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.

Call for biotechnological approach to degrade plastic in the era of COVID-19 pandemic.

Plastic pollution is a global issue and has become a major concern since Coronavirus disease (COVID)-19. In developing nations, landfilling and illegal waste disposal are typical ways to dispose of COVID-19-infected material. These technologies worsen plastic pollution and other human and animal health problems. Plastic degrades in light and heat, generating hazardous primary and secondary micro-plastic. Certain bacteria can degrade artificial polymers using genes, enzymes, and metabolic pathways. Microorganisms including bacteria degrade petrochemical plastics slowly. High molecular weight, strong chemical bonds, and excessive hydrophobicity reduce plastic biodegradation. There is not enough study on genes, enzymes, and bacteria-plastic interactions. Synthetic biology, metabolic engineering, and bioinformatics methods have been created to biodegrade synthetic polymers. This review will focus on how microorganisms' degrading capacity can be increased using recent biotechnological techniques.

The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity.

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.

Recurrent upper extremity arterial thrombosis preceding a diagnosis of COVID-19.

Arterial thrombosis occurs when there is endothelial damage in the setting of hypercoagulability and arterial blood stasis. COVID-19 has been theorized to cause both endothelial damage and promote hypercoagulability by causing an imbalance of clotting factors. In many studies, there have been a large proportion of COVID-19 patients that suffered a thromboembolic event, in both the venous and arterial systems. Our patient, who did not have a significant past medical history, presented with a recurrent brachial artery occlusion despite medical and surgical management, and subsequently tested positive for COVID-19 late in his admission. In conclusion, there is high suspicion that there is a relationship between COVID-19 infection and recurrent arterial thrombosis.

Case series of nebulizing r-tPA for COVID-19 induced acute respiratory distress syndrome.

Fibrin deposition in the alveolar spaces during pulmonary involvement of COVID-19 impairs the O2/CO2 exchange and leads to respiratory symptoms. In this report, Recombinant Tissue Plasminogen Activator (r-tPA) has been nebulized to 3 critically ill COVID-19 patients in order to resolve the deposited fibrin while avoiding the risk of bleeding. Based on these observations, nebulization of r-tPA may be a potential therapeutic approach and new area of research for future studies.

Cerebral venous sinus thrombosis in pregnancy presenting with hemiplegia: A case report.

Cerebral venous sinus thrombosis (CVST) is a rather uncommon disorder. CVST is potentially lethal, therefore early detection and treatment is critical. CVST has been linked to pregnancy and puerperium, while COVID-19 infection has been linked to a hypercoagulable state. CVST can be difficult to detect and treat due to the wide range of neurological manifestations, especially in patients with hypercoagulability. The goal of this study is to conduct a literature review and present a unique case of a pregnant woman with CVST who had left hemiplegia and headache. After 6 months of treatment in the hospital, the patient's hemiplegia was fully resolved. Here, we discuss the treatment of CVST in pregnant women who have a suspected past COVID-19 infection.

Intrapleural Tissue Plasminogen Activator and Dornase Alfa Administration for a Multiloculated Recurrent Malignant Pleural Effusion: A Case Report.

Malignant pleural effusions (MPEs) can often be very difficult to manage despite conservative interventions including thoracentesis and indwelling pleural catheter placement. These effusions can be septated and loculated, leading to complexities in drainage and symptomatic relief for patients. As such, physicians have experimented with the use of tissue plasminogen activator (t-PA) and dornase alfa (DNase) in attempts to drain complex malignant pleural effusions. Although the use of t-PA and DNase has been well studied in the context of empyema, the literature is limited in regards to the use of these medications in MPEs. Here, we present the case of a patient with a history of metastatic lung adenocarcinoma complicated by recurrent MPEs. Bedside ultrasonography revealed a septated fluid pocket in the pleural space of the right hemithorax. An indwelling pleural catheter (IPC) was placed with minimal symptomatic relief. The decision was made to administer t-PA and DNase through the IPC, resulting in the resolution of symptoms and radiographic findings. This case highlights the potential benefit of using t-PA and DNase to help drain complex malignant pleural effusions.

Artery of Percheron Strokes: Three Cases in Three Months.

The artery of Percheron (AOP) is a rare variant of thalamic vasculature and is a single dominant thalamoperforating artery supplying bilateral paramedian thalamic territories. Occlusion of the AOP results in a characteristic pattern of bilateral paramedian thalamic infarcts and is estimated to represent between 0.1%-0.3% of all ischemic strokes and 4% to 35% of all thalamic strokes. Four distinct ischemic patterns of AOP infarcts have been identified: bilateral paramedian thalamic region with midbrain (43%), bilateral paramedian thalamic without midbrain (38%), bilateral paramedian thalamic with anterior thalamus and midbrain involvement (14%), and bilateral paramedian thalamic with anterior thalamus without midbrain involvement (5%). Despite our knowledge of the characteristic radiologic features of an AOP stroke, the true incidence of AOP strokes is challenging to estimate due to non-specific clinical symptoms and subtle findings on computed tomography (CT) and/or magnetic resonance imaging (MRI). Here, we present a case series of three patients seen within a 3-month span at one community hospital seen by one single neurologist with confirmed AOP stroke by radiologic imaging. The frequency of these cases suggests that the incidence of AOP infarctions may be higher than previously estimated and instead are underreported due to broad differential on clinical and imaging presentation.

Acute Ischemic Stroke in Children - Should We Thrombolyze?

Ischemic stroke is a major cause of acute neurological symptoms in children with significant long-term neurological sequelae. Unlike in the adult population, the clinical presentation of strokes in children may not be stereotyped. Hence, many other differential diagnostic possibilities might have to be considered in the emergency setting. Due to this heterogeneous presentation and the resultant clinical dilemma in the early detection, acute thrombolysis even now remains as a very rarely tried therapeutic option in children. Many case reports over these years have shown consistently good results of acute intravenous thrombolysis in children with tissue plasminogen activator (tPA) administered within the time frame. There are also some recent reports of endovascular interventions. However, unlike in the adult population, class 1 clinical studies and good Randomized controlled trials (RCT) are yet to emerge in children. The absence of age-appropriate safety and outcome data for the commonly used thrombolytic agents in children is another major roadblock for developing clinical guidelines and recommendations for this age group. The ambitious Thrombolysis in Pediatric Stroke (TIPS) trial had to be terminated prematurely due to poor patient enrolment. This review critically looks at the current status of the acute management of ischemic strokes in children with a specific emphasis on thrombolytic therapy. Until we have better evidence-based guidelines for this age group, it will be prudent to develop robust institutional pathways to provide this important intervention for all eligible children with acute strokes.

Borderline and weakly positive antibody levels against the S-protein of SARS-CoV-2 exhibit limited agreement with virus neutralization titres.

The presence of neutralizing antibodies against SARS-CoV-2 in a large number of people is - besides cellular immunity - important to overcome the SARS-CoV-2 pandemic. While determination of neutralizing antibodies via virus neutralization tests are laborious, assays to determine the antibody levels serologically are fully automated and widely available. Correlations between these methodologies were recently given by the manufacturers, however performance in samples close to the cut off value have not yet been fully validated. Thus, we analysed 22 borderline and low positive (<100 BAU/ml) samples and 9 high positive (≥ 100 BAU/ml) from infected and/or vaccinated individuals and compared the SARS-CoV-2 IgG II Quant assay (Abbott), LIAISON SARS-CoV-2 TrimericS IgG (Diasorin), Elecsys Anti-SARS-CoV-2 S (Roche), and SARS-CoV-2 IgG (Siemens) with results obtained from a virus neutralization test. Based on the cut off values given by Abbott, Diasorin, Roche, and Siemens, the positive serologic results were concordant with the virus neutralization test in 100%, 76%, 88%, and 71%, respectively, while in turn, negative ones were in agreement in 29%, 79%, 93%, and 86%, respectively. In conclusion, weakly positive, serologic results are challenging to correctly predict the presence of neutralizing antibodies. Our study suggests, that different cut off values (for positivity vs. presence of neutralizing antibodies) could improve the test's performance, but determination thereof requires more samples to be analysed.

Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection.

BACKGROUND: SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood. METHODS: A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, performed between 04/2020 and 10/2020. Markers of coagulation, endothelial cell function [angiopoietin-1,-2, P-selectin, von Willebrand Factor Antigen (WF:Ag), von Willebrand Factor Ristocetin Cofactor, ADAMTS13, thrombomodulin, soluble Endothelial cell Protein C Receptor (sEPCR), Tissue Factor Pathway Inhibitor], neutrophil activation (elastase, citrullinated histones) and fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor-1) were evaluated using ELISA. Tissue Factor (TF) was estimated by antithrombin-FVIIa complex (AT/FVIIa) and microparticles-TF (MP-TF). We correlated each marker and determined its association with severity. Expression of pulmonary TF, thrombomodulin and EPCR was determined by immunohistochemistry in 9 autopsies. FINDINGS: Comorbidities were frequent in both groups, with older age associated with severe disease. All patients were on prophylactic anticoagulants. Three patients (4.5%) developed pulmonary embolism. Mortality was 7.5%. Patients presented with mild alterations in the coagulogram (compensated state). Biomarkers of endothelial cell, neutrophil activation and fibrinolysis were elevated in severe vs moderate disease; AT/FVIIa and MP-TF levels were higher in severe patients. Logistic regression revealed an association of D-dimers, angiopoietin-1, vWF:Ag, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWF:Ag identified as independent factors. Notably, postmortem specimens demonstrated epithelial expression of TF in the lung of fatal COVID-19 cases with loss of thrombomodulin staining, implying in a shift towards a procoagulant state. INTERPRETATION: Coagulation dysregulation has multifactorial etiology in SARS-Cov-2 infection. Upregulation of pulmonary TF with loss of thrombomodulin emerge as a potential link to immunothrombosis, and therapeutic targets in the disease. FUNDING: John Hopkins University School of Medicine.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series.

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.

A Case of Bilateral Thalamic Infarcts Involving the Artery of Percheron in the Setting of COVID-19.

The artery of Percheron (AOP) is a rare anatomic variant, characterized by a single thalamoperforating artery arising from the P1 segment of the posterior cerebral artery that bifurcates to supply bilateral thalami with variable vascular supply to the midbrain. The occlusion of this artery is responsible for bilateral thalamic stroke with or without midbrain involvement. Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic. Acute ischemic stroke is a rare but known manifestation of COVID-19. There have only been a few reports of bilateral deep cerebral involvement in COVID-19 infection. In the absence of risk factors for such events, we suspect COVID-19 may have a contributory role. In this case report, we present a case of AOP infarction presenting as transient loss of consciousness, intermittent anisocoria, dysarthria, and right-sided weakness in the setting of COVID-19 infection. Given the degree of variation in clinical presentation for AOP infarcts and lack of evidence of ischemia on initial imaging studies, many patients may miss the time window for tissue plasminogen activator (tPA) administration. This case highlights the importance of timely neurological evaluation in patients presenting with COVID-19 and neurological complaints. Increased community awareness of neurological manifestations of AOP infarctions is of utmost importance as early detection and intervention improve clinical outcomes.

Continued Underutilization of stroke care during the COVID-19 pandemic.

OBJECTIVE: This study aims to investigate the utilization of acute ischemic stroke (AIS) services during the Corona Virus Disease 2019 (COVID-19) pandemic. Based on early observations among healthcare utilization on stroke and other healthcare services, we hypothesized that there would be a persistent significant decline in AIS patients presenting to hospitals as the pandemic has progressed for over a year. METHOD: TriNetX, a large research network, is used to collect real-time electronic medical data. Data on utilization of acute ischemic stroke service was collected for the years 2018, 2019, and 2020 for variables including overall stroke volume and the number of patients that received intravenous tissue plasminogen activator (tPA) and mechanical thrombectomy (MT). RESULT: We found a 13.2-15.4% decrease in total number of AIS patients in 2020 (n 77231) compared with the years 2018 and 2019 (n 88948 and 91270 respectively, p â€‹< â€‹0.001). In the year 2020 Stroke volume was significantly lower in Q4 comparing to Q1 (Q1 vs Q4, p â€‹< â€‹0.01, while there were no significant differences in stroke volume between Quarters 2, 3, and 4 in 2020 (Q2 vs Q3, p â€‹= â€‹0.39, Q2 vs Q4, p â€‹= â€‹0.61, Q3 vs Q4, p â€‹= â€‹0.18). The Proportion of patients receiving tPA in 2020 was significantly lower compared to prior years (5.4% in 2020 vs 6.4% in 2018 and 6.0% in 2019, p â€‹< â€‹0.01), however, the proportion of patients receiving MT was significantly higher in 2020 than in 2018 (0.024 vs 0.022, p â€‹< â€‹0.01). CONCLUSION: Despite significant alteration in practices to optimize healthcare delivery and mitigate the collateral impact of the pandemic on care for other conditions, a persistent decline in AIS volumes remains. Delayed presentation, fear-of-contagion, reallocation, and poor availability of health care resources are potential contributors. Prospective evaluation and further investigation for these trends is needed.

Management and Prevention of Cerebrovascular Accidents in SARS-CoV-2-Positive Patients Recovering from COVID-19: a Case Report and Review of Literature.

We discuss the current understanding of COVID-19's neurological implications, their basis, and the evolving clinical consensus with a focus on cerebrovascular stroke. We further illustrate the potential significance of these implications with the aid of an accompanying case report outlining the disease course and treatment of a COVID-19 patient suffering from ischemic stroke and pulmonary embolism. The ever-growing strain on the global healthcare system due to the spread of the novel coronavirus SARS-CoV-2 requires focused attention on urgent care of independent, coexisting, and associated comorbidities, including cerebrovascular accidents. For illustration purposes, we outline the case of a 68-year-old female presenting with COVID-19 subsequently complicated by bilateral pulmonary embolism and a right-sided cerebrovascular accident. The patient was successfully managed pharmacologically and discharged without significant neurological deficit. The evidence for a hypercoagulable state in this patient along with discussion of mechanistic bases, corroborative evidence from the literature, along with relevant guidance on screening, treatment, and prophylaxis is offered. Greater study of the pathogenesis of COVID-19-related cerebrovascular complications and revisiting current guidelines on their management including potentially heightened levels of thromboprophylaxis are warranted.

Pulmonary Embolism in COVID-19 Treated with VA-ECLS and Catheter tPA.

BACKGROUND: Novel coronavirus 2019 (COVID-19) has been the focus of the medical world since being declared a pandemic in March 2020. While the pathogenesis and heterogeneity of COVID-19 manifestations is still not fully understood, viral evasion of cellular immune responses and inflammatory dysregulation are believed to play essential roles in disease progression and severity. CASE PRESENTATION: We present the first case of a patient with COVID-19 with massive pulmonary embolism treated successfully with systemic thrombolysis, VA-ECLS, and bail out catheter directed thrombolysis. He was discharged from the hospital after an eventful hospital course on therapeutic anticoagulation with warfarin. CONCLUSIONS: We present the first case of a patient with COVID-19 with massive pulmonary embolism (PE) treated successfully with systemic thrombolysis, VA-ECLS and bail out catheter directed thrombolysis. In our experience catheter directed thrombolysis comes with an acceptable bleeding risk despite use of mechanical circulatory support, particularly with meticulous attention to vascular access and dose response monitoring.

Effects of the COVID-19 Pandemic on Stroke Patients.

Introduction The severe acute respiratory syndrome coronavirus 2 (SARS2-CoV-2) induced pandemic (COVID-19 pandemic) has affected healthcare in all aspects, including stroke care. We sought to investigate this effect with analysis of our hospital's stroke treatment protocols as well as stroke volume on state, regional, and national levels. Methods This was a retrospective review of prospectively collected data from our stroke registry to assess the impact of the SARS2-CoV-2 induced pandemic on the volume of stroke patients presenting to our facility. Demographics collected included age, sex, race, National Institute of Health Stroke Scale (NIHSS) on admission, discharge modified Rankin Score (mRS), type of stroke (ischemic, hemorrhagic, or transient ischemic attack), time of symptom onset, and time to initial imaging. Data were also stratified by date and comparison was made between the intra-COVID-period (March and April 2020), pre-COVID period (March and April 2019), and peri-COVID period (January and February 2020). To determine stroke trends on a national level, we utilized the Get with the Guidelines (GWTG) stroke database to compare stroke volumes in the pre-COVID, peri-COVID, and intra-COVID periods between our hospital, all California hospitals, and the West and Pacific regions. Results There was a significant increase in last known well time (LKWT) to arrival to the emergency department (ED) (LKWT to door) as well as time from arrival to the ED to obtaining a computed tomography (CT) of the head (door to CT) in March 2020 compared to 2019 (p=0.0220 and p=0.0475, respectively). There were significantly fewer transient ischemic attacks (TIAs) in California hospitals as well as in March and April 2020 in comparison to January and February 2020 (p=0.0417). Similarly, there were significantly fewer TIAs in March and April 2019 compared to March and April 2020 (p=0.0360). The decrease in TIAs was also seen at our hospital in both time frame comparisons as well as in West Regional Hospitals in March and April 2020 compared to March and April 2019 (p=0.0111, p=0.0215, and p=0.0414, respectively). Conclusion Stroke care has been disrupted by the COVID-19 pandemic worldwide. We identified a delay in LKWT to door as well as time from door to CT in March 2020 compared to March 2019 at our institution. There was a statistically significant decrease in final diagnosis of TIA at our hospital, all California hospitals, and all West Regional hospitals during the March-April 2020 window, suggesting that some patients with minor stroke symptoms may not be presenting to the hospital in the midst of the pandemic. Strategies to minimize delays in care and maximize functional recovery must continue to evolve as new challenges are met during the COVID-19 pandemic.