Galectin-3 as a Marker for Increased Thrombogenicity in COVID-19.

Galectin-3 is a beta-galactoside-binding lectin involved in inflammation and lung fibrosis and postulated to enhance thrombosis. In COVID-19, it is considered to be a prognostic marker of severity. The aim of this study was to evaluate whether galectin-3 is associated with thrombogenicity in COVID-19. Patients with moderate-to-severe COVID-19 (COVpos; n = 55) and patients with acute respiratory diseases, but without COVID-19 (COVneg; n = 35), were included in the study. We measured the amount of galectin-3, as well as other platelet and coagulation markers, and correlated galectin-3 levels with these markers of thrombogenicity and with the SOFA Score values. We found that galectin-3 levels, as well as von Willebrand Factor (vWF), antithrombin and tissue plasminogen activator levels, were higher in the COVpos than they were in the COVneg cohort. Galectin-3 correlated positively with vWF, antithrombin and D-dimer in the COVpos cohort, but not in the COVneg cohort. Moreover, galactin-3 correlated also with clinical disease severity, as measured by the SOFA Score. In patients with acute respiratory diseases, galectin-3 can be considered as a marker not only for disease severity, but also for increased hypercoagulability. Whether galectin-3 might be a useful therapeutic target in COVID-19 needs to be assessed in future studies.

In-Hospital Delays for Acute Stroke Treatment Delivery During the COVID-19 Pandemic.

BACKGROUND: We investigated the impact of regionally imposed social and healthcare restrictions due to coronavirus disease 2019 (COVID-19) to the time metrics in the management of acute ischemic stroke patients admitted at the regional stroke referral site for Central South Ontario, Canada. METHODS: We compared relevant time metrics between patients with acute ischemic stroke receiving intravenous tissue plasminogen activator (tPA) and/or endovascular thrombectomy (EVT) before and after the declared restrictions and state of emergency imposed in our region (March 17, 2020). RESULTS: We identified a significant increase in the median door-to-CT times for patients receiving intravenous tPA (19 min, interquartile range (IQR): 14-27 min vs. 13 min, IQR: 9-17 min, p = 0.008) and/or EVT (20 min, IQR: 15-33 min vs. 11 min, IQR: 5-20 min, p = 0.035) after the start of social and healthcare restrictions in our region compared to the previous 12 months. For patients receiving intravenous tPA treatment, we also found a significant increase (p = 0.005) in the median door-to-needle time (61 min, IQR: 46-72 min vs. 37 min, IQR: 30-50 min). No delays in the time from symptom onset to hospital presentation were uncovered for patients receiving tPA and/or endovascular reperfusion treatments in the first 1.5 months after the establishment of regional and institutional restrictions due to the COVID-19 pandemic. CONCLUSION: We detected an increase in our institutional time to treatment metrics for acute ischemic stroke patients receiving tPA and/or endovascular reperfusion therapies, related to delays from hospital presentation to the acquisition of cranial CT imaging for both tPA- and EVT-treated patients, and an added delay to treatment with tPA.

Délais dans le traitement en milieu hospitalier des AVC aigus dans le contexte de la pandémie de COVID-19. CONTEXTE: Nous nous sommes penchés, dans le contexte de la pandémie de COVID-19, sur l'impact de restrictions régionales imposées dans le domaine social et dans les soins de santé sur les délais de prise en charge de patients victimes d'un AVC aigu. À noter que ces patients ont été admis dans un centre régional de traitement des AVC situé dans le centre-ouest de l'Ontario (Canada). MÉTHODES: Nous avons comparé entre eux les délais de prise en charge de patients ayant bénéficié d'activateurs tissulaires du plasminogène par intraveineuse (tPA) et/ou d'une procédure de thrombectomie endovasculaire (TE) avant et après la mise sur pied de restrictions et l'imposition d'un état d'urgence sanitaire dans notre région (17 mars 2020). RÉSULTATS: Après la mise sur pied de ces restrictions, nous avons identifié, par rapport aux 12 mois précédent, une augmentation notable des délais médians entre l'arrivée à l'hôpital et un examen de tomodensitométrie dans le cas de patients bénéficiant de tPA (19 minutes, EI : 14­27 minutes contre 13 minutes, EI : 9­17 minutes ; p = 0,008) et/ou d'une procédure de TE (20 minutes, EI : 15­33 minutes contre 11 minutes, EI : 5­20 minutes ; p = 0,035). Pour ce qui est des patients bénéficiant de tPA, nous avons également observé une augmentation importante (p = 0,005) des délais médians entre leur arrivée à l'hôpital et l'injection d'un traitement (61 minutes, EI : 46­72 minutes contre 37 minutes, EI : 30­50 minutes). Enfin, dans le premier mois et demi suivant la mise sur pied des restrictions régionales et institutionnelles attribuables à la pandémie de COVID-19, aucun délai supplémentaire entre l'apparition des premiers symptômes d'un AVC et l'arrivée à l'hôpital n'a été remarqué pour des patients bénéficiant de tPA et/ou d'une procédure de TE. CONCLUSION: En somme, nous avons détecté une augmentation de nos délais de traitement dans le cas de patients victimes d'un AVC aigu ayant bénéficié de tPA et/ou d'une procédure de TE. Cela peut être attribué à une augmentation des délais de présentation à l'hôpital mais aussi à des délais dans l'obtention d'images de tomodensitométrie pour des patients traités avec des tPA et une procédure de TE, sans compter des délais accrus pour bénéficier d'un traitement de tPA.

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).

Biomarkers of endothelial dysfunction are associated with poor outcome in COVID-19 patients: A systematic review and meta-analysis.

Numerous studies have linked coronavirus disease 2019 (COVID-19) with endothelial dysfunction and reported elevated levels of endothelial biomarkers in this disease. We conducted a systematic review and meta-analysis of the published evidence in this respect. A systematic literature search of PubMed and Scopus databases was performed to find studies investigating biomarkers of endothelial dysfunction in COVID-19 patients. Pooled standardized mean differences and their 95% confidence intervals were calculated for each biomarker using random effect model. 74 studies with 7668 patients were included. In comparison to patients with good outcome, those with poor outcome had higher levels of von Willebrand factor (vWF) (SMD: 0.83, 95% CI: 0.59-1.07, p < 0.00001), vWF:ADAMTS13 (1.23, (0.77-1.7), p < 0.00001), angiopoietin-2 (Ang-2) (1.06 (0.6-1.51), p < 0.0001), E-selectin (1.09 (0.55-1.63), p < 0.0001), P-selectin (0.59 (0.24-0.94), p = 0.001), syndecan-1 (0.99 (0.6-1.37), p < 0.00001), mid-regional pro-adrenomedullin (MR-proADM) (1.52 (1.35-1.68), p < 0.00001), vascular endothelial growth factor (0.27 (0.02-0.53), p = 0.03), soluble fms-like tyrosine kinase-1 (sFLT-1) (1.93 (0.65-3.21), p = 0.03) and lower levels of ADAMTS13 antigen (-0.69 (-0.9 to -0.47) p < 0.00001) and activity (-0.84 (-1.06 to -0.61) p < 0.0000). Plasminogen activator inhibitor-1 and tissue plasminogen activator levels were not different between the two groups (p < 0.05). There were elevated levels of endothelial dysfunction biomarkers in COVID-19 patients with poor outcome, indicating their possible role in disease severity and prognosis. In particular, MR-proADM, vWF, syndecan-1 and sFLT-1 showed a significant association with poor outcome in these patients.

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.

Recombinant tissue plasminogen activator (rTPA) management for first onset acute ischemic stroke with covid -19 and non-covid -19 patients.

OBJECTIVES: Cerebrovascular stroke (CVS) is one of the well-known complications of coronavirus-2019 (Covid-19), but less is known about the outcome and safety of thrombolytic therapy in these patients. In this study we compare the efficacy and safety of Tissue plasminogen activator (rTPA) in acute ischemic stroke (AIS) patients with or without Covid-19 infection. MATERIALS AND METHODS: A comparative prospective study in which all patients who presented with AIS and eligible for rTPA were recruited from the emergency department and classified into 2 groups (AIS with Covid-19 infection and AIS without Covid-19 as controls). Demographic data, symptoms of Covid-19, clinical examination, neuroimaging, and laboratory investigations were obtained in each patient. National Institute of Health Stroke Scale (NIHSS) and the Modified Rankin Scale (mRS) were assessed before, immediately after rTPA, and 3 months later. RESULTS: There were 22 patients in the COVID-19 group and 25 control patients. Those with COVID-19 were more likely to have a history of smoking and Diabetes Mellitus than controls. On admission, motor symptoms were more severe in patients with COVID-19. COVID-19 patients were more likely to have symptomatic intra-cerebral hemorrhage and radiological hemorrhagic transformation than controls. Onset to door time (ODT) and onset to successful reperfusion time were significantly longer in Covid-19 patients than controls. Clinical improvement and frequency of re-occlusion and recurrent ischemic stroke at 3 months follow-up did not differ between groups, although there was higher number of deaths (27.3%) in the Covid-19 group than controls (16%). CONCLUSIONS: Using rTPA is safe and effective in patients with AIS with or without COVID-19 infection despite the high frequency of hemorrhagic transformation and high number of deaths.

The effects of the coronavirus disease pandemic on intravenous thrombolytic therapy among patients with acute ischemic stroke in Dalian, China.

BACKGROUND: We investigated the influence of the coronavirus disease 2019 (COVID-19) pandemic on the number of patients with acute ischemic stroke who received intravenous thrombolytic therapy (ITT) in Dalian, China, in 2020. METHODS: This retrospective descriptive study, conducted from February 1, 2020, to August 31, 2020, examined 13 hospitals in Dalian that participated in the "stroke emergency map". To use this "stroke emergency map" of China, patients followed the official "Stroke Map" WeChat account and dialed 120 for emergency medical services. We analyzed the number of patients with acute ischemic stroke who underwent ITT. In particular, we examined the onset-to-door time (ODT), door-to-needle time (DNT), onset-to-needle time (ONT), mode of transportation to the hospital, and National Institutes of Health Stroke Scale (NIHSS) scores before and after ITT. Data were collected for the aforementioned period and compared with the 2021 baseline data from the same time of year. The Mann‒Whitney U test was performed for data analysis. RESULTS: Compared with the data from 2020, the number of patients with acute ischemic stroke who underwent ITT increased (from 735 to 1719 cases) in 2021, but the DNT decreased (from 59 to 45 min; P = 0.002). Moreover, 83.9% of patients in 2020 presented to the hospital without ambulance transport, compared to 81.1% of patients in the 2021 non-COVID-19 pandemic period. Patients with NIHSS scores of 6-14 were more likely to call an ambulance for transport to the hospital than to transport themselves to the emergency department. CONCLUSIONS: During the 2020 COVID-19 pandemic, the DNT was prolonged as a result of strengthened fever surveillance. In 2021, the number of patients with acute ischemic stroke who underwent ITT increased compared to the previous year. Notably, the growth in the number of patients with acute ischemic stroke who underwent ITT benefited from both the "stroke emergency map" of China and the "green channel," a novel treatment approach that focuses on the rational design of the rescue process. TRIAL REGISTRATION: Our study was a retrospective descriptive study, not a clinical trial, thus we did not have to register for clinical trials.

Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients.

Severe coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin-33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients.

Treatments in Ischemic Stroke: Current and Future.

BACKGROUND AND AIM: Despite progress made over the last 30 years, stroke is still a leading cause of disability and mortality; likewise, its burden is expected to increase over the next decades, due to population growth and aging. The development of drugs with better safety-efficacy profiles as well as strategies able to improve ischemic stroke management from the pre-hospital setting is needed. SUMMARY: The pathophysiology of ischemic stroke involves multiple pathways resulting in cerebral artery obstruction and brain tissue ischemia. To date, the only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase. Intravenous thrombolysis (IVT) can be administered alone or in combination with endovascular treatment (EVT) with mechanical thrombectomy, in case of large vessel occlusion and generally within 6 h from symptoms onset. The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. Tenecteplase is a promising alternative fibrinolytic agent, having a better safety profile than alteplase. Moreover, recent evidences have allowed an extension of the IVT ± EVT time window for patients with unknown onset time and for those with a known onset time thanks to the new "tissue-window" approach guided by advanced neuroimaging techniques, which also helps in collateral circulation estimation. Regarding primary-secondary prevention, researchers are focused on improving the efficacy of antithrombotic drugs with a "hemostasis-sparing" approach. Neuroprotective agents are also under development, particularly stem cells. The COVID-19 pandemic has critically stressed global healthcare systems, with collateral damage resulting in access delivery of only emergency care, such as ischemic stroke. Regarding telemedicine, it has had a minor role in acute stroke management, and with the onset of COVID-19, this role will most likely be adopted to increase access and delivery in stroke assessment, but also in the follow-up.

Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19.

Background. Fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT) rapidly improves hemodynamic parameters and reverses right ventricular dysfunction caused by acute pulmonary embolism (PE). The effectiveness of USAT for acute PE associated with coronavirus disease 2019 (COVID-19) is unknown. Methods and results. The study population of this cohort study consisted of 36 patients with an intermediate-high- or high-risk acute PE treated with a fixed low-dose USAT protocol (r-tPA 10-20 mg/15 h). Of these, 9 patients tested positive for COVID-19 and were age-sex-matched to 27 patients without COVID-19. The USAT protocol included, beyond the infusion of recombinant tissue plasminogen activator, anti-Xa-activity-adjusted unfractionated heparin therapy (target 0.3-0.7 U/mL). The study outcomes were the invasively measured mean pulmonary arterial pressure (mPAP) before and at completion of USAT, and the National Early Warning Score (NEWS), according to which more points indicate more severe hemodynamic impairment. Twenty-four (66.7%) patients were men; the mean age was 67 ± 14 years. Mean &nbsp;± &nbsp;standard deviation mPAP decreased from 32.3 ± 8.3 to 22.4 ± 7.0 mmHg among COVID-19 patients and from 35.4 ± 9.7 to 24.6 ± 7.0 mmHg among unexposed, with no difference in the relative improvement between groups (p = 0.84). Within 12 h of USAT start, the median NEWS decreased from six (Q1-Q3: 4-8) to three (Q1-Q3: 2-4) points among COVID-19 patients and from four (Q1-Q3: 2-6) to two (Q1-Q3: 2-3) points among unexposed (p = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Conclusions. Among patients with COVID-19-associated acute PE, mPAP rapidly decreased during USAT with a concomitant progressive improvement of the NEWS. The magnitude of mPAP reduction was similar in patients with and without COVID-19.

Low stroke incidence in the TEMPiS telestroke network during COVID-19 pandemic: Effect of lockdown on thrombolysis and thrombectomy.

BACKGROUND: During the COVID-19 pandemic emergency departments have noted a significant decrease in stroke patients. We performed a timely analysis of the Bavarian telestroke TEMPiS "working diagnosis" database. METHODS: Twelve hospitals from the TEMPiS network were selected. Data collected for January through April in years 2017 through 2020 were extracted and analyzed for presumed and definite ischemic stroke (IS), amongst other disorders. In addition, recommendations for intravenous thrombolysis (rtPA) and endovascular thrombectomy (EVT) were noted and mobility data of the region analyzed. If statistically valid, group-comparison was tested with Fisher's exact test considering unpaired observations and ap-value < 0.05 was considered significant. RESULTS: Upon lockdown in mid-March 2020, we observed a significant reduction in recommendations for rtPA compared to the preceding three years (14.7% [2017-2019] vs. 9.2% [2020], p = 0.0232). Recommendations for EVT were significantly higher in January to mid-March 2020 compared to 2017-2019 (5.4% [2017-2019] vs. 9.3% [2020], p = 0.0013) reflecting its increasing importance. Following the COVID-19 lockdown mid-March 2020 the number of EVT decreased back to levels in 2017-2019 (7.4% [2017-2019] vs. 7.6% [2020], p = 0.1719). Absolute numbers of IS decreased in parallel to mobility data. CONCLUSIONS: The reduced stroke incidence during the COVID-19 pandemic may in part be explained by patient avoidance to seek emergency stroke care and may have an association to population mobility. Increasing mobility may induce a rebound effect and may conflict with a potential second COVID-19 wave. Telemedical networks may be ideal databases to study such effects in near-real time.

The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.

BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis. CONCLUSION: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.

TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19.

D-dimer is an established biomarker of thromboembolism and severity in COVID-19. We and others have recently reported the dysregulation of tissue factor pathway inhibitor (TFPI), FXIII, fibrinolytic pathway, inflammatory markers, and tissue injury markers, particularly in severe COVID-19. However, association of these markers with thromboembolism in COVID-19 remains elusive. The correlation analyses between these markers in patients with moderate (non-ICU) and severe COVID-19 (ICU) were performed to delineate the potential pathomechanisms and impact of thromboembolism. We observe a negative correlation of plasma TFPI (r2 = 0.148, P = 0.035), FXIII (r2 = 0.242, P = 0.006), and plasminogen (r2 = 0.27, P = 0.003) with D-dimer, a biomarker of thromboembolism, levels in these patients. Further analysis revealed a strong positive correlation between fibrinolytic markers tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) (r2 = 0.584, P < 0.0001). Interestingly, a significant positive correlation of PAI-1, but not tPA, was observed with platelets and endothelial cells dysfunction markers P-selectin (r2 = 0.184, P = 0.01) and soluble CD40 ligand (sCD40 L) (r2 = 0.163, P = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other (r2 = 0.339, P = 0.0007) and with the level of D-dimer independently in COVID-19. Finally, the tissue injury marker myoglobin demonstrated a strong positive correlation with D-dimer (r2 = 0.408, P = 0.0001). Taken together, inverse correlations of TFPI and FXIII with D-dimer suggest the TF pathway activation and aberrant fibrin polymerization in COVID-19 patients. The elevated level of PAI-1 is potentially contributed by activated platelets and endothelial cells. S100A8/A9 may also play roles in impaired fibrinolysis and thromboembolism, in part, through regulating the CST3. These findings strengthen the understanding of thromboembolism and tissue injury and may help in better management of thromboembolic complications in COVID-19 patients.

Concealment of Allergic Reactions to Alteplase by Face Masks in Non-Communicating Acute Stroke Patients: A Warning Call to Improve Our Physical Examination Practices during the COVID-19 Pandemic.

Neurological emergencies, such as acute stroke, are especially challenging during the current Coronavirus disease-2019 (COVID-19) pandemic. Symptoms as aphasia or dysarthria are severely impacting cooperation and communication with patients. During physical examination, both the patient and the medical team are fitted routinely with surgical masks to minimize potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, such a practice can lead to concealment of particularly relevant physical signs. We report a case series of four acute stroke patients who were transferred for endovascular mechanical thrombectomy to our institute after intravenous thrombolysis was initiated at primary stroke centers. Upon arrival, after removing their masks, we observed oral angioedema, as a reaction to thrombolytic agent alteplase. Symptoms remained obscured by face masks through patient care at the referring stroke unit and during transportation, nevertheless they resolved after treatment. Most probably, there are a number of similar cases encountered at emergency departments and acute stroke units. To improve patient safety, a compromise between ensuring protection against the novel coronavirus and facilitating detection of potentially life-threatening physical signs must be found.

Injection of Recombinant Tissue Plasminogen Activator into Extracorporeal Membrane Oxygenators Postpones Oxygenator Exchange in COVID-19.

Coronavirus disease 2019 (COVID-19) has drastically increased the number of patients requiring extracorporeal life support. We investigate the efficacy and safety of low-dose recombinant tissue-type plasminogen activator (rtPA) injection into exhausted oxygenators to delay exchange in critically ill COVID-19 patients on veno-venous extracorporeal membrane oxygenation (V-V ECMO). Small doses of rtPA were injected directly into the draining section of a V-V ECMO circuit. We compared transmembrane pressure gradient, pump head efficiency, membrane arterial partial oxygen pressure, and membrane arterial partial carbon dioxide pressure before and after the procedure. Bleeding was compared with a matched control group of 20 COVID-19 patients on V-V ECMO receiving standard anticoagulation. Four patients received 16 oxygenator instillations with rtPA at 5, 10, or 20 mg per dose. Administration of rtPA significantly reduced transmembrane pressure gradient (Δ pm = 54.8 ± 18.1 mmHg before vs . 38.3 ± 13.3 mmHg after, p < 0.001) in a dose-dependent manner (Pearson's R -0.63, p = 0.023), allowing to delay oxygenator exchange, thus reducing the overall number of consumed oxygenators. rtPA increased blood flow efficiency η (1.20 ± 0.28 ml/revolution before vs . 1.24 ± 0.27 ml/r, p = 0.002). Lysis did not affect membrane blood gases or systemic coagulation. Minor bleeding occurred in 2 of 4 patients (50%) receiving oxygenator lysis as well as 19 of 20 control patients (95%). Lysis of ECMO oxygenators effectively delays oxygenator exchange, if exchange is indicated by an increase in transmembrane pressure gradient. Application of lysis did not result in higher bleeding incidences compared with anticoagulated patients on V-V ECMO for COVID-19.

The Role of Fibrinolytic System in Health and Disease.

The fibrinolytic system is composed of the protease plasmin, its precursor plasminogen and their respective activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), counteracted by their inhibitors, plasminogen activator inhibitor type 1 (PAI-1), plasminogen activator inhibitor type 2 (PAI-2), protein C inhibitor (PCI), thrombin activable fibrinolysis inhibitor (TAFI), protease nexin 1 (PN-1) and neuroserpin. The action of plasmin is counteracted by α2-antiplasmin, α2-macroglobulin, TAFI, and other serine protease inhibitors (antithrombin and α2-antitrypsin) and PN-1 (protease nexin 1). These components are essential regulators of many physiologic processes. They are also involved in the pathogenesis of many disorders. Recent advancements in our understanding of these processes enable the opportunity of drug development in treating many of these disorders.