key: cord-0878846-862kffnb
authors: Carneiro, Thiago; Dashkoff, Jonathan; Leung, Lester Y.; Nobleza, Christa O'Hana S.; Marulanda-Londono, Erika; Hathidara, Mausaminben; Koch, Sebastian; Sur, Nicole; Boske, Alexandra; Voetsch, Barbara; Nour, Hassan Aboul; Miller, Daniel J; Daneshmand, Ali; Shulman, Julie; Curiale, Gioacchino; Greer, David M.; Romero, Jose Rafael; Anand, Pria; Cervantes-Arslanian, Anna M.
title: Intravenous tPA for Acute Ischemic Stroke in Patients with COVID-19
date: 2020-07-27
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2020.105201
sha: 333beb7cf07cf901730be0d9a1a36baf72ea7d74
doc_id: 878846
cord_uid: 862kffnb

Background/Purpose: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19. Methods: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA. Results: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male). All received IV tPA and 3 cases also underwent mechanical thrombectomy. All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients). The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3-26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0-25). No systemic or symptomatic intracranial hemorrhages were seen. Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient). Three patients were determined to have transient ischemic attacks or aborted strokes. Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml). Conclusions: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results.

Financial disclosures: All authors have no disclosures to report.

Background/Purpose: Coronavirus disease 2019 (COVID-19) is associated with increased risk of acute ischemic stroke (AIS), however, there is a paucity of data regarding outcomes after administration of intravenous tissue plasminogen activator (IV tPA) for stroke in patients with COVID-19.

Methods: We present a multicenter case series from 9 centers in the United States of patients with acute neurological deficits consistent with AIS and COVID-19 who were treated with IV tPA.

Results: We identified 13 patients (mean age 62 (±9.8) years, 9 (69.2%) male). All received IV tPA and 3 cases also underwent mechanical thrombectomy. All patients had systemic symptoms consistent with COVID-19 at the time of admission: fever (5 patients), cough (7 patients), and dyspnea (8 patients) . The median admission NIH stroke scale (NIHSS) score was 14.5 (range 3-26) and most patients (61.5%) improved at follow up (median NIHSS score 7.5, range 0-25). No systemic or symptomatic intracranial hemorrhages were seen.

Stroke mechanisms included cardioembolic (3 patients), large artery atherosclerosis (2 patients), small vessel disease (1 patient), embolic stroke of undetermined source (3 patients), and cryptogenic with incomplete investigation (1 patient). Three patients were determined to have transient ischemic attacks or aborted strokes. Two out of 12 (16.6%) patients had elevated fibrinogen levels on admission (mean 262.2 ± 87.5 mg/dl), and 7 out of 11 (63.6%) patients had an elevated D-dimer level (mean 4284.6 ±3368.9 ng/ml).

Conclusions: IV tPA may be safe and efficacious in COVID-19, but larger studies are needed to validate these results.

Preliminary reports suggest that patients with Coronavirus Disease 2019 (COVID-19) are at high risk of hematologic complications, including disseminated intravascular coagulation (DIC). 1, 2, 3 Patients with COVID-19 may exhibit hemostatic abnormalities with the potential to precipitate both hemorrhagic and thromboembolic events, including mild thrombocytopenia, prolongation of both prothrombin time and international normalized ratio, and shortened activated partial thromboplastin time, and both ischemic stroke and intracerebral hemorrhage have been described in infected patients. 4, 5, 6, 7 However, limited evidence exists in the literature for management of acute stroke in COVID-19 given the concomitant risk of hemorrhage, and recommendations are based on consensus only. 8 The safety and efficacy of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke in patients with COVID-19 remain unknown. 1 We present the outcomes of a multicenter series of patients with confirmed COVID-19 infection who were treated with IV tPA for suspected acute ischemic stroke.

All patients with COVID-19 who received IV tPA for acute neurological deficits between March 1, 2020 and July 1, 2020 were identified at the participating hospitals by the corresponding stroke provider at each institution. The study protocol was approved or given exemptions by local institutional review boards. All patients included were diagnosed with COVID-19 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR from a nasopharyngeal swab, presented with acute neurological deficits (< 24 hours), received IV tPA per acute ischemic stroke American Heart Association guidelines, and underwent brain and intracranial vessel imaging. 9 Laboratory values were obtained within 24 hours of admission (Table 1) . Stroke mechanism was primarily defined using the TOAST classification, with some strokes classified as embolic strokes of undetermined source (ESUS). 10, 11 Results:

A total of 13 patients were identified at 9 centers. Mean age was 62 (±9.8) years, and 9

(69.2%) were male ( Table 1) 

No patients had symptomatic systemic or intracranial hemorrhage. One patient developed asymptomatic petechial hemorrhage in the area of infarction noted on routine follow-up imaging at 24 hours. Median NIHSS score for patients with stroke at follow-up was 7.5 (range 0-25), and 8 (61.5%) patients had an improvement in their NIHSS score of 4 points or more. All patients survived to hospital discharge however one elderly patient was discharged to hospice because of severe respiratory symptoms.

We describe a series of patients with COVID-19 who presented from the community and received IV tPA for acute ischemic stroke. In our series, intravenous thrombolysis was not associated with symptomatic complications, and the majority of patients had clinical improvement at follow-up. Preliminary reports found a 1% incidence of stroke among hospitalized patients with COVID-19. 4, 12 More recently, acute ischemic strokes have been noted in the early stages of illness, and LVO has been reported as the presenting symptom of COVID-19. 1, 13, 14 Patients with COVID-19 can also present with delirium, meningoencephalitis, and fever, which may be considered stroke mimics, posing a challenge in the evaluation for thrombolysis eligibility. 6, 12 In 2 case series of LVO in patients with COVID-19, 45% of patients had encephalopathy at admission, suggesting that reduced level of consciousness could be a common presenting symptom in patients with COVID-19-associated stroke. 1, 13 In our series, 61.5 % patients had large vessel occlusion, but only 7% developed encephalopathy. Of note, although the Wuhan findings suggested that stroke was more common among critically ill patients, the patients in our series presented from the community with mild viral illness. 4 Preliminary reports also suggest more severe illness in male patients with COVID-19, an observation that may be reflected in the male predominance of our cohort.

Growing evidence suggests SARS-CoV-2 infection is associated with a pro-thrombotic state. This process is mediated by an inflammatory cascade that leads to elevated D-dimer and fibrinogen levels, low anti-thrombin III levels and pulmonary congestion with microvascular thromboses, especially in critically ill patients. 2 A clot waveform analysis study in patients with COVID-19 demonstrated that hypercoagulability preceded or coincided with severe illness. 15 Anti-phospholipid antibodies have been detected in some COVID-19 patients with thromboembolic events, including those with LVOs and strokes. 13, 16 Our study shows a wide distribution of stroke etiologies, suggesting that COVID-19 may increase the risk for stroke through a variety of mechanisms, including those seen in other viral disorders. 17 Further studies are required to elucidate stroke etiology and any causal relationship between SARS-CoV-2 infection and stroke.

IV tPA has been used anecdotally in COVID-19 to treat acute respiratory distress syndrome, but no published data exist specifically on the safety of IV tPA for acute ischemic stroke treatment. 2 COVID-19 may also increase the risk of systemic or cerebral hemorrhagic complications, and has also been reported in association with acute hemorrhagic necrotizing encephalopathy. 18 Our series suggests that symptomatic hemorrhagic complications with IV tPA in patients with COVID-19 are infrequent and lower than the rate of complications in the general population (between 2 and 3.3%), reiterating a pro-coagulable state rather than a bleeding disorder. 19,20 Larger studies correlating outcomes post-thrombolysis with hemostatic measures such as d-dimer, fibrinogen levels, and thromboelastography are needed to better understand which patients are most likely to safely benefit from IV tPA administration.

Post-mortem studies have found additional evidence of fibrin-rich thrombi in patients with COVID-19, raising concern that IV tPA may be of limited benefit in this patient population in the setting of prior studies demonstrating a lower efficacy of tPA thrombolysis in thrombi with high fibrin content compared with with erythrocyte-rich emboli. 21,22 However, the majority of included patients had an NIHSS score improvement of 4 or more points and were discharged home, suggesting that IV tPA is efficacious in these patients. Given the small number of patients in our series, our observations should be taken with caution. The majority of patients in the study had moderate to severe strokes (median NIHSS 14.5) and presented from the community. Therefore, our results may not be generalizable to those with mild strokes or who are critically ill.

In spite of the uncertain hematologic effects of COVID-19, our findings suggest that IV tPA may be used safely in acute ischemic stroke patients with COVID-19 and is associated with improved outcomes. Larger studies are needed to better understand safety and efficacy in this patient population. 

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The authors have no acknowledgement.Author Contributions: