In some reports, antiphospholipid antibodies (aPL) prevalence is higher in COVID-19 patients. This study intended to compare aPL prevalence between COVID-19 patients and healthy controls, and differences in aPL types using meta-analysis.

This work retrieved published literature about association between COVID-19 and aPL from Embase, Web of Science, PubMed, and The Cochrane Library databases. The observation group was COVID-19 patients, and the control group was healthy individuals. Outcome measures contained any of following aPLs: classic aPL: anti-cardiolipin antibodies (aCL) and anti-β2-glycoprotein-1 antibodies (Anti-β2GP1); other non-criteria aPL: anti-phosphatidylserine/prothrombin antibodies (aPS/PT) and anti-annexin-V antibodies (AnV). Meta-analysis was done on Review Manager 5.4.

10 studies involving 2288 patients were deemed eligible for inclusion. The results of the meta-analysis showed that the prevalence of Classic aPL and Any aPL in the COVID-19 group was significantly higher than in the healthy group (Classic aPL, RR = 2.55, 95 % CI = 1.83-3.55, P < 0.00001; Any aPL, RR = 2.34, 95 % CI = 1.46-3.77, P = 0.0005). Anti-β2GP1 IgA antibodies were the most common aPL in COVID-19 patients, with a significantly higher prevalence than in the healthy group (RR = 4.26, 95 % CI = 2.84-6.40, P < 0.00001). The prevalence of the four types of IgM aPL was significantly higher in the COVID-19 group compared to the healthy group, while there was no significant difference in aPL IgG between the two groups.

The prevalence of aPL in COVID-19 patients was significantly higher than in the healthy control group. IgM aPL was more easily detectable in the early stages of COVID-19 infection, while IgG aPL may be of more concern in the later time points of the immune epidemiology following SARS-CoV-2 infection.

ARDS is a heterogeneous syndrome involving different subphenotypes with different clinical features and different responses to treatment strategies. The prone position (PP) is an effective treatment for ARDS; however, whether the effects of prone positioning vary among ARDS patients with different subphenotypes remains unknown.

To evaluated the impact of PP on ventilation-perfusion matching(VQ matching) by contrast-enhanced Electrical impedance tomography (EIT) in ARDS patients with different subphenotypes.

This was a prospective, observational study at the medical ICU of Zhongda Hospital, Southeast University. ARDS patients undergoing mechanical ventilation were screened and allocated to different subphenotypes based on lung morphology (focal/non-focal) and D-dimer level (low/high D-dimer). EIT was used in the supine position and 3 h, 6 h, and 12 h after the PP during the first PP session.

From July 1, 2021, to July 1, 2022, 25 patients were included in this study. 10 patients (40%) were focal ARDS, and 15 were non-focal ARDS based on baseline morphology. 12 patients (48%) were high D-dimer ARDS, and 13 were low D-dimer ARDS based on baseline D-dimer levels. PaO2/FiO2 increased significantly 3 h after prone positioning in focal ARDS patients (130.30[109.94-147.30] vs. 213.50[176.00-256.50] mmHg, p < 0.001), while the effect of improved oxygenation was not apparent until 6 h after prone positioning in non-focal ARDS patients (104.60[95.20-127.00] vs. 190.20[160.10-213.20] mm Hg, p < 0.001). VQ matching improved after 3 h in the prone position in the focal ARDS group (69.93 ± 6.69 vs. 78.22 ± 5.07, p = 0.006) but improved after only 6 h in the prone position in the non-focal ARDS group (67.32 ± 4.78 vs. 78.70 ± 5.93, p < 0.001). In ARDS patients with varying levels of D-dimer, increased PaO2/FiO2 (126.60[99.30-146.20] vs. 185.20[112.10-236.00] mmHg, p = 0.013) and improved VQ matching (67.60 ± 4.60 vs. 72.97 ± 6.48, p = 0.023) were observed at 3 h in the PP in patients with low D-dimer ARDS. In contrast, increased PaO2/FiO2(105.20[95.20-124.10] vs. 195.2[183.20-213.20], p < 0.001) and improved VQ matching (67.19 ± 6.70 vs. 72.50 ± 6.37, p < 0.001) were revealed only after 6 h in the prone position in high D-dimer ARDS patients.

For moderate to severe ARDS patients, non-focal and high D-dimer ARDS patients need longer PP to improve oxygenation and VQmatching than the focal and low D-dimer patients.

This was a prospective, observational study registered in the Chinese Clinical Trial Registry (ChiCTR2200055442, https://www.chictr.org.cn/ ), on June 30, 2021.

Pulmonary infections are a leading cause of morbidity and mortality worldwide, a situation exacerbated by the COVID-19. Azithromycin (AZM) is used orally to treat pulmonary infections due to its ability to accumulate in lung tissues and immune cells after oral administration. Sulfated polysaccharides, such as heparin, are known to inhibit SARS-CoV-2 entry. This study presents a novel approach focused on developing a dry powder inhaler of AZM-loaded microparticles composed of either heparin or its derivatives. The microparticle formulations exhibited potent antiviral activity against SARS-CoV-2 (IC50 ≤ 95 nM) while retaining superior antibacterial efficacy against Streptococcus pneumoniae and Pseudomonas aeruginosa compared to free AZM (MIC ≤15 μg/mL). Importantly, at bactericidal concentrations, no cytotoxic effects were observed on mammalian cells, including Calu-3 cells and red blood cells. The formulations demonstrated effective alveolar aerodynamic deposition (MMAD ranging from 1 μm to 3 μm) with a Fine Particle Fraction below 5 μm close to 50 %. Adopting a conservative estimate of 20 mL for the pulmonary epithelial lining fluid volume in healthy adults, efficacious local concentrations of sulfated polysaccharides and AZM would be delivered to the lung using this multifaceted strategy which holds promise for the treatment of bacterial pulmonary infections associated with COVID-19.

Cerebral venous sinus thrombosis (CVST) is a rare yet significant neurological disorder with high mortality. Understanding its evolving characteristics, risk factors, and outcomes, particularly in Chinese patients after the COVID-19 pandemic, is critical for developing effective preventive and therapeutic strategies.

A retrospective analysis was conducted on 471 CVST cases from Xuanwu Hospital, comparing data before (2013-2017, n = 243) and after (2021-2023, n = 228) the COVID-19 pandemic. Data on demographics, clinical features, risk factors, and outcomes were evaluated, with subgroup analyses based on gender and age.

The mean patient age was 38 ± 14 years, with a female preponderance (55.0%). After the COVID-19 pandemic, significant changes in symptoms and neuroimaging findings were observed, including increased visual impairment and decreased headache, neurological deficits, and seizures. Infection emerged as a prominent risk factor, including eight cases related to COVID-19 or vaccination. At discharge, favorable outcomes (mRS 0-2) were noted in 86.6% of patients. Poor outcomes were associated with central nervous system (CNS) infection, oral contraceptive use or hormone replacement therapy (HRT), hematologic disorders, anemia, and prothrombotic conditions. Anemia was identified as an independent predictor of survival.

The pandemic has significantly altered the clinical and epidemiological profile of CVST in China. Infections have emerged as key risk factors, while anemia remains a critical prognostic indicator. These findings highlight the need for targeted clinical strategies to improve outcomes.

This study protocol was reviewed and approved by the ethics committee of Xuanwu Hospital, Capital Medical University (No. 2022-004, dated on November 20, 2022). The clinical trial was registered at Chinese Clinical Trial Registry (ChiCTR2200057621).

In multiple trauma patients, the occurrence of trauma-induced coagulopathy (TIC) is closely associated with tissue damage and coagulation function abnormalities in the pathophysiological process.

This study established a multiple trauma and shock model in Sprague-Dawley (SD) rats and comprehensively utilized histological staining and radiographic imaging techniques to observe injuries in the intestine, liver, skeletal muscles, and bones. Monitoring activated partial thromboplastin time (APTT), platelet (PLT) count, respiratory rate, blood pressure, and other physiological indicators revealed time-dependent alterations in coagulation function and physiological indicators. Enzyme-linked immunosorbent assay (ELISA) measurements of inflammatory factors Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and vascular endothelial injury marker (Syndecan-1) were also conducted.

Experimental results demonstrated significant changes in tissue structure after multiple traumas, although widespread necrosis or hemorrhagic lesions were not observed. There were time-dependent alterations in coagulation function and physiological indicators. ELISA measurements showed a strong positive correlation between the significant decrease in PLT count and the increase in TNF-α and IL-6 concentrations.

The study provides crucial information for the early diagnosis and treatment of TIC. The findings suggest that structured monitoring of coagulation and inflammatory indicators can help in understanding the pathophysiological changes and aid in the management of TIC in multiple trauma patients.

Inflammation contributes to the development of thrombosis, but the mechanistic basis for this association remains poorly understood. Innate immune responses and coagulation pathways are activated in parallel following infection or injury, and represent an important host defense mechanism to limit pathogen spread in the bloodstream. However, dysregulated proinflammatory activity is implicated in the progression of venous thromboembolism and arterial thrombosis. In this review, we focus on the role of myeloid cells in propagating thromboinflammation in acute inflammatory conditions, such as sepsis and coronavirus disease 2019 (COVID-19), and chronic inflammatory conditions, such as obesity, atherosclerosis, and inflammatory bowel disease. Myeloid cells are considered key drivers of thromboinflammation via upregulated tissue factor activity, formation of neutrophil extracellular traps (NETs), contact pathway activation, and aberrant coagulation factor-mediated protease-activated receptor (PAR) signaling. We discuss how strategies to target the intersection between myeloid cell-mediated inflammation and activation of blood coagulation represent an exciting new approach to combat immunothrombosis. Specifically, repurposed anti-inflammatory drugs, immunometabolic regulators, and NETosis inhibitors present opportunities that have the potential to dampen immunothrombotic activity without interfering with hemostasis. Such therapies could have far-reaching benefits for patient care across many thromboinflammatory conditions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily a respiratory virus causing coronavirus disease 2019 (COVID-19) pneumonia, induces a hypercoagulable state. Previous studies comparing the prevalence of venous thromboembolism (VTE) in patients with COVID-19 pneumonia and those with influenza pneumonia revealed a higher risk of pulmonary embolism (PE) and deep vein thrombosis (DVT) associated with COVID-19 pneumonia. However, these studies have not adequately accounted for the severity and acuity of the presenting viral pneumonia.

In this retrospective study, we rigorously adjusted for critical illness using a nationally representative dataset to investigate whether COVID-19 pneumonia is independently linked to a higher risk of PE and DVT.

After comprehensive multivariate adjustment, our findings demonstrated that patients with COVID-19 pneumonia maintained significantly higher odds of developing acute inpatient PE [adjusted odds ratio (aOR): 2.48; 95% confidence interval (CI): 2.16-2.86; P<0.01] and DVT (aOR: 1.66; 95% CI: 1.41-1.96; P<0.01) during the early pandemic compared to patients with influenza pneumonia. Furthermore, we identified congenital heart disease and malnutrition as novel risk factors for acute PE in COVID-19 patients.

Our study suggests that the higher prevalence of acute inpatient PE over DVT in patients with COVID-19 pneumonia may support a "thrombus in situ" mechanism of SARS-CoV-2-mediated pulmonary thrombosis. Consequently, clinicians should maintain a high index of suspicion for PE, even in the absence of DVT, among patients with COVID-19 pneumonia and should follow evidence-based guidelines for diagnosis and management.

Pandemics like COVID-19 have illuminated the significant disparities in the performance of national healthcare systems (NHCSs) during rapidly evolving crises. The challenge of comparing NHCS performance has been a difficult topic in the literature. To address this gap, our study introduces a bi-criteria longitudinal algorithm that merges fuzzy clustering with Data Envelopment Analysis (DEA). This new approach provides a comprehensive and dynamic assessment of NHCS performance and efficiency during the early phase of the pandemic. By categorizing each NHCS as an efficient performer, inefficient performer, efficient underperformer, or inefficient underperformer, our analysis vividly represents performance dynamics, clearly identifying the top and bottom performers within each cluster of countries. Our methodology offers valuable insights for performance evaluation and benchmarking, with significant implications for enhancing pandemic response strategies. The study's findings are discussed from theoretical and practical perspectives, offering guidance for future health system assessments and policy-making.

Background: Multiple studies have linked COVID-19 to a higher incidence of thromboembolic disorders. However, the association of COVID-19 with other potentially life-threatening complications, such as splanchnic vein thrombosis, is less well understood. This study aims to assess the prevalence, patient characteristics, clinical presentation, and outcomes of patients with portal vein thrombosis (PVT) and COVID-19. Methods: This was a retrospective observational study. From all positive patients for a reverse-transcription polymerase chain reaction (RT-PCR) swab test from March 2020 to June 2020, we included those who were older than 18 years, had received abdominal contrast-enhanced computed tomography (CT) in the 6 months following the positive RT-PCR swab, and had no previously known splanchnic vein thrombosis. Results: A total of 60 patients with abdominal CT were selected from all those positive for SARS-CoV-2 (n = 2987). The prevalence of PVT was 3/60 (5%). The mean age was 66.1 ± 16.5 years and 51.7% were male. In two of the three patients, there was no underlying pathology as a risk factor for PVT and one of them presented cirrhosis. The number of days from the start of COVID-19 symptoms until the PVT diagnosis were 21, 12, and 10 days. Anticoagulation treatment achieved recanalization in 100% of cases. During a mean follow-up of 803 days, none of the patients experienced long-term complications. Conclusions: Portal vein thrombosis is uncommon, and its incidence may be higher in COVID-19 patients. A greater understanding of the features of this disease in the context of COVID-19 could aid towards its diagnosis and allow for early detection and management.

With many available data sources, clinicians need to consider the benefit-risk profile of individual anticoagulants when balancing the need for anticoagulation, including evaluating the risks in patients with comorbidities and potential drug-drug interactions. This narrative review presents clinical data across multiple phases of drug development for the use of apixaban, a selective factor Xa inhibitor, when taken concomitantly with other agents, and evaluates the benefit-risk profile of apixaban with these interacting medications. Key subgroup analyses from the phase 3 ARISTOTLE trial (NCT00412984) are presented using data from patients who received either concomitant inhibitors or inducers of cytochrome P450 3A4 and/or P‑glycoprotein. We also review the available evidence for the use of apixaban in patients with cancer-associated thromboembolism, as well as the use of apixaban in patients with COVID-19.

Background: Histidine-rich glycoprotein (HRG), a potential prognostic factor in sepsis, lacks clarity regarding its relevance in septic-induced shock, disseminated intravascular coagulation (DIC), and acute respiratory distress syndrome (ARDS) pathogenesis. This study investigated the association between HRG concentrations and these critical conditions. Methods: Blood samples were collected from 53 critically ill patients on days 1, 3, 5, and 7 after ICU admission at the Kyushu University Hospital. Daily clinical and laboratory data were recorded, and patient survival was assessed 28 days after ICU admission. Results: Serum HRG concentrations were significantly reduced on days 3, 5, and 7 in patients with septic shock and DIC but not in those with ARDS. While initial HRG levels on day one were not correlated with survival, nonsurvivors displayed decreased HRG levels, notably on days 3, 5, and 7 post-ICU admissions. The HRG levels remained stable in survivors. A progressive decrease was associated with higher mortality rates, particularly on days 5 and 7. On day 5, an HRG level with a cutoff of 25.5 μg/mL showed a sensitivity of 0.77 and a specificity of 0.75, indicating significantly lower survival rates (log-rank test, P < 0.05). Conclusion: HRG presents a potential intervention for critically ill sepsis patients, providing a novel strategy to enhance outcomes. Further research is needed to explore the therapeutic potential of HRG in sepsis management.

Several studies have shown the efficacy and safety of low-molecular-weight heparin use in coronavirus disease 2019 (COVID-19), but that of unfractionated heparin (UFH) has not been investigated. We investigated the prevalence of bleeding complications during UFH administration, its impact on mortality, and the risk factors of bleeding outcomes associated with UFH.

This retrospective cohort study was conducted at a single-center tertiary care hospital, including hospitalized patients with COVID-19. The primary outcomes were measured as the prevalence of bleeding complications during hospitalization, and the secondary outcomes were thromboembolic events and 60-day mortality rates. Logistic regression analysis and propensity score matching were used to assess risk factors for bleeding complications and their impact on mortality.

Among 1035 included patients, 516 patients were treated with UFH. Twelve (2.3%) patients in the UFH group experienced major bleeding. The prevalence of major bleeding in patients treated with therapeutic-dose UFH was 9.2%. Logistic regression analysis showed that age ≥ 60 years (adjusted odds ratio [aOR], 3.89; 95% confidence interval [CI], 1.01-15.0; P＜.05) and COVID-19 severity (aOR, 35.9; 95% CI, 4.57-282; P＜.05) were associated with major bleeding complications. After propensity score matching, 11 major and 11 non-major bleeding cases (including minor bleeding) were matched. The 60-day cumulative mortality rate between the two groups did not differ significantly (P=.13, log-rank test).

The incidence of major bleeding in COVID-19 patients using therapeutic-dose UFH was relatively high. Critical COVID-19 and older age were risk factors for bleeding complications.

BACKGROUND Thrombosis poses a grave threat to patients undergoing kidney transplants, with a heightened risk of mortality. While previous studies have established a link between COVID-19 and thrombosis, the specific association between COVID-19 and thrombosis in this patient population remains unexplored. MATERIAL AND METHODS We conducted a retrospective analysis utilizing data from 394 individuals who underwent kidney transplantation within the period of September 1, 2015, to April 1, 2023. To evaluate overall survival, we employed Kaplan-Meier analysis and utilized a logistic regression model for risk analysis. Furthermore, we developed a prediction model and assessed its accuracy through calibration curves. RESULTS Out of the 394 patients included in our study, a total of 51 individuals experienced thrombosis, resulting in 2 deaths. Our analysis revealed that COVID-19 infection significantly increased the risk of thrombosis (odds ratio [OR] 8.60, 95% confidence interval 3.13-24.74, P<0.01). Additionally, the use of cyclosporine was found to elevate the risk of death (OR 20.86, 95% CI 7.93-59.24, P<0.01) according to multifactorial analysis. Logistic models were employed to screen variables, and predictive models were constructed based on the presence of COVID-19 infection and the usage of cyclosporine. A nomogram was developed, demonstrating promising accuracy in estimating the risk of thrombosis during internal validation, with a corrected C-index of 0.869. CONCLUSIONS Our study suggests that both COVID-19 infection and the use of cyclosporine can serve as reliable predictors of thrombosis risk in patients undergoing renal transplantation. Furthermore, we developed a mortality risk prediction model based on COVID-19 in assessing thrombosis.

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.

Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets.

GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population.

Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively.

Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications.

Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.

Aberrant adrenal function has been frequently reported in COVID-19 patients, but histopathological evidence remains limited. This retrospective autopsy study aims to scrutinize the impact of COVID-19 duration on adrenocortical zonational architecture and peripheral corticosteroid reactivity. The adrenal glands procured from 15 long intensive care unit (ICU)-stay COVID-19 patients, 9 short ICU-stay COVID-19 patients, and 20 matched controls. Subjects who had received glucocorticoid treatment prior to sampling were excluded. Applying hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, we disclosed that the adrenocortical zonational structure was substantially disorganized in COVID-19 patients, which long ICU-stay patients manifested a higher prevalence of severe disorganization (67%) than short ICU-stay patients (11%; P = 0.0058). The adrenal cortex of COVID-19 patients exhibited a 40% decrease in the zona glomerulosa (ZG) area and a 74% increase in the zona fasciculata (ZF) area (both P < 0.0001) relative to controls. Furthermore, among long ICU-stay COVID-19 patients, the ZG area diminished by 31% (P = 0.0004), and the ZF area expanded by 27% (P = 0.0004) in comparison to short ICU-stay patients. The zona reticularis (ZR) area remained unaltered. Nuclear translocation of corticosteroid receptors in the liver and kidney of long ICU-stay COVID-19 patients was at least 43% lower than in short ICU-stay patients (both P < 0.05). These findings underscore the necessity for clinicians to monitor adrenal function in long-stay COVID-19 patients.

Endothelial instability is reported to be involved in the pathogenesis of COVID-19. The mechanism that regulates the endothelial dysfunction and disease virulence is not known. Studies on proteins that are released into circulation by activated endothelial cells may provide some means to understand the disease manifestation. The study investigated the circulating levels of two molecules Endoglin (Eng) and Syndecan-1 (SDC-1) that are presumed to be involved in the maintenance of endothelial integrity and their association with hypercoagulation marker in COVID-19 patients. The serum levels of Eng, SDC-1, D-mer were evaluated using ELISA at the time of admission (DOA) and day 7 post-admission among COVID-19 patients (N = 39 with 17 moderate and 22 severe cases). Compared to the time of admission, there was an increase in sEng and sSDC1 levels in all COVID-19 cases on day 7 post admission. The serum levels of sEng and sSDC-1 was significantly (P ≤ 0.001 & P ≤ 0.01 respectively) elevated in severe cases including the four deceased group compared to moderate cases on day 7 post admission. Further, the study molecules showed a strong positive association (P ≤ 0.001) with the hypercoagulation marker D-mer. The results show an early shedding of the endothelial proteins sEng and sSDC-1 into circulation as a host response to the viral infection during the febrile phase of infection. Increased levels of sEng and sSDC-1 along with D-mer could be beneficial in predicting COVID-19 disease severity.

Concerns about COVID-19-associated coagulopathy (CAC) in pregnant individuals were raised in early pandemic.

An ISTH-sponsored COVID-19 coagulopathy in pregnancy (COV-PREG-COAG) international registry was developed to describe incidence of coagulopathy, VTE, and anticoagulation in this group.

All pregnant patients with COVID-19 from participating centers were entered, providing 430 pregnancies for the first pandemic wave. Isolated abnormal coagulation parameters were seen in 20%; more often with moderate/severe disease than asymptomatic/mild disease (49% vs 15%; p < 0.0001). No one met the ISTH criteria for disseminated intravascular coagulopathy (DIC), though 5/21 (24%) met the pregnancy DIC score. There was no difference in antepartum hemorrhage (APH) with asymptomatic/mild disease versus moderate/severe disease (3.4% vs 7.7%; p = 0.135). More individuals with moderate/severe disease experienced postpartum hemorrhage (PPH) (22.4% vs 9.3%; p = 0.006). There were no arterial thrombotic events. Only one COVID-associated venous thromboembolism (VTE) was reported.

Low rates of coagulopathy, bleeding, and thrombosis were observed among pregnant people in the first pandemic wave.

Coagulation decompensation is one of the complications most frequently encountered in COVID-19 patients with a poor prognosis or long-COVID syndrome, possibly due to the persistence of SARS-CoV-2 infection in the cardiovascular system. To date, the mechanism underlying the alteration of the coagulation cascade in COVID-19 patients remains misunderstood and the anticoagulant protein S (PROS1) has been described as a potential risk factor for complications related to COVID-19, due to PLpro SARS-CoV-2 enzyme proteolysis.

Biopsies and blood samples were collected from SARS-CoV-2 positive and negative swab test subjects with coagulopathies (peripheral arterial thrombosis), and SARS-CoV-2 presence, ACE2 and CD147 expression, and plasmatic levels of PROS1 were evaluated.

We reported a significant decrease of plasmatic PROS1 in the coagulopathic SARS-CoV-2 swab positive cohort, in association with SARS-CoV-2 in situ infection and CD147 peculiar expression. These data suggested that SARS-CoV-2 associated thrombotic/ischemic events might involve PROS1 cleavage by viral PLpro directly in the site of infection, leading to the loss of its anticoagulant function.

Based on this evidence, the identification of predisposing factors, such as CD147 increased expression, and the use of PLpro inhibitors to preserve PROS1 function, might be useful for COVID-19 coagulopathies management.

ARDS is a syndrome that can develop as a result of various underlying diseases. For a long time, the prevailing belief was that the course of the disease was comparable regardless of the underlying disease. However, even before the COVID-19 pandemic, it was suspected that there were different manifestations that could be treated more individually and thus reduce the high mortality rate of ARDS, which has remained unchanged for years. The various findings on the heterogeneity of the course of the disease in COVID-related ARDS appear to confirm these assumptions. It is therefore to be expected that the diagnosis and treatment of non-COVID-related ARDS will also have to be individualised according to such phenotypes in the future. However, as long as the effectiveness of such strategies has not been proven in clinical trials, the current recommendations for ARDS therapy will remain valid for the time being. However, the adjustments already formulated in this context to individual pathophysiological conditions with regard to respiratory mechanics, ventilation-perfusion distribution and possible cardiac dysfunction should be made more meticulously than has usually been the case to date.

Acute pulmonary embolism (PE) is a common cardiovascular disorder, potentially associated with high morbidity and mortality rates.

Herein, we report on a patient with COVID-19 infection and bilateral PE, who presented after cardiovascular resuscitation with return of spontaneous circulation. Initially, an acute coronary syndrome was suspected but bedside echocardiography showed dilatation of the right ventricle (RV) and RV dysfunction, helping to establish the diagnosis of acute intermediate-to-high-risk PE, which was subsequently confirmed by contrast-enhanced computed tomography pulmonary angiography. The patient was successfully treated using low-dose (12 mg of tissue plasminogen) ultrasound-assisted catheter-directed thrombolysis, which resulted in prompt clinical improvement and reversal of RV dysfunction without bleeding complications.

This case demonstrates the importance of echocardiography for the differential diagnosis of PE and of catheter-directed thrombolysis for its treatment in patients with intermediate-to-high-risk and high-risk PEs.

The viral agent SARS-CoV-2 clearly affects several organ systems, including the cardiovascular system. Angiopoietins are involved in vascular integrity and angiogenesis. Angiopoietin-1 (Ang1) promotes vessel stabilization, while angiopoietin-2 (Ang2), which is usually expressed at low levels, is significantly elevated in inflammatory and angiogenic conditions. Interleukin-6 (IL-6) is known to induce defective angiogenesis via the activation of the Ang2 pathway. Vasculitis and vasculopathy are some of the defining features of moderate to severe COVID-19-associated systemic disease. We investigated the serum levels of angiopoietins, as well as interleukin-6 levels and anti-SARS-CoV2 IgG titers, in hospitalized COVID-19 patients across disease severity and healthy controls. Ang2 levels were elevated in COVID-19 patients across all severity compared to healthy controls, while Ang1 levels were decreased. The patients with adverse outcomes (death and/or prolonged hospitalization) had relatively lower and stable Ang1 levels but continuously elevated Ang2 levels, while those who had no adverse outcomes had increasing levels of both Ang1 and Ang2, followed by a decrease in both. These results suggest that the dynamic levels of Ang1 and Ang2 during the clinical course may predict adverse outcomes in COVID-19 patients. Ang1 seems to play an important role in controlling Ang2-related inflammatory mechanisms in COVID-19 patients. IL-6 and anti-SARS-CoV2 spike protein IgG levels were significantly elevated in patients with severe disease. Our findings represent an informative pilot assessment into the role of the angiopoietin signaling pathway in the inflammatory response in COVID-19.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global healthcare crisis. While SARS-CoV-2-associated COVID-19 affects primarily the respiratory system, patients with COVID-19 frequently develop extrapulmonary manifestations. Notably, changes in the hematological system, including lymphocytopenia, neutrophilia and significant abnormalities of hemostatic markers, were observed early in the pandemic. Hematological manifestations have since been recognized as important parameters in the pathophysiology of SARS-CoV-2 and in the management of patients with COVID-19. In this narrative review, we summarize the state-of-the-art regarding the hematological and hemostatic abnormalities observed in patients with SARS-CoV-2-associated COVID-19, as well as the current understanding of the hematological system in the pathophysiology of acute and chronic SARS-CoV-2-associated COVID-19.

Covid-19 infection is characterized by several acute complications, as well long-term sequelae, mostly sustained by endothelial dysfunction; several studies show that complications as pulmonary embolism (PE) are described both in the acute phase and after negativization. Aim of research was to evaluate anthropometric, bio-humoral, instrumental parameters in a group of patients affected by PE after recent Covid-19 infection compared to PE patients without previous Covid-19 infection. We enrolled 72 consecutive patients (35M, 37F) with acute PE, distinguished in relation to previous acute Covid-19 infection: 54 pts without previous acute Covid-19 infection and 18 pts with previous Covid-19 infection within negativity at least 2 months before PE diagnosis; 44 healthy subjects (21M, 23F) were recruited as control group. Patients who had previously developed Covid-19 needed hospitalization in high percentage (84%); this group showed significantly higher prevalence of diabetes mellitus than Covid-19-free PE patients, reduced serum levels of C-reactive protein, sST2 and PESI score. In post-Covid-19 PE group, we observed higher mean IMPROVE risk score, whereas in Covid-19-free group lower P/F ratio, higher radiological severity, and worse PESI score and severity index. Covid-19 infection affects not just the lung parenchyma but also other organs; endothelial damage plays pivotal role in long-term alterations; in high thrombotic risk group (recent hospitalization due to acute Covid-19 infection), we have described thrombotic complications characterized by persistent prothrombotic state after recovery, highlighted by well-known markers as PCR and D-Dimer as well as novel vascular marker (sST2).

Since the outbreak of COVID-19, countries around the world have faced huge economic and social burdens. SARS-COV-2 may exist in nature for a long time due to the diversity of its different variants. Pregnant women and newborns as vulnerable groups will suffer serious health threats. Bibliometrics as a method of summarizing publications can be used to extract important achievements and hot topics in this field. We search the target publications from the Web of Science Core collection database, and then use Microsoft Office Excel, CiteSpace, R, Scimago, and VOSviewer for visual analysis. Finally, we included 1709 publications from 2998 institutions in 104 countries. The number of publications has exploded since the COVID-19 pandemic in 2019. Among them, the USA, China, Britain, and Italy have higher quantity and quality. We identified important journals, authors, keywords, and references in this field. Anxiety, stress, risk of pregnancy complications, and vaccine safety and acceptance have received extensive attention from scholars during the COVID-19 pandemic and will continue to be urgent issues to be addressed in the future. Most of the current studies fall into the category of case reports and clinical data analysis. COVID-19 has been linked to serious pregnancy complications and mental illness, and vaccination during pregnancy is recommended to protect both mother and fetus. Further large-scale cohort studies and discovery of molecular mechanisms are needed in this field.

A link between inflammation and venous thromboembolism (VTE) in COVID-19 disease has been suggested pathophysiologically and clinically. The aim of this study was to investigate the association between inflammation and disease outcomes in adult hospitalized COVID-19 patients with VTE.

This was a retrospective observational study, including quantitative and qualitative data collected from COVID-19 patients hospitalized at the Infectious Diseases Unit (IDU) of the University Hospital of Ioannina, from 1 March 2020 to 31 May 2022. Venous thromboembolism was defined as a diagnosis of pulmonary embolism (PE) and/or vascular tree-in-bud in the lungs. The burden of disease, assessed by computed tomography of the lungs (CTBoD), was quantified as the percentage (%) of the affected lung parenchyma. The study outcomes were defined as death, intubation, and length of hospital stay (LoS). A chi-squared test and univariate logistic regression analyses were performed in IBM SPSS 28.0.

After propensity score matching, the final study cohort included 532 patients. VTE was found in 11.2% of the total population. In patients with VTE, we found that lymphocytopenia and a high neutrophil/lymphocyte ratio were associated with an increased risk of intubation and death, respectively. Similarly, CTBoD > 50% was associated with a higher risk of intubation and death in this group of patients. The triglyceride-glucose (TyG) index was also linked to worse outcomes.

Inflammatory indices were associated with VTE. Lymphocytopenia and an increased neutrophil-to-lymphocyte ratio negatively impacted the disease's prognosis and outcomes. Whether these indices unfavorably affect outcomes in COVID-19-associated VTE must be further evaluated.

COVID-19 is associated with a prothrombotic state. Current guidelines recommend prophylactic anticoagulation upon hospitalization.

COVID-PREVENT, an open-label, multicenter, randomized, clinical trial enrolled patients (≥ 18 years) with moderate to severe COVID-19 and age-adjusted D-dimers > 1.5 upper limit of normal (ULN). The participants were randomly assigned (1:1) to receive either therapeutic anticoagulation with rivaroxaban 20 mg once daily or thromboprophylaxis with a heparin (SOC) for at least 7 days followed by prophylactic anticoagulation with rivaroxaban 10 mg once daily for 28 days or no thromboprophylaxis. The primary efficacy outcome was the D-dimer level and the co-primary efficacy outcome the 7-category ordinal COVID-19 scale by WHO at 7 days post randomization. The secondary outcome was time to the composite event of either venous or arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause death or progression to intubation and invasive ventilation up to 35 days post randomization.

The primary efficacy outcome D-dimer at 7 days was not different between patients assigned to therapeutic (n = 55) or prophylactic anticoagulation (n = 56) (1.21 mg/L [0.79, 1.86] vs 1.27 mg/L [0.79, 2.04], p = 0.78). In the whole study population D-dimer was significantly lower at 7 days compared to baseline (1.05 mg/L [0.75, 1.48] vs 1.57 mg/L [1.13, 2.19], p < 0.0001). Therapy with rivaroxaban compared to SOC was not associated an improvement on the WHO 7-category ordinal scale at 7 days (p = 0.085). Rivaroxaban improved the clinical outcome measured by the score in patients with a higher baseline D-dimer  > 2.0 ULN (exploratory analysis; 0.632 [0.516, 0.748], p = 0.026). The secondary endpoint occurred in 6 patients (10.9%) in the rivaroxaban group and in 12 (21.4%) in the SOC group (time-to-first occurrence of the components of the secondary outcome: HR 0.5; 95% CI 0.15-1.67; p = 0.264). There was no difference in fatal or non-fatal major or clinically relevant non-major bleeding between the groups.

Therapeutic anticoagulation with rivaroxaban compared to prophylactic anticoagulation with a heparin did not improve surrogates of clinical outcome in patients with moderate to severe COVID-19. Whether initial rivaroxaban at therapeutic doses might be superior to thromboprophylaxis in patients with COVID-19 and a high risk as defined by D-dimer  > 2 ULN needs confirmation in further studies.

Even after 3 years from SARS-CoV-2 identification, COVID-19 is still a persistent and dangerous global infectious disease. Significant improvements in our understanding of the disease pathophysiology have now been achieved. Nonetheless, reliable and accurate biomarkers for the early stratification of COVID-19 severity are still lacking. Long noncoding RNAs (LncRNAs) are ncRNAs longer than 200 nucleotides, regulating the transcription and translation of protein-coding genes and they can be found in the peripheral blood, thus holding a promising biomarker potential. Specifically, peripheral blood mononuclear cells (PBMCs) have emerged as a source of indirect biomarkers mirroring the conditions of tissues: they include monocytes, B and T lymphocytes, and natural killer T cells (NKT), being highly informative for immune-related events.

We profiled by RNA-Sequencing a panel of 2906 lncRNAs to investigate their modulation in PBMCs of a pilot group of COVID-19 patients, followed by qPCR validation in 111 hospitalized COVID-19 patients.

The levels of four lncRNAs were found to be decreased in association with COVID-19 mortality and disease severity: HLA Complex Group 18-242 and -244 (HCG18-242 and HCG18-244), Lymphoid Enhancer Binding Factor 1-antisense 1 (LEF1-AS1) and lncCEACAM21 (i.e. ENST00000601116.5, a lncRNA in the CEACAM21 locus). Interestingly, these deregulations were confirmed in an independent patient group of hospitalized patients and by the re-analysis of publicly available single-cell transcriptome datasets. The identified lncRNAs were expressed in all of the PBMC cell types and inversely correlated with the neutrophil/lymphocyte ratio (NLR), an inflammatory marker. In vitro, the expression of LEF1-AS1 and lncCEACAM21 was decreased upon THP-1 monocytes exposure to a relevant stimulus, hypoxia.

The identified COVID-19-lncRNAs are proposed as potential innovative biomarkers of COVID-19 severity and mortality.

Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability.

To determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation.

We analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline.

Increased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes.

Moderately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

Covid-19 disease causes an immense burden on the healthcare system. It has not yet been finally clarified which patients will suffer from a severe course and which will not. Coagulation disorders can be detected in many of these patients. The aim of the present study was therefore to identify variables of the coagulation system including standard and viscoelastometric tests as well as components of glycocalyx damage that predict admission to the intensive care unit.

Adult patients were included within 24 h of admission. Blood samples were analyzed at hospital admission and at ICU admission if applicable. We analyzed group differences and furthermore performed receiver operator characteristics (ROC).

This study included 60 adult COVID-19 patients. During their hospital stay, 14 patients required ICU treatment. Comparing ICU and non-ICU patients at time of hospital admission, D-dimer (1450 µg/ml (675/2850) vs. 600 µg/ml (500/900); p = 0.0022; cut-off 1050 µg/ml, sensitivity 71%, specificity 89%) and IL-6 (47.6 pg/ml (24.9/85.4 l) vs. 16.1 pg/ml (5.5/34.4); p = 0.0003; cut-off 21.25 pg/ml, sensitivity 86%, specificity 65%) as well as c-reactive protein (92 mg/dl (66.8/131.5) vs. 43.5 mg/dl (26.8/83.3); p = 0.0029; cutoff 54.5 mg/dl, sensitivity 86%, specificity 65%) were higher in patients who required ICU admission. Thromboelastometric variables and markers of glycocalyx damage (heparan sulfate, hyaluronic acid, syndecan-1) at the time of hospital admission did not differ between groups.

General inflammatory variables continue to be the most robust predictors of a severe course of a COVID-19 infection. Viscoelastometric variables and markers of glycocalyx damage are significantly increased upon admission to the ICU without being predictors of ICU admission.

Antiphospholipid antibodies (APLA) are strongly associated with thrombosis seen in patients with antiphospholipid syndrome. In COVID-19, thrombosis has been observed as one of the main comorbidities. In patients hospitalised for COVID-19, we want to check whether APLA positivity is associated with COVID-19-related thrombosis, inflammation, severity of disease, or long COVID-19. We enrolled 92 hospitalised patients with COVID-19 between March and April 2020 who were tested for 18 different APLAs (IgG and IgM) with a single line-immunoassay test. A total of 30 healthy blood donors were used to set the cut-off for each APLA positivity. Of the 92 COVID-19 inpatients, 30 (32.61%; 95% CI [23.41-43.29]) tested positive for APLA, of whom 10 (33.3%; 95% CI [17.94-52.86]) had more than one APLA positivity. Anti-phosphatidylserine IgM positivity was described in 5.4% of inpatients (n = 5) and was associated with the occurrence of COVID-19-related thrombosis (p = 0.046). Anti-cardiolipin IgM positivity was the most prevalent among the inpatients (n = 12, 13.0%) and was associated with a recorded thrombosis in their clinical history (p = 0.044); however, its positivity was not associated with the occurrence of thrombosis during their hospitalisation for COVID-19. Anti-phosphatidylinositol IgM positivity, with a prevalence of 5.4% (n = 5), was associated with higher levels of interleukin (IL)-6 (p = 0.007) and ferritin (p = 0.034). Neither of these APLA positivities was a risk factor for COVID-19 severity or a predictive marker for long COVID-19. In conclusion, almost a third of COVID-19 inpatients tested positive for at least one APLA. Anti-phosphatidylserine positivity in IgM class was associated with thrombosis, and anti-phosphatidylinositol positivity in IgM class was associated with inflammation, as noticed by elevated levels of IL-6. Thus, testing for non-criteria APLA to assess the risk of clinical complications in hospitalised COVID-19 patients might be beneficial. However, they were not related to disease severity or long COVID-19.

The course of COVID-19 is highly dependent on the associated cardiometabolic comorbidities of the patient, which worsen the prognosis of coronavirus infection, mainly due to systemic inflammation, endothelium dysfunction, and thrombosis. A search on the recent medical literature was performed in five languages, using the PubMed, Embase, Cochrane, and Google Scholar databases, for the review of data regarding the management of patients with a high risk for severe COVID-19, focusing on the associated coagulopathy. Special features of COVID-19 management are presented, based on the underlying conditions (obesity, diabetes mellitus, and cardiovascular diseases), emphasizing the necessity of a modern, holistic approach to thromboembolic states. The latest findings regarding the most efficient therapeutic approaches are included in the article, offering guidance for medical professionals in severe, complicated cases of SARS-CoV-2 infection. We can conclude that severe COVID-19 is closely related to vascular inflammation and intense cytokine release leading to hemostasis disorders. Overweight, hyperglycemia, cardiovascular diseases, and old age are important risk factors for severe outcomes of coronavirus infection, involving a hypercoagulable state. Early diagnosis and proper therapy in complicated SARS-CoV-2-infected cases could reduce mortality and the need for intensive care during hospitalization in patients with cardiometabolic comorbidities.

The endothelium is supposedly activated and damaged in COVID-19 because of endothelin-1 over-secretion. This study evaluates the effect of bosentan as an endothelin receptor blocker on the progression of disease in high-risk outpatients with COVID-19 infection.

From 15 December 2021 to 15 May 2022, high-risk outpatients were randomly assigned to receive bosentan, 62.5 mg or placebo twice daily from enrollment for 30 days. Both groups received standard medical treatment too. On day 30 of the trial, the patients underwent complete doppler ultrasound of the lower extremities to detect asymptomatic thromboembolic events. The primary outcome in this study was hospitalization or death from any cause within the first 15 days. Secondary outcomes included thromboembolic events, hospital-free days and death from any cause within 30 days after randomization (IRCT.ir, IRCT20211203053263N1).

Basal characteristics of the two groups were similar. Primary outcomes occurred in 3 (2.3%) of the 129 patients in the bosentan group versus 15 (11.5%) of the 130 patients in the placebo group [risk difference: -9.2% (95% CI: -15.3 to -3.1), P = 0.006]. Median hospital-free days was significantly higher in the bosentan group (P = 0.004). A total of three deaths occurred and all were in the control group. Bosentan was associated with a nonsignificant reduction in mortality compared with placebo (P = 0.24). Thromboembolic events occurred in one (1%) of 97 patients in the bosentan group versus nine (8.7%) of 104 patients in the placebo group within 30 days after randomization [risk difference: -8.3% (95% CI: -14.4 to -2.2), P = 0.008].

Early administration of bosentan may prevent disease progression and thromboembolic events in high-risk outpatients with COVID-19.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

We carried out a meta-analysis since there is not enough evidence to recommend for or against therapeutic-dose anticoagulation compared with thromboprophylaxis in noncritically ill patients hospitalized with Covid-19.

We performed a systematic literature search using PubMed, Embase, Cochrane Library, and MedRxiv for randomized trials that included therapeutic-dose with low-molecular-weight heparin (LMW) or thromboprophylaxis with LMW heparin in noncritically ill patients admitted to the hospital with Covid-19. We identified five open-label studies for analysis with a total of 3220 patients. Two independent researchers selected, assessed, and extracted the data in duplicate. The outcomes evaluated were all-cause mortality, progression to invasive mechanical ventilation, incidence of venous thromboembolism, and major bleeding. The studies did not show risk for selection, detection, attrition, or reporting bias.

Therapeutic-dose anticoagulation with LMW heparin compared with thromboprophylaxis with LMW heparin had no significant effect of all-cause death (risk ratio [RR] 0.85; 95% confidence interval [CI] 0.67-1.07; P = 0.16; I2 = 48%), or progression to invasive mechanical ventilation (RR 0.89; CI 0.73-1.08; P = 0.24; I2: 0%). Therapeutic-dose anticoagulation significantly reduced the risk of venous thromboembolic disease (RR 0.42; 95% CI 0.28-0.62; P = 0.0001; I2 = 0%) [Number needed to treat = 37]. Major bleeding occurred in 1.79% of the patients receiving therapeutic-dose anticoagulation and in 0.97% of those receiving thromboprophylaxis [Number needed to harm 125].

Therapeutic-dose anticoagulation in noncritically ill patients with Covid-19 could be indicated for patients at high risk of venous thromboembolic disease and low risk of bleeding.