Consistent findings from few autopsies series have shown significantly high incidence of pulmonary embolism and thrombotic phenomenon in patients dying due to COVID19 [3,4,5]. These series have shown presence of fibrin rich microthrombi and macrothrombi developing in lungs of critically ill COVID19 patients. Probably COVID Induced Coagulopathy (CIC) mimics presentation of subclinical pulmonary thromboembolism: both disease have significant pulmonary vascular shunting without hypotension initially, with significantly raised markers like D-dimer and BNP. But unlike sub-massive PE (in which there is a well-defined clot), there is widespread microthrombi and continuous ongoing inflammation causing hypercoagulability in COVID19. In sub-massive PTE, mortality is in the range of 3–5%, so thrombolysis is not advised routinely due to risk of thrombolysis induced life threatening bleeding (1%). But in COVID19 which can cause severe hypercoagulable state in some patients, mortality rates varies from 30 to 50% in critically ill patients on HFNC to 80–90% in patients on mechanical ventilation . Surprisingly, very few cases of bleeding have been reported with COVID; probably coagulation pathway is significantly tilted towards hypercoagulable state rather than bleeding tendency. One study showed complete fibrinolysis shutdown, as evidenced by elevated D-Dimer and complete failure of clot lysis at 30 min on thromboelastography in critically ill patients with COVID-19 .
Two case series have used thrombolysis with tPA in COVID19 related ARDS who were on mechanical ventilation and were in deteriorating with varying success [8, 9]. Out of seven patients in these two series: two patients expired, paO2 improvement occurred in four patients and inotropes dose was decreased in one patient.
After learning from the autopsy findings, we changed practice at our institute and we started giving therapeutic anticoagulation (in addition to methylprednisolone and pantoprazole) to all critically ill COVID19 patients presenting in ICU as a standard protocol. Even on therapeutic anticoagulation, some patients continue to deteriorate. So, we extrapolated low dose and ultralow dose used in MOPETT trial and The Ultra-slow PROMETEE Trial, where tPA doses of 50 mg and 25 mg were used for sub massive PE and prosthetic valve thrombosis respectively [10, 11]. In both the trials, efficacy was similar to conventional high dose tPA with significant low fatal bleeding rates (nil and 0.8% in MOPETT and PROMOTEE trial respectively).
Our first case was deteriorating rapidly; was getting fatigued and agitated; he had a respiratory rate of 45/min and intubation was imminent. So decision to thrombolyse (with 30 mg tPA over 15 h) was taken on compassionate basis after interdisciplinary discussion. With the significant improvement in first case, we used tPA (50 mg over 3 h) in next two patients who were rapidly deteriorating. Third case had the highest d-Dimer level (4583 ng/ml) and she had the fastest response to tPA (Fig. 1).
Low dose UFH (500 U/h) was transfused along with tPA in first case. Anticoagulation (I.V. UFH) was suspended during thrombolysis in second and third case and was restarted after 3 h of completion of tPA with target aPTT of 70–90 s. With an intense hyperinflammation continuing in COVID19, we believe therapeutic anticoagulation should not be stopped for too long. So that’s why we shifted to a shorter duration (3 h) of tPA after our first case. Patients were shifted from UFH to Enoxaparin twice a day once patient was stabilised.
These three patients had significantly early improvement compared to other patients earlier admitted with COVID19 in our ICU with similar severe condition. In our experience, avoiding intubation is the best strategy since survival results are very poor in intubated COVID19 patients . So thrombolysing might be an attractive alternative in carefully selected individuals with rapidly deteriorating respiratory failure, as it may avoid intubation. Importantly, the decision of thrombolysis was always taken in consultation in interdisciplinary team after ruling out any other cause of hypoxemia. We could not get C.T. Pulmonary Angiography of these patients before thrombolysis due to poor general condition; although there was no evidence of PTE on echocardiography or of DVT on compression USG. So there was no conventional indication of thrombolysis (like cardiogenic shock or RV dilatation) in these patients, yet after thrombolysis, we saw dramatic changes in oxygenation of all patients.
We are of the opinion that tPA 50 mg (over 3 h) can be given in critically ill COVID19 patients who fulfil following all five criteria:
Rapidly rising FiO2 requirement ≥0.7 (on HFNC or NIV)
P/F ratio of <100
D dimer >1000 ng/ml
No absolute contraindications of thrombolysis
No other cause of deterioration like secondary infection, fluid overload.
Traditionally considered “high risk” fibrinolytic agents have a major bleeding risk of 1–3% and < 1% chances of fatal bleed [10,11,12]. This is significantly less than mortality rates of 50–88% seen in critically ill COVID19 patients on ventilatory support . We did not encounter any bleeding episode in any of our cases.
In this unprecedented pandemic with high mortality rates, thrombolysis is a relatively safe and effective option in carefully selected critically ill patients of COVID19. However usefulness of fibrinolytic agents in management will be more clear, once results of randomised trial of tPA will be available .