Successful use of tPA for thrombolysis in COVID related ARDS: a case series

Design

Case 1

A 45-year-old male with uncontrolled diabetes was diagnosed with COVID-19. Upon admission, he had a sPO₂ of 92% and therapeutic doses of low molecular weight heparin (LMWH) were started. On day two, the patient suddenly became breathless and FiO₂ increased overnight from 0.21 to 0.7 while on non-invasive ventilation (NIV). Respiratory rate (RR) was 40 to 45 breaths per minute.

The patient became irritable due to worsening dyspnea. Echocardiogram and compression ultrasonography of legs was normal. D-dimer was 1,350 ng/mL and fibrinogen was 670 mg/dL. Tissue plasminogen activator (tPA) was started at 2 mg/hour and was given 30 mg over 15 hours concurrently with unfractionated heparin (UFH) at 500 units/hour. Thereafter, heparin was increased to 1000 units per hour, with a target goal aPTT of 80 to 90 seconds.

The UFH was changed to LMWH to better control bleeding episodes. After tPA transfusion, his RR decreased to 25 to 28 breaths per minute, FiO₂ decreased from to 0.5 and then to 0.35 three days after. On day six, the patient was maintaining spO₂ > 95% on room air. He was discharged on day 10 following negative COVID-19 PCR report.

A 60-year-old female with a history of coronary artery disease and hypertension was admitted with breathlessness, cough, and vomiting for the prior four days. Upon admission, her room air sPO₂ was 52%, D-dimer 1,787 ng/mL, and fibrinogen 704 mg/dL. After one day of intensive care unit (ICU) management, her P/F ratio was 90 on NIV and FiO₂ 0.75.

The patient was noted to be fatigued, with worsening dyspnea. Echocardiogram was normal. Tissue plasminogen activator (tPA) was started at 50 mg over 3 hours. Three hours after stopping tPA, heparin was started at 1,000 units/hour. Within a few hours of tPA administration, her respiratory rate decreased from 45 to 20 breaths per minute. The patient's FiO₂ remained at 0.6 for two days, decreased to 0.4 on day three, and 0.21 day seven. She was discharged on day 13 following negative COVID-19 PCR report.

A 59-year-old female with a history of obesity and hypothyroidism presented with breathlessness, fever, and decreased appetite for the prior two days. Her sPO₂ was 58% on room air. After one day of ICU management, P/F ratio was 80 and FiO2 was 0.7 on high flow nasal canula (HFNC).

Echocardiogram was normal, D-dimer was 4,583 ng/mL, and fibrinogen was 415 mg/dL. Due to rapid deterioration, she was intubated. Tissue plaminogen activator (tPA) was started at 50 mg over 3 hours. Three hours after stopping tPA, UFH was started at 1,000 units/hour. Within two hours post tPA, her respiratory rate decreased from 40 to 20 breaths per minute. Within three hours of completion of tPA, FiO₂ decreased from 0.7 to 0.35. After three days, the patient was on room air. She was discharged on day eight following a negative COVID-19 PCR report.

Study Author Conclusions

COVID-19 is associated with a hyperinflammatory state, causing activation of the coagulation cascade and micro or macro thrombi in various organs. Abnormally high levels of coagulation markers such as D-dimer and fibrinogen have been significantly correlated with disease severity. One of the most important reasons for mortality is extensive pulmonary micro thrombosis leading to acute respiratory distress syndrome (ARDS). In lieu of this correlation, therapeutic anticoagulation via Tissue plasminogen activator (tPA) has been advocated for the management of COVID-19.

These three cases demonstrated that thrombolysis could be safe, effective, and prevent mortality in select critically ill patients of COVID-19 ARDS. The case investigators conclude that tPA 50 mg over 3 hours can be given to critically ill COVID-19 patients who fulfill all of the following criteria: (1) rapidly rising FiO₂ ≥ 0.7 (on HFNC or NIV), (2) P/F ratio of < 100, (3) D-dimer > 1000 ng/mL, (4) no absolute contraindications of thrombolysis, and (5) no other cause of deterioration like secondary infection or fluid overload.

Abdominal pain in a patient with COVID-19 infection: A case of multiple thromboemboli

Design

Case report

Case Presentation

A 61-year-old female with type 2 diabetes mellitus admitted with three days of dry cough and one day of non-radiating abdominal pain. She reported sharp, severe, periumbilical pain started that morning. The patient denied nausea, vomiting, diarrhea, fevers, shortness of breath, and chest pain. Her husband was diagnosed with COVID-19 the day before.

In ED, her vital signs were 34 breaths/minute, room air sPO2 97%, pulse 112 beats/minute, BP 144/83 mmHg. With 4 L/minute of supplemental oxygen, her hypoxemia improved and she was able to speak. The patient's chest x-ray represented COVID-19 infection and her D-dimer was at 8,264 ng/mL.

Computerized tomography (CT) demonstrated multiple filling defects in the thoracic and abdominal aorta, representing thromboemboli with diffuse bilateral opacities in the lungs. Also, a right ventricular(RV) filling defect concerning thrombus was found via CT scans.

Unfractionated heparin was initiated. Within 24 hours, she developed worsening dyspnea and hypoxemia, so tissue plasminogen activator was initiated to treat her RV clot in transit and presumed PE. Her COVID-19 RT-PCR returned positive the same day. This case report is left unresolved.

Study Author Conclusion

COVID-19 clinical presentations often mimic pulmonary embolism (PE). In COIVID-19 patients, elevated D-dimer levels are common thus, emergency physicians should carefully interpret D-dimer levels and consider thromboembolic workup in elevated D-dimer paitients. Recommendations are needed regarding anticoagulation in COVID-19 paitents presenting with moderate to severe respiratory symptoms.

In this study, the patient's D-dimer was > 16 x normal which confirmed thromboembolism, which was treated with tPA. COVID-19 may develop thromboemboli in situ without distal origin. The International Society on Thrombosis and Haemostasis (ISTH) recommends prophylactic anticoagulation in patients with moderate to severe COVID-19 symptoms along with a D-dimer >6x normal limit due to COVID-19 associated thromemboli such as PE, proximal Deep Vein Thrombosis (DVT) and arterial thrombus. 

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

Case series

A 75-year-old male with a history of hypertension, hyperlipidemia, type 2 diabetes mellitus, and coronary artery disease presented to the hospital with 1 week of cough, fatigue, and fevers. He had a positive test for COVID-19 and CT chest revealed bilateral ground-glass opacities with peripheral and basilar predominance. On presentation, his oxygen saturation (SpO2) was 91% on room air.

He was started on hydroxychloroquine and azithromycin for five days. His oxygen requirement increased to 100% FiO2 on a non-rebreather mask (NRB) by day 3, with SpO2 improving from 85% to 91% with positioning in the awake prone position. His severe hypoxemia persisted and he was intubated on hospital day 6, and his PaO2/FiO2 (P/F) ratio was 73. His D-dimer levels were consistently > 50,000 ng/mL for the four days following intubation and his fibrinogen levels ranged between 375 to 541 mg/dL. On day 8 his P/F ratio ranged between 140 to 240 and he became anuric for which he was initiated on continuous renal replacement therapy (CRRT).

Alteplase 25 mg was administered intravenously over 2 hours, followed by a 25 mg tPA infusion over the subsequent 22 hours. The patient tolerated tPA therapy without bleeding or any other apparent complication, and his P/F ratio improved to 408 11 hours into tPA infusion. Heparin infusion was started at 10 units/kg/hour with a PTT goal of 60-80 following the completion of tPA infusion.

His P/F ratio worsened to 136 one hour into heparin infusion. He was 1 liter positive on his fluid balance for the prior 24 hours and remained anuric on CRRT, but efforts to remove volume via CRRT were complicated by the development of rapid atrial fibrillation and hypotension which made it difficult to achieve a negative fluid balance. His vasopressor requirements increased from one to three (norepinephrine, phenylephrine, and vasopressin).

His P/F was 188-250 at 48 hours post-tPA, similar to his pre-tPA status. His fibrinogen levels remained similar at 351 mg/dL and his D-dimer had decreased to 16,678 ng/mL. By hospital day 11, the patients continued to descend into multiple organ failure with refractory hypotension secondary to arrhythmia and superimposed bacterial infection. He expired shortly after.

A 59-year-old female with a history of hypertension presented to an outside hospital after two days of rhinorrhea, cough, myalgias, and headaches. She had tested positive for COVID-19 and a chest CT demonstrated bibasilar predominantly ground-glass opacities.

She was initiated on hydroxychloroquine and azithromycin. Her oxygen requirement progressed over two days from nasal cannula O2 supplementation to 100% NRB with a PaO2 of 137. On day 4, she required intubation for hypoxemic respiratory failure and was transferred. She required one vasopressor for hemodynamic support. Her P/F ratio was 82 supine and improved to the 130s while prone. On day 6, her D-dimer was 545 ng/mL and this increased to 20,293 ng/mL by day 9 with a fibrinogen level of 939 mg/dL.

After 4 days of intubation and 2 days in the prone position with no durable improvements, IV tPA with alteplase was administered as a 25 mg intravenous bolus over 2 hours, followed by a 25 mg tPA infusion over the subsequent 22 hours. The patient was transitioned to heparin therapy without any bleeding complications. Her P/F was 135 (prone) 4 hours after completing tPA, 150 (prone) 12 hours after completing tPA, and D-dimer increased to 40,490 ng/mL.

By 38 hours after completing the tPA infusion, the patient continued to improve and was placed back in the supine position where the P/F ratio was now 135, a 50% improvement in supine position P/F ratio compared to the P/F of 90 in the supine position three days earlier.

A 49-year-old male with no known medical history presented with 6 days of cough, progressive dyspnea, fever, and myalgia. SpO2 was 40% on room air in the Emergency Department and improved to 90% on 100% FiO2 via NRB. He was intubated due to increased tachypnea and required one vasopressor for hemodynamic support.

A CT chest revealed bibasilar ground-glass opacities. Positive end-expiratory pressure (PEEP) of 20 was initially used, but he developed pneumopericardium, so his PEEP was reduced. He was started on hydroxychloroquine plus azithromycin, as well as a heparin drip for suspicion of venous thromboembolism. On day 1, his D-dimer was 33,228 ng/mL, but it reduced to 17,301 ng/mL on day 2. His P/F ratio was 120 while prone and ranged from 72-90 in the supine position.

His heparin drip was held and IV tPA (Alteplase) was started with a 25 mg 2-hour bolus followed by 25 mg infusion for 22 hours. The heparin drip resumed immediately after tPA completion. His supine P/F improved from 72-90 pre-tPA to a P/F of 125 by 3 hours after completion of tPA, a 38-73% increase. There were no bleeding complications.

After tPA, his D-dimer increased from 17,301 ng/mL to 37,215 ng/mL and his fibrinogen decreased from 874 mg/dL (pre-tPA) to 544 mg/dL (35 hours post-tPA). His P/F ratio declined to 71 by 33-hours after completing the tPA infusion, and the patient was placed back in the prone position with recovery to a P/F ratio of 118.

In all 3 cases the patients demonstrated an initial improvement in their P/F ratio, with improvements ranging from a 38% improvement (Case 3) to a ~100% improvement (Case 1). The observed improvements were transient and lost over time in all 3 patients after completion of their tPA infusion.

Further studies are needed to determine whether the observations in these cases were the result of tPA therapy or the result of unrelated/random effects, and (if effective) to determine the optimal dosing regimen of tPA with or without therapeutic anticoagulation in COVID-19 ARDS to include whether a re-dosing protocol is needed if the benefits are transient.

Case series

A 67-year-old male with PMH significant for hypertension, thyroid cancer (post thyroidectomy and radioactive iodine) presented to the hospital with a ten-day history of worsening shortness of breath, fatigue, fevers, and dry cough. Upon presentation, he displayed hypoxia with an oxygen saturation of 80% on room air and chest radiography demonstrated bilateral patchy opacities. Admission laboratory work was notable for a fibrinogen 257 mg/dL, D-dimer 6,070 ng/mL, and a platelet count of 212 k/uL. He was admitted to the ICU with acute hypoxemic respiratory failure with lung-protective ventilator settings and PEEP 16 on 100% FiO2, sedated and chemically paralyzed. A diagnosis of COVID-19 was confirmed by PCR analysis.

Following admission to the ICU, his ventilator strategy was changed to airway pressure release ventilation (APRV) with a decrease in his FIO2 requirement to 50%. He was treated with ampicillin/sulbactam, hydroxychloroquine, and deemed not a candidate for other study trial medications. By day 2 his renal function deteriorated, and he progressed to oligo-anuric acute kidney injury. Due to limited access to dialysis machines, only short courses of continuous renal replacement therapy (approximately 8-12 hours per day) were able to be completed. He remained with a severe mixed respiratory and metabolic acidosis as his ventilator requirements were necessarily increased.

By day 6, his D-dimer was noted to be above 35,000 ng/mL and was started on enoxaparin. Unfortunately, his pulmonary function continued to deteriorate and he was no longer responding to 100% FiO2 despite multiple changes on the ventilator with P/F ratios now ranging from 70-105. He was deemed not to be a candidate for prone positioning given his tenuous hemodynamic status, large body habitus, severe acidosis (pH 7.1-7.2), and ongoing renal replacement requirements.

On day 16 the patient deteriorated (P/F ratio 77) and was commenced on a trial of inhaled nitric oxide with limited benefit. Respiratory system and lung mechanics remained preserved throughout the entire course despite the severe hypoxemia with a large alveolar-arterial oxygen gradient, consistent with what would be observed in pulmonary vascular occlusive phenomena.

A 27-year-old female with PMH significant for morbid obesity (BMI 57) and non-insulin-dependent diabetes mellitus presented to the hospital with a seven-day history of cough, fever, and progressive dyspnea. She was profoundly hypoxic on hospital presentation with an oxygen saturation of 60% on room air, improved to 80% on FiO2 100% non-rebreather mask (NRB), and she was subsequently intubated. Chest radiography demonstrated bilateral patchy opacities with dense peripheral infiltrates. Admission laboratory work was notable for a fibrinogen 750 mg/dL and a D-dimer of 2,240 ng/mL.

She was admitted to the ICU with acute hypoxemic respiratory failure with lung-protective ventilator settings and PEEP 15 on 100% FiO2 with a P/F ratio of 61 despite sedation, chemical paralysis, and prone positioning. A diagnosis of COVID-19 was confirmed by PCR analysis.

The patient’s respiratory status remained tenuous with O2 saturations dipping to as low as 82% with a very modest improvement upon changing ventilator mode to APRV and was too unstable for consideration of extracorporeal membrane oxygenation (ECMO). Given her instability with P/F ratios (in the 60s while prone) and maximal therapy, the decision was made to administer a bolus of 50 mg tPA over 2 hours while on a concomitant heparin drip at 500 units/hr, followed by a tPA drip at 2 mg/hr for 22 hours while on a therapeutic heparin drip.

Her pre-tPA fibrinogen was 756 mg/dL and D-dimer was 4,040 ng/mL, post-tPA fibrinogen was 856 mg/dL and there was a spike in D-dimer above 20,000 ng/mL consistent with fibrinolysis/clot degradation occurring after tPA administration. The patient had a rapid improvement following administration of tPA allowing for return to the supine position within 3 hours, and at 5 hours post-tPA initiation her FiO2 was down to 50% and P/F ratio was 217.

At the time of completion of her tPA infusion she had partial regression in that her P/F ratio had fallen to 71, but she remained in the supine position instead of prone and overall this was an improvement relative to her pre-tPA prone P/F ratio. No bleeding complications were noted during or after tPA therapy. While some sustained respiratory status improvements persist, she remains critically ill as of the time of this publication.

A 52-year-old male with PMH significant for aortic valve disease, Hodgkin’s lymphoma, and hyperlipidemia presented to a community hospital with a four-day history of fatigue, shortness of breath, body aches, and fever. Upon presentation, he displayed hypoxia with an oxygen saturation of 82% on room air, which improved on 100% FiO2 via non-rebreather mask (NRB), and chest radiography demonstrated bilateral infiltrates. Admission laboratory work was notable for a fibrinogen of 836 mg/dL, D-dimer of 843 ng/mL, INR of 1.2, PTT of 27.8 seconds, and platelet count of 265 k/uL. He was immediately transferred to a tertiary care center for further management, where upon arrival to the ICU his O2 saturations were now 82% on 100% FiO2 NRB so he was intubated, sedated, and placed on mechanical ventilation. A diagnosis of COVID-19 was confirmed by PCR analysis.

He was treated with ceftriaxone, azithromycin, hydroxychloroquine, a therapeutic heparin drip, and supported with a lung-protective ventilation strategy, and on day 3 was also chemically paralyzed. On day 6 his respiratory failure had continued to progress with P/F ratio of 97 and he was placed in the prone position with the recovery of P/F ratio to above 100. By day 12 his P/F ratio was consistently below 100 despite prone positioning and maximal ventilator strategies.

Salvage therapy was initiated with 50 mg tPA (alteplase) bolus over 2 hours with his heparin drip turned down to 500 units/hr during the tPA bolus, with resumption of a therapeutic rate of his heparin drip after the tPA bolus was completed. His pre-tPA fibrinogen was 365 mg/dL and D-dimer was 15,061 ng/mL, post-tPA fibrinogen was 373 mg/dL and there was a spike in D-dimer to 17,613 ng/mL consistent with fibrinolysis/clot degradation occurring after tPA administration.

His P/F ratio immediately improved from 82 pre-tPA to 105 post-tPA, which continued to improve throughout the day and his FiO2 was weaned from 80% to 70% that evening. At 24 hours post-tPA his P/F ratio had improved to 141 and he was returned to the supine position shortly after, which he tolerated. At 60 hours post-tPA he did develop some rectal bleeding felt to be related to the prolonged presence of a rectal tube in the setting of an ongoing therapeutic heparin drip, which required a 1 unit transfusion of packed red blood cells and temporary cessation of his heparin drip that was subsequently resumed without complication.

The 5 patients who were treated with intravenous administration of tPA (alteplase) for profound COVID-19 respiratory failure in the setting of an apparent thrombotic coagulopathy appeared to have improved respiratory status. A prior case series of 3 patients treated with tPA (alteplase) for COVID-19 respiratory failure that used lower doses of tPA over longer periods of time and without concomitant heparin anticoagulation demonstrated less dramatic effects that were less durable than what was observed with larger doses of tPA and concomitant heparin anticoagulation as described in this present case series.

Larger studies with a control group will be required to demonstrate efficacy and safety, as well as identify the patient population that benefits most from tPA and the optimal dose and route for tPA administration. Currently, a Phase 2 multi-center randomized control trial of TPA in COVID-19 respiratory failure is in recruitment to answer these questions. Until such studies are published, individual clinician considerations for off-label tPA therapy in COVID-19 patients with thrombotic coagulopathy and respiratory failure may be warranted when there is an imminent risk of death and no available options for escalation of care.