Intravenous Thrombolysis for Acute Ischemic Stroke during COVID-19 Pandemic in Srinagarind Hospital

Background: Stroke is the leading cause of death and disability worldwide. In COVID-19 pandemic, stroke remains to be a medical emergency. To treat patients with acute ischemic stroke [AIS], early intravenous thrombolysis is highly time sensitive. This research investigated the impact of regionally imposed social and healthcare restrictions of COVID-19 on the time metrics in the management of AIS patients admitted at the stroke unit center in Srinagarind Hospital. Objective(s): Comparison of door to needle time for intravenous thrombolysis for AIS patients before and after the COVID-19 outbreak. Material(s) and Method(s): The present study is a retrospective analysis of patients with AIS who received intravenous tissue plasminogen activator [tPA] from 1 January 2019 to 31 December 2020 in Srinagarind Hospital, Khon Kaen. The patients admitted before and after the COVID-19 outbreak [January 13, 2020, as officially announced by the World Health Organization] were screened to collect sociodemographic data, medical history information, and symptom onset status from clinical medical records and to compared door-to-needle time (DNT) for intravenous thrombolysis before and after the outbreak. Result(s): A total of 239 patients were included, of which 113 were enrolled before and 126 after the COVID-19 outbreak. According to the findings, DNT is 35.3 minutes before the pandemic and 35.8 minutes after the epidemic. Conclusion(s): COVID-19 has remarkable impacts on the management of AIS. However, DNT for before and after COVID-19 outbreak is nearly identical. It was established that administering intravenous thrombolysis to patients in the emergency room rather than the stroke unit allowed for speedier access. Therefore, a policy which provides quick AIS treatments in COVID-19 situations should be implemented.Copyright © 2023 Journal of the Medical Association of Thailand.

Efficacy and safety of thrombolysis in COVID19 related ARDS.

INTRODUCTION: COVID19 causes significant pulmonary microthrombi in some individuals, which can lead to ARDS and death. Thrombolysis could be an effective approach in some patients with severe ARDS. We describe our experience with usage of thrombolytic agents in COVID19 critically ill patients, who were in worsening respiratory failure. METHODOLOGY: Retrospective chart analysis was done in patients who were thrombolysed between May 2020- Sept 2020. Analysis was done to find out factors associated with improvement in oxygenation and survival. RESULTS: Twenty seven patients with severe ARDS [all had respiratory rate >30, FiO2 >0.6(on NIV/HFNC) and PiO2/FiO2 ratio<120] were thrombolysed in our ICU for COVID19 causes. C.T. Pulmonary Angiography could not be done in any of the 27 patients due to poor general condition, but 2D echo was normal in most (5 had dilated RA,RV) and none of the patients was in shock. So there was no conventional indication of thrombolysis in these patients, yet after thrombolysis, we saw dramatic changes in oxygenation (defined by decrease in FiO2 by ≥0.2) in twenty patients. Five patients had major bleed. Eleven patients survived (survival rate of 40.7%) and survival rate was high { 66% (8/12)} in patients who were thrombolysed within 2 days of oxygen requirement. CONCLUSION: In this unprecedented pandemic with high mortality rates, efficacy of early thrombolysis needs to be further explored in randomised controlled trials.

Intravenous thrombolysis for acute ischemic stroke during two COVID-19 outbreaks in China: Wuhan pandemic and Beijing pandemic.

INTRODUCTION: The COVID-19 pandemic has had an impact on the emergency department (ED). Door-to-needle time (DNT) could be prolonged for intravenous thrombolysis (IVT) treatment. We aimed to investigate the impact of two COVID-19 pandemics on the workflow of IVT in our neurovascular ED. METHOD: We performed a retrospective analysis of patients who received IVT treatment in the neurovascular ED of Beijing Tiantan Hospital, Beijing, from January 20, 2020, to October 30, 2020, covering two COVID-19 pandemics in China. The time-based performances of IVT treatment including onset-to-arrival time, arrival-to-CT time, CT-to-needle time, door-to-needle time, and onset-to-needle time were recorded. Data on clinical characteristics and imaging information were also collected. RESULTS: Four hundred forty patients that received IVT were enrolled in this study. The number of patients admitted to our neurovascular ED began to decrease in December 2019 and was the lowest in April 2020 (n = 95). Longer DNT (Wuhan pandemic: 49.00 [35.00, 64.00] min; Beijing pandemic: 55.00 [45.50, 77.00] min) interval delays were observed during the two pandemics (p = .016). More patients admitted during the two pandemics had an 'unknown' subtype (Wuhan pandemic: 21.8%; Beijing pandemic: 31.4%. p = .008). The percentage of the cardiac embolism subtype was higher during the Wuhan pandemic (20.0%) than during other periods. The median admission NIHSS score increased during the Wuhan pandemic and the Beijing pandemic (8.00 [4.00, 12.00], 7.00 [4.50, 14.00], respectively, p < .001). CONCLUSION: The number of patients who received IVT decreased during the Wuhan pandemic. Higher admission NIHSS scores and prolonged DNT intervals were also observed during the Wuhan pandemic and the Beijing pandemic.

Multisystem Inflammatory Syndrome in Children Requiring ECMO: Anticoagulation strategies and Lessons Learned

Intro: Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious inflammatory response after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which can cause acute cardiac dysfunction requiring mechanical circulatory support (MCS). MCS utilization for MIS-C is complicated by a propensity for thrombosis, which threatens circuit integrity. This study describes a cohort of MIS-C patients requiring MCS, their outcomes, and the anticoagulation strategies utilized. Method(s): A retrospective case series of patients diagnosed with MIS-C needing veno-arterial extracorporeal membrane oxygenation (VA-ECMO) at Children's Healthcare of Atlanta from March 1, 2020 to June 30, 2022. VA-ECMO variables, laboratory data, complications, and outcomes were collected. Result(s): Seven patients (all male) with severe MIS-C required VA-ECMO for acute cardiac dysfunction. Median age was 13 years (range 4-15 years). Median ICU stay was 13 days (range 6-17 days) with a median ECMO duration of 7 days (IQR 3-8 days) and median mechanical ventilation duration of 8 days (IQR 5-11 days). All seven patients survived to hospital discharge with good neurologic outcomes. Median time to qualitatively normal ventricular function by echocardiogram was 9.5 days (IQR 3-21 days). Heparin was initially used in 6 patients, bivalrudin initially used in 1 patient, and 1 patient converted from heparin to bivalirudin for refractory systemic thrombosis. Median heparin dose was 206u/kg/d (IQR 192-276u/kg/d) with median anti-Xa levels of 0.75 (IQR 0.1-1.1) and median daily PTT 102 seconds (IQR 83-107 seconds). Median daily PTT of patients receiving bivalirudin was 86 seconds (80-93 seconds). Median R-values by thromboelastography were 38 seconds (IQR 25-55 seconds). Two patients required catheter directed thrombolysis with tissue plasminogen activator (t-PA) for refractory intracardiac thrombi, both were initially started on heparin. Significant cannula thrombosis occurred in 2 patients, 1 initially started on heparin and 1 initially on bivalrudin. Bleeding resulting in compartment syndrome occurred in one patient on heparin requiring fasciotomy of the upper extremities, this patient was not receiving t-PA. Conclusion(s): Anticoagulation management for MIS-C patients requiring ECMO is fraught with challenges. A successful management strategy may necessitate higher heparin assay levels, the use of direct thrombin inhibitors for refractory thrombosis, and the deployment of catheter directed thrombolysis. In this case series, CDT was safely and successfully used in two patients. Further studies are required to understand the optimal anticoagulation strategy for these patients to minimize complications.

Early Inflammatory Profiles Predict Maximal Disease Severity in Covid-19

Background: Better understanding of host inflammatory changes that precede development of severe COVID-19 could improve delivery of available antiviral and immunomodulatory therapies, and provide insights for the development of new therapies. Method(s): In plasma from individuals with COVID-19, sampled <=10 days from symptom onset from the All-Ireland Infectious Diseases Cohort study, we measured 61 biomarkers, including markers of innate immune and T cell activation, coagulation, tissue repair, lung injury, and immune regulation. We used principal component analysis (PCA) and k-means clustering to derive biomarker clusters, and univariate and multivariate ordinal logistic regression to explore association between cluster membership and maximal disease severity, adjusting for risk factors for severe COVID-19, including age, sex, ethnicity, BMI, hypertension and diabetes. Result(s): From March 2020-April 2021, we included 312 individuals, (median (IQR) age 62 (48-77) years, 7 (4-9) days from symptom onset, 54% male) in the analysis. PCA and clustering derived 4 clusters. Compared to cluster 1, clusters 2-4 were significantly older and of higher BMI but there were no significant differences in sex or ethnicity. Cluster 1 had low levels of inflammation, cluster 2 had higher levels of markers of tissue repair and endothelial activation (EGF, VEGF, PDGF, TGFalpha, serpin E1 and p-selectin). Cluster 3 and 4 were both characterised by higher overall inflammation, but compared to cluster 4, cluster 3 had downregulation of growth factors, markers of endothelial activation, and immune regulation (IL10, PDL1), but higher alveolar epithelial injury markers (RAGE, ST2). In univariate analysis, compared to cluster 1, cluster 3 had the highest odds of severe disease (OR (95% CI) 9.02 (4.62-18.31), followed by cluster 4: 5.59 (2.75-11.72) then cluster 2: 4.5 (2.38-8.81), all p < 0.05). Cluster 3 remained most strongly associated with severe disease in fully adjusted analyses;cluster 3: OR(95% CI) 5.99 (2.69-13.35), cluster 2: 3.14 (1.54-6.42), cluster 4: 3.13 (1.36-7.19), all p< 0.05). Conclusion(s): Distinct early inflammatory profiles predicted maximal disease severity independent of known risk factors for severe COVID-19. A cluster characterised by downregulation of growth factor and endothelial markers and early evidence of alveolar injury was associated with highest risk of developing severe COVID19. Whether this reflects a dysregulated inflammatory response that could improve targeted treatment requires further study. Heatmap of biomarker derived clusters and forest plot of association between clusters and disease severity. A: Heatmap demonstrating differences in biomarkers between clusters B: Forest plot demonstrating odds ratio of specific clusters for progressing to moderate or severe disease (reference Cluster 1), calculated using ordinal logistic regression. Odds ratio (95% CI) presented as unadjusted and fully adjusted (for age, sex, ethnicity, BMI, hypertension, diabetes, immunosuppression, smoking and baseline anticoagulant use). Maximal disease severity graded per the WHO severity scale.

"Super" SERPINs-A stabilizing force against fibrinolysis in thromboinflammatory conditions.

The superfamily of serine protease inhibitors (SERPINs) are a class of inhibitors that utilise a dynamic conformational change to trap and inhibit their target enzymes. Their powerful nature lends itself well to regulation of complex physiological enzymatic cascades, such as the haemostatic, inflammatory and complement pathways. The SERPINs α2-antiplasmin, plasminogen-activator inhibitor-1, plasminogen-activator inhibitor-2, protease nexin-1, and C1-inhibitor play crucial inhibitory roles in regulation of the fibrinolytic system and inflammation. Elevated levels of these SERPINs are associated with increased risk of thrombotic complications, obesity, type 2 diabetes, and hypertension. Conversely, deficiencies of these SERPINs have been linked to hyperfibrinolysis with bleeding and angioedema. In recent years SERPINs have been implicated in the modulation of the immune response and various thromboinflammatory conditions, such as sepsis and COVID-19. Here, we highlight the current understanding of the physiological role of SERPINs in haemostasis and inflammatory disease progression, with emphasis on the fibrinolytic pathway, and how this becomes dysregulated during disease. Finally, we consider the role of these SERPINs as potential biomarkers of disease progression and therapeutic targets for thromboinflammatory diseases.

A Case of Bilateral Cerebral Venous Sinus Thrombosis: More Than Meets the Eye.

Cerebral venous sinus thrombosis (CVST) is a rare etiology of stroke that results from inherited and/or acquired conditions, which can present in a variety of symptoms. CVST in the setting of the 2019 coronavirus disease (COVID-19) has rarely been observed. Herein, we present the case of a 32-year-old female with a recent history of COVID-19 subsequently found to have CVST involving bilateral transverse sinuses. Further workup demonstrated several hypercoagulable conditions, which were likely exacerbated by the viral infection. This case demonstrates an atypical outcome for young, COVID-19-positive patients, which emphasizes the importance of diligence when examining symptomatic patients with a history of COVID-19 infection. The patient was treated with apixaban therapy with radiographic resolution of bilateral CVST and improved vision.

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

Comparison of Perindopril vs. Losartan With Regard to Pro-Coagulation Factors in Adipocytes Exposed to Sars-Cov-2 Spike Protein

Background: Obesity is a strong risk factor for more severe Covid-19 infection as adipocytes play an important role in intermediating the spreading, replication, and release of SARS-COV-2. An increase in pro-coagulation factors (tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)) was observed in Covid-19 patients with moderate to severe symptoms and is reported to be associated with Angiotensin-converting enzyme 2 (ACE2) overexpression. Cardiovascular medications affecting ACE2, such as Perindopril and Losartan, are hypothesized to have an effect on Covid-19 infection-related coagulopathy. This study aims to identify and compare the effect of perindopril and losartan on TF and PAI-1 levels in adipocytes exposed to SARS-COV-2 spike protein. Method(s): Adipocytes were isolated enzymatically from adipose tissue obtained from an obese male donor. Adipocytes were then exposed to SARS-COV-2 S1 spike protein for 24 hours. After exposure, perindopril and losartan were added to the culture medium. ACE2, TF, and PAI-1expression were measured 2 hours later using ELISA. Result(s): SARS-CoV-2 spike protein exposure increased ACE2, TF, and PAI-1 expression. Perindopril addition discernible reduced the tissue factor (TF) expression (4.843 +/- 0.396) compared to a positive control (6.857 +/- 0.228) (p=0.005) but not losartan (5.624 +/- 0.606) (p=0.111). Perindopril was also able to lower PAI-1 expressions (3.484 +/- 0.252) compared to a positive control (4.865 +/- 0.115) (p=0.001), but the losartan did so more effectively (2.633 +/- 0.269) (p=0.000). Conclusion(s): Losartan and perindopril both have the ability to lower pro-coagulation factors, proving the value of ACEIs/ARBs in preventing thrombotic complications in Covid-19 patients.Copyright © 2023

Coagulopathies after vaccination against SARS-CoV-2: The sole solution might lead to another problem

The common reported adverse impacts of COVID-19 vaccination include the injection site's local reaction followed by various non-specific flu-like symptoms. Nevertheless, uncommon cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) following viral vector vaccines (ChAdOx1 nCoV-19 vaccine, Ad26.COV2 vaccine) have been reported. This literature review was performed using PubMed and Google Scholar databases using appropriate keywords and their combinations: SARS-CoV-2, adenovirus, spike protein, thrombosis, thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia (VITT), NF-kappaB, adenoviral vector, platelet factor 4 (PF4), COVID-19 Vaccine, AstraZeneca COVID vaccine, ChAdOx1 nCoV-19 COVID vaccine, AZD1222 COVID vaccine, coagulopathy. The s and titles of each article were assessed by authors for screening and inclusion English reports about post-vaccine CVST and VITT in humans were also collected. Some SARS-CoV-2 vaccines based on viral vector, mRNA, or inactivated SARS-CoV-2 virus have been accepted and are being pragmatic global. Nevertheless, the recent augmented statistics of normally very infrequent types of thrombosis associated with thrombocytopenia have been stated, predominantly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The numerical prevalence of these side effects seems to associate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the meticulous molecular mechanisms are still not clear. The present review summarizes the latest data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis demonstrating that coagulopathies, including thromboses, thrombocytopenia, and other associated side effects, are correlated to an interaction of the two components in the COVID-19 vaccine.Copyright © 2022, Iranian Pediatric Hematology and Oncology Society. All rights reserved.

Comparison of Activity and Safety of DSPAα1 and Its N-Glycosylation Mutants.

DSPAα1 is a potent rude thrombolytic protein with high medicative value. DSPAα1 has two natural N-glycan sites (N153Q-S154-S155, N398Q-K399-T400) that may lead to immune responses when administered in vivo. We aimed to study the effect of its N-glycosylation sites on DSPAα1 in vitro and in vivo by mutating these N-glycosylation sites. In this experiment, four single mutants and one double mutant were predicted and expressed in Pichia pastoris. When the N398Q-K399-T400 site was mutated, the fibrinolytic activity of the mutant was reduced by 75%. When the N153Q-S154-S155 sites were inactivated as described above, the plasminogen activating activity of its mutant was reduced by 40%, and fibrin selectivity was significantly reduced by 21-fold. The introduction of N-glycosylation on N184-G185-A186T and K368N-S369-S370 also considerably reduced the activity and fibrin selectivity of DSPAα1. The pH tolerance and thermotolerance of all mutants did not change significantly. In vivo experiments also confirmed that N-glycosylation mutations can reduce the safety of DSPAα1, lead to prolonged bleeding time, non-physiological reduction of coagulation factor (α2-AP, PAI) concentration, and increase the risk of irregular bleeding. This study ultimately demonstrated the effect of N-glycosylation mutations on the activity and safety of DSPAα1.

Relationship of fibrinolysis system proteins with severity of COVID-19. A review of current clinical data and promising therapeutic strategies

Modern clinical studies show the association of fibrinolysis system factors with complications following COVID-19. This review includes the studies describing the relationship of urokinase plasminogen activator proteins uPA and its receptor uPAR, plasmin-ogen activator inhibitor PAI-1 and plasmin itself with severity of COVID-19. Potential of diagnosis based on analysis of concen-trations and activities of these proteins, as well as expression of their encoding genes is described. These data can predict severe course and possible complications of COVID-19 including thrombosis, respiratory failure and cytokine storm. © 2022, Media Sphera Publishing Group. All rights reserved.

Androgen deprivation therapy and hormonal status in men with COVID-19.

Severe course of cOVID-19 among men compared to the female led to a detailed study of the hormonal status of men with cOVID-19. The earliest works about this focused on the incidence and severity of cOVID-19 depending on the intake of androgen deprivation therapy. At the same time, different classes of androgen deprivation therapy have different effects on androgen concentration that was not always considered in the analysis. In this regard, we conducted a review of the available literature data with a targeted study of works that included androgen deprivation therapy with a unidirectional effect on the concentration of male sex hormones. In addition, we conducted a review of studies focused on the relationship between cOVID-19 and androgens (testosterone and dihydrotestosterone).Copyright © 2022 Authors. All rights reserved.

Plasminogen activator inhibitor-1 (PAI-1) like the best mortality predictor of in the COVID-19-associated pneumonia

The aim was to estimate the prognostic role of PAI-1 on admission in hospitalized patients with confirmed COVID-19 pneumonia. Material(s) and Method(s): We observed 2 groups: Main - 85 patients (59 (52;65) years, men - 45 (52.9%)), hospitalized with COVID-19 pneumonia;Control - 25 healthy volunteers (50.0 (35;65) years, men - 13 (52.0%)). General tests, PAI-1 (ELISA Kit, Elabscience) before anticoagulants, autopsy data, statistic. Result(s): At admission the level of PAI-1 in Main group was in 60 times higher than in Control group (6.1 [0.15;18] ng/ml versus 0.1 [0.09;0.11] ng/ml, p=0,000). Despite the adequate treatment 12 patients died from COOVID-19 pneumonia. Maximal levels of PAI-1 were in died patients. ROC analysis shows the powerful reliable connection between increased level of PAI-1 higher than 20,6 ng/ml at admission and COVID-19 mortality (OR=219;CI=95% (7,7056 to 6224,1404);p=0,0016). Conclusion(s): 1) problem in fibrinolysis plays the crucial role in thrombogenesis in COVID-19;2) increased PAI-1 more than 20 ng/l is associated with 200-times higher risk of mortality. (Figure Presented).

The diagnostic and prognostic role of plasminogen activator inhibitor-1 (PAI-1) in hospitalized patients with pneumonias of different etiologies

Aim: to estimate the diagnostic and prognostic role of PAI-1 on admission in hospitalized patients with confirmed COVID-19 pneumonia, comparing with bacterial pneumonia. Material(s) and Method(s): We observed 3 groups: Main (1) - 85 patients (59 (52;65) years, men - 45 (52.9%)), hospitalized with COVID-19 pneumonia (40 patients with moderate, 25 patients with severe, 20 patients with critical);Comparative (2) - 55 patients (48.9 (34;62) years, men - 30 (54.5%)), hospitalized with communityacquired pneumonia of bacterial etiology (CABP) without COVID-19;Control (3) - 25 healthy volunteers (50.0 (35;65) years, men - 13 (52.0%)). General tests, plasma level of PAI-1 (ELISA Kit, Elabscience) before starting of anticoagulants, statistic. Result(s): The highest level of PAI-1 (6.1 [0.15;18] ng/ml) was in Main group and exceeds the Control group (0.1 [0.09;0.11] ng/ml), p1-3=0,000) in more than 60 times. PAI-1 in CABP didn't differ from Control group (Fig.1) The highest levels of PAI-1 at admission had patients with severe and critical course of COVID-19. Conclusion(s): 1) significantly increase of PAI-1 in COVID-19 pneumonia demonstrates the cornerstone in thrombogenesis of this disease - problems in fibrinolysis system, which is the main difference between CABP;2) PAI-1 is associated with COVID-19 severity and could be the crucial marker for patients' distribution. (Figure Presented).

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

PORTAL VEIN THROMBOSIS WHILE TAKING A COMBINED ORAL CONTRACEPTIVE AFTER EXPERIENCED CORONAVIRUS INFECTION.

Background: Contraceptives are an important component of women's reproductive health care, as they not only reduce the number of unwanted pregnancies, but also improve reproductive function. However, oral contraceptives are known to increase the risk of venous thromboembolism. This risk is increased by infection with the COVID-19 virus that predisposes patients to both venous and arterial thrombosis as a result of excessive inflammation, platelet activation, aggravated endothelial dysfunction, and congestive events. If these patients have hereditary thrombophilia, the risk of venous thromboembolism becomes fatal. Case report: The paper describes a clinical case of a patient with total portal vein thrombosis, who have been taking oral contraceptives for a long time and recovering from the novel coronavirus infection. Studying the blood coagulation system and folate cycle genes, by using PCR, has revealed a gene mutation in the plasminogen activator inhibitor (serpine). The authors demonstrate the data of spiral computed tomography of the abdominal organs, as well as changes in laboratory parameters. Conclusion(s): A balanced approach is required when prescribing combined oral contraceptives during the COVID-19 pandemic, especially in women with prothrombotic mutations.Copyright © A group of authors, 2023.

SARS-CoV-2 Therapy: Old Drugs as New Interventions

An outburst of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a grave threat to global health and the economy. As of May 13, 2020, a total of 42,81,838 cases have been confirmed, with over 2,92,376 deaths worldwide. In India, 75,048 cases have been reported to date with 2,440 deaths. Management of this new coronavirus (COVID19) has mainly focused on infection prevention, case detection, monitoring, and supportive care. As there is no vaccine or specific antiviral treatment for human SARS-CoV-2, therefore identifying the drug treatment options as soon as possible is critical for the response to the COVID19 outbreak. Pro-inflammatory cascade and cytokine storm play a key role in the pathogenesis of new coronavirus. A large number of therapeutic interventions such as antiviral, antimalarial, convalescent plasma therapy, BCG vaccine, mTOR inhibi-tors, Tissue Plasminogen Activator, Human monoclonal antibodies, Anti-parasitic agents, Immunoen-hancers, Nutritional interventions, JAK-STAT signaling inhibitors, ACE2 receptor modulators, and An-giotensin II receptor blockers have been either tried or suggested for effective treatment of patients with SARS-CoV-2 disease. Hence, we recommend that all the above potential interventions must be imple-mented in terms of their safety and efficacy through proper clinical experiments to control the emerging SARS-CoV-2 disease.Copyright © 2021 Bentham Science Publishers.

COVID-19-associated lung microvascular endotheliopathy: a "from the bench" perspective

Rationale: Autopsy and biomarker studies suggest that endotheliopathy contributes to coronavirus disease (COVID-19)-associated acute respiratory distress syndrome. However, the effects of COVID-19 on the lung endothelium are not well defined. We hypothesized that the lung endotheliopathy of COVID-19 is caused by circulating host factors and direct endothelial infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objectives: We aimed to determine the effects of SARS-CoV-2 or sera from patients with COVID-19 on the permeability and inflammatory activation of lung microvascular endothelial cells. Methods: Human lung microvascular endothelial cells were treated with live SARS-CoV-2;inactivated viral particles;or sera from patients with COVID-19, patients without COVID-19, and healthy volunteers. Permeability was determined by measuring transendothelial resistance to electrical current flow, where decreased resistance signifies increased permeability. Inflammatory mediators were quantified in culture supernatants. Endothelial biomarkers were quantified in patient sera. Measurements and Main Results: Viral PCR confirmed that SARS-CoV-2 enters and replicates in endothelial cells. Live SARS-CoV-2, but not dead virus or spike protein, induces endothelial permeability and secretion of plasminogen activator inhibitor 1 and vascular endothelial growth factor. There was substantial variability in the effects of SARS-CoV-2 on endothelial cells from different donors. Sera from patients with COVID-19 induced endothelial permeability, which correlated with disease severity. Serum levels of endothelial activation and injury biomarkers were increased in patients with COVID-19 and correlated with severity of illness. Conclusions: SARS-CoV-2 infects and dysregulates endothelial cell functions. Circulating factors in patients with COVID-19 also induce endothelial cell dysfunction. Our data point to roles for both systemic factors acting on lung endothelial cells and viral infection of endothelial cells in COVID-19-associated endotheliopathy.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).