Lisette van Dam

Chapter 12 184 Differences between patients with COVID-19 associated PE and the control patients related to thrombosis risk (e.g. sex or BMI) may explain our observations. The relatively small sample size did not allow performing multivariate analyses to adjust for these differences. Nevertheless, sex and BMI have been shown not to be associated with clot burden or distribution in previous studies so we feel this explanation is less likely. 20 It is however possible that prophylactic anticoagulation, which was prescribed in all COVID-19 patients, and a shorter diagnostic delay may have influenced the radiological parameters of the PE. An alternative explanation is that in situ immunothrombosis indeed plays a role in the pathophysiology of COVID-19 associated PE. Alveolar injury and the inflammatory storm caused by COVID-19 pneumonia as well as disruption of the thrombo-protective state of the pulmonary vascular endothelial cells contribute to profound small vessel thrombus formation. 15,16,20 Even so, since 93% of lung segments was affected by infection, a ‘true’ association between location of the thrombotic and COVID-19 lesions could not be established, simply because unaffected segments were hardly present. The markedly higher D-dimer levels in COVID-19 patients with PE nonetheless underline the extreme coagulopathy and pro-thrombotic state associated with COVID-19 infection. The absence of clinical signs of deep vein thrombosis (DVT) in the COVID-19 patients may also support the concept of in situ immunothrombosis, although the prevalence of clinical signs of DVT was equally low in the control group. Importantly, the fact that the majority of PEs was located in the segmental arteries and 17% even centrally in the pulmonary artery tree is strongly compatible with the conventional thromboembolic origin of PE. This was also seen in previous publications in which COVID-19 associated PE was located in the central/lobar pulmonary artery in 44-56% of the cases. 22,23 Our findings are in line with histologic findings in autopsy studies were multiple thrombi in small to mid-sized pulmonary arteries were observed supporting the concept of immunothrombosis. 21,24 The observation by others that the incidence of DVT in COVID-19 patients was high upon screening also suggests that the conventional thromboembolic origin of PE plays indeed a role in COVID-19 associated PE. 9, 25 Of note, increased prevalence of PE and not of DVT has been described before in pulmonary conditions such as COPD and pneumonia. 26 The main limitations of our study include the relatively small sample size and the lack of screening ultrasonograms of the leg veins. Furthermore, selection bias may have occurred as the threshold for PE screening may have been lower in COVID-19 patients than in the control group resulting in less extensive PE in the COVID-19 patients. Another limitation may be that blinded CT assessment by the