrial metabolic reprogramming and potential alteration of Phospho-proteome.

Continued efforts to reduce the risk of transfusion-transmitted infections (TTIs) through blood and blood components led to the development of ultraviolet (UV) light irradiation technologies known as pathogen reduction technologies (PRT) to enhance blood safety. While these PRTs demonstrate germicidal efficiency, it is generally accepted that these photoinactivation techniques have limitations as they employ treatment conditions shown to compromise the quality of the blood components. During ex vivo storage, platelets having mitochondria for energy production suffer most from the consequences of UV irradiation. Recently, application of visible violet-blue light in the 400-470 nm wavelength range has been identified as a relatively more compatible alternative to UV light. Hence, in this report, we evaluated 405 nm light-treated platelets to assess alterations in energy utilization by measuring different mitochondrial bioenergetic parameters, glycolytic flux, and reactive oxygen species (ROS). Furthermore, we employed untargeted data-independent acquisition mass spectrometry to characterize platelet proteomic differences in protein regulation after the light treatment. Overall, our analyses demonstrate that ex vivo treatment of human platelets with antimicrobial 405 nm violet-blue light leads to mitochondrial metabolic reprogramming to survive the treatment, and alters a fraction of platelet proteome.

What can we learn from the platelet lipidome?

Besides their proteome, platelets use, in all responses to the environmental cues, a huge and diverse family of hydrophobic and amphipathic small molecules involved in structural, metabolic and signaling functions; the lipids. Studying how platelet lipidome changes modulate platelet function is an old story constantly renewed through the impressive technical advances allowing the discovery of new lipids, functions and metabolic pathways. Technical progress in analytical lipidomic profiling by top-of-the-line approaches such as nuclear magnetic resonance and gas chromatography or liquid chromatography coupled to mass spectrometry enables either large-scale analysis of lipids or targeted lipidomics. With the support of bioinformatics tools and databases, it is now possible to investigate thousands of lipids over a concentration range of several orders of magnitude. The lipidomic landscape of platelets is considered a treasure trove, not only able to expand our knowledge of platelet biology and pathologies but also to bring diagnostic and therapeutic opportunities. The aim of this commentary article is to summarize the advances in the field and to highlight what lipidomics can tell us about platelet biology and pathophysiology.

What is the context? Lipids are a huge and diverse family of molecules strongly involved in biological membranes organization and dynamics, signal transduction, cell metabolism and intercellular communication.Earlier seminal works using conventional lipid biochemistry methods have shown the essential role of certain classes of lipids in platelet biology and platelet-related pathologiesWhat is new? The important development of modern lipidomic analyses using mass-spectrometry now provides opportunities to investigate the entire platelet lipidome in different conditions.The application of lipidomic approaches to analyze large-scale lipid species allows platelet clinical lipidomics development.What is the impact? Study of the lipidomic landscape of platelets will expand our knowledge of platelet biology and should bring new diagnosis and therapeutic opportunities.Evaluating the functional and clinical significance of the data generated by modern platelet lipidomics appears as a vast and exciting challenge.

[Research Progress of High-intensity Interval Training in Cardiac Rehabilitation of Patients with Acute Coronary Syndrome].

Acute coronary syndrome (ACS),with increasing mortality year by year,has become a major public health problem in China.Exercise rehabilitation as an important part of the out-of-hospital rehabilitation for the patients with heart diseases can further reduce the mortality of patients on the basis of drug treatment.The available studies have proved that high-intensity interval training (HIIT) is more effective and efficient than moderate-intensity continuous training (MICT) such as walking and jogging on chronic cardiovascular diseases such as heart failure,stable coronary heart disease,and hypertension and has high security.According to the latest research,HIIT can reduce the platelet response,mitigate myocardial ischemia-reperfusion injury,and increase the exercise compliance of ACS patients more significantly than MICT.Moreover,it does not increase the risk of thrombotic adverse events or malignant arrhythmia.Therefore,HIIT is expected to become an important part of exercise prescription in out-of-hospital cardiac rehabilitation strategy for the patients with ACS.

An agent-based approach for modelling and simulation of glycoprotein VI receptor diffusion, localisation and dimerisation in platelet lipid rafts.

Receptor diffusion plays an essential role in cellular signalling via the plasma membrane microenvironment and receptor interactions, but the regulation is not well understood. To aid in understanding of the key determinants of receptor diffusion and signalling, we developed agent-based models (ABMs) to explore the extent of dimerisation of the platelet- and megakaryocyte-specific receptor for collagen glycoprotein VI (GPVI). This approach assessed the importance of glycolipid enriched raft-like domains within the plasma membrane that lower receptor diffusivity. Our model simulations demonstrated that GPVI dimers preferentially concentrate in confined domains and, if diffusivity within domains is decreased relative to outside of domains, dimerisation rates are increased. While an increased amount of confined domains resulted in further dimerisation, merging of domains, which may occur upon membrane rearrangements, was without effect. Modelling of the proportion of the cell membrane which constitutes lipid rafts indicated that dimerisation levels could not be explained by these alone. Crowding of receptors by other membrane proteins was also an important determinant of GPVI dimerisation. Together, these results demonstrate the value of ABM approaches in exploring the interactions on a cell surface, guiding the experimentation for new therapeutic avenues.

Vitronectin promotes immunothrombotic dysregulation in the venular microvasculature.

Microvascular immunothrombotic dysregulation is a critical process in the pathogenesis of severe systemic inflammatory diseases. The mechanisms controlling immunothrombosis in inflamed microvessels, however, remain poorly understood. Here, we report that under systemic inflammatory conditions the matricellular glycoproteinvitronectin (VN) establishes an intravascular scaffold, supporting interactions of aggregating platelets with immune cells and the venular endothelium. Blockade of the VN receptor glycoprotein (GP)IIb/IIIa interfered with this multicellular interplay and effectively prevented microvascular clot formation. In line with these experimental data, particularly VN was found to be enriched in the pulmonary microvasculature of patients with non-infectious (pancreatitis-associated) or infectious (coronavirus disease 2019 (COVID-19)-associated) severe systemic inflammatory responses. Targeting the VN-GPIIb/IIIa axis hence appears as a promising, already feasible strategy to counteract microvascular immunothrombotic dysregulation in systemic inflammatory pathologies.