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Table of Contents
Year : 2022  |  Volume : 12  |  Issue : 4  |  Page : 181-183

What's New in Critical Illness and Injury Science? Alteplase for severe coronavirus disease 2019: Not quite ready to clot bust just hypoxemia

1 Department of Medicine, Case Western University School of Medicine, University Hospitals of Cleveland; Department of Pediatrics, Case Western University School of Medicine, Rainbow Babies and Children's Hospital, Cleveland, OH, USA
2 Department of Medicine, Case Western University School of Medicine, University Hospitals of Cleveland, OH, USA

Date of Submission10-Dec-2022
Date of Acceptance10-Dec-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Dr. Kenneth E Remy
The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University and University Hospitals, Cleveland, OH, USA. Departments of Medicine and Pediatrics, University Hospitals of Cleveland, 11110 Euclid Avenue, Cleveland 44106, OH
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijciis.ijciis_82_22

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How to cite this article:
Areti S, Maki MK, Remy KE. What's New in Critical Illness and Injury Science? Alteplase for severe coronavirus disease 2019: Not quite ready to clot bust just hypoxemia. Int J Crit Illn Inj Sci 2022;12:181-3

How to cite this URL:
Areti S, Maki MK, Remy KE. What's New in Critical Illness and Injury Science? Alteplase for severe coronavirus disease 2019: Not quite ready to clot bust just hypoxemia. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Mar 20];12:181-3. Available from: https://www.ijciis.org/text.asp?2022/12/4/181/364745

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated very interesting and unique variant-to-variant pathophysiology in risk associated with thromboembolic disease.[1] Multiple mechanisms after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have demonstrated direct and indirect associations with endothelial dysfunction, altered vascular tone, oxidative stress, inflammation, mitochondrial dysfunction, virus-induced immune exhaustion, cytokine storm, and hemostatic or coagulopathic perturbations leading to morbidity and mortality.[2] In the first wave, microthrombotic disease as a manifestation leading to altered pulmonary vascular resistance was posited to cause increase mortality, and those with the most severe forms of COVID-19 disease demonstrating multifactorial hypercoagulability, increased fibrinogen, factor VIII, and D-dimer levels with demonstrated decreased protein C, S, and antithrombin levels.[3] Patients with COVID-19 pneumonia in the intensive care unit were reported to have a 31% incidence of thrombotic complications, with pulmonary embolism (PE) being the most common complication.[1] As such, numerous strategies have been attempted to control this phenomenon including prophylactic anticoagulation at treatment dosing for hospitalized and/or critically ill patients with equivocal findings.[4],[5],[6]

Presently no single large randomized controlled trial (RCT) that has been completed has demonstrated the benefit of one strategy in timing, dosage, choice of anticoagulant, or duration for the treatment or prevention of thromboembolic disease in COVID-19.[4],[5],[6] Most RCTs and observational studies published have recruited patients during the first wave with the initial variants of SARS-CoV-2 and may not reflect variant changes, nor consider alterations in thromboembolic disease after increased vaccination strategies have been employed. As anticoagulation strategies have been challenging, once a demonstration of massive PE has been shown in a patient, determining the best practice for the deployment of thrombolytics including dosing has equally been exigent.

Historically, thrombolytic therapies such as tissue plasminogen activator (tPA) have been a treatment option for those with massive PE. In such cases, thrombolytic therapies have been shown to reduce cardiovascular collapse, with improvement in the right ventricular function and reduction in clot burden.[7],[8] However, tPA is associated with hemorrhagic stroke at a rate exceeding 2%, thus consideration for a titrated lowered dose has been utilized to minimize this complication.[8] No guidelines are currently available to directly address the use of tPA to treat PE in COVID-19 patients; however, various studies have been performed.[9],[10],[11]

In the current issue of IJCIIS, two separate evaluations of the use of tPA for PE management in COVID-19-related critically illness are reported.[12],[13] First, in a case series of five patients with COVID-19-induced PE (ages 30–75 years) and pretreated with anticoagulation, all received differing doses of alteplase.[12] However, not all patients that received tPA had evidence of massive PE or hypotension.[12] In addition, all five treated patients had improvement in their PO2/FiO2 ratio ranging from 29% to 218% within 48 h of thrombolytic therapy initiation.[12] All patients were discharged to home.[12]

In the second retrospective observational study, 13 critically ill patients with acute respiratory distress syndrome (ARDS) from COVID-19 were treated with an initial alteplase 25 mg intravenous bolus followed by a 25 mg infusion over 22 h and compared to 21 similar patients that did not receive thrombolysis (aged 50–64 years vs. 29–84 years).[13] All patients had PE and were similarly matched by acute physiology and chronic health evaluation II scores. Mortality in the thrombolysis group compared to the nonthrombolysis group was significantly improved (23.1% vs. 71.4%; P = 0.006), as was the PaO2/FiO2 ratio (97.0 [86.3–118.6] to 135.6 [100.7–171.4]; P = 0.03) 24 h postthrombolysis.[13] Of note, all patients had severe ARDS with a PaO2/FiO2 ratio range in both groups of 66–90. The reported indication for thrombolysis was evidence of acute pulmonary hypertension and right ventricular dysfunction.[13] In both studies, major bleeding complications were not seen.[12],[13]

Both studies differently highlight a potential benefit for the administration of thrombolytic treatment; however, these reports must be taken with caution. Most notably, none of the patients in the first case series demonstrated massive PE and only a marginal number of patients in the second study had meaningfully elevated right heart pressures. Thus, patients in the two studies/series were receiving thrombolytic therapy principally for hypoxemia. Thrombolytic therapy has been shown to improve pulmonary artery pressure, hypoxemia, pulmonary perfusion, and induced pulmonary artery hypertension by echocardiography, and to reduce mortality; however, this benefit has been best demonstrated in hemodynamically unstable patients as the risk of bleeding in these patients may not outweigh the potential benefit.[14] Deploying thrombolytic therapies in patients without evidence of cardiopulmonary compromise or hemodynamic instability may unjustifiably increase the risk of life-threatening hemorrhage and mitigate any perceived benefit. Fortunately, in the included studies, bleeding was not a major consequence; however, the reports were not sufficiently powered to assess this outcome. Even so, the use of lower or titrated dose thrombolytic treatment protocols may warrant further study, which is recommended before larger-scale deployment of such a strategy.

Invariably, understanding which patients may benefit from thrombolytic therapy has been quite challenging, especially as functional hemostatic testing including thromboelastography has not adequately been able to discriminate thrombotic events in patients with COVID-19.[15] Furthermore, variant-to-variant SARS-CoV-2 differences have demonstrated differing hemostatic and thrombotic phenotypes, which further complicate the use of thrombolytic therapies, especially in the absence of traditionally accepted indications when hemodynamic instability is not present. Before departure from these canonical approaches for thrombolytic therapies can occur, the field first needs to best understand the potential influence of immunization and variant evolution upon the true incidence of life-threatening thromboembolic disease instead of just potentially bystander thrombotic disease not contributing to mortality. Undeniably in COVID-19 disease endothelial cell damage along with increased production of inflammatory markers such as interleukin (IL)-1 and IL-6 occurs in some patients with a related reduced fibrinolysis capacity; however, other patients have demonstrated worsened coagulopathy.[2] However, an inability to functionally quantify this risk and its related clinical relevance challenge the usage of thrombolytic therapies without compelling prospective multicenter randomized control trials to support its usage.

The decision to perform thrombolysis for PE in COVID-19 patients should remain one that includes an evaluation of risk versus benefit decision analyses. As SARS-CoV-2 viral infection has become endemic and “normalized” to other viral illnesses, a departure from standard best practices should be exercised with extreme caution. More research is needed and is paramount to discriminate precisely which patients may benefit and under what conditions (patient phenotype and viral variant) from thrombolytic deployment, while balancing potential harm to patients. This mainstay tenant of medicine remains, whereas ongoing intellectual curiosity and rigorous study bring the field into new advances.

Research quality and ethics statement

This report was exempt from the requirement of approval from the Institutional Review Board/Ethics Committee. No specific EQUATOR Network (http://www.equator-network.org/) guideline is available for editorials.

Financial support and sponsorship

Dr. Remy's effort is supported by the National Institutes of Health, National Institute of General Medical Sciences (Grant No. 7K08GM129763).

Conflicts of interest

There are no conflicts of interest.

   References Top

Dutch COVID & Thrombosis Coalition, Kaptein FH, Stals MA, Grootenboers M, Braken SJ, Burggraaf JL, et al. Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave. Thromb Res 2021;199:143-8.  Back to cited text no. 1
Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin 2022. Available at: https://www.nature.com/articles/s41401-022-00998-0 [Last accessed on 2022 Dec 09].  Back to cited text no. 2
Calvet L, Thouy F, Mascle O, Sapin AF, Grapin K, Liteaudon JM, et al. Hypercoagulability in critically ill patients with COVID 19, an observational prospective study. PLoS One 2022;17:e0277544.  Back to cited text no. 3
Baumann Kreuziger L, Sholzberg M, Cushman M. Anticoagulation in hospitalized patients with COVID-19. Blood 2022;140:809-14.  Back to cited text no. 4
Bradbury CA, McQuilten Z. Anticoagulation in COVID-19. Lancet 2022;399:5-7.  Back to cited text no. 5
Chowdhury JF, Moores LK, Connors JM. Anticoagulation in hospitalized patients with COVID-19. N Engl J Med 2020;383:1675-8.  Back to cited text no. 6
Tapson VF, Sterling K, Jones N, Elder M, Tripathy U, Brower J, et al. A randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism: The OPTALYSE PE trial. JACC Cardiovasc Interv 2018;11:1401-10.  Back to cited text no. 7
Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, et al. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: The SEATTLE II study. JACC Cardiovasc Interv 2015;8:1382-92.  Back to cited text no. 8
Barrett CD, Moore HB, Moore EE, Wang J, Hajizadeh N, Biffl WL, et al. Study of alteplase for respiratory failure in SARS-CoV-2 COVID-19: A vanguard multicenter, rapidly adaptive, pragmatic, randomized controlled trial. Chest 2022;161:710-27.  Back to cited text no. 9
Barrett CD, Moore HB, Moore EE, Benjamin Christie D 3rd, Orfanos S, Anez-Bustillos L, et al. MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study. Res Pract Thromb Haemost 2022;6:e12669.  Back to cited text no. 10
Moore HB, Barrett CD, Moore EE, Jhunjhunwala R, McIntyre RC, Moore PK, et al. Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial. Res Pract Thromb Haemost 2020;4:984-96.  Back to cited text no. 11
Aribawa IG, Ryalino C, Pradhana A, Dewi P, Sinardja C, Mulyantari N. Pulmonary embolism in patients with severe COVID-19 treated with systemic low-dose thrombolytic therapy: A case series. Int J Crit Illn Inj Sci 2022;12:235-8.  Back to cited text no. 12
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Ashwathappa PG, Jacob I, Rangappa P, Rao K. Thrombolysis as a rescue therapy in coronavirus disease 2019 patients with acute respiratory distress syndrome: A retrospective observational study. Int J Crit Illn Inj Sci 2022;12:197-203.  Back to cited text no. 13
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Martin C, Sobolewski K, Bridgeman P, Boutsikaris D. Systemic thrombolysis for pulmonary embolism: A review. P T 2016;41:770-5.  Back to cited text no. 14
Kartiko S, Koizumi N, Yamane D, Sarani B, Siddique AB, Levine AR, et al. Thromboelastography Parameters do not Discriminate for Thrombotic Events in Hospitalized Patients With COVID-19. J Intensive Care Med 2022. Available at: https://journals.sagepub.com/doi/10.1177/08850666221142265 [Last accessed on 2022 Dec 09].  Back to cited text no. 15


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