Pulmonary embolism in patients with severe COVID-19 treated with systemic low-dose thrombolytic therapy: A case series

Abstract

Coronavirus disease 2019 (COVID-19) has been associated with respiratory failure and high mortality. Hypercoagulability and thromboembolic complications have been found in a high percentage of patients amongst which, pulmonary embolism (PE) is the most common. Currently, there are no guidelines on using thrombolysis therapy in COVID-19 patients who developed PE. We present five survivors aged 30–75 years old with confirmed COVID-19. All cases were proven by computed tomography pulmonary angiogram (CTPA) to have PE treated with low-dose recombinant tissue plasminogen activator (rtPA). PE should be suspected in all COVID-19 patients with rapid worsening of dyspnea, desaturation, unexplained shock, and increased level of D-dimer and fibrinogen. In our cases, PE developed despite preventative anticoagulation regimens with low molecular weight heparin. After thrombolytic therapy, all patients showed improvement in partial-arterial-oxygen-pressure to inspired oxygen-fraction ratio (arterial partial pressure of oxygen/inspired oxygen fraction ratio). D-dimer showed elevation after thrombolytic therapy and decreased in the following days. Fibrinogen levels decreased following thrombolytic therapy. Current anticoagulation regimens seem insufficient to halt the course of thrombosis, and thrombolytic therapy may be beneficial for patients with severe COVID-19 and PE. Systemic thrombolysis therapy is a double-edged sword, and clinicians must balance between benefit and risk of bleeding.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is a disease caused by the severe acute respiratory syndrome coronavirus-2 that was first reported in Wuhan, China, in December 2019.[1] The clinical presentation varies between asymptomatic infection, mild respiratory infection, and severe pneumonia with respiratory failure and death. Patients with severe COVID-19 may experience features of systemic inflammation or cytokine storm and coagulopathy. This has been confirmed in larger studies, with nearly 50% of COVID-19 patients demonstrating elevated D-dimer and fibrin degradation products, with the degree of elevation correlating with illness severity in cohorts.[2]

A study in Spanish population showed that the incidence of pulmonary embolism (PE) in COVID-19 patients was 4.92%, or ninefold higher compared to non-COVID population.[3] The study found immobilization and congestive heart failure (CHF) are risk factors of PE in COVID-19. Another publication has documented severe hemostatic derangement using whole blood thromboelastography, resulting in a hypercoagulable state.[4] This may result in thromboembolic complications, the most common of which is PE.

PE is known to lead to significant morbidity and mortality and treating it could lead to marked clinical improvement. A review about PE in COVID-19 cases reported that there was no detectable origin of PE in 80% of COVID-19 cases and that PE was diagnosed at 11 days after the onset of COVID-19.[5] The review also stated that 10% died despite thrombolytic treatment, recombinant tissue plasminogen activator (rtPA), or full-dose low molecular weight heparin therapy.

CASE REPORTS

Case 1

A 75-year-old male known hypertensive presented with dyspnea, rales on both lungs, and fever of 12-day duration. Demographics and case details are presented in Table 1. He was also confirmed for COVID-19 from nasopharyngeal swab by reverse transcription polymerase chain reaction (RT-PCR) test. He complained of worsening breathlessness the next day and his peripheral oxygen saturation (SpO2) dropped to 87%. His respiratory rate (RR) was 35–40 per minute, blood pressure (BP) 145/71 mmHg, heart rate (HR) 120 bpm, and he was anxious. Arterial blood gas (ABG) showed partial pressure of oxygen (pO2) 78 mmHg and partial pressure of carbon dioxide (pCO2) 48.2 mmHg (under 80% inspired oxygen fraction [FiO₂]). A computed tomography pulmonary angiogram (CTPA) identified pulmonary emboli as described in Table 2. Thrombolytic therapy was given using intravenous (IV) alteplase 5 mg over 2 h followed by 45 mg in the next 22 h, which resulted in improved saturation and ABG. Two days later, he again desaturated to 85% with increased D-dimer (3417 ng/ml) and worsening ABG. We administered a second dose of IV alteplase with similar dose, resulting in improved clinical condition without re-bleeding episode.

Table 1.

Case summary

	Case number 1	Case number 2	Case number 3	Case number 4	Case number 5
Age (years)	75	54	38	35	30
Sex	Male	Male	Female	Female	Man
Estimated body weight (kg)	55	67	80	96	107
Days since start of symptoms	12	3	12	9	3
Co-existing condition	HTN	-	-	Obese, HTN, CHF	Obese
Physical examinations
HR (bpm)	120	110	84	100	100
Respiration rate (breaths/min)	35-40	30-35	24-28	32-36	35-40
SpO2	88	90	97	87	96
Initial oxygen supplement (L/min)	15	15	15	15	15
Auxiliary oxygenation device	NRM	NRM	NRM	NRM	NRM
Switched to HFNC after worsening	Yes	Yes	Yes	Yes	Yes
HFNC setting (FiO2/Lmin−1)	1.0/60	0.8/30	0.7/40	0.8/40	1.0/60
PE severity classification	Low-risk	Low-risk	Low-risk	Low-risk	Low-risk
Prethrombolytic findings
D-dimer (ng/mL)	1613	1606	951	2498	5310
Fibrinogen (mg/dL)	554	768	345	879	799
Confirmed PE by CTPA	Yes	Yes	Yes	Yes	Yes
Indication for thrombolytic therapy
Worsening clinical condition	Yes	Yes	Yes	Yes	Yes
Worsening blood gas analysis	Yes	Yes	Yes	Yes	Yes
Alteplase dose
Days after hospital treatment	2	2	11	6	7
Loading (mg/2 h)	5	5	25	30	25
Maintenance (mg/22 h)	45	45	25	50	25
Second dose required	Yes	No	No	No	No
Bleeding observed	Yes	No	Yes	Yes	No
SC enoxaparin resumed	Yes	Yes	Yes	Yes	Yes
P/F ratio in relation to timing of thrombolytic therapy
12 h prethrombolytic	96	196	237	68	172
12 h after thrombolytic	72	132	337	78	139
24 h after thrombolytic	97	230	321	74	198
36 h after thrombolytic	94	404	255	180	193
48 h after thrombolytic	145	195	366	215	222
Hospital length of stay (days)	18	16	22	20	10

−12: P/F ratio at 12 h prealteplase, +X: P/F ratio at X h postalteplase. P/F ratio: PaO₂/FiO₂ ratio, HTN: Hypertension, CHF: Congestive heart failure, NRM: Nonrebreather mask, HFNC: High-flow nasal cannula, PE: Pulmonary embolism, CTPA: Computed tomography pulmonary angiogram, PaO₂: Arterial partial pressure of oxygen, FiO₂: Inspired oxygen fraction, SpO₂: Peripheral oxygen saturation, SC: Subcutaneous, HR: Heart rate

Table 2.

Summary of computed tomography pulmonary angiogram findings in our cases

Case	Sex, age (years)	CTPA findings
1	Male, 75	Partial filling defect on subsegmental ascending branch right pulmonary artery
2	Male, 54	Multiple filling defect on distal branches right pulmonary artery and vein
3	Female, 38	Multiple filling defect seen on subsegmental branch ascending and posterior branch superior lobe right pulmonary artery and partial thrombus on lingular branch superior left pulmonary vein and posterior branch superior right pulmonary vein
4	Female, 35	Partial filling defect on subsegmental branches right pulmonary artery and filling defect on distal branches of bilateral pulmonary vein
5	Male, 30	Partial filling defect on right ascending branch pulmonary artery and upper lobe branches left pulmonary artery and multiple filling defect middle lobe and inferior branch right pulmonary vein

CTPA: Computed tomography pulmonary angiogram

Case 2

A 54-year-old male with no comorbidities presented with dyspnea and fever for 3 days. He tested positive for COVID-19 via RT-PCR. Physical examination showed RR 30–35 per minute, BP 121/73 mmHg, HR 105–110 bpm, and SpO2 of 90%. We managed this case aggressively without waiting for deterioration signs by providing high-flow nasal cannula at 30 L/minutes flow and FiO₂ 80%. ABG showed pH 7.369, pCO2 42.0 mmHg, and pO2 108 mmHg. His D-dimer level was 1606 ng/mL. CTPA revealed thrombosis on distal branches of the right pulmonary vein [Table 2]. We administered IV alteplase (5 mg over 2 h followed by 45 mg over the next 22 h) and subcutaneous enoxaparin 60 mg 12-hourly afterward. His vital signs remained stable, and no bleeding was noted. After 16 days in intensive care, he was discharged home.

Case 3

A 38-year-old female with confirmed COVID-19 with no comorbidities was admitted to isolation on the 9^th day of symptoms (fever and severe coughing). She deteriorated and was transferred to the intensive care unit (ICU) after 3 days of treatment. Her RR was 24–28 per minute, BP 135/75 mmHg, and HR 80–85 bpm. She developed atypical chest pain, shortness of breath, lightheadedness, and desaturated to 70% (under 100% FiO₂) after 11 days of ICU treatment. After confirming the presence of PE by CTPA [Table 2], we started a more aggressive therapy using IV alteplase 25 mg over 2 h followed by continuous infusion of 25 mg over the next 22 h. Superficial bleeding was noted. Her condition improved and she was discharged home 22 days after hospitalization.

Case 4

A 35-year-old female was referred with fever and shortness of breath for 9 days. Besides COVID-19 positive, she also had a history of hypertension and CHF. On the 6^th day of ICU treatment, she experienced several intermittent episodes of desaturation (down to 80%), tachypnea (45 breaths per minute), tachycardia (120–130 bpm), and intermittent mild hemoptysis. Laboratory analysis revealed pH 7.498, pCO2 37.3 mmHg, pO2 51 mmHg, and D-dimer 2,498 ng/dL. After confirming with CTPA [Table 2], IV alteplase was started immediately with a dosage of 30 mg over 2 h and continued with 50 mg over the next 22 h. A larger dose was deemed required due to her obese condition. Hematuria was noted during alteplase administration but improved after alteplase was finished. Her condition was gradually improved, and she was moved to ward after 20 days in ICU. She was then discharged home 6 days later.

Case 5

A 30-year-old male with no other medical history presented with dyspnea for 3 days. Upon ICU admission, with a confirmed COVID-19 RT-PCR result, he complained about sudden palpitations and dizziness, his RR was 35–40 per minute, HR 95–100 bpm, BP 143/106 mmHg, and SpO2 96%. Initial blood gas analysis showed pH 7.42, pCO2 36 mmHg, and pO2 83 mmHg. On the 7^th day of ICU treatment, his D-dimer increased to 2866 ng/ml and SpO2 dropped to 85%. After CTPA confirmation of PE, we initiated alteplase 25 mg over 2 h and continued with 25 mg over the next 22 h. No bleeding was noted. Clinical improvement was noted after alteplase, and although D-dimer level was increased to 5310 ng/ml on the next day, it decreased to 827 ng/ml 2 days after. He was discharged after 10 days of treatment in hospital.

DISCUSSION

The current guideline suggests the use of systemic thrombolysis in patients who are at high risk of developing PE.[5] In patients with intermediate-risk PE, thrombolytic therapy with standard dosage of rtPA was associated with a significant reduction in the risk of hemodynamic decompensation but was paralleled by an increased risk of severe bleeding.

Tissue plasminogen activator is one of the essential components in the dissolution of blood clots. Its primary function is to convert plasminogen to plasmin, the primary enzyme involved in dissolving blood clots by breaking up the molecules of fibrin. Examples of these drugs are alteplase, urokinase, streptokinase, reteplase, and tenecteplase. Alteplase is the biosynthetic form of human plasminogen activator and is approved by the United States Food and Drug Administration for managing ischemic stroke, ST-elevation myocardial infarction, and PE.[6]

The standard dosage of alteplase for PE is 100 mg over 2 h.[6] A recent report compared the 100 mg/2 h and 50 mg/2 h regimens which found that the reduced dosage exhibits similar efficacy and perhaps better safety profile.[7] Another case series used rtPA for sub-massive PE using 10 mg IV bolus over 1 min and continued with 40 mg IV over 2 h.[8]

Currently, there is no guideline in using thrombolysis therapy in COVID-19 patients who developed PE. A French study[9] reported seven cases using rtPA in COVID-19 patients with PE, with standard protocol of 10 mg over 15 min, and continued with 90 mg over 120 min. They reported a reduced Brescia-COVID Respiratory Severity Scale in all patients and no major bleeding events.

Alteplase was associated with an increased risk of severe bleeding, with up to 20.6% of patients experiencing major bleeding and 7.4% experiencing intracranial bleeding.[10] Because of this, we used a lowered dose of rtPA in our patients. Case 1 had bleeding from a central venous catheter insertion site, case 3 had superficial bleeding from the enoxaparin injection site, and case 4 had hematuria. All bleedings were conservatively managed. None of our patients had evidence of intracranial bleeding.

While this case series presents the effectiveness of low-dose rtPA in our patients, there are several limitations that need to be acknowledged. First, this case series only showed success in five patients with CTPA-proven PE. Second, the regimen used was not homogenous, and the decision was mainly clinically based. Third, no CTPA or echocardiography evaluation was done after thrombolytic therapy. Although the clinical improvement is substantial, we still need to prove the resolution of thrombosis by imaging studies.

CONCLUSION

Systemic thrombolysis therapy is a double-edged sword and clinicians must balance benefits with risk of bleeding. Our case series provides examples of using low-dose rtPA with excellent result and minimal complication. Nevertheless, we are not sure whether this regimen could be generalized to all COVID-19 patients with PE, and larger studies are needed to determine the best possible treatment and construct better guidelines.

Research quality and ethics statement

This case report did not require approval by the Institutional Review Board/Ethics Committee. The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guideline, specifically the CARE guideline, during the conduct of this research project.

Declaration of patient consent

The authors certify that each subject provided written informed consent for the publication of de-identified findings, but that anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.