Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 million deaths, it has become evident that COVID-19 is not solely a pulmonary disease. Emerging evidence has shown that, in a subset of patients, certain symptoms - including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain - all indicate a role of vascular, neurological and gastrointestinal (GI) pathology in the disease process. Many of these disease processes persist long after the acute disease has been resolved, resulting in 'long COVID' or post-acute sequelae of COVID-19 (PASC). The molecular mechanisms underlying the acute and systemic conditions associated with COVID-19 remain incompletely defined. Appropriate animal models provide a method of understanding underlying disease mechanisms at the system level through the study of disease progression, tissue pathology, immune system response to the pathogen and behavioral responses. However, very few studies have addressed PASC and whether existing models hold promise for studying this challenging problem. Here, we review the current literature on cardiovascular, neurological and GI pathobiology caused by COVID-19 in patients, along with established animal models of the acute disease manifestations and their prospects for use in PASC studies. Our aim is to provide guidance for the selection of appropriate models in order to recapitulate certain aspects of the disease to enhance the translatability of mechanistic studies.

The novel coronavirus, COVID-19, which was first identified in December 2019 rapidly spread worldwide and was declared a global pandemic. Beyond respiratory symptoms, COVID-19 often results in coagulation and vascular endothelium disorders, causing increased clotting and bleeding, which are closely linked to the acute phase of the infection. Factor VIII is a crucial protein in the blood coagulation cascade, and elevated FVIII levels have been linked to thrombotic events in COVID-19, highlighting the need to understand its behavior during treatment. Remdesivir is an antiviral drug that has shown promise in reducing recovery time and mortality rates in COVID-19 patients. This study aims to examine the changes in blood factors and the expression of the factor VIII gene in patients treated with Remdesivir. Blood samples were collected from 30 COVID-19 patients before and after Remdesivir treatment and from 20 healthy individuals. Patients with underlying diseases were excluded from the study. RNA was extracted from these samples, followed by cDNA synthesis. The expression of the factor VIII gene was analyzed using Real-Time PCR. The results indicated that blood factors such as Urea, ALK, AST, WBC, and CRP were elevated in the patient group compared to the control group. At the same time, FBS, Urea, ALK, AST, WBC, RDW, INR, and K levels increased in the Remdesivir treatment group (P < 0.001). Conversely, MCHC, RBC, and Ca levels decreased in both patient and treatment groups compared to the control group (P < 0.001). The expression of the FVIII gene was upregulated approaching 2 times in COVID-19 patients and 1.5-fold in the treatment group compared to the control group (P < 0.001). However, no significant changes were observed in FVIII expression before and after Remdesivir treatment. However, a positive correlation between RBC, FBS, and Urea in the patient group and a negative correlation between RDW and FVIII expression levels was observed. In the treatment group, FVIII expression level correlated negatively with Urea, P, and RDW. These findings suggest that elevated FVIII levels are associated with disease severity and excessive coagulation in COVID-19 patients. Additionally, Remdesivir does not appear to exacerbate the coagulation process.

This study investigated the incidence of new retinal artery occlusion (RAO) and retinal vein occlusion (RVO) during the coronavirus disease-19 (COVID-19) pandemic compared to pre-outbreak periods in South Korea.

Nationwide population-based retrospective cohort study.

Individuals diagnosed with RAO or RVO.

We evaluated data from 326 154 patients diagnosed with RAO (n = 32 028), RVO (n = 304 405), or both (n = 10 279) from January 1, 2017 to December 31, 2022. We calculated the incidence rate ratios (IRR) of RAO and RVO using 2019 as the reference year, making comparisons across the total population and within age and sex subgroups. We examined correlations between the number of new RVO patients and COVID-19 infected or vaccinated persons. Additionally, we compared the systemic characteristics of individuals with RAO and RVO, adjusting for multiple comparisons with Bonferroni correction.

Annual IRRs of RAO and RVO.

The IRR for RAO showed no significant increase across all age and sex subgroups. Contrastingly, RVO exhibited a consistent IRR in 2020; however, significant increases were observed in 2021 and 2022 among those aged 20-39 years (adjusted IRR in 2021, 1.22, 95% CI, 1.15-1.29; adjusted IRR in 2022, 1.12, 95% CI, 1.06-1.18) as well as those aged 40-64 years (adjusted IRR in 2021, 1.11; 95% CI, 1.09-1.13; adjusted IRR in 2022, 1.11, 95% CI, 1.08-1.12). No correlations were found between the monthly number of patients with RVO and the number of individuals infected with or vaccinated against COVID-19. Additionally, a higher proportion of patients with RVO having hypertension, diabetes, dyslipidemia, and chronic liver disease were seen in 2021 and 2022, as analyzed by ANOVA with Bonferroni correction.

The incidence of RAO did not increase during the COVID-19 outbreak. However, the incidence of RVO increased during the pandemic, especially in 2021 and 2022, with the highest rates observed in the 40-64 years age group, likely linked to increases in metabolic diseases rather than COVID-19 infection and vaccination. Further research is warranted to confirm these findings.

COVID-19 is currently one of the most important medical challenges as it affects the entire population, with children and adolescents being infected as easily as adults.

The objective of this study was to evaluate the prevalence of mortality in children and adolescents aged <19 years, compared to that of adults.

This retrospective, observational study analyzed the medical records of all patients diagnosed with COVID-19 by real-time reverse transcription-quantitative polymerase chain reaction who were hospitalized at Hospital de Base and the Infant and Maternal Hospital of São José do Rio Preto, São Paulo, Brazil. Out of a total of 8986 hospitalized patients who were COVID-19 positive, 383 (4.26%) were children and adolescents aged <19 years (group 1), and 8603 (95.74%) were adults (group 2).

Overall, mortality was significantly higher (P<.001) in group 2 (2185/8603, 25.4%) compared to group 1 (12/383, 3.1%). A total of 11 (92%) of the 12 patients in group 1 that died had associated diseases. The mortality rates by age group were as follows: infants aged <1 year, 1.6% (2/123); children aged 1-4 years, 4% (4/95); children aged 5-9 years, 2% (1/47); adolescents aged 10-14 years, 2% (1/40); and adolescents aged 15-19 years, 5% (4/78).

Mortality from COVID-19 in children and adolescents was significantly lower than that in adults and was associated with other comorbidities.

The coronavirus disease 2019 (COVID-19) global health crisis, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented unprecedented challenges to global healthcare systems, leading to rapid advances in treatment development. This review comprehensively examines the current therapeutic approaches for managing COVID-19, including direct-acting antivirals, immunomodulators, anticoagulants, and adjuvant therapies, as well as emerging and experimental approaches. Direct-acting antivirals target various stages of the viral life cycle, offering specific intervention points, while immunomodulators aim to modulate the host's immune response, reducing disease severity. Anticoagulant therapies address the coagulopathy frequently observed in severe cases, and adjuvant treatments provide supportive care to improve overall outcomes. We also explore the challenges and limitations of implementing these treatments, such as drug resistance, variable patient responses, and access to therapies, especially in resource-limited settings. The review also discusses future perspectives, including the potential of next-generation vaccines, personalized medicine, and global collaboration in shaping future COVID-19 treatment paradigms. Continuous innovation, combined with an integrated and adaptable approach, will be crucial to effectively managing COVID-19 and mitigating the impact of future pandemics.

Coronavirus disease 2019 (COVID-19) is often associated with thrombosis. Elevated levels of soluble C-type lectin-like receptor 2 (sCLEC-2), a biomarker for platelet activation, have been reported in COVID-19. Therefore, we examined the behavior of sCLEC-2 levels and their relationship with thrombosis.The clinical course of inflammatory and thrombotic biomarkers was assessed in 271 patients with COVID-19.Inflammatory biomarkers such as C-reactive protein, procalcitonin, and presepsin levels were significantly increased in patients with COVID-19, and these behaviors differed among the clinical course or stages. The plasma D-dimer levels increased slightly and gradually. Platelet counts were within the normal range, and plasma sCLEC-2 levels were markedly increased in most patients with COVID-19. There were 17 patients with thrombosis in this study. Although there was no significant difference in various biomarkers between COVID-19 patients with and without thrombosis, the super formula of sCLEC-2xD-dimer/platelet count in patients with thrombosis was significantly higher than in those without thrombosis. Furthermore, this super formula was significantly higher in COVID-19 patients with severe or critical illness than in those with mild or moderate illness.Elevation of the super formula of sCLEC-2xD-dimer/platelet count was associated with the thrombosis in patients with COVID-19 suggesting the thrombosis in COVID-19 may be caused by the development of microthrombosis.

Acute pulmonary embolism (PE) is frequently diagnosed in the Emergency Department (ED), and the management approach can be nuanced.

In this narrative review, we synthesize the literature in selected areas of ongoing controversy regarding the diagnostic and management approaches for acute PE in the ED, and provide evidence-based recommendations to empower emergency physicians (EPs) to provide optimal care in these situations.

d-Dimer is used to clinically exclude the diagnosis of PE patients who are stratified as low risk. However by utilizing likelihood ratio and with certain scoring tools, patient historically considered moderate or high risk for PE may safely be able to have the diagnosis excluded with a negative d-dimer. Traditional risk stratification and management strategies can be cautiously applied to patients with concomitant Coronavirus-19 infection while awaiting more definitive studies. There is an increasing trend in the diagnosis of isolated subsegmental PE, and many patients receiving this diagnosis may be treated without anticoagulation provided that they have no evidence of associated deep vein thrombosis (DVT) and can be closely followed as an outpatient. There is a persistent hesitancy to discharge patients with newly diagnosed acute PE, and existing well-supported risk stratification tools and clinical decision frameworks can support the EP's decision to safely discharge low-risk patients.

tThis review of the literature empowers emergency clinicians to manage challenging PE cases in the ED.

Atrial fibrillation (AF) is associated with a high burden of cardiovascular disease, which has been worsened during the coronavirus disease 2019 (COVID-19) pandemic. The purpose of this study was to assess the association between clinical markers, especially interleukin-6 (IL-6) and other inflammatory biomarkers, and the severity of COVID-19 in patients with AF.

This retrospective cohort study categorized patients based on clinical presentations and laboratory results to investigate the prognostic significance of inflammatory markers in COVID-19 outcomes among those with AF. The study included 100 hospitalized COVID-19 patients aged between 40 to 80 years and was conducted at the Chapidze Hospital in Tbilisi, Georgia. Patients were then grouped by disease severity according to computed tomography (CT) scores, clinical symptoms, respiratory rate and oxygen saturation. Levels of IL-6 were obtained at three time points during hospitalization. A broad range of laboratory tests, including C-reactive protein (CRP), ferritin, and D-dimer, were also conducted.

Patients with AF demonstrated significantly elevated levels of IL-6 (P = 0.024), CRP (P = 0.001), and ferritin (P < 0.001), suggesting a severe inflammatory response. D-dimer levels were also notably higher in the AF group (P < 0.005), indicating an increased risk of thrombotic complications. Oxygen saturation levels were significantly lower (P = 0.004) and CT scores higher in patients with AF. Furthermore, the length of hospitalization was longer among patients with AF (median duration significantly higher, P = 0.032), indicating a more severe disease course.

The proinflammatory markers such as IL-6 are independent predictive markers of COVID-19 severity in AF patients. Overall, it highlights urgent treatment approaches, such as available anti-inflammatory drugs, for COVID-19 patients with arrhythmias. Combining these biomarkers into clinical routines helps us better identify patients at risk and how to treat them.

COVID-19-related critical and acute illness is associated with an increased risk of venous thromboembolism (VTE). These evidence-based recommendations of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about using anticoagulation for thromboprophylaxis for patients with COVID-19-related critical illness; patients with COVID-19-related acute illness; and those being discharged from the hospital, who do not have suspected or confirmed VTE.

ASH formed a multidisciplinary panel, including patient representatives. The Michael G. DeGroote Cochrane Canada and MacGRADE Centres at McMaster University supported guideline development, including performing systematic reviews (up to June 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess certainty in the evidence and make recommendations.

This is an executive summary of 3 updated recommendations that have been published, which concludes the living phase of the guidelines. For patients with COVID-19-related critical illness, the panel issued conditional recommendations suggesting (a) prophylactic-intensity over therapeutic-intensity anticoagulation and (b) prophylactic-intensity over intermediate-intensity anticoagulation. For patients with COVID-19-related acute illness, conditional recommendations were suggested (a) prophylactic-intensity over intermediate-intensity anticoagulation, and (b) therapeutic-intensity over prophylactic-intensity anticoagulation. The panel issued a conditional recommendation suggesting against the use of postdischarge anticoagulant thromboprophylaxis.

These conditional recommendations were made based on low or very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials for patients with COVID-19.

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.

Introduction: Severely ill COVID-19 patients receiving prophylactic-dose anticoagulation exhibit high rates of thrombosis and mortality. The escalation of anticoagulation also does not reduce mortality and has an uncertain impact on thrombosis rates. The reasons why escalated doses fail to outperform prophylactic doses in reducing risks of thrombosis and death in severely ill COVID-19 patients remain unclear. We hypothesized that escalated anticoagulation would not effectively prevent hypercoagulability and, consequently, would not reduce the risk of thrombosis and death in some severely ill patients. Methods: We conducted a prospective multicenter study that enrolled 3860 COVID-19 patients, including 1654 severely ill. They received different doses of low-molecular-weight or unfractionated heparin, and their blood coagulation was monitored with activated partial thromboplastin time, D-dimer, and Thrombodynamics. A primary outcome was hypercoagulability detected by Thrombodynamics. Blood samples were collected at the trough level of anticoagulation. Results: We found that escalated anticoagulation did not prevent hypercoagulability in 28.3% of severely ill patients at the trough level of the pharmacological activity. Severely ill patients with such hypercoagulability had higher levels of inflammation markers and better creatinine clearance compared to severely ill patients without it. Hypercoagulability detected by Thrombodynamics was associated with a 1.68-fold higher hazard rate for death and a 3.19-fold higher hazard rate for thrombosis. Elevated D-dimer levels were also associated with higher hazard rates for thrombosis and death, while shortened APTTs were not. The simultaneous use of Thrombodynamics and D-dimer data enhanced the accuracy for predicting thrombotic events and fatal outcomes in severely ill patients. Conclusions: Thrombodynamics reliably detects hypercoagulability in COVID-19 patients and can be used in conjunction with D-dimer to assess the risk of thrombosis and death in severely ill patients. The pharmacological effect of LMWH at the trough level might be too low to prevent thrombosis in some severely ill patients with severe inflammation and better creatinine clearance, even if escalated doses are used.

COVID-19 pneumonia patients encounter the potential risk of venous thromboembolism (VTE) and mortality during hospitalization. This study aimed to analyzed risk factors of all-cause mortality in hospitalized patients with COVID-19 pneumonia, and investigated the effectiveness of prophylactic anticoagulation and hospital stays on the mortality in hospitalized patients with nonVTE.

We retrospectively analyzed all COVID-19 pneumonia patients who were admitted to our medical center from December 2022 to January 2023. Clinical data and outcome events were collected from patients' electronic medical records. Cox regression was used to identify poor prognostic factors of COVID-19 pneumonia patients with VTE and nonVTE. Landmark analysis was conducted to identify time points of hospital stays between anticoagulation treatment and in-hospital survival outcomes in COVID-19 pneumonia patients with nonVTE. Binary logistic regression analysis was performed to investigate factors related to prolonged hospital stays.

Among 2,520 COVID-19 pneumonia patients, 1047 received prophylactic anticoagulation and 76 complicated with VTE during hospitalization. Survival curve analysis showed no statistically significant difference in mortality between COVID-19 pneumonia patients with VTE and nonVTE in prophylactic anticoagulant group (P = 0.63). Multivariate cox regression analysis revealed that male(HR = 1.398, 95%CI= [1.021,1.915]), BMI (HR = 0.935, 95%CI= [0.900,0.972]), lymphocytes (HR = 0.576, 95%CI= [0.409,0.809]), platelets (HR = 0.997, 95%CI= [0.995,0.999]), albumin (HR = 0.950, 95%CI= [0.926,0.975]), lactate dehydrogenase (HR = 1.001, 95%CI= [1.001,1.002]) were risk factors for mortality in COVID-19 pneumonia patients with nonVTE, while sCRP (HR = 1.010, 95%CI= [1.004,1.015]), anticoagulant therapy (HR = 0.247, 95%CI= [0.096,0.632]) were risk factors for mortality in COVID-19 pneumonia patients with VTE. Landmark analysis showed that for the hospital stays of 11 days, the difference in the impact of prophylactic anticoagulation on mortality was statistically significant in COVID-19 pneumonia patients with nonVTE (≤ 11days, P = 0.014; > 11days, P = 0.01). CVD (OR = 1.717, 95%CI= [1.248,2.363]), CRD (OR = 1.605, 95%CI= [1.133,2.274]), sCRP (OR = 1.003, 95%CI= [1.000,1.006]), Alb (OR = 0.959, 95%CI = [0.932,0.987]) and use of glucocorticoid (OR = 1.428, 95%CI= [1.057,1.930]) were independent factors associated with hospital stays > 11 days in anticoagulant group.

This study indicated that Male, lower BMI, peripheral blood lymphocytes, platelets, albumin and elevated lactate dehydrogenase were associated with poor hospitalisation outcomes in COVID-19 pneumonia patients with nonVTE. As for COVID-19 pneumonia patients with VTE, poor hospitalisation outcomes were associated with elevated sCRP levels and no given anticoagulant therapy. No significant difference in mortality between hospitalized COVID-19 pneumonia patients with VTE and nonVTE when receiving prophylactic anticoagulation. Prolonged hospital stays (> 11 days) may limit the effectiveness of prophylactic anticoagulation on lower in-hospital mortality for COVID-19 pneumonia patients with nonVTE.

Characterizing the paradigm and impact of long COVID is crucial for addressing this worldwide health challenge. This study aimed to investigate the prevalence of long COVID one year after primary Omicron infection and characterize differences in long-term health consequence between participants with persistent long COVID and those who fully recovered.

This a community-based cross-sectional study conducted from December 2023 to March 2024 at the China-Japan Friendship Hospital and 16 administrative districts in Beijing. 12,789 participants infected with Omicron between December 2022 and January 2023 were recruited through stratified multistage random sampling and included in the final analysis. Of them, 376 participants with persistent long COVID and 229 without long COVID were matched for further physical examinations. The primary outcome was the prevalence of long COVID one year after infection. Secondary outcomes included muscle strength, exercise capacity, health-related quality of life (HRQoL), mental health, work status, laboratory tests, and examinations.

Among 12,789 participants (media [IQR] age, 48.4 [37.3 to 61.4] years; 7817 females [61.1%]), 995 of them (7.8%) experienced long COVID within one year, with 651 (5.1%) having persistent symptoms. Fatigue (598/995 [60.1%]) and post-exertional malaise (367/995 [36.9%]) were the most common symptoms. Brain fog had the lowest resolution proportion as 4.2% within one year. The odds of long COVID increased with reinfections (odds ratios for one reinfection 2.592 [95% CI: 2.188 to 3.061]; two or more: 6.171 [3.227 to 11.557]; all p < 0.001). Participants with persistent long COVID had markedly lower muscle strength (upper-limb: 26.9 ± 12.4 vs. 29.1 ± 14.5 Kg; lower-limb: 40.0 [27.0 to 62.0] vs. 43.0 [28.0 to 59.0] s), worse exercise capacity and poorer HRQoL, and meaningful difference in laboratory tests results compared to those without long COVID. They also exhibited significantly higher proportions of abnormal lung function (FEV1 %pred<80%: 13.0% vs. 2.0%; DLco %pred<80%: 32.7% vs. 19.9%) and lung imaging abnormalities (23.5% vs. 13.6%).

The considerable health burden of long COVID and the progression of neurological symptoms following Omicron infection warrant close monitoring. Utilizing professional questionnaires and developing reliable diagnostic tools are necessary for improving diagnosis and treatment of long COVID.

This work was supported by Beijing Research Center for Respiratory Infectious Diseases (BJRID2024-012), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-CoV19-005/CIFMS 2021-I2M-1-048), the National Natural Science Foundation of China (82241056/82200114/82200009), the New Cornerstone Science Foundation.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a significant impact on global health. While the virus primarily affects the respiratory system, the intricate interplay between immune cells and the virus remains poorly understood. This study investigates the causal relationship between 731 immune cell phenotypes and COVID-19 using Mendelian randomization (MR) analysis.

A bidirectional two-sample MR analysis was conducted using genetic variants strongly associated with immune cell phenotypes as instrumental variables. Data for 731 immune cell phenotypes were sourced from the Genome-Wide Association Study (GWAS) catalog, while data for COVID-19 susceptibility were obtained from the OPEN GWAS database. Five MR methods (inverse variance weighted [IVW], MR-Egger, weighted median, simple mode, and weighted mode) were used to estimate causal effects, with IVW as the primary analysis method.

The study identified 57 immune cell phenotypes causally associated with COVID-19 risk across two independent GWAS datasets. Five immune cell phenotypes were consistently associated with COVID-19 risk across both datasets: CD3- lymphocyte %lymphocyte (protective), CD27 on CD20- (protective), CD20 on IgD+ CD38- unsw mem (increased risk), CD27 on IgD- CD38- (increased risk), and CD19 on B cell (increased risk). Sensitivity analyses confirmed the robustness of the findings.

This study provides compelling evidence for a causal relationship between specific immune cell phenotypes and COVID-19 risk. These findings highlight the potential for targeting these immune cell phenotypes as novel therapeutic targets for COVID-19 treatment and prevention.

Background: Elderly patients with COVID-19 often exhibit a complex interplay between hypercoagulability and coagulopathy, key factors in determining the risk of severe complications and mortality. This study aimed to analyze coagulation and inflammatory markers to identify critical predictors of adverse outcomes in this vulnerable population. Material and Methods: The retrospective study was conducted on a sample of 1429 elderly patients (≥60 years) diagnosed with COVID-19, hospitalized in "Sf. Ap. Andrei" St. Apostle Andrew's County Emergency Hospital in various wards between March 2020 and August 2022. Data were collected from medical records and included inflammatory markers (C-reactive protein, procalcitonin, ESR) and coagulation markers (prothrombin time, INR, fibrinogen, D-dimer). The SPSS 2.0 statistical software was used to conduct the study. Results:Coagulation markers: Prothrombin activity averaged 74.22%, below normal levels, indicating a heightened bleeding risk, while fibrinogen levels were significantly elevated (mean: 531.69 mg/dL), reflecting hypercoagulability. Prolonged prothrombin time (mean: 17.28 s) and elevated INR (International normalized ratio) (mean: 1.51) were associated with increased mortality, emphasizing their role in risk stratification. Elevated D-dimer levels (mean: 2.75 mg/L) further highlighted thromboembolic risks. Inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) showed marked elevations (mean CRP: 92.09 mg/L, mean ESR: 58.47 mm/h), correlating with heightened systemic inflammation and poor outcomes. Bacterial infections: Elevated procalcitonin (mean: 1.98 ng/mL) suggested secondary bacterial infections, particularly in mechanically ventilated patients, significantly worsening prognosis. Conclusions: The duality of hypercoagulability and coagulopathy in elderly COVID-19 patients underscores the importance of consistently monitoring coagulation markers such as prothrombin time, INR, D-dimer, and fibrinogen. Simultaneously, elevated inflammatory markers and secondary bacterial infections require prompt therapeutic interventions. This study highlights the critical need for personalized management strategies to mitigate complications and reduce mortality in this high-risk population.

Background/Objectives: People affected by COVID-19 are exposed to abnormal clotting and endothelial dysfunction, which may trigger thromboembolic events. This study aimed at retrospectively investigating whether oral anticoagulant therapy (OAT), encompassing either direct oral anticoagulants (DOACs), mainly apixaban, or the vitamin K antagonist (VKA) warfarin, could have impacted medium-term mortality in a cohort of SARS-CoV-2 patients. Methods: Among 1238 COVID-19 patients, hospitalized from 17 March 2020 to 15 June 2021, 247 survivors and 247 deceased within 90 days from hospitalization were matched 1:1 based on age, sex, and intensive care unit (ICU) admission within three days. Conditional logistic regression was used to estimate associations by means of odds ratio (OR) with a 95% confidence interval (CI). Results: A univariate regression analysis suggested that OAT, no differently from subcutaneous low-molecular-weight heparins (LMWHs) during hospitalization, has no significant impact (p value > 0.05) on medium-term mortality. A multivariate analysis, limited to baseline variables (i.e., comorbidities and pharmacotherapies at hospital admission) showing significant association (p < 0.05) to mortality in a univariate analysis, revealed that, compared to patients living at 90 days from hospitalization, deceased patients had cancer histories (OR 1.75, CI 1.06-2.90, p = 0.029) or suffered from asthma (OR 2.25, CI 1.13-4.47, p = 0.021). In contrast, heart failure (HF), atrial fibrillation (AF), arteriopathy, chronic obstructive pulmonary disease (COPD), and kidney failure (KF), which, in a univariate analysis, were found to be associated with the endpoint (p < 0.05), lost significance in a multivariate analysis. Therapy at admission with aldosterone antagonists also appeared to be associated with medium-term mortality (OR 2.49, CI 1.52-4.08, p < 0.001); whereas, vitamin D supplementation during hospitalization appeared to be beneficial. Although not conclusive, a search into the Eudravigilance database, combined with consulting a digital predictive platform (PLATO, polypharmacology platform prediction), suggested potential off-target activities, which might contribute to increasing the severity of SARS-CoV-2 infection. Conclusions: This retrospective clinical study furnished evidences of the impact of OAT, comorbidities and other pharmacological treatments on COVID-19 clinical course.

Background/ Objectives: Long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC) are symptoms that manifest despite passing the acute infection phase. These manifestations encompass a wide range of symptoms, the most common being fatigue, shortness of breath, and cognitive dysfunction. Genetic predisposition is clearly involved in the susceptibility of individuals to developing these persistent symptoms and the variation in the severity and forms. This review summarizes the role of genetic factors and gene polymorphisms in the development of major pulmonary vascular disorders associated with long COVID. Methods: A comprehensive review of current literature was conducted to examine the genetic contributions to pulmonary complications following SARS-CoV-2 infection. Studies investigating genetic polymorphisms linked to pulmonary hypertension, pulmonary thromboembolism, and pulmonary vascular endothelialitis were reviewed and summarized. Results: Findings show that specific genetic variants contribute to increased susceptibility to pulmonary vascular complications in long COVID patients. Variants associated with endothelial dysfunction, coagulation pathways, and inflammatory responses have been implicated in the development of pulmonary hypertension and thromboembolic events. Genetic predispositions influencing vascular integrity and immune responses appear to influence disease severity and progression. Conclusions: Understanding these mechanisms and genetic predispositions could pave the way for targeted therapeutic interventions to alleviate the burden on patients experiencing long COVID.

This review article discusses the role of vascular endothelial growth factor A (VEGF-A) in the pathogenesis of SARS-CoV-2 and HIV infection, both conditions being renowned for their impact on the vascular endothelium. The processes involved in vascular homeostasis and angiogenesis are reviewed briefly before exploring the interplay between hypoxia, VEGF-A, neuropilin-1 (NRP-1), and inflammatory pathways. We then focus on SARS-CoV-2 infection and show how the binding of the viral pathogen to the angiotensin-converting enzyme 2 receptor, as well as to NRP-1, leads to elevated levels of VEGF-A and consequences such as coagulation, vascular dysfunction, and inflammation. HIV infection augments angiogenesis via several mechanisms, most prominently, by the trans-activator of transcription (tat) protein mimicking VEGF-A by binding to its receptor, VEGFR-2, as well as upregulation of NRP-1, which enhances the interaction between VEGF-A and VEGFR-2. We propose that the elevated levels of VEGF-A observed during HIV/SARS-CoV-2 co-infection originate predominantly from activated immune cells due to the upregulation of HIF-1α by damaged endothelial cells. In this context, a few clinical trials have described a diminished requirement for oxygen therapy during anti-VEGF treatment of SARS-CoV-2 infection. The currently available anti-VEGF therapy strategies target the binding of VEGF-A to both VEGFR-1 and VEGFR-2. The blocking of both receptors could, however, lead to a negative outcome, inhibiting not only pathological, but also physiological angiogenesis. Based on the examination of published studies, this review suggests that treatment targeting selective inhibition of VEGFR-1 may be beneficial in the context of SARS-CoV-2 infection.

The pathophysiology of myocardial injury following COVID-19 remains uncertain. COVID-HEART was a prospective, multicentre study utilising cardiovascular magnetic resonance (CMR) to characterise COVID-related myocardial injury. In this pre-specified analysis, the objectives were to examine (1) the frequency of myocardial ischaemia following COVID-19, and (2) the association between ischaemia and myocardial injury. We studied 59 patients hospitalised with COVID-19 and elevated serum troponin (COVID + /troponin + , age 61 ± 11 years) and 37 control subjects without COVID-19 or elevated troponin and similar by age and cardiovascular comorbidities (COVID -/comorbidity + , 64 ± 10 years). Subjects underwent multi-parametric CMR (comprising assessment of ventricular volumes, stress perfusion, T1/T2 mapping and scar). The primary endpoint was the frequency of inducible myocardial ischaemia. Inducible ischaemia was evident in 11 (19%) COVID + /troponin + patients and in 8 (22%) control subjects (p = 0.72). In COVID + /troponin + patients with ischaemia, epicardial coronary disease pattern ischaemia was present in eight patients and microvascular disease pattern, in three patients. There was no significant difference in the frequency of inducible ischaemia in COVID + /troponin + patients with previous myocardial infarction and/or revascularisation compared to those without (2/12 [17%] vs. 9/47 [19%] respectively, p = 0.84), or in those with and without scar (7/27 [26%] vs. 4/32 [13%] respectively, p = 0.19). Myocardial ischaemia was present in ~ 20% of patients recently hospitalised with COVID-19 and with elevated cardiac troponin, but this was not different to matched comorbid controls. This finding coupled with the lack of an association between ischaemia and myocardial scar suggests that coronary artery abnormalities are unlikely to be the predominant mechanism underlying COVID-19 induced myocardial injury.

Background: Acute lung injury (ALI) is a severe complication of sepsis, characterized by inflammation, edema, and injury to alveolar cells, leading to high mortality rates. Septic ALI is a complex disease involving multiple factors and signaling pathways. STEAP family member 1 (STEAP1) has been reported to be upregulated in a sepsis-induced ALI model. However, the role of STEAP1 in the regulation of septic ALI is not yet fully understood. Methods: The study stimulated human pulmonary microvascular endothelial cells (HPMECs) using lipopolysaccharides (LPS) to establish an in vitro ALI model. The study used quantitative real-time polymerase chain reaction to measure mRNA expression, and western blotting assay or immunohistochemistry assay to analyze protein expression. Cell Counting Kit-8 assay was performed to assess cell viability. Flow cytometry was conducted to analyze cell apoptosis. Tube formation assay was used to analyze the tube formation rate of human umbilical vein endothelial cells. Enzyme-linked immunosorbent assays were used to measure the levels of interleukin 1beta and tumor necrosis factor alpha. The levels of Fe 2+ and reactive oxygen species were determined using colorimetric and fluorometric assays, respectively. The glutathione level was also determined using a colorimetric assay. m6A RNA immunoprecipitation assay, dual-luciferase reporter assay, and RNA immunoprecipitation assay were performed to identify the association of STEAP1 with methyltransferase 14, N6-adenosine-methyltransferase noncatalytic subunit (METTL14) and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2). The transcript half-life of STEAP1 was analyzed by actinomycin D assay. Finally, a rat model of polymicrobial sepsis was established to analyze the effects of STEAP1 knockdown on lung injury in vivo . Results: We found that the mRNA expression levels of STEAP1 and METTL14 were upregulated in the blood of ALI patients induced by sepsis compared to healthy volunteers. LPS treatment increased the protein levels of STEAP1 and METTL14 in HPMECs. STEAP1 depletion attenuated LPS-induced promoting effects on HPMECs' apoptosis, inflammatory response, and ferroptosis, as well as LPS-induced inhibitory effect on tube formation. We also found that METTL14 and IGF2BP2 stabilized STEAP1 mRNA expression through the m6A methylation modification process. Moreover, METTL14 silencing attenuated LPS-induced effects by decreasing STEAP1 expression in HPMECs, and STEAP1 silencing ameliorated cecal ligation and puncture-induced lung injury of mice. Conclusion: METTL14/IGF2BP2-mediated m6A modification of STEAP1 aggravated ALI induced by sepsis. These findings suggest potential therapeutic targets for the treatment of this disease.

Patients with Diabetic ketoacidosis (DKA) have increased critical illness and mortality during coronavirus diseases 2019 (COVID-19). The aim of our study was to develop a predictive model for the occurrence of critical illness and mortality in COVID-19 patients with DKA utilizing machine learning. Blood samples and clinical data from 242 COVID-19 patients with DKA collected from December 2022 to January 2023 at Second Xiangya Hospital. Patients were categorized into non-death (n = 202) and death (n = 38) groups, and non-severe (n = 146) and severe (n = 96) groups. We developed five machine learning-based prediction models-Extreme Gradient Boosting (XGB), Logistic Regression (LR), Random Forest (RF), Support Vector Machine (SVM), and Multilayer Perceptron (MLP)-to evaluate the prognosis of COVID-19 patients with DKA. We employed 5-fold cross-validation for model evaluation and used the Shapley Additive Explanations (SHAP) algorithm for result interpretation to ensure reliability. The LR model demonstrated the highest accuracy (AUC = 0.933) in predicting mortality. Additionally, the LR model excelled (AUC = 0.898) in predicting progression to severe disease. This study developed a machine learning-based predictive model for the progression to severe disease or death in COVID-19 patients with DKA, which can serve as a valuable tool to guide clinical treatment decisions.

The hemostatic system prevents and stops bleeding, maintaining circulatory integrity after injury. It directly interacts with the complement system, which is key to innate immunity. In coronavirus disease 2019 (COVID-19), dysregulation of the hemostatic and complement systems has been associated with several complications. To understand the essential balance between activation and regulation of these systems, a quantitative systems immunology model can be established. The dynamics of the components are examined under three distinct conditions: the disease state representing symptomatic COVID-19 state, an intervened disease state marked by reduced levels of regulators, and drug interventions including heparin, tranexamic acid, avdoralimab, garadacimab, and tocilizumab. Simulation results highlight key components affected, including thrombin, tissue plasminogen activator, plasmin, fibrin degradation products, interleukin 6 (IL-6), the IL-6 and IL-6R complex, and the terminal complement complex (C5b-9). We explored that the decreased levels of complement factor H and C1-inhibitor significantly elevate these components, whereas tissue factor pathway inhibitor and alpha-2-macroglobulin have more modest effects. Furthermore, our analysis reveals that drug interventions have a restorative impact on these factors. Notably, targeting thrombin and plasmin in the early stages of thrombosis and fibrinolysis can improve the overall system. Additionally, the regulation of C5b-9 could aid in lysing the virus and/or infected cells. In conclusion, this study explains the regulatory mechanisms of the hemostatic and complement systems and illustrates how the biopathway machinery sustains the balance between activation and inhibition. The knowledge that we have acquired could contribute to designing therapies that target the hemostatic and complement systems.

Covid 19 patients often present with elevated D-dimer levels. The purpose of this study is to evaluate the role of D-Dimer levels in Covid 19 patients to predict mortality and venous thromboembolism (VTE) events. This is a retrospective chart review study from 1 April 2020 to 30 June 2020, during the peak Covid pandemic. A total of 350 patients were enrolled in this study; 69 (19.7%) patients died; 12 (3.4%) had a deep venous thrombosis; and 8 (2.3%) had a pulmonary embolism outcome. Peak D-dimer levels were collected with median levels of 765 ng/ml (266, 3135). Patients with VTE outcomes had significantly higher levels of peak D-dimers than patients in the non-VTE group (4876 vs 680, p < 0.0001). Patients who died had higher peak D-dimer levels than those who survived (4690 vs 501, p < 0.0001). The optimal cutoff point in peak D-dimer in predicting VTE events was 1437, yielding a sensitivity of 84.2% and a specificity of 65.0%. The optimal cutoff point in peak D-dimer in predicting mortality was 2004, yielding a sensitivity of 71.0% and a specificity of 77.9%. This study suggests that D-dimer levels can be elevated in Covid 19 hospitalized patients and can serve as indicators for mortality and VTE events.

Thrombosis plays an important role in induction of Coronavirus disease 19 (COVID-19) complications including heart attack and stroke. Reliable biomarkers are needed to predict thrombosis risk for better management and improve patient outcomes. This study aimed to investigate the relationship between homocysteine, a thrombosis-related biomarker, and other thrombosis-related parameters, such as D-dimer and platelet count with disease outcome in COVID-19 patients. This case-control study including 50 intensive care unit hospitalized patients with Covid-19 with a positive RT-PCR test for SARS-CoV-2 infection and 50 healthy individuals as a control group was conducted. Both groups were matched for age and body mass index (BMI) and had no history of underlying diseases such as cardiovascular, liver, kidney or smoking. Blood samples were collected from both groups to measure serum homocysteine, platelet count and D-dimer levels. Data were analyzed using GraphPad Prism version 8.3 software. The study found no statistically significant difference in homocysteine levels between COVID-19 patients and the control group. However, D-dimer levels were significantly higher in the patient group. Platelet count analysis revealed a significant difference between patients who died and those who were discharged from the hospital (P < 0.05). Despite previous studies suggesting a link between homocysteine and thrombosis, this study found no significant difference in homocysteine levels between COVID-19 patients and the control group. The significantly elevated D-dimer levels in the death group patient suggest that D-dimer and thrombocytopenia may be more reliable predictors of thrombosis and worse outcome in COVID-19 patients without underlying diseases.

A heightened risk for thrombosis is a hallmark of COVID-19. Expansive clinical experience and medical literature have characterized small (micro) and large (macro) vessel involvement of the venous and arterial circulatory systems. Most events occur in patients with serious or critical illness in the hyperacute (first 1-2 weeks) or acute phases (2-4 weeks) of SARS-CoV-2 infection. However, thrombosis involving the venous, arterial, and microcirculatory systems has been reported in the subacute (4-8 weeks), convalescent (> 8-12 weeks) and chronic phases (> 12 weeks) among patients with mild-to-moderate illness. The purpose of the current focused review is to highlight the distinguishing clinical features, pathological components, and potential mechanisms of venous, arterial, and microvascular thrombosis in patients with COVID-19. The overarching objective is to better understand the proclivity for thrombosis, laying a solid foundation for screening and surveillance modalities, preventive strategies, and optimal patient management.

The aim of this study was to evaluate how COVID-19 affected acute stroke care and outcome in patients with acute ischemic or hemorrhagic stroke. We performed a retrospective analysis on patients who were admitted with acute ischemic (AIS) or hemorrhagic (ICH) stroke from September 2020 to May 2021 with and without COVID-19. We recorded demographic and clinical data, imaging parameters, functional outcome and mortality at one year. Beside descriptive statistics we performed χ2-probe, Mann-Witney U-test, Student t-probe and multivariate testing. We found a 29%-reduction in the number of AIS cases during the pandemic. The number of the large vessel occlusions /LVOs/ (N = 83, 41.7%), from them 37 (17.7%) had mechanical thrombectomy (MT), was higher than before the COVID-19 period (p = 0.02 and p = 0.001, respectively). From all patients needing acute revascularization therapy (N = 137) 118 patients received it, among them 20 (16.9%) had COVID-19. Those positive for COVID-19 were more likely to have a higher median NIHSS score at baseline and at 24 h (p = 0.02 and p = 0.03, respectively). They also had a lower rate of favourable outcome at discharge (15% vs. 41.8%; p = 0.024) and at three months (25% vs. 52%, p = 0.02), longer median hospitalization (p < 0.0001), and a higher mortality rate (52% vs. 25%; p = 0.03). The incidence of symptomatic intracerebral hemorrhage (sICH) did not differ between the groups. Regarding the ICH patients, NIHSS score at 24 h (p = 0.036), mortality at 3 months (p = 0.004) and at one year (p = 0.00) were higher in the COVID-19 group. We concluded that the pandemic resulted fewer admission due to AIS with an increased number of LVOs and MTs. AIS patients with concomitant SARS-CoV-2 infection have more severe strokes and unfavorable long term outcome. The risk of sICH was not increased in COVID-19 positive patients therefore reperfusion therapies appear to be safe and beneficial for some individuals. Patients with ICH and comorbid COVID-19 have a very poor prognosis.

Background/Objectives: A novel patient group with chronic pulmonary fibrosis is emerging post COVID-19. To identify patients at risk of developing post-COVID-19 lung fibrosis, we here aimed to identify systemic proteins that overlap with fibrotic markers identified in patients with idiopathic pulmonary fibrosis (IPF) and may predict COVID-19-induced lung fibrosis. Methods: Ninety-two proteins were measured in plasma samples from hospitalized patients with moderate and severe COVID-19 in Sweden, before the introduction of the vaccination program, as well as from healthy individuals. These measurements were conducted using proximity extension assay (PEA) technology with a panel including inflammatory and remodeling proteins. Histopathological alterations were evaluated in explanted lung tissue. Results: Connecting to IPF pathology, several proteins including decorin (DCN), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) and chemokine (C-X-C motif) ligand 13 (CXCL13) were elevated in COVID-19 patients compared to healthy subjects. Moreover, we found incrementing expression of monocyte chemotactic protein-3 (MCP-3) and hepatocyte growth factor (HGF) when comparing moderate to severe COVID-19. Conclusions: Both extracellular matrix- and inflammation-associated proteins were identified as overlapping with pulmonary fibrosis, where we found DCN, TNFRSF12A, CXCL13, CXCL9, MCP-3 and HGF to be of particular interest to follow up on for the prediction of disease severity.

To determine if preoperative infection with COVID-19 increased risk for postoperative venous thromboembolism (VTE) in patients undergoing arthroscopic knee surgery.

PearlDiver Mariner 165 database was queried for patients undergoing knee arthroscopy between 2010 and October 2022. Patients were categorized by history of COVID-19 diagnosis and timing in relation to surgery. Multivariate logistic regression was performed to isolate the effect of COVID-19 diagnosis on postoperative VTE rates. Covariates included age, obesity, smoking, oral contraceptive pill use, hypertension, coronary artery disease, congestive heart failure, malignancy, renal disease, and diabetes.

A total of 954,294 patients met inclusion criteria, and 7,637 patients experienced VTE, including deep vein thrombosis (n = 5,830, 0.61%) and pulmonary embolism (n = 2,790, 0.29%). Patients with a COVID-19 diagnosis before surgery (7,858) had an overall higher incidence of VTE (1.72%) compared to patients without a preoperative COVID-19 diagnosis (0.81%) (P < .001). There was no difference in VTE incidence among patients with a preoperative COVID-19 diagnosis undergoing knee arthroscopy in the pre- and post-COVID-19 vaccination eras (odds ratio, 0.82; 95% CI, 0.51-1.31; P = .48). Multivariate regression accounting for covariates showed that patients with a preoperative COVID-19 diagnosis within 6 weeks before arthroscopy had significantly increased odds of experiencing postoperative VTE (odds ratio, 1.68; 95% CI, 1.09-2.45; P = .012). There was no significant difference in VTE risk among patients with a preoperative COVID-19 diagnosis between 6 and 12 weeks before arthroscopy and more than 12 weeks before arthroscopy compared to those with no prior COVID-19 diagnosis.

COVID-19 diagnosis within 6 weeks preceding arthroscopic knee surgery leads to a significantly higher risk for postoperative VTE.

Level III, retrospective case control study.

We aimed to investigate the incidence of new acute myocardial infarction (AMI), in patients with Coronavirus disease (COVID-19) who had old MI. We hypothesized that COVID-19 increases the rate of repeated AMI in this population regardless of age and gender.

A retrospective analysis was conducted for adult patients admitted with COVID-19 and developed thromboembolic event (TEE) in 2020. Patients were categorized based on the history of old MI, new MI, age, and gender.

Among 16,903 patients with COVID-19 who were admitted, 210 (1.2%) developed TEE (89% were males, 55% were <55 years old, and 80.5% had an old MI). COVID-19 was severe in 32% of cases. AMI occurred in 160 patients (42.5% STEMI and 57.5% NSTEMI). In patients with prior MI, 92.5% developed another AMI. NSTEMI was higher in patients with severe COVID-19 than STEMI (33% vs 21%). Patients with severe COVID-19 had higher mortality (39.4% vs 5.6%), fewer rates of prior MI (74% vs 83%), hypertension (40% vs 60%), and STEMI (31.8% vs 46.5%) than mild COVID-19 patients. On multivariable analysis, COVID-19 severity was an independent predictor of mortality (OR10; 95%CI 1.62-67.19) after adjustment for age, gender, diabetes mellitus, C-reactive protein, serum Ferritin, Procalcitonin, and Fibrinogen values, and prior or new MI.

Patients with old MI could develop a new AMI in 80% of COVID-19. However, the mortality was higher in patients without a history of MI due to the severity of COVID-19. Attention should be given to patients who possess thrombotic risk factors in pandemics.

The impact of COVID-19 on pregnant women and newborns continues to be a critical societal concern. However, the majority of research focuses on the disease resulting from the early pandemic variants, without sufficient study on the more recent BA.5.2/BF.7. We retrospectively recruited pregnant women giving birth during the surge of the BA.5.2/BF.7 and analysed the risk impact of COVID-19 on maternal and neonatal outcomes. Furthermore, subjects matched through propensity scores were used for the analysis of clinical laboratory tests. A total of 818 pregnant women were enrolled, among 276 (33.7%) were diagnosed with SARS-CoV-2 during childbirth. COVID-19 significantly increased the risk of a hospital length of stay equal to or greater than seven days and neonatal admission to the neonatal intensive care unit, with an aHR of 2.03 (95% CI, 1.22-3.38) and 1.51 (95% CI, 1.12-2.03), respectively. In the analysis of 462 matched subjects, it was found that subjects infected with SARS-CoV-2 tended slight leucopenia and coagulation abnormalities. We found that during the surge of the BA.5.2/BF.7, COVID-19 increased the risk of maternal and neonatal outcomes among Chinese pregnant women. This finding offers significant insights to guide clinical practices involving pregnant women infected with the recently emerged Omicron subvariants.

SARS-CoV-2, the causative agent of COVID-19, can infect various tissues in the body apart from the lungs. Although placental infection remains controversial, COVID-19-associated placental abnormalities have been reported worldwide. Therefore, COVID-19 poses a significant risk for fetal distress as well. Scientists are currently debating whether such distress results from direct viral induced assault or placental damage caused by the mother's immune response. The placenta develops different histopathological lesions in response to maternal SARS-CoV-2 infection. While some studies support both theories, the transmission rate through the placenta remains low. Therefore, a more in-depth study is necessary to determine the primary cause of maternal SARS-CoV-2-induced fetal distress. This comprehensive review is aimed to shed light on the possible reasons towards fetal distress among mothers with COVID-19. This review describes the various mechanisms of viral entry along with the mechanisms by which the virus could affect the placenta. Reported cases of placental abnormalities and fetal distress symptoms have been collated to provide an overview of the current state of knowledge on vertical transmission of COVID-19.

Few epidemiological data are available for venous thromboembolism (VTE) at French national and subnational levels.

To quantify VTE events in France in 2022 and describe the features of hospital management and outcomes.

Adults hospitalized for a VTE as the primary reason for hospitalization or treatment in a medical unit in 2022 were identified from medical administrative data. Data were stratified as pulmonary embolism (PE) and deep vein thrombosis (DVT), and by French department and various sociodemographic indicators. VTE prevalence at 1 January 2023 was defined as the number of people alive at that date with a history of hospitalization for VTE or a chronic long-term disease status due to VTE (2012-2022).

VTE cases reached 896,846 adults on 1 January 2023. VTE was the primary diagnosis for a hospital stay or medical unit in 62,055 patients hospitalized in 2022. The age-standardized rate of hospitalized patients was 23.0% higher for men versus women. There were considerable variations between departments of residence, while Martinique had the highest age-standardized rate. The prevalence of triggering factors was high, with almost 30% having cancer and 20% a recent long hospitalization. One-year mortality was approximately 20% for both PE and DVT, despite rehospitalization rates <5%.

The high prevalence of cancer among patients hospitalized due to VTE partly explains the high 1-year mortality. As VTE is partially avoidable, the prevention of VTE needs to be improved in France and whether thromboprophylaxis guidance is being followed should regularly be assessed.

Platelet-rich microvascular thrombi are common in severe COVID-19. Endogenous nitric oxide (NO)-signaling limits thrombus formation and previously we identified platelet subpopulations with a differential ability to produce NO based on the presence or absence of endothelial nitric oxide synthase (eNOS). eNOS expression is counter-regulated by cytokines, and COVID-19-associated immune/inflammatory responses may affect the transcriptome profile of megakaryocytes and their platelet progeny.

We investigated whether the percentage of eNOS-negative to eNOS-positive platelets increases in COVID-19 patients and whether this change may be due to the actions of pro-inflammatory cytokines on megakaryocytes.

Platelets were isolated from hospitalized COVID-19 patients and COVID-19-negative controls. Platelet eNOS was measured by flow cytometry and plasma inflammatory cytokines by ELISA. Megakaryocytes from eNOS-GFP transgenic mice and the Meg-01 cell line were characterized to identify an appropriate model to study eNOS-based platelet subpopulation formation in response to inflammatory cytokines.

COVID-19 patients demonstrated a significant increase in eNOS-negative and a concomitant decrease in eNOS-positive platelets compared to controls, and this change was associated with disease severity as assessed by ICU admission. A higher eNOS-negative to -positive platelet percentage was associated with enhanced platelet activation as measured by surface CD62P. Accordingly, COVID-19 patients demonstrated higher TNF-α, IL-6, and IL-1β plasma concentrations than controls. Inflammatory cytokines associated with COVID-19 promoted eNOS-negative Meg-01 formation and enhanced subsequent eNOS-negative platelet-like particle formation.

COVID-19 patients have a higher percentage of eNOS-negative to -positive platelets, likely as a result of inflammatory response reducing megakaryocyte eNOS expression, which predisposes to thrombosis.

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.