Systemic reduced‐dose alteplase for diffuse pulmonary thrombi in a COVID‐19 patient

Abstract

Pulmonary embolism has a high frequency in COVID‐19 patients admitted to the intensive care unit. Low level of fibrinolysis is one of the asserted contributors to a prothrombotic state in COVID‐19. Thrombotic coagulopathy is mostly encountered as diffuse pulmonary thrombi. Diffuse pulmonary microemboli was treated successfully with reduced dose thrombolysis.

INTRODUCTION

High incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia is well documented.¹ Deep venous thrombosis (DVT)² and pulmonary embolism (PE) are the most frequently diagnosed thromboembolic complications in general ward and intensive care unit (ICU) despite adequate thromboprophylaxis.³ Pulmonary microvascular thrombosis is a predominant finding⁴ The incidence is higher than influenza patients.^5,6 Mortality is increased fivefold with PE.¹

Presented case is a PE treated successfully with systemic thrombolysis. PE appeared as diffuse pulmonary thrombi which was cleared away with reduced-dose tissue plasminogen activator (tPA, Alteplase). The efficacy was determined by post-treatment contrast-enhanced computed tomography (CT).

CASE REPORT

An 44-year-old nonobese nonsmoker male with unremarkable medical history presented to the Corona Department with fever and tested positive for COVID-19. He was given oral favipiravir (3200 mg loading dose and 1200 mg/day) for 5 days at home. He has never received vaccination before. He presented to the emergency department due to acute progressive dyspnea and deterioration in his condition. On arrival, his oxygen saturation was 85% on room air, PaO₂ was 55 mmHg, respiratory rate was 18 breaths/min, heart rate was 145 beats/min, and body temperature was 38.8°C. On a reservoir oxygen mask at 10 L/min, his SpO₂ elevated to 92%. His consciousness was clear. Treatment was undertaken in the ICU. On admission, methylprednisolone, aspirin, and subcutaneous enoxaparin were added to his medication regimen. He did not develop severe respiratory failure, therefore did not undergo endotracheal intubation. Inflammatory markers such as c-reactive protein, ferritin, and lactate dehydrogenase were elevated. D-Dimer and Troponin-I were within normal limits (Table 1). Chest CT demonstrated diffuse consolidation and ground glass opacities (Figure 1A). Initially, he was treated by continuous positive airway pressure lasting at least 4 h daily and continued to receive oxygen with a reservoir mask. On hospital Day 5, SpO₂ elevated to 99% on a reservoir oxygen mask at 10 L/min and on ambient air SpO₂ was 90%. Therefore, he was transferred to general ward. On Day 7, patient suddenly deteriorated and collapsed. Desaturated patient was transferred back to ICU that his SpO₂ was 57% on ambient air, which raised to 93% on a reservoir oxygen mask at 12 L/min. The P/F (PaO₂/FiO₂) ratio was 57 (PaO₂ of 44 mmHg and FiO₂ of 76%). D-Dimer was elevated (Table 1). Transthoracic echocardiographic evaluation showed McConnell sign. CT pulmonary angiography examination was performed immediately to rule out PE. CT acquisitions were performed with multidetector CT units on a 128-slice CT scanner (Philips Ingenuity Core128; Philips Medical Systems) using standard CT pulmonary angiography protocols.

TABLE 1 Blood workup at hospital course.

	D-dimer (normal value <500 ng/mL)	Troponin-I (normal range 0–0.1 ng/mL)
On admission	250	0.032
Day 7 (thrombolytic therapy)	3748	0.528
Day 8	>10,000	0.746
Day 9	3343	–
Day 10	1093	0.041
On discharge	1010	–

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Diffuse pulmonary microthrombi was confirmed (Figure 1B,D). A venous Doppler study of the lower limbs was performed to rule out DVT, which was negative for thrombus formation. Alteplase was administered (Actilyse Boehringer Ingelheim) 50 mg infused over 2 h. There was no contraindication for thrombolysis. To avoid any type of bleeding complication, all therapeutic anticoagulation at the time of tPA receipt were stopped. He had an adequate response to systemic thrombolysis. After the regimen, patient's oxygenation improved. The P/F ratio increased to 78 (PaO₂ of 73 mmHg on an FiO₂ of 93%) on the following day. D-Dimer level decreased. No major or minor bleeding complications have occurred during or after fibrinolytic therapy. Patient was not intubated and continued to receive oxygen through a reservoir mask. Subsequently, clinical course was uneventful. A post-treatment contrast CT revealed successful fibrinolysis of thrombi (Figure 1C,E).

Patient was discharged with oxygen at home and rivaroxaban for 6 months. On a follow-up telephone conversation after 6 months, patient declares that his oxygen saturation is 94% on ambient air.

DISCUSSION

The efficacy of thrombolytic therapy in PE is well documented.⁷ Although there is no controlled trial data, the use of fibrinolytic therapy is encouraged in critically ill patients with COVID-19 due to increased risk of extensive pulmonary microthrombi.⁸ In an observational study, PE was confirmed radiologically in 20% of critically ill patients and they received tPA. tPA was also given during cardiac arrest which comprised 10% of the study group. Administration of fibrinolytics did not improve oxygenation or hemodynamics in the cohort.⁹ Contrast-enhanced CT should be more often used due to high cumulative incidence of PE.^1,10 In addition, prophylactic anticoagulation may not avoid the occurrence of PE in hospitalized patients.⁹ Conversely, anticoagulant thromboprophylaxis may cause major bleeding in critically ill patients. The risk is threefold when D-dimer level is over 2500 ng/mL which is an independent predictor of major bleeding. Theoretically, a pathophysiologically distinct viral coagulopathy or coagulation system activation in the setting of severe inflammation is attributed as the underlying cause.¹⁰

The recommended regimen of tPA in guidelines is 100 mg over 2 h as the standard therapy. The greatest benefit is acquired when treatment is started within 48 h, and the benefit is much gained with accelerated i.v. administration compared to prolonged infusions.⁷ Serious bleeding may occur with recommended dosing.⁹ Approximately 10% of COVID-19 patients may experience a major bleed after tPA administration. Mortality is higher with major bleeding.⁹ Half-dose tPA is shown to display similar efficacy and safety when compared with standard regimen (i.e., 100 mg over 2 h). Bleeding rates and recurrent PE were comparable between half-dose and full-dose tPA regimens.¹¹ Despite the data of randomized controlled trials lack in COVID-19 patients with PE, half-dose tPA may be used to diminish the risks.^11,12 Anticoagulant thromboprophylaxis, elevated D-Dimer levels, and tPA (100 mg) together might have increased the bleeding risk in the presented case. Therefore, the decision on 50 mg of tPA was made in the light of the given information. Data lack regarding the ineffectiveness of fibrinolytic therapy in PE. Increasing the dosage or catheter-directed intervention should be decided upon patient's clinical condition.

CONCLUSION

Early suspicion and confirmation of PE before decompensation is essential in COVID-19 patients. Initial intervention may prevent forming critical condition and save a life. The presented case summarizes early detection of PE and therapy with 50 mg of alteplase. Resolution of thrombi was verified post-treatment.

AUTHOR CONTRIBUTIONS

The author listed is the sole author.

ACKNOWLEDGMENTS

None.

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

None.

DATA AVAILABILITY STATEMENT

None.

ETHICS STATEMENT

None.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

References

Klok FA, Kruip MJHA, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID‐19: an updated analysis. Thromb Res. 2020;191:148‐150.

So M, Steiger DJ, Takahashi M, Egorova NN, Kuno T. The characteristics and outcomes of critically ill patients with COVID‐19 who received systemic thrombolysis for presumed pulmonary embolism: an observational study. J Thromb Thrombolysis. 2021;8:1061‐1067.

Dobesh PP, Trujillo TC. Coagulopathy, venous thromboembolism, and anticoagulation in patients with COVID‐19. Pharmacotherapy. 2020;40(11):1130‐1151.

Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac pathology in African American patients with COVID‐19: an autopsy series from New Orleans. Lancet Respir Med. 2020;8(7):681‐686.

Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS‐CoV‐2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089‐1098.

Poissy J, Goutay J, Caplan M, et al. Pulmonary embolism in patients with COVID‐19: awareness of an increased prevalence. Circulation. 2020;142(2):184‐186.

Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543‐603.

Barrett CD, Moore HB, Moore EE, et al. Fibrinolytic therapy for refractory COVID‐19 acute respiratory distress syndrome: scientific rationale and review. Res Pract Thromb Haemost. 2020;4:524‐531.

Douin DJ, Shaefi S, Brenner SK, et al. Tissue plasminogen activator in critically ill adults with COVID‐19. Ann Am Thorac Soc. 2021;18(11):1917‐1921.

Al‐Samkari H, Karp Leaf RS, Dzik WH, et al. COVID‐19 and coagulation: bleeding and thrombotic manifestations of SARS‐CoV‐2 infection. Blood. 2020;136(4):489‐500.

Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue‐type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;137:254‐262.

Ross AM, Gao R, Coyne KS, et al. A randomized trial confirming the efficacy of reduced dose recombinant tissue plasminogen activator in a Chinese myocardial infarction population and demonstrating superiority to usual dose urokinase: the TUCC trial. Am Heart J. 2001;142(2):244‐247.