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2.
Clin Pharmacokinet ; 61(10): 1331-1343, 2022 10.
Article in English | MEDLINE | ID: covidwho-2075730

ABSTRACT

The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only for continuous intravenous infusion. In vitro human lung cell line studies with nafamostat demonstrate high antiviral potency against SARS-CoV-2 (half maximal inhibitory concentration [IC50] of 0.0022 µM [compared to remdesivir 1.3 µM]), ostensibly via inhibition of the cellular enzyme transmembrane protease serine 2 (TMPRSS2) preventing viral entry into human cells. In addition, the established antithrombotic activity is hypothesised to be advantageous given thrombosis-associated sequelae of COVID-19. Clinical reports to date are limited, but indicate a potential benefit of nafamostat in patients with moderate to severe COVID-19. In this review, we will explore the pre-clinical, pharmacokinetic and clinical outcome data presently available for nafamostat as a treatment for COVID-19. The recruitment to ongoing clinical trials is a priority to provide more robust data on the safety and efficacy of nafamostat as a treatment for COVID-19.


Subject(s)
COVID-19 , Pancreatitis , Acute Disease , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzamidines , COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Guanidines , Humans , Pancreatitis/drug therapy , SARS-CoV-2 , Serine/therapeutic use
3.
Arterioscler Thromb Vasc Biol ; 42(11): 1307-1320, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2053481

ABSTRACT

Increasing evidence indicates that inflammation promotes thrombosis via a VWF (von Willebrand factor)-mediated mechanism. VWF plays an essential role in maintaining the balance between blood coagulation and bleeding, and inflammation can lead to aberrant regulation. VWF is regulated on a transcriptional and (post-)translational level, and its secretion into the circulation captures platelets upon endothelial activation. The significant progress that has been made in understanding transcriptional and translational regulation of VWF is described in this review. First, we describe how VWF is regulated at the transcriptional and post-translational level with a specific focus on the influence of inflammatory and immune responses. Next, we describe how changes in regulation are linked with various cardiovascular diseases. Recent insights from clinical diseases provide evidence for direct molecular links between inflammation and thrombosis, including atherosclerosis, chronic thromboembolic pulmonary hypertension, and COVID-19. Finally, we will briefly describe clinical implications for antithrombotic treatment.


Subject(s)
COVID-19 , Thrombosis , von Willebrand Diseases , Humans , von Willebrand Factor/genetics , Fibrinolytic Agents/therapeutic use , Blood Platelets , Inflammation/genetics
5.
Thromb Res ; 218: 151-156, 2022 10.
Article in English | MEDLINE | ID: covidwho-1996587

ABSTRACT

BACKGROUND: Coagulation dysfunction represents a serious complication in patients during the COVID-19 infection, while fulminant thrombotic complications emerge as critical issues in individuals with severe COVID-19. In addition to a severe clinical presentation, comorbidities and age significantly contribute to the development of thrombotic complications in this disease. However, there is very little data on association of congenital thrombophilia and thrombotic events in the setting of COVID-19. Our study aimed to evaluate the risk of COVID-19 associated thrombosis in patients with congenital thrombophilia. METHODS: This prospective, case-control study included patients with confirmed COVID-19 infection, followed 6 months post-confirmation. The final outcome was a symptomatic thrombotic event. In total, 90 COVID-19 patients, 30 with known congenital thrombophilia and 60 patients without thrombophilia within the period July 2020-November 2021, were included in the study. Evaluation of hemostatic parameters including FVIII activity and D-dimer was performed for all patients at 1 month, 3 months and 6 months post-COVID-19 diagnosis. RESULTS: Symptomatic thrombotic events were observed in 7 out of 30 (23 %) COVID-19 patients with thrombophilia, and 12 out of 60 (20 %) without thrombophilia, P = 0.715. In addition, the two patient groups had comparable localization of thrombotic events, time to thrombotic event, effect of antithrombotic treatment and changes in FVIII activity, while D-dimer level were significantly increased in patients without thrombophilia. CONCLUSION: Our findings suggest that patients with congenital thrombophilia, irrespective of their age, a mild clinical picture and absence of comorbidities, should receive anticoagulant prophylaxis, adjusted based on the specific genetic defect.


Subject(s)
COVID-19 , Hemostatics , Thrombophilia , Thrombosis , Anticoagulants/therapeutic use , COVID-19/complications , COVID-19 Testing , Case-Control Studies , Fibrinolytic Agents/therapeutic use , Hemostatics/therapeutic use , Humans , Prospective Studies , Risk Assessment , Thrombophilia/complications , Thrombosis/drug therapy
6.
JAMA Intern Med ; 182(10): 1063-1070, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-1990370

ABSTRACT

Importance: The risk of venous thromboembolism (VTE) in ambulatory COVID-19 is controversial. In addition, the association of vaccination with COVID-19-related VTE and relevant clinical and genetic risk factors remain to be elucidated. Objective: To quantify the association between ambulatory COVID-19 and short-term risk of VTE, study the potential protective role of vaccination, and investigate clinical and genetic risk factors for post-COVID-19 VTE. Design, Setting, and Participants: This population-based cohort study of patients with COVID-19 from UK Biobank included participants with SARS-CoV-2 infection that was confirmed by a positive polymerase chain test reaction result between March 1, 2020, and September 3, 2021, who were then propensity score matched to COVID-19-naive people during the same period. Participants with a history of VTE who used antithrombotic drugs (1 year before index dates) or tested positive in hospital were excluded. Exposures: First infection with SARS-CoV-2, age, sex, ethnicity, socioeconomic status, obesity, vaccination status, and inherited thrombophilia. Main Outcomes and Measures: The primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection. Hazard ratios (HRs) with 95% CIs were calculated using cause-specific Cox models. Results: In 18 818 outpatients with COVID-19 (10 580 women [56.2%]; mean [SD] age, 64.3 [8.0] years) and 93 179 matched uninfected participants (52 177 women [56.0%]; mean [SD] age, 64.3 [7.9] years), the infection was associated with an increased risk of VTE in 30 days (incidence rate of 50.99 and 2.37 per 1000 person-years for infected and uninfected people, respectively; HR, 21.42; 95% CI, 12.63-36.31). However, risk was substantially attenuated among the fully vaccinated (HR, 5.95; 95% CI, 1.82-19.5; interaction P = .02). In patients with COVID-19, older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 1.87 (95% CI, 1.50-2.33) per 10 years, 1.69 (95% CI, 1.30-2.19), and 1.83 (95% CI, 1.28-2.61), respectively. Further, inherited thrombophilia was associated with an HR of 2.05 (95% CI, 1.15-3.66) for post-COVID-19 VTE. Conclusions and Relevance: In this population-based cohort study of patients with COVID-19, ambulatory COVID-19 was associated with a substantially increased risk of incident VTE, but this risk was greatly reduced in fully vaccinated people with breakthrough infection. Older age, male sex, and obesity were clinical risk factors for post-COVID-19 VTE; factor V Leiden thrombophilia was additionally associated with double the risk, comparable with the risk of 10-year aging. These findings may reinforce the need for vaccination, inform VTE risk stratification, and call for targeted VTE prophylaxis strategies for unvaccinated outpatients with COVID-19.


Subject(s)
COVID-19 , Thrombophilia , Venous Thromboembolism , Venous Thrombosis , COVID-19/complications , COVID-19/epidemiology , Cohort Studies , Female , Fibrinolytic Agents/therapeutic use , Humans , Male , Middle Aged , Obesity/complications , Obesity/epidemiology , Risk Factors , SARS-CoV-2 , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology
7.
Eur Neurol ; 85(5): 349-366, 2022.
Article in English | MEDLINE | ID: covidwho-1973983

ABSTRACT

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.


Subject(s)
Brain Ischemia , COVID-19 , Endovascular Procedures , Ischemic Stroke , Neuroprotective Agents , Stroke , Brain Ischemia/complications , Brain Ischemia/drug therapy , COVID-19/complications , Endovascular Procedures/methods , Fibrinolytic Agents/therapeutic use , Humans , Neuroprotective Agents/therapeutic use , Pandemics , Stroke/diagnosis , Stroke/drug therapy , Tenecteplase/therapeutic use , Thrombectomy/methods , Thrombolytic Therapy , Tissue Plasminogen Activator/therapeutic use , Treatment Outcome
8.
9.
ASAIO J ; 68(7): 920-924, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1967929

ABSTRACT

Extracorporeal membrane oxygenation (ECMO) contributes to coagulopathy, necessitating systemic anticoagulation to prevent thrombosis. Traditionally, unfractionated heparin (UFH) has been the anticoagulant of choice, however, due to many inadequacies new evidence suggests benefit with the use of direct thrombin inhibitors. This retrospective cohort sought to evaluate the safety and efficacy of bivalirudin compared to UFH in ECMO patients. Primary endpoints included incidence of bleeding and thrombosis. Percent time in therapeutic range (TR), time to achieve TR and number of dose titrations required to maintain TR were calculated to assess efficacy of institutional protocols. Overall incidence of thrombosis was low, with one event in the bivalirudin group and no events in the UFH group. No difference was found in rates of bleeding between groups (6% vs . 10%, P = 0.44). Bivalirudin yielded higher percent time in TR (86% vs. 33%, P < 0.001), faster time to TR (2 vs . 18 hr, P < 0.001) and required fewer dose adjustments to maintain TR (2 vs . 11, P < 0.001) compared to UFH. These results suggest bivalirudin and UFH are associated with similar rates of bleeding and thrombosis in patients requiring ECMO support. Our results demonstrate the favorable pharmacokinetic profile of bivalirudin, and its ability to consistently maintain TR when compared to UFH.


Subject(s)
Extracorporeal Membrane Oxygenation , Thrombosis , Adult , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/therapeutic use , Extracorporeal Membrane Oxygenation/adverse effects , Fibrinolytic Agents/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/complications , Hemorrhage/prevention & control , Heparin/adverse effects , Heparin/therapeutic use , Hirudin Therapy , Hirudins/adverse effects , Humans , Peptide Fragments/adverse effects , Peptide Fragments/therapeutic use , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Retrospective Studies , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Treatment Outcome
11.
J Thromb Haemost ; 20(10): 2226-2236, 2022 10.
Article in English | MEDLINE | ID: covidwho-1916260

ABSTRACT

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries.


Subject(s)
COVID-19 , Fibrinolytic Agents , Anticoagulants/therapeutic use , COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Hemostasis , Humans , Platelet Aggregation Inhibitors/therapeutic use , Thrombosis/drug therapy , Thrombosis/prevention & control , Venous Thromboembolism/prevention & control
12.
Rinsho Ketsueki ; 63(5): 471-480, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1879649

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 and is known to have thrombotic complications. Various-sized thrombosis occurs in the arteries and veins, especially in lung tissue. The prevention and treatment of thrombosis is an important issue that is directly linked to its prognosis. Additionally, the drastic fibrinolytic enhancement and lethal bleeding in some severe COVID-19 are important issues. The efficacy of antiplatelet for COVID-19 is controversial. Thus, warfarin or tranexamic acid alone should be avoided. Heparin is effective for mild to moderate COVID-19 but is ineffective in severe cases since the anticoagulant activity of heparin is insufficient or heparin increases major bleeding. In severe COVID-19 cases with drastic fibrinolytic enhancement, heparin and nafamostat combination therapy may avoid lethal bleeding. In COVID-19 clinical practice, not only the coagulation activation was evaluated but also the fibrinolytic activation to consider treatment strategies.


Subject(s)
COVID-19 , Thrombosis , Anticoagulants/therapeutic use , COVID-19/complications , Fibrinolytic Agents/therapeutic use , Hemorrhage/drug therapy , Heparin , Humans , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control
13.
Thromb Res ; 213 Suppl 1: S72-S76, 2022 05.
Article in English | MEDLINE | ID: covidwho-1867825

ABSTRACT

Cancer patients are at risk for a more severe COVID-19 infection as well as an adverse outcome of such infection. This may be caused by the cancer itself (e.g haematological malignancies and lung cancer) or due to immune suppression caused by anti-cancer treatment. Severe COVID-19 infections are often complicated by a coagulopathy that clinically results in a high incidence of venous thromboembolic disease. Cancer itself is associated with a hypercoagulable state and a markedly increased incidence of thromboembolic complications, hence the combination of cancer and COVID-19 may amplify this risk. COVID-19 vaccination seems safe and effective in most cancer patients although adapted and bespoke vaccination schemes may increase the seroconversion rate and immune response in selected patients. Specific management strategies to improve outcomes of cancer patients in COVID-19 (e.g. higher intensity antithrombotic prophylaxis) are lacking and should be evaluated in clinical studies simultaneously focusing on efficacy and safety.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Neoplasms , Thromboembolism , Thrombosis , Anticoagulants/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/drug therapy , COVID-19/complications , COVID-19 Vaccines , Fibrin Fibrinogen Degradation Products/therapeutic use , Fibrinolytic Agents/therapeutic use , Humans , Neoplasms/drug therapy , Neoplasms/therapy , SARS-CoV-2 , Thromboembolism/drug therapy , Thrombosis/drug therapy
15.
Thromb Res ; 215: 14-18, 2022 07.
Article in English | MEDLINE | ID: covidwho-1821499

ABSTRACT

Anticoagulation with Vitamin K antagonists (VKA) has always posed challenges in terms of monitoring requirements. These challenges were further exacerbated in the setting of the COVID-19 pandemic, with limited access to and/or avoidance of laboratory testing. The importance of utilizing point of care (POC) health technology for individualized patient management is salient. The foundation of effective home INR monitoring is establishing patient knowledge about their therapy and INR testing proficiency. The eKITE series was developed to support patients in establishing foundational knowledge required for VKA (warfarin) management and INR monitoring. The primary objectives were to evaluate eKITE, a patient-oriented innovative online education program for warfarin therapy, participant learning stress, and patient preference for online learning. This multi-center prospective study provided patients access to warfarin online education. Participants were required to complete written quizzes assessing warfarin knowledge of key concepts proficiency and identifying knowledge deficits. Patient preference, evaluating calm (lack of anxiety) while learning, and an INR on a home meter was completed. Participants performed INR tests at home and reported INRs by telephone. The analysis included 144 children and caregivers enrolled at five US and CDN sites. Most indications for anticoagulation were cardiac (congenital or acquired heart disease) with varied INR target ranges. Mean knowledge scores for warfarin and INR self-testing modules were 97%, with low anxiety with TTR of 84%. Patient preferred online learning. eKITE is an effective teaching modality for warfarin/home INR monitoring with safe INR testing and warfarin management that is appropriate for pediatrics and adults alike. PROLOGUE: The whir in the hallways is deafening. Lights bright, alarms are ringing in a chorus of unsynchronized beeps and screeches. It has been more than a week since I have slept. Snuggled beside me is my precious child, whining and equally irritated with the asynchronous symphony, further compounded by anxiety, procedures, and pain. The sun has broken. The staff smiles are welcoming and incessant, as one after one, they approach hurried, urgent, assiduous, their need to coach me for our upcoming departure to the warmth of home. Each provides essential information that I will require to keep my child, my treasure, safe and healthy. Yet, my eyes are heavy, blurred, and my brain foggy, trapped in a dark heavy cloud. How am I to follow? Comprehend? and retain anything? As they instruct, my precious child yearns for loving arms, compassion and love, whining, crying in disquiet. Overwhelmed does not adequately describe my ineffable exhaustion. Amidst this, how am I to learn about warfarin? Such a challenging medication, with so much to know. Concentrate, I tell myself, focus; now is my only opportunity to learn. I must be alert. It seems to be nonsensical.


Subject(s)
COVID-19 , Education, Distance , Adult , Anticoagulants/therapeutic use , COVID-19/drug therapy , Child , Fibrinolytic Agents/therapeutic use , Humans , International Normalized Ratio/methods , Pandemics , Prospective Studies , Warfarin/therapeutic use
18.
J Investig Med ; 70(4): 892-898, 2022 04.
Article in English | MEDLINE | ID: covidwho-1784873

ABSTRACT

The aim of the study was to evaluate the diagnostic significance of ST-segment re-elevation episodes registered with telemetric ECG monitoring in patients with ST-segment elevation myocardial infarction (STEMI) treated with thrombolytic therapy (TLT). The study included 117 patients with STEMI following effective TLT. The elective coronary angiography followed by percutaneous coronary interventions was performed in the interval from 3 to 24 hours after a successful systemic TLT. Before and after cardiac catheterization, the telemetric ECG monitoring was performed using AstroCard Telemetry system (Meditec, Russia). During the study, two groups of patients were formed. Group 1 included 85 patients (72.6%) without new ST-segment deviations on telemetry. 77 patients (90.6%) had no recurrent coronary artery thrombosis at angiography. Eight patients (9.4%) from group 1 were diagnosed with thrombosis of the infarct-related coronary artery. Group 2 included 32 patients (27.4%) who underwent TLT and then had ST-segment re-elevation episodes of 1 mV or more in the infarct-related leads, lasting for at least 1 minute. In group 2, in 27 of 32 patients (84.4%), thrombosis of the infarct-related coronary artery was confirmed (p<0.01 compared with group 1). In 71.9% cases, the recurrent ischemic episodes were asymptomatic ('painless myocardial ischemia') (p<0.01). Thus, in patients with STEMI and successful TLT, re-elevation of ST-segment during remote ECG monitoring is strongly related to angiographically documented coronary artery thrombotic reocclusion. The absence of chest pain during recurrent myocardial ischemia requires continuous ECG telemetry to select patients for the rescue percutaneous coronary interventions at an earlier stage.


Subject(s)
Coronary Artery Disease , Myocardial Infarction , Myocardial Ischemia , ST Elevation Myocardial Infarction , Coronary Angiography , Coronary Artery Disease/etiology , Electrocardiography , Fibrinolytic Agents/therapeutic use , Humans , Myocardial Ischemia/diagnosis , Myocardial Ischemia/drug therapy , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/drug therapy , Thrombolytic Therapy/adverse effects
19.
J Neurointerv Surg ; 14(7): 642-649, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1779409

ABSTRACT

OBJECTIVES: COVID-19 presents a risk for delays to stroke treatment. We examined how COVID-19 affected stroke response times. METHODS: A literature search was conducted to identify articles covering stroke during COVID-19 that included time metrics data pre- and post-pandemic. For each outcome, pooled relative change from baseline and 95% CI were calculated using random-effects models. Heterogeneity was explored through subgroup analyses comparing comprehensive stroke centers (CSCs) to non-CSCs. RESULTS: 38 included studies reported on 6109 patients during COVID-19 and 14 637 patients during the pre-COVID period. Pooled increases of 20.9% (95% CI 5.8% to 36.1%) in last-known-well (LKW) to arrival times, 1.2% (-2.9% to 5.3%) in door-to-imaging (DTI), 0.8% (-2.9% to 4.5%) in door-to-needle (DTN), 2.8% (-5.0% to 10.6%) in door-to-groin (DTG), and 19.7% (11.1% to 28.2%) in door-to-reperfusion (DTR) times were observed during COVID-19. At CSCs, LKW increased by 24.0% (-0.3% to 48.2%), DTI increased by 1.6% (-3.0% to 6.1%), DTN increased by 3.6% (1.2% to 6.0%), DTG increased by 4.6% (-5.9% to 15.1%), and DTR increased by 21.2% (12.3% to 30.1%). At non-CSCs, LKW increased by 12.4% (-1.0% to 25.7%), DTI increased by 0.2% (-2.0% to 2.4%), DTN decreased by -4.6% (-11.9% to 2.7%), DTG decreased by -0.6% (-8.3% to 7.1%), and DTR increased by 0.5% (-31.0% to 32.0%). The increases during COVID-19 in LKW (p=0.01) and DTR (p=0.00) were statistically significant, as was the difference in DTN delays between CSCs and non-CSCs (p=0.04). CONCLUSIONS: Factors during COVID-19 resulted in significantly delayed LKW and DTR, and mild delays in DTI, DTN, and DTG. CSCs experience more pronounced delays than non-CSCs.


Subject(s)
COVID-19 , Stroke , Fibrinolytic Agents/therapeutic use , Humans , Pandemics , Reaction Time , Stroke/therapy , Thrombolytic Therapy/methods , Time-to-Treatment , Treatment Outcome
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