COVID-19-Associated Thrombotic Complication: Is It Pulmonary Embolism or In Situ Thrombosis?

Objectives Acute pulmonary embolism is a protentional fatal complication of COVID-19. The aim of this study is to investigate whether pulmonary embolism is due to thrombus migration from the venous circulation to the pulmonary arteries or due to local thrombus formation secondary to local inflammation. This was determined by looking at the distribution of pulmonary embolism in relation to lung parenchymal changes in patients with COVID-19 pneumonia. Methods Retrospectively, we identified pulmonary computed tomography angiography (CTPA) of patients admitted to the Royal Hospital between November 1st, 2020, and October 31, 2021, with a confirmed diagnosis of COVID-19. The CTPAs were examined for the presence of pulmonary embolism and the distribution of the pulmonary embolism in relation with lung parenchymal changes. Results A total of 215 patients admitted with COVID-19 pneumonia had CTPA. Out of them, 64 patients had pulmonary embolisms (45 men and 19 women; mean age: 58.4 years with a range of 36–98 years). The prevalence of pulmonary embolism (PE) was 29.8% (64/215). Pulmonary embolism was more frequently seen in the lower lobes. 51 patients had PE within the diseased lung parenchyma and 13 patients had PE within normal lung parenchyma. Conclusion The strong association between pulmonary artery embolism and lung parenchymal changes in patients admitted with COVID-19 pneumonia suggests local thrombus formation.


Introduction
Trombotic complications including disseminated intravascular coagulation, deep vein thrombosis, and pulmonary embolisms are common complications among patients admitted with COVID-19 pneumonia [1][2][3]. However, the pathophysiology behind the increased incidence of thrombotic complications among patients with COVID-19 pneumonia is unclear. It has been suggested that the endothelial infammation and damage caused by COVID-19 infection can lead to local thrombus formation mediated by the activation of complement pathways and associated procoagulant state [4]. Tis would mean that pulmonary embolism is formed locally in the lung parenchyma in patients afected with COVID-19 pneumonia. As per the author's knowledge, only one study with a very limited number of patients has looked at the distribution of PE in relation with the lung parenchymal changes [5]. Terefore, the aim of our study was to investigate if pulmonary embolism is due to thrombus migration from the venous circulation to the pulmonary arteries or due to local thrombus formation secondary to local infammation.

Methods
We conducted a retrospective study to identify all computed tomography pulmonary angiography (CTPA) scans performed for patients admitted to our tertiary hospital with a confrmed diagnosis of COVID-19 infection, between November 1st, 2020, and October 31, 2021.
Te diagnosis of COVID-19 was based on a laboratoryconfrmed positive RT-PCR for SARS-CoV-2 obtained from the nasopharynx and oropharynx of all patients. Medical records of included patients were reviewed and demographic characteristics, vital signs, presenting symptoms, comorbidities, and D-dimer were documented.
Te computed tomography pulmonary angiography (CTPA) was performed using a dual source 256 slice (2 × 128) scanner (SOMATOM Defnition Flash, Siemens AG), with a rotation time of 280 minutes. All scans started with a tomogram followed by a contrast-enhanced scan of the pulmonary arteries with a slice thickness of 1 mm which was acquired during breath holding after inspiration or free breathing if the patient was not able to follow the breathing instruction. CTPAs were initially reported by the attending radiologist for the presence of pulmonary embolism (PE). Ten, they were again analyzed by 4 board-certifed radiologists for the distribution of PEs in relation with lung parenchymal changes. All CTPAs were reviewed using a dedicated radiology PACS system. Lungs were divided into 18 segments and each segment was evaluated for parenchymal changes and for the presence of pulmonary embolism. Pulmonary embolism was called in situ if it was within a segment with lung changes, and not in situ if the segment had no parenchymal changes.
Te ethical approval was obtained from the scientifc research committee at our institute. Informed consents were waived.

Statistics
Continuous variables were presented as mean, median, and standard deviation whereas, categorical variables were presented as frequency and percentage. Te comparison of means between the two groups was assessed using the independent samples t-test or the Mann−Whitney U test, as appropriate. Te association between two categorical variables was assessed using an appropriate chi-square test (likelihood ratio test or Fisher's exact test). A P value of less than 0.05 was considered statistically signifcant. All analysis was carried out using the IBM SPSS statistics version 26.0.

Results
Over a one-year period, we identifed 215 patients admitted with COVID-19 pneumonia and had CTPA. Out of the 215 patients, 64 (29.8%, 95% CI � 23.7%-36.4%) of them had positive CTPA for pulmonary embolism (45 men and 19 women; mean age, 58.4 years with range 36-98 years) and they were included in the statistical analysis. Te demographical and clinical features of the included patients are summarized in Table 1.
Te analysis of the distribution of pulmonary embolism on the lung lobe level showed that 51 (79.7%) patients had PE within the diseased lung parenchyma (in situ) and 13(20.3%) patients had PE within the normal lung parenchyma (not in situ) ( Table 1). Tere was a predilection for right lower lobe involvement (71.9%) followed by left lower lobe (59.4%) with a statistically signifcant diference (Tables 2-4).

Discussion
Coagulopathy, including pulmonary embolism (PE), is a common complication among patients admitted with COVID-19 infection, and it is usually associated with a poor prognosis [1,6]. In this study, the prevalence of PE among the patients admitted with COVID-19 infection who had PCTA was 29.8%. In the literature, the incidence of PE among patients admitted with COVID-19 pneumonia is variable. In a systematic review and meta-analysis by Liu et al. [7], the reported overall incidence of PE was 17.6% (95% CI: 12.3%-23.5%) and 21.7% (95% CI: 14.8%-29.3%) in the patients with a severe disease.
Te exact mechanism behind the increased thrombotic complications among patients with COVID-19 infection is not clear. However, there are several potential mechanisms that might be responsible for promoting the risk of coagulopathy such as the severe infammatory response and disseminated intravascular coagulation [8], blood vessel endothelial damage caused directly by the virus and the associated local infammatory process [9], drug-drug reactions, and the limited mobility among patients with COVID-19 pneumonia admitted to the intensive care unit (ICU) [8].
Te standard management of patients admitted with COVID-19 pneumonia and those who were found to have PE is therapeutic doses of anticoagulation. Diferent agents can be used including unfractionated heparin, low-molecular-weight heparin (LMWH), and direct oral anticoagulant [8]. If we consider that platelets play an important role in local pulmonary thrombosis compared with pulmonary embolism, then it might be necessary to treat these patients with antiplatelet agents along with anticoagulation agents. Te latter works mainly on pulmonary embolism, whereas antiplatelet agents, such as aspirin and clopidogrel, block antiplatelet activation [10][11][12]. Te hypothesis of our study is that PE is due to local clot formation secondary to local infammation and damage caused directly by the virus. Mueller−Peltzer et al. have shown that PE is more frequently encountered in the opacifed regions of the lungs and concluded that this might be due to a local clot formation [5]. However, the population in their study was small. In our study, we included 215 patients admitted at our institute with a confrmed diagnosis of COVID-19 pneumonia between November 1st, 2020, and October 31, 2021, and out of them 64 patients had PE, 23.7% of patients had PE within the diseased lung parenchyma (in situ), and 6% of patients had PE within the normal lung parenchyma (not in situ). Tis shows a strong association between PE and lung parenchymal changes suggesting that PE is locally formed. Local thrombosis in the pulmonary artery is likely due to the strong infammatory process that results in pulmonary artery endothelial damage. In addition, SARS-CoV-2 might activate the coagulation pathway by binding the ACE-2 receptor of type II pneumocytes and then dysregulating the kallikrein/kinin system [13]. If COVID-19 is associated with local thrombus formation rather than PE, then the management of coagulopathy in patients with COVID-19 infection might need to be adjusted by adding antiplatelets 2 Radiology Research and Practice     [14], which would not be relevant in local pulmonary artery thrombosis.

Limitation
Tis study has a few limitations. First, this study is a retrospective study with a relatively small sample size, and still, data need to be confrmed in a larger population to prove a local clot formation. Second, most of our patients were ventilated and this can result in a motion artifact during the scan that limits the assessment of the pulmonary arteries. Tird, we cannot exclude deep vein thrombosis in our population as Doppler ultrasound of the lower limbs was not routinely performed.

Conclusion
Pulmonary embolism is a relatively common complication among patients admitted with COVID-19 pneumonia. A high frequency of PE in the diseased lungs might suggest that PE in patients with COVID-19 pneumonia is due to local thrombus formation. Tis requires specifc assessment and an appropriate therapeutic response.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.