key: cord-339455-b8nu34vv
authors: Sakr, Yasser; Giovini, Manuela; Leone, Marc; Pizzilli, Giacinto; Kortgen, Andreas; Bauer, Michael; Tonetti, Tommaso; Duclos, Gary; Zieleskiewicz, Laurent; Buschbeck, Samuel; Ranieri, V. Marco; Antonucci, Elio
title: The clinical spectrum of pulmonary thromboembolism in patients with coronavirus disease-2019 (COVID-19) pneumonia: A European case series
date: 2020-09-25
journal: J Crit Care
DOI: 10.1016/j.jcrc.2020.09.021
sha: 
doc_id: 339455
cord_uid: b8nu34vv

PURPOSE: To describe the clinical characteristics and outcomes of coronavirus disease-2019 (COVID-19)-associated pulmonary thromboembolism (PTE). MATERIALS AND METHODS: A case series of five patients, representing the clinical spectrum of COVID-19 associated PTE. Patients were admitted to four hospitals in Germany, Italy, and France. Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was confirmed using a real-time reverse transcription polymerase chain reaction test. RESULTS: The onset of PTE varied from 2 to 4 weeks after the occurrence of the initial symptoms of SARS-CoV-2 infection and led to deterioration of the clinical picture in all cases. PTE was the primary reason for hospital admission after a 2-week period of self-isolation at home (1 patient) and hospital readmission after initial uncomplicated hospital discharge (2 patients). Three of the patients had no past history of clinically relevant risk factors for venous thromboembolism (VTE). Severe disease progression was associated with concomitant increases in IL-6, ferritin, and D-Dimer levels. The outcome from PTE was related to the extent of vascular involvement, and associated complications. CONCLUSION: PTE is a potential life-threatening complication, which occurs frequently in patients with COVID-19. Intermediate therapeutic dose of anticoagulants and extend thromboprophylaxis are necessary after meticulous risk-benefit assessment.

Pulmonary thromboembolism (PTE) is a potentially fatal complication that has been frequently reported in patients with coronavirus disease-2019 (COVID-19) [1] [2] [3] [4] . Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with coagulation abnormalities [4] [5] [6] [7] , which predispose to considerable procoagulant effects [4, 5, 8] .

In this report, we describe the clinical characteristics and outcomes of five patients admitted to four hospitals in Germany, Italy, and France with COVID-19-associated PTE and discuss the diagnostic and therapeutic implications of PTE in COVID-19.

A 66-year-old male patient was admitted to the interdisciplinary intensive care unit (ICU) of Jena University Hospital with rapidly progressive dyspnea and swelling of the right thigh. Two weeks prior to ICU admission, the patient had complained of cough, malaise, and fever up to 38°C. He self-isolated at home after being tested positive for SARS-CoV-2 using a real-time reverse Angiographic ultrasound-enhanced lysis was performed with infusion of recombinant tissue-type plasminogen activator (r-tPA) and heparin (800-1200 IU/hour).

Twenty-four hours following ICU admission, the patient's dyspnea and preexisting hypoxemia worsened despite oxygen therapy. Non-invasive ventilation was started but when there was no marked improvement in the respiratory condition after 2 hours, tracheal intubation and controlled invasive mechanical ventilation were necessary and prone positioning was started. The hemodynamic situation deteriorated rapidly after intubation and a CTA scan revealed progression of J o u r n a l P r e -p r o o f Journal Pre-proof the PTE into the segmental arteries of the right upper lobe and both lower lung lobes, in addition to progression of the GGO bilaterally. Systemic lysis was performed using intravenous r-tPA. Over subsequent days, the patient developed progressive multi-organ failure (Table 1) . Despite maximal supportive therapy, the patient died on the 6 th day in the ICU due to therapeutic refractory shock and multi-organ failure.

A 65-year-old male patient presented to the emergency room of Ospedale Guglielmo da Saliceto (Piacenza, Italy) with thoracic pain and dyspnea. He had no history of comorbid conditions. Two weeks prior to his emergency room presentation, he had been discharged home from the same hospital, where he had been admitted for 7 days because of a 10-day history of cough and fever. A CT scan of the lungs at that time had shown bilateral peripheral GGO ( Figure 1 of the electronic supplement material) and a nasopharyngeal swab confirmed SARS-CoV-2 infection using RT-PCR.

During this presentation to the emergency room, his SO 2 was 82% while breathing ambient air. The initial blood gas analysis showed mild hypoxemia (arterial partial pressure of oxygen (PaO 2 )73 mmHg) on 4 L/minute oxygen via nasal prongs. Transthoracic echocardiography showed mild dilatation of the right ventricle, with preserved left ventricular function ( Figure 2 of the electronic supplement material). Compression ultrasound of the lower extremities excluded deep vein thrombosis. A CTA scan showed evidence of subtotal occlusion of the right pulmonary artery at the level of the middle lung lobe and subsegmental obstruction at the level of the inferior lobes ( Figure   2 ). The patient was admitted to the intermediate care unit (IMC) and treated with 8000 IU b.i.d. of low molecular weight heparin (LMWH, enoxaparin sodium) and standard oxygen therapy. The clinical picture improved over the subsequent 5 days and the patient was discharged home after resolution of the respiratory dysfunction to continue therapeutic anticoagulation using LMWH.

A 56-year-old male patient was admitted to the emergency room of Ospedale Guglielmo da Saliceto (Piacenza, Italy) because of sudden-onset, progressive dyspnea. He had no past history of comorbid conditions. Two days before presentation, he had been discharged from the same hospital, where he had been admitted for 13 days because of confirmed SARS-CoV-2 infection with dyspnea. A CT scan of the lungs had shown extended bilateral GGO and inferior lobar pneumonia in the right lung At day 3, the patient developed ventilator-associated pneumonia due to Enterobacter cloacae and was treated with cefepime for 7 days. His clinical condition improved over the subsequent days, and he was successfully weaned from mechanical ventilation; his trachea was extubated on day 7 in the ICU. However, the patient suddenly developed severe hypoxemia (PaO 2 :FiO 2 ratio at 90 mmHg) on day 8, so that invasive mechanical ventilation and prone positioning were again necessary.

Hemodynamics deteriorated rapidly after intubation and high dose norepinephrine was needed.

Tranesophageal echocardiography showed acute right heart failure with paradoxical septal motion phenotype in these patients [9] . The pronounced inflammation of the lung tissue due to viral infection triggers activates hemostasis and may induce the formation of thrombi in the microvasculature as a physiological effort to limit the viral load. This may be explained by the interaction between platelets and endothelium, inducing endothelial dysfunction, which may play a major role in COVID-19 associated microthrombosis [10, 11] . Subsequent platelet aggregation and leukocytes' recruitment may extend PMT to sufficiently occlude large pulmonary vessels [10] .

These aggregates continue to grow until they become sufficiently large to induce extended PMT.

Few studies [12] [13] [14] [15] [16] [17] [18] , mostly retrospective [13] [14] [15] [16] [17] [18] , have reported the epidemiology and clinical characteristics of patients with COVID-19 requiring ICU admission. The incidence of PTE was 13.6-35.3% in this population despite of prophylactic anticoagulation. The hypercoagulable state observed in these patients is probably multifactorial and can be explained by several mechanisms, including cytokine release [19] , complement activation [20] , endothelial dysfunction [21, 22] , and interactions between hemostatic and immune systems [21] . Taken together, intermediate dose of LMWH (e.g., enoxaparin 1 mg/kg/day in patients with normal renal function) is a reasonable option in patients with risk factors for VTE [23] , especially those who require ICU admission [1, 2, [12] [13] [14] [15] [16] [17] [18] [24] [25] [26] [27] .

We may also speculate that COVID-19 may predispose to a resistance to heparin therapy as evident from the relatively high dose of heparin needed to achieve the therapeutic target in Case #1.

Similarly, Beun et al. [16] reported that high dose unfractionated heparin (UFH) of more than 35,000 IU/day was required in 4 patients with PTE to achieve therapeutic targets. Monitoring and dose-adjustment of anticoagulation therapy in these patients is, therefore, of utmost importance to avoid life-threatening thromboembolic events. In particular, obese patients may require higher weight-based doses [28, 29] .

Another important observation in patient #1 was that the severe disease progression was associated with concomitant increases in IL-6, ferritin, and D-Dimer levels, which highlights the potential role of these markers for identifying severe cases of COVID-19 who may warrant a more meticulous diagnostic assessment to exclude the presence of PTE. These abnormalities were shown to be associated with poor prognosis these patients [5] and have been reported to predict VTE in COVID-19 patients and monitor the effectiveness of anticoagulant therapy [30] . They should be interpreted, however, within the clinical context and should not be used, per se, to establish the diagnosis of VTE or indicate the need for diagnostic procedures [30, 31] . Clinical deterioration of the respiratory function or the lack of improvement despite of supportive therapy, together with laboratory evidence of severe inflammation and hypercoagulable state should prompt rapid diagnostic procedures to identify patients with PTE. Indeed, the International Society of Thrombosis and Haemostasis (ISTH) did not recommend the routine screening for DVT in COVID-19 patients.Nonetheless, high index of clinical suspicion of PTE should be adopted in these patients, especially those at increased risk of VTE [31] .

In case #1, PTE was the primary reason for hospital and ICU admission after a 2-week period of self-isolation at home, raising concerns about the possible influence of self-isolation on potentiating the procoagulant effects of COVID-19 because of relative restrictions in physical activity. The magnitude of this problem is probably underestimated because of the lack of reliable data on the epidemiology of thromboembolic events in this population. It may reasonable, therefore, to consider prophylactic anticoagulation for 1-2 weeks in the pre-hospital phase during home self isolation, especially in patients with VTE risk factors, such as reduced mobility, obesity, and previous VTE [23] .

Two patients (Cases #2 and #3) were readmitted after being discharged from the same hospital, suggesting that the assumed procoagulant effect of COVID-19 may extend some weeks after hospital discharge of apparently stable, asymptomatic patients. It would be prudent, therefore, to J o u r n a l P r e -p r o o f Journal Pre-proof have a high degree of clinical suspicion of PE in COVID-19 patients readmitted to the hospital after surviving an initial hospitalization. Extended post-discharge prophylactic anticoagulation for 1-2 weeks may also be useful in some patients after meticulous assessment of the risk-benefit ratio of this treatment [7, 8, 23] . Further studies are needed to assess these aspects.

The outcome from PTE seems to be related to the extent of the thromboembolism, associated complications (e.g., superinfections) and associated organ dysfunction/failure, especially cardiovascular failure. Highly invasive treatment options, such as ECMO, may be useful in selected cases but require long durations of therapy and adequate supportive treatment (Case #4). Indeed, therapeutic anticoagulation is the cornerstone in the management of these patients and should be adapted according to the preexisting comorbidities, such as renal dysfunction [7] . LMWH has been suggested as the first-line treatment, unless closer dose adjustment is required due to expected invasive procedures or in patients with severe renal impairment [32] . In the later cases intravenous UFH followed by the subcutaneous route is recommended to allow regular monitoring and dose adjustment. Urgent thrombolytic therapy should be considered in case of hemodynamic instability, evidence of new onset increased right-ventricular load, or pulmonary arterial hypertension [7, 32] .

PTE is a potential life-threatening complication, which occurs frequently in patients with COVID- 

Informed consents were waived by the corresponding institutional review boards due to the retrospective and anonymous nature of data collection.

The datasets used and analysed during the current report are available from the corresponding author on reasonable request 

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography

Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism

Thrombotic risk in COVID-19: a case series and case-control study

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Diagnosing Pulmonary Thromboembolism in COVID-19: A Stepwise Clinical and Imaging Approach

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review

Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action

SARS-2 Coronavirus-Associated Hemostatic Lung Abnormality in COVID-19: Is It Pulmonary Thrombosis or Pulmonary Embolism?

Microthrombotic Complications of COVID-19 Are Likely Due to Embolism of Circulating Endothelial Derived Ultralarge Von Willebrand Factor (eULVWF) Decorated-Platelet Strings

Endotheliitis and Endothelial Dysfunction in Patients with COVID-19: Its Role in Thrombosis and Adverse Outcomes

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients

Pulmonary Embolism in Patients With COVID-19: Awareness of an Increased Prevalence

Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2

Incidence of venous thromboembolism in hospitalized patients with COVID-19

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past

Systemic endothelial dysfunction: A common pathway for COVID-19, cardiovascular and metabolic diseases

COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET)

Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-Dimer Levels

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study

Pulmonary embolism in patients with COVID-19 pneumonia

Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom

Enoxaparin 40 mg per Day Is Inadequate for Venous Thromboembolism Prophylaxis After Thoracic Surgical Procedure

Efficacy and safety of highdose thromboprophylaxis in morbidly obese inpatients

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Prevention and Treatment of Venous Thromboembolism Associated with Coronavirus Disease 2019 Infection: A Consensus Statement before Guidelines