key: cord-0818713-w8nv0qf8
authors: Arachchillage, Deepa J.; Stacey, Arthur; Akor, Frances; Scotz, Martin; Laffan, Mike
title: Thrombolysis restores perfusion in COVID‐19 hypoxia
date: 2020-08-17
journal: Br J Haematol
DOI: 10.1111/bjh.17050
sha: b203e5f04a2127d1fcf6a45148d8c6a9018bc385
doc_id: 818713
cord_uid: w8nv0qf8

Thrombolysis with tissue plasminogen activator (tPA) is an established treatment strategy for patients with intermediate and high-risk pulmonary embolism (PE) and signs of haemodynamic instability. The use of tPA in coronavirus disease -19 (COVID-19) patients with PE and acute respiratory distress syndrome (ARDS) may be of benefit due to the unusually high incidence of pulmonary embolism and pulmonary thrombosis, particularly microvascular thrombosis which are thought to contribute significantly to hypoxemia(1).

Thrombolysis with tissue plasminogen activator (tPA) is an established treatment strategy for patients with intermediate and high-risk pulmonary embolism (PE) and signs of haemodynamic instability. The use of tPA in coronavirus disease 2019 (COVID-19) patients with PE and acute respiratory distress syndrome (ARDS) may be of benefit due to the unusually high incidence of pulmonary embolism and pulmonary thrombosis, particularly microvascular thrombosis, which are thought to contribute significantly to hypoxaemia. 1 It may also ameliorate the effects of extravascular and intra-alveolar fibrin deposition described in ARDS. 2 Inhaled delivery of tPA and two doses of tPA against placebo 3 are currently under trial. Small case series have reported transient improvements in oxygenation without significant bleeding from systemic fibrinolytic therapy in patients with ARDS and COVID-19. 4 Here, we describe the largest cohort to date of patients with COVID-19 treated with alteplase for severe hypoxia. This retrospective observational study was approved by the institutional review board as a service evaluation project and no further ethical approval was required.

All alteplase prescriptions from 17 April 2020 to 25 May 2020 were retrieved from pharmacy electronic records and those used for COVID-19 were identified. Clinical and laboratory parameters were extracted from patient electronic records. Statistical analyses were performed using GraphPad Prism v8Á4 (GraphPad Software, San Diego, CA, USA). Descriptive statistics were used to summarize the data; results are reported as medians and ranges or means and standard deviations, as appropriate. Categorical variables were summarized as counts and percentages. Pre-and postthrombolysis parameters were compared using a paired ttest. A two-sided P value < 0Á05 was considered statistically significant.

During the study period, 12 patients received thrombolysis with alteplase for profound hypoxia on mechanical ventilation (except patient 5 on continuous positive airway pressure) and failed proning, with or without evidence of pulmonary thrombosis on computed tomography pulmonary angiography (CTPA). Baseline demographic features, clinical history, CTPA and echocardiographic findings prior to thrombolysis, dose of alteplase with infusion time and days since admission to thrombolysis are summarized in Table I . Only one patient 4 was on antithrombotic therapy (warfarin) and aspirin prior to admission due to a previous history of left apical mural thrombus. None of the patients had previous malignancy or autoimmune disease. Median (range) age of the group was 61Á5 (51-75) years and 7/12 patients were male. Median duration from admission to thrombolysis was nine days (range 2-22). All patients received therapeutic heparin pre and post thrombolysis. Five of the 12 patients had multiorgan failure (defined as failure of two or more organ supports) and required renal replacement therapy. All except one (patient 5 on continuous positive airway pressure) were retained on mechanical ventilation following thrombolysis. The decision to use thrombolysis was made due to moderate to severe hypoxia with ratios of arterial pressure to inspired oxygen (PaO 2 /FiO 2 , PF ratio) <200 mm Hg on mechanical ventilation and failing all other interventions including proning and nitrates.

PF ratios pre and 24 h post thrombolysis are shown in Fig  1, which showed a significant improvement in all patients (P = 0Á002). Only three patients had a follow-up CTPA and echocardiogram. These showed marked improvement in thrombotic occlusions and right ventricular strain (patients 5, 11 and 12). Seven patients survived to hospital discharge whilst others died from 2 to 11 days following thrombolysis due to multiorgan failure (patient 2, 3 4, 6 and 9). Overall mortality was 41Á67%.

Twenty-four hours after thrombolysis, median fibrinogen level fell from 7Á0 (range 4Á95-8Á9) g/l to 3Á40 (2Á50-6Á30) g/l (P = 0Á03) and median D-dimer level increased from 3502 (range 862-9929) ng/ml to 19450 (11495->20000) (P = 0Á002). There were no differences in haemoglobin, platelet count, C-reactive protein, prothrombin time, activated partial thromboplastin time, renal or liver function tests pre and 24 h post thrombolysis.

There were no major or clinically significant minor bleeding complications of thrombolysis. However, one patient had intracranial bleeding 17 days after thrombolysis whilst on unfractionated heparin.

This report comprises the largest cohort to date of patients with severe COVID-19 treated using alteplase. The indication in each case was progressive hypoxia with or without evident PE, despite mechanical ventilation (one on continuous positive airway pressure), nitrates, therapeutic anticoagulation and proning. The median PF ratio prior to thrombolysis was 73Á87(range 49Á5-153Á57) mm Hg which improved to 122Á86 (range 84Á65-321Á46) mm Hg 24 h following thrombolysis (Fig 1) . Previous studies of ARDS have shown a PF ratio of < 100 mm Hg is associated with a mortality rate of 53%, and 40% for a ratio of 100-300. 5 This group, therefore, had a very poor prognosis but current mortality rates for COVID-19 after ICU admission are even correspondence higher, being 88% in a large series. 6 The mortality in this small series was 41Á6% and assuming an expected mortality of 75% 3 in patients requiring advanced respiratory and renal support based on the intensive care national audit and research report (ICNARC) represents a significant improvement (P = 0Á01, v 2 ). The rationale for use of tPA is straightforward. Patients with COVID-19 have a systemic hypercoagulable state with an incidence of venous thrombosis (VT) and PE that exceeds that seen in other pneumonias. In addition, there appears to be gross inflammation of endothelium leading to inflammation-driven local pulmonary thrombosis in medium and small vessels. Large and small thrombi cause vascular shunting and hypoxaemia which may be relieved by clot lysis. In addition, inflammation results in a vascular leak allowing extravascular fibrin formation in lung parenchyma tissue and in alveoli with associated hypofibrinolytic shutdown. 7 Therefore, improvement of the PF ratio following alteplase may reflect both improvement in alveolar perfusion and ventilation. In the absence of significant bleeding with preserved fibrinogen levels 24 h post thrombolysis and a significantly improved PF ratio this report suggests that fibrinolysis may be beneficial in a carefully selected group of patients with close monitoring. Therapeutic strategies targeting the pulmonary circulation in COVID-19 require a multimodal approach. Thrombolysis in a carefully selected group of patients may be beneficial as shown in our cohort of patients. However, with the profound immune activation and intravascular thrombosis, and the short half-life of thrombolytic agents, the lack of a sustained effect and absence of a control group are potential concerns. Randomized clinical trials with larger numbers may provide more solid evidence.

Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series

Assessment of PaO₂/FiO₂ for stratification of patients with moderate and severe acute respiratory distress syndrome

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized With COVID-19 in the New York City Area

Pulmonary angiopathy in severe COVID-19: physiologic, imaging and hematologic observations

Authors would like to thank all clinical staff at adult intensive care units, haemostasis and thrombosis consultants on call, the radiology department and the cardiology unit at St Mary's Hospital, Imperial College Healthcare NHS Trust. Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).

No funding was received for this work.

DRJA was involved in the study concept and design, analysis and interpretation of data, review of the literature and prepared the first draft of the manuscript. FA and AS collected the data and reviewed the manuscript. MLinterpreted the data, reviewed the literature and revised the manuscript. MS interpreted the data and reviewed the manuscript. All authors approved the final version of the manuscript.

The authors state that they have no conflict of interest.