The coronavirus disease 2019 (COVID-19) pandemic and high rate of associated acute respiratory distress syndrome (ARDS) are placing an overwhelming burden on the health care system nationally. As mechanical ventilators and extracorporeal membrane oxygenation (ECMO) resources become exhausted, therapies to attenuate the severity of COVID-19–associated respiratory failure are urgently needed.
Approximately three quarters of patients who die of COVID-19 meet the International Society for Thrombosis and Hemostasis criteria for disseminated intravascular coagulation, which is almost exclusively prothrombotic in COVID-19 patients with a thromboembolic complication rate in COVID-19 intensive care unit (ICU) patients of 31.4%.1–3 In contrast, only 0.6% of patients who survive meet disseminated intravascular coagulation criteria.1 Laboratory hallmarks of COVID-19 critical illness include highly elevated fibrinogen levels together with elevated levels of D-dimer.4 The COVID-19 pathology reports are demonstrating diffuse pulmonary and systemic microvascular thrombosis and occlusion.5 Although these findings seem much more marked in COVID-19 patients, this is in keeping with ARDS, regardless of cause.5,6 Numerous preclinical studies and a single clinical trial have shown improved survival in ARDS following the institution of fibrinolytic therapy.7,8 The pronounced clinical constellation of pulmonary and systemic thrombotic coagulopathy in COVID-19 critical illness with relatively normal lung compliance and high alveolar-arterial oxygen gradients,9 along with the autopsy findings of diffuse pulmonary microvascular thrombosis, endorses the rationale that fibrinolytic therapy may have a biologically plausible role in treatment. The following is a case series using intravenous tissue plasminogen activator (tPA; alteplase) in five critically ill mechanically ventilated COVID-19 patients with thrombotic coagulopathy and ARDS.
A 39-year-old man with no past medical history (PMH) presented to a community hospital with a 4-day history of shortness of breath, cough, and chest pain. Upon presentation, he was hypoxic (room air oxygen saturation of 90%) and demonstrated bilateral patchy opacities on chest radiography and positive COVID-19 polymerase chain reaction (PCR) testing. He rapidly declined within hours of admission to require endotracheal intubation, mechanical ventilation, and ICU admission. He was treated with ceftriaxone, azithromycin, and hydroxychloroquine and supported with a lung protective ventilation strategy. On hospital day (HD) 5, he was transferred to a tertiary care facility for further management given the persistent severe, refractory hypoxemic respiratory failure; his organ failure was limited to single system (pulmonary). Admission laboratory work was notable for fibrinogen of 1,116 mg/dL (also his peak), D-dimer of 7,434 ng/mL, International Normalized Ratio (INR) of 2.2, Partial Thromboplastin Time (PTT) of 34.1 seconds, and platelet count of 344 K/μL.
Despite sedation, neuromuscular blockade, and lung protective ventilation with optimized Positive End-Expiratory Pressure (PEEP) of 16 cm H2O guided by esophageal manometry, his PaO2/FiO2 (P/F) ratio was 81 on FiO2 of 80%. Prone positioning led to some improved oxygenation (P/F, 110), but unfortunately, over the subsequent 72 hours and trials of both inhaled epoprostenol and inhaled nitric oxide, his P/F ratios resided between 60 and 100, with the lowest ratios correlating with failed trials of supination from the prone position. Transthoracic echocardiography demonstrated normal biventricular systolic function. Throughout the clinical course, his laboratory studies remained notable for extremely elevated fibrinogen and D-dimer levels consistent with a prothrombotic coagulopathy. Respiratory system and lung mechanics remained preserved throughout (static respiratory system compliance, 35–45 mL/cm H2O; driving pressure, <15 cm H2O) despite severe hypoxemia and a large alveolar-arterial oxygen gradient, consistent with pulmonary vascular occlusive phenomena as the primary pathophysiology.
Given the lack of clinical improvement, a trial of tPA was initiated using a 25-mg bolus for 2 hours, with an additional 25 mg infused for the following 22 hours.8,10 Pre-tPA and post-tPA bolus thromboelastography testing showed a low-normal value of fibrinolysis (LY30, %) of 0.2% (reference range, 0–2.6%) (Table 1). D-dimer was already above reference range, so it was unable to be used as a marker of fibrinolysis/clot degradation resulting from tPA therapy. A modest initial improvement in P/F ratio was observed within 4 hours (Fig. 1A); however, the response mostly subsided during the low-dose tPA maintenance infusion. Importantly, the patient was not anticoagulated during the maintenance tPA infusion. His fibrinogen went from 731 mg/dL pre-tPA to 628 mg/dL at completion of the 22-hour tPA infusion. Based on the lack of sustained clinical improvement, further therapies were considered, including the interleukin-6 receptor antagonist tocilizumab, which was administered.
His limited response to initial tPA therapy prompted concern for underdosing of tPA based on the expected high levels of Plasminogen Activator Inhibitor-1 (PAI-1)11 and the modest dose he received relative to what is used in other thrombotic occlusive conditions,12 with further concern that lack of concomittant anticoagulation may have allowed for early rethrombosis. Therefore, a second bolus of 50 mg of tPA for 2 hours was administered, this time with a simultaneous heparin infusion at 500 U/h. Thromboelastography showed low-normal LY30 values before and after tPA (0.2% and 1.6%, respectively), with an appropriate increase to LY30 >22% during the tPA bolus (Table 1). After tPA bolus completion, heparin therapy was advanced to a target PTT of 60 to 80 seconds.
The patient's oxygenation and P/F ratio progressively improved thereafter (Fig. 1A), increasing to 197 after 24 hours and 227 at 36 hours despite returning the patient to the supine position, cessation of inhaled nitric oxide, and lifting of neuromuscular blockade. Seven days post-tPA, the patient was successfully extubated and neurologically intact with no apparent complications of tPA therapy.
A 58-year-old man with PMH significant for hypertension and non–insulin-dependent diabetes mellitus presented to the hospital with a 2-week history of shortness of breath and feeling “unwell” in the setting of a known outpatient diagnosis of COVID-19 confirmed by PCR analysis 4 days before admission. Upon presentation, he displayed hypoxia with an oxygen saturation of 78% on room air, which initially improved on 100% FiO2 via nonrebreather mask (NRB), and chest radiography demonstrated bilateral infiltrates. Admission laboratory work was notable for a fibrinogen of 482 mg/dL (peak, 1,021 mg/dL on HD 5), D-dimer of 1,462 ng/mL, INR of 1.2, PTT of 30.2 seconds, and platelet count of 181 K/μL. Upon arrival to the ICU from the emergency department, he was noted to have increased work of breathing, tachypnea to the 40s, and recurrent desaturations despite 100% FiO2 on NRB, so he was intubated on HD 1.
He was treated with ceftriaxone, azithromycin, and a therapeutic heparin drip and supported with a lung protective ventilation strategy, and by HD 3, he was also chemically paralyzed. His respiratory status continued to deteriorate, so a trial of prone positioning was attempted; however, this movement led to significant respiratory decompensation, so he was returned to his left side with some recovery. On HD 5, his respiratory failure had continued to progress with P/F ratios persistently in the 90s despite maximal ventilator strategies and FiO2 ranging from 80% to 100%. Tissue plasminogen activator salvage therapy was initiated with a 50-mg tPA (alteplase) bolus for 2 hours with his heparin drip turned down to 500 U/h 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 980 mg/dL, D-dimer was 2,124 ng/mL, post-tPA fibrinogen was 944 mg/dL, and there was a spike in D-dimer to 7,094 ng/mL consistent with fibrinolysis of clot occurring after tPA administration. His P/F ratio immediately dipped into 77 to 80 range but then began to steadily climb up to 136 at 24 hours post-tPA, a 48% increase in P/F from pre-tPA (Fig. 1B). The decision was made to repeat the 50 mg tPA bolus to attempt further gains, which again led to an initial transient decrease in his P/F to the mid-90s (that was also in the setting of a position change), but his P/F ratio then climbed up to 114 and then 175. His respiratory status remains improved as of the time of this submission with his P/F ratio up to 90% from pre-tPA levels and measured in the same position (left side) he started tPA therapy in. No bleeding complications were noted during or after tPA therapy.
A 67-year-old man with PMH significant for hypertension, thyroid cancer status post thyroidectomy, and radioactive iodine presented to the hospital with a 10-day history of worsening shortness of breath, fatigue, fever, 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 of 257 mg/dL (peak, 709 mg/dL on HD 14), D-dimer of 6,070 ng/mL, INR of 1.3, PTT of 32.1 seconds, and a platelet count of 212 K/μL. He was admitted to the ICU with acute hypoxemic respiratory failure with lung-protective ventilator settings and PEEP of 16 cm H2O 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%. In consultation with infectious diseases, he was treated with ampicillin/sulbactam and hydroxychloroquine and deemed not a candidate for other study trial medications. By HD 2, his renal function deteriorated, and he progressed to oligoanuric acute kidney injury. Only short courses of continuous renal replacement therapy (approximately 8–12 hours per day) were able to be completed given excess demand for use of the limited dialysis machines among other critically ill patients throughout the hospital. He therefore remained with a severe mixed respiratory and metabolic acidosis as his ventilator requirements were necessarily increased (APRV Phigh, 30–34; FiO2, 50–75%). By HD 6, his D-dimer was noted to be >35,000 ng/mL, and therapeutic anticoagulation was commenced using enoxaparin, titrated to anti–factor Xa activity levels (0.7–1.0). 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 to 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 HD 16, the patient deteriorated (P/F ratio, 77) and was commenced on a trial of inhaled nitric oxide with limited benefit, up to 30 ppm. Respiratory system and lung mechanics remained preserved throughout the entire course despite the severe hypoxemia with a large A-a gradient, similar to the previous two cases and consistent with what would be observed in pulmonary vascular occlusive phenomena.
The patient continued to decompensate with O2 saturation of 70% on 100% FiO2 (imputed P/F ratio, 41; no arterial blood gas was available) and was unstable, so a trial of tPA (alteplase) was initiated using a 50-mg bolus for 2 hours, and he was transitioned to a therapeutic heparin drip instead of enoxaparin. At 4 hours post-tPA initiation, his P/F ratio was up to 92, a more than twofold increase and marked improvement (Fig. 1C). Just over 24 hours after his initial bolus of tPA, his P/F ratio was back down to 85, prompting a second 50 mg tPA bolus with improvement of his P/F to 105 at 3 hours post-tPA initiation. The patient remained therapeutically heparinized during the second tPA challenge without any interruption in heparin administration. Unfortunately, his respiratory status declined again, and a third 50 mg tPA bolus was administered on HD 18 given his prior improvements after tPA, but this time, there was no response, his multiple organ failure progressed, and he expired a short time later.
A 27-year-old woman with PMH significant for morbid obesity (body mass index, 57) and non–insulin-dependent diabetes mellitus presented to the hospital with a 7-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 100% FiO2 NRB, and she was subsequently intubated. Chest radiography demonstrated bilateral patchy opacities with dense peripheral infiltrates. Admission laboratory work was notable for a fibrinogen of 750 mg/dL (peak, 856 mg/dL on HDs 2 and 4), D-dimer of 2,240 ng/mL, INR of 1.0, and PTT of 34.1 seconds. She was admitted to the ICU with acute hypoxemic respiratory failure with lung-protective ventilator settings and PEEP of 15 cm H2O 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 ECMO because it was felt that she would not survive returning to the supine position to facilitate cannulation. Given her instability with P/F ratios in the 60s despite prone positioning and maximal therapy, the decision was made to administer a bolus of 50 mg tPA for 2 hours while on a concomitant heparin drip at 500 U/h, followed by a tPA drip at 2 mg/h for 22 hours while on a therapeutic heparin drip with goal PTT of 60 to 80 seconds. Her pre-tPA fibrinogen was 756 mg/dL, D-dimer was 4,040 ng/mL, post-tPA fibrinogen was 856 mg/dL, and there was a spike in D-dimer to >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 (Fig. 1D). 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. Although some sustained respiratory status improvement persisted, she remains critically ill as of the time of this submission.
A 52-year-old man with PMH significant for aortic valve disease, Hodgkin lymphoma, and hyperlipidemia presented to a community hospital with a 4-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 NRB, and chest radiography demonstrated bilateral infiltrates. Admission laboratory work was notable for a fibrinogen of 836 mg/dL (peak, 1,070 mg/dL on HD 4), D-dimer of 843 ng/mL, INR of 1.2, PTT of 27.8 seconds, and platelet count of 265 K/μL. 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, and a therapeutic heparin drip and supported with a lung protective ventilation strategy, and by HD 3, he was also chemically paralyzed. On HD 6, his respiratory failure had continued to progress with P/F ratio of 97, and he was placed in the prone position with recovery of P/F ratio to >100. By HD 12, his P/F ratio was consistently below 100 despite prone positioning and maximal ventilator strategies. Tissue plasminogen activator salvage therapy was initiated with a 50-mg tPA (alteplase) bolus for 2 hours with his heparin drip turned down to 500 U/h 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, 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 (Fig. 1E), 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 (>50% increase from pre-tPA), 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 U transfusion of packed red blood cells and temporary cessation of his heparin drip that was subsequently resumed without complication.
In summary, we report a case series of five patients who were treated with off-label intravenous administration of tPA (alteplase) for profound COVID-19 respiratory failure in the setting of an apparent thrombotic coagulopathy. All five patients appeared to have an improved respiratory status following tPA administration: one patient had an initial marked improvement that partially regressed after several hours, one patient had transient improvements that were not sustained, and three patients had sustained clinical improvements following tPA administration (one of whom was successfully extubated 7 days after tPA administration). A prior case series of three patients treated with tPA (alteplase) for COVID-19 respiratory failure that used lower doses of tPA over longer periods and without concomitant heparin anticoagulation13 demonstrated less dramatic effects that were less durable than what was observed with larger doses of tPA and concomitant heparin anticoagulation as described in the present case series. The universally observed spike in D-dimer following tPA administration also served to verify that clot was present in these patients and fibrinolysis/clot degradation occurred in response to tPA.
Although the cases put forth in this article all demonstrate what seems to be a temporal relationship between administration of tPA and improved respiratory status, there are no controls for comparison, so causation and efficacy cannot be ascribed to tPA with certainty. In a resource-limited crisis such as the COVID-19 pandemic with possible shortages of ventilators and ECMO circuits, fibrinolytic therapy may be useful in select cases where laboratory markers and respiratory parameters point toward thrombotic coagulopathy with vascular occlusive pulmonary physiology. Notable in this regard is the near universal availability of tPA in most hospitals and the potential for rapid escalation of industrial production and distribution to areas most affected by COVID-19.
Formal studies with larger patient groups, including a control group, will be required to demonstrate efficacy and safety, and identify the patient population that most benefits from tPA and the optimal dose and route for tPA administration. A Phase 2 multicenter randomized control trial of tPA in COVID-19 respiratory failure to answer these questions is now planned and about to open for enrollment (clinicaltrials.gov registration number NCT04357730). 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.
C.D.B., S.S., A.M.I., A.O.-G., E.C., A.H.M., M.U., M.J.M., S.H.R., and M.B.Y. prepared the article with critical input and revisions from E.E.M., H.B.M., R.J., E.N.B.-K., M.L.K., and D.S.T.
C.D.B., H.B.M., E.E.M., and M.B.Y. have patents pending related to both coagulation/fibrinolysis diagnostics and therapeutic fibrinolytics, and are passive cofounders and hold stock options in Thrombo Therapeutics, Inc. H.B.M. and E.E.M. have received grant support from Haemonetics and Instrumentation Laboratories. M.B.Y. has previously received a gift of alteplase (tPA) from Genentech and owns stock options as a cofounder of Merrimack Pharmaceuticals. All other authors have nothing to disclose.
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