key: cord-269105-yuphgyrn authors: Dumantepe, Mert; Aydın, Selim; Yildiz, Erdem; Okur, Hacer Kuzu; Kocagöz, A. Sesin; Gundogdu, Yasemin; Okten, Murat; Isbir, Selim; Karabulut, Hasan title: Subsegmental Thrombus in COVID-19 Pneumonia: Immunothrombosis or Pulmonary Embolism? Data Analysis of Hospitalised Patients With Coronavirus Disease date: 2020-08-24 journal: Heart Lung Circ DOI: 10.1016/j.hlc.2020.08.003 sha: doc_id: 269105 cord_uid: yuphgyrn Background The new coronavirus disease (SARS-CoV-2) has caused more than 350,000 deaths worldwide. Thrombotic complications due to considerable inflammation, cytokine-mediated microvascular damage and pulmonary immunothrombosis formation seem to have emerged as an important issue in people infected with COVID-19. Methods This study reviewed consecutive symptomatic patients with proven COVID-19 infection admitted to Acibadem University Hospital in Istanbul, Turkey (15 March–25 May 2020). The primary outcome was any venous thromboembolic (VTE) complication. The secondary outcome was the incidence of subsegmental pulmonary embolism with or without deep vein thrombosis (DVT), which represented immunothrombosis development. Results The mean age was 55.7±17.4 years (range, 29–84); 224 (63.6%) were men. Of those patients, 12 (3.4%) died, 273 (77.5%) were discharged alive and 67 (19.1%) were still hospitalised as of 25 May 2020. VTE events occurred in 58 patients with a cumulative rate of 16.4% during the study period. The surprising discovery was that DVT was not identified in 20 (86.9%) of the 23 patients with subsegmental pulmonary embolism, which corroborated the pulmonary immunothrombosis theory. Conclusions The high incidence of VTE events suggests an important role of COVID-19-induced coagulopathy. Thus, repeated assessment and optimised treatment are necessary to reduce the occurrence of VTE and prevent fatal pulmonary embolism events. Further studies are needed to investigate the molecular mechanism of this immunothrombosis development. The coronavirus disease of 2019 (COVID-19) is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). It has been extensively reported and now considered a pandemic by the World Health Organization (WHO) [1, 2] . COVID-19 infection has a number of important thrombotic and cardiovascular complications, and people with previous cardiovascular disease are at higher risk of mortality from COVID-19 infection [3] . Cytokine-mediated microvascular damage, hypoxia, systemic inflammation, microangiopathy, coagulation pathway activation, and eventual immunothrombosis development have been described as key features of severe COVID-19 [4] . Recent reports have recommended that haemostatic abnormalities -including arterial and venous thrombotic events, myocardial or cerebral infarction -may occur in COVID-19 patients [5] . Furthermore, elevated D-dimer level, thrombocytopenia and prolonged prothrombin time are very frequent in COVID-19-related deaths [4, 5] . COVID-19 infection is related with high morbidity and mortality, mainly due to respiratory failure, with microvascular hyaline membrane and pulmonary immunothrombosis formation presumably playing a crucial role. Histopathology of pulmonary immunothrombosis consists of diffuse alveolar damage, hyaline membrane activated pneumocytes, microvascular thromboemboli, capillary congestion, and protein-enriched interstitial oedema [6] . In patients with COVID-19 pneumonia, presenting with disease progression or worsening of respiratory symptoms and significant elevation of D-Dimer levels, more attention should be paid to the occurrence of potential pulmonary embolism (PE) with or without deep venous thrombosis (DVT). Therefore, a contrast-enhanced computed tomography (CT) scan should be performed to detect superimposed acute high-risk PE. In J o u r n a l P r e -p r o o f recanalisation was achieved in 10 patients (77%), and partial recanalisation was achieved in three (23%). The operative data and adjunctive treatments details are reported in Table 3 . During the study period, four COVID-19 pneumonia patients in conjunction with high-risk PE were treated with EKOS ™ Acoustic Pulse Thrombolysis ( [11] . High plasma levels of proinflammatory cytokines were observed in a subgroup of patients with severe COVID-19 infection [12] . The notion that direct activation of the coagulation cascade is caused by a cytokine storm is reasonable. Severe hypoxaemia develops in some patients with COVID-19. Thrombus formation under hypoxic conditions is facilitated both in animal and human models of thrombosis. The vascular response to hypoxia is primarily controlled by hypoxia-inducible transcription factors, whose target genes include several factors that regulate thrombus formation [13] . In the recent autopsy study by Wichmann et al., a high incidence of DVT (58%) was found in patients who died of COVID-19 [14] . They also reported that one-third of the patients [23] . Active intrapulmonary infusion of thrombolytic drugs has been performed in patients with a high risk of PE and demonstrated good safety and efficiency [24, 25] . The current results compare favourably, with complete lysis in 87.5% of the treated patients, with a mean of 14.5 hours thrombolysis time. Despite the fact that most of the patients with COVID-19 have coagulation disorders, there were no major haemorrhagic complications in the APT treatment group. A 39% reduction in the mean pulmonary artery pressure, indicating a reduced RV overload, was obtained with APT. These findings are consistent with other studies, which show that pulmonary artery pressure reduction using catheter-directed thrombolytic treatment is associated with resolution in RV dysfunction [25] . Current radiology guidelines suggest a low-dose, non-contrast chest CT scan to assess the pulmonary status of COVID-19 patients [26, 27] . However, many publications have shown VTE studies may be reasonable, even in the very early phases of COVID-19 infection [28] . The current results showed frequent VTE in patients with COVID-19 infection. Most of the patients with subsegmental PE were diagnosed from the general ward and they had no proven DVT or significant VTE risk factors such as prolonged immobilisation or advanced age. Important clinical markers were available that may explain or be associated with pulmonary embolism, including D-dimer and Pro-BNP. The main limitations of this study were the relatively small patient population and the retrospective nature. Future prospective studies with larger patient populations may be needed. 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