Rescue therapy for severe COVID-19–associated acute respiratory distress syndrome with tissue plasminogen activator: A case series

Barrett, Christopher D.; Oren-Grinberg, Achikam; Chao, Edward; Moraco, Andrew; Martin, Matthew J.; Reddy, Srinivas H.; Ilg, Annette; Jhunjhunwala, Rashi; Uribe, Marco; Moore, Hunter B.; Moore, Ernest E.; Baedorf‐Kassis, Elias N.; Krajewski, Megan L.; Talmor, Daniel; Shaefi, Shahzad; Yaffe, Michael B.

doi:10.1097/ta.0000000000002786

Cited by 31 publications

(37 citation statements)

References 11 publications

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“…The current explanations for the elevated D-dimer in critically ill patients are multiple, including "suppression of fibrinolysis", "secondarily hyperactive fibrinolysis", "consumption of fibrinolysis", "fibrinolysis resistance", and "fibrinolysis shutdown" 21,22 . To address the coagulopathic changes complicating COVID-19, two diametrically different therapeutic regimes are in practice: fibrinolytic (alteplase-tPA) 10,11,[23][24][25][26][27][28] and antifibrinolytic therapies (nafamostat and tranexamic acid (TXA)) [29][30][31] . It is therefore imperative to clarify the role of pathophysiologic derangements of fibrinolysis in clinical outcomes that occur in COVID-19 patients.…”

Section: Introductionmentioning

confidence: 99%

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Zhao

et al. 2020

Preprint

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Background How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists. To investigate whether abnormal fibrinolysis is a culprit or protector or both, we associated elevated plasma D-dimer with clinical variables to identify a panoramic view of the derangements of fibrinolysis that contribute to the pathogenesis of COVID-19 based on studies available in the literature. Methods We performed this systematic review based on both meta-analysis and meta-regression to compute the correlation of D-dimer at admission with clinical features of COVID-19 patients in retrospective studies or case series. We searched the databases until Aug 18, 2020, with no limitations by language. The first hits were screened, data extracted, and analyzed in duplicate. We did the random-effects meta-analyses and meta-regressions (both univariate and multivariate). D-dimer associated clinical variables and potential mechanisms were schematically reasoned and graphed. Findings Our search identified 42 observational, or retrospective, or case series from six countries (n=14,862 patients) with all races and ages from 1 to 98-year-old. The weighted mean difference of D-dimer was 0.97 μg/mL (95% CI 0.65, 1.29) between relatively mild (or healthy control) and severely affected groups with significant publication bias. Univariate meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels, including 3 demographics, 5 comorbidies, 22 laboratory tests, 18 organ injury biomarkers, 8 severe complications, and 2 outcomes (discharge and death). Of these, 11 readouts were negatively associated with the level of plasma D-dimer. Further, age and gender were confounding factors for the identified D-dimer associated variables. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN, bilirubin, ALT, AST, systolic blood pressure, and CK. We thus propose that "insufficient hyperfibrinolysis (fibrinolysis is accelerated but unable to prevent adverse clinical impact for clinical deterioration COVID-19)" as a peculiar mechanism. Interpretation The findings of this meta-analysis- and meta-regression-based systematic review supports elevated D-dimer as an independent predictor for mortality and severe complications. D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and locally (i.e., in the lung) hyperactive derangements of fibrinolysis. D-dimer and associated clinical biomarkers and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.

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Section: Introductionmentioning

confidence: 99%

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Zhao

et al. 2020

Preprint

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“…62 Indeed, some groups have published case series for patients with COVID-19 ARDS who were treated with salvage antithrombolytic agents. [63][64][65] All patients had some level of improvement in oxygenation and/or hemodynamics after the administration of tissue plasminogen activator, but in most cases, patients ultimately died. Nonetheless, the scientific rationale for using fibrinolytic therapy in COVID-19 ARDS-namely, the consistent findings of pulmonary microvascular thrombosis-has resulted in the initiation of urgently needed clinical trials studying the role of antithrombotic agents in COVID-19 ARDS.…”

Section: Anticoagulation and Thrombolyticsmentioning

confidence: 99%

Acute Respiratory Distress Syndrome

et al. 2020

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A cute respiratory distress syndrome (ARDS) is defined as hypoxemia secondary to a rapid onset of noncardiogenic pulmonary edema. 1 Etiologic risk factors for ARDS encompass both direct and indirect lung injuries including but not limited to pneumonia, sepsis, noncardiogenic shock, aspiration, trauma, contusion, transfusion, and inhalation injuries. Although clinical recognition and management of ARDS have improved significantly over the past 25 yr, it is still a leading cause of death in critically ill patients, with mortality rates consistently reported around 30 to 40%. 2 An important factor in the high mortality rate in ARDS is that treatment is mainly focused on clinical management and no targeted therapies currently exist. Furthermore, ARDS management is often challenging as it commonly occurs in a clinical setting of multiple organ failure and can also lead to the development of nonpulmonary organ injury, such as acute kidney injury. 3 Recently, the pandemic caused by coronavirus disease 2019 (COVID-19), which results from infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to a dramatic incidence in COVID-19-related ARDS. Thirty to forty percent of COVID-19 hospitalized patients develop ARDS, and it is associated with 70% of fatal cases. 4,5 At the time of this writing (July 31, 2020), there are more than 4.5 million COVID-19 cases and 152,000 related deaths in the United States. 6 Here, we describe select management strategies that have become foundations of ARDS clinical management and provide an update of emerging approaches for the treatment of ARDS related to COVID-19.

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“…All the 3 patients demonstrated improvement in their oxygenation after initiation of tPA therapy. Barrett and colleagues 44 used tPA and heparin in 5 COVID-19 infected patients with refractory respiratory failure and thrombotic coagulopathy. The authors reported that these 3 patients had sustained improvements after fibrinolytic therapy (including 1 patient extubated 7 days post-tPA), while the other 2 had non-sustained improvements (1 patient remained mechanically ventilated and 1 patient died from multi-organ failure).…”

Section: Thromboembolismmentioning

confidence: 99%

“…The authors reported that these 3 patients had sustained improvements after fibrinolytic therapy (including 1 patient extubated 7 days post-tPA), while the other 2 had non-sustained improvements (1 patient remained mechanically ventilated and 1 patient died from multi-organ failure). 44 Though not yet reported in the context of COVID-19 lung disease, nebulized tPA is an attractive option for selective pulmonary fibrinolysis with fewer systemic bleeding risks. 30 Further investigation with controlled studies and larger patient groups are needed in order to determine the efficacy and safety of anticoagulation and fibrinolytic therapies use in this context.…”

Section: Thromboembolismmentioning

confidence: 99%

COVID-19-Related Cardiovascular Disease and Practical Considerations for Perioperative Clinicians

Gerstein

Venkataramani

Goumas

et al. 2020

Semin Cardiothorac Vasc Anesth

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Coronavirus disease 2019 (COVID-19) has a clinical course predominated by acute respiratory failure due to viral pneumonia with possible acute respiratory distress syndrome. However, nearly one third of infected patients, especially those with preexisting cardiovascular (CV) disease, are reported to present with some combination of acute cardiac injury, myocarditis, heart failure, cardiogenic shock, or significant dysrhythmias. In addition, COVID-19 infections are also associated with high rates of thromboembolic and disseminated intravascular coagulation complications. Severe myocarditis and heart failure have both been reported as the initial presenting conditions in COVID-19 infection. This review highlights the important considerations related to the CV manifestations of COVID-19 infections, describes the mechanisms and clinical presentation of CV injury, and provides practical management and therapy suggestions. This narrative review is based primarily on the multiple case series and cohorts from the largest initial COVID-19 outbreak centers (ie, Wuhan, China, and Italy); hence, nearly all presented data and findings are retrospective in nature with the attendant limitations of such reports.

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Rescue therapy for severe COVID-19–associated acute respiratory distress syndrome with tissue plasminogen activator: A case series

Cited by 31 publications

References 11 publications

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Acute Respiratory Distress Syndrome

COVID-19-Related Cardiovascular Disease and Practical Considerations for Perioperative Clinicians

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