key: cord-0932495-87rl2ioh
authors: Vernuccio, F.; Lombardo, F. P.; Cannella, R.; Panzuto, F.; Giambelluca, D.; Arzanauskaite, M.; Midiri, M.; Cabassa, P.
title: Thromboembolic complications of COVID-19: the combined effect of a pro-coagulant pattern and an endothelial thrombo-inflammatory syndrome
date: 2020-08-04
journal: Clin Radiol
DOI: 10.1016/j.crad.2020.07.019
sha: 784680e72c1a19020b747158e99eb7b07b9279d0
doc_id: 932495
cord_uid: 87rl2ioh

Abstract Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly become a worldwide threat to health, mainly causing severe acute respiratory syndrome. In addition to the widely described respiratory syndrome, COVID-19 may cause life-treating complications directly or indirectly related to this infection. Among these, thrombotic complications have emerged as an important issue in patients with COVID-19 infection, particularly in patients in intensive care units. Thrombotic complications due to COVID-19 are likely to occur due to a pro-coagulant pattern encountered in some of these patients or to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease. In the present authors’ experience, from five different hospitals in Italy and the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance. The aim of this review is to illustrate thromboembolic complications directly or indirectly related to COVID-19 disease. Specifically, this review will show complications related to thromboembolism due to a pro-coagulant pattern from those likely related to an endothelial thrombo-inflammatory syndrome.

pro-coagulant pattern from those likely related to an endothelial thromboinflammatory syndrome.

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease that has quickly spread worldwide, mainly causing a severe acute respiratory syndrome [1, 2] . In addition to lung disease, COVID-19 may cause a wide spectrum of non-respiratory COVID-19 disease due to involvement of organs by the virus or to complications directly or indirectly related to this infection. Among these, thrombotic complications due to abnormal coagulation status has emerged as an important issue in patients with COVID-19 infection [3, 4] , and may occur in up to 31% of intensive care unit (ICU) COVID-19 patients [5, 6] . Bikdeli et al. [7] suggested some possible causative mechanisms for COVID-19-associated thrombotic disease, including direct effects of COVID-19 through severe illness and hypoxia or severe inflammatory response, or an indirect effect of infection related to investigational therapies used for treating COVID-19, which may have adverse drug-drug interactions with antiplatelet agents and anticoagulants.

Interestingly, some COVID-19 patients have haemostatic abnormalities, including mild thrombocytopenia, increased D-dimer levels, increased clot strength, and hyperfibrinogenaemia, which all indicate a pro-coagulant pattern. Increased levels of D-dimer and fibrin degradation products and prothrombin time prolongation are associated with a higher risk of death in these patients [8, 9] . In addition, anticoagulant therapy mainly with low molecular weight heparin appears to be J o u r n a l P r e -p r o o f associated with better prognosis in severe COVID-19 patients meeting sepsisinduced coagulopathy criteria or with markedly elevated D-dimer [3].

The pro-coagulant pattern identified in many patients with COVID-19 explains the relatively high rate of thrombotic complications, including pulmonary embolism, deepvein thrombosis of leg, catheter-related upper extremity thrombosis, renal infarct, and ischaemic stroke, which have also been identified in patients without known prior hypercoagulable conditions and no prior history of atrial fibrillation [5, 10].

Thrombotic complications due to COVID-19 have also been suggested to occur due to a progressive endothelial thrombo-inflammatory syndrome causing microvascular disease [11] . Some theories have suggested that this endothelial thromboinflammatory syndrome may be related to the presence of ACE2, which is the target receptor of COVID-19, in the endothelial cells of many small vessels [12, 13] or to complement-mediated microvascular injury [14] . Varga et al. [15] also recently demonstrated at histopathology endothelial cell involvement across the vascular beds of different organs in a series of patients with COVID-19, including glomerular capillary loops of the kidney, vessels feeding the small bowel in three patients causing mesenteric ischaemia, and lymphocytic endotheliitis in the lung, heart, kidney, and liver causing multi-organ failure in one patient. In one of the three Although evidence regarding the mechanism of thromboembolic complications of COVID-19 is accumulating rapidly, there are few imaging presentation reports of these complications in COVID-19. In the authors' experience from four different COVID hospitals in Italy, including three centres in the Lombardy region and one in Sicily, and a hospital in the UK, imaging has proved its utility in identifying these COVID-19-related thrombotic complications, with translational clinical relevance.

The aim of this review is to illustrate the direct or indirect thromboembolic effects of COVID-19 disease, including those caused by pro-coagulation thrombosis and endothelial thrombo-inflammatory syndromes.

Pulmonary embolism has been demonstrated radiologically in up to 30% of patients with COVID-19 on pulmonary CT angiography, and in 14% patients with proven COVID-19 pneumonia admitted to the ICU [5, 16, 17] . Pulmonary emboli detected in COVID-19 patients are located in main pulmonary artery in 22% of the cases, lobar artery in 34%, segmental artery in 28%, and subsegmental artery in 16% (Figs. 1-2) [16] . COVID-19 patients with pulmonary embolism have higher D-dimer levels than those without pulmonary emboli and are more likely to be admitted to the ICU [16, 17] . In case of elevated D-dimer levels on hospital admission or sudden clinical worsening, CT pulmonary angiography should be considered, as pulmonary embolism is a life-threatening, but potentially curable, condition [18] . Interestingly, in patients with COVID-19 infection, D-dimer >2,660 µg/l had a sensitivity of 100% and a specificity of 67% for predicting the diagnosis of pulmonary embolism [16] . [30] showed that 44% of ICU COVID-19 patients with neurological symptoms who underwent brain magnetic resonance imaging (MRI) had abnormal findings, such as (Fig. 7) .

COVID-19 has been also associated with cardiac, renal, and gastrointestinal thromboembolic complications [15] . Bhayana pulmonary artery, bilateral pleural effusion with atelectasis, and a small clot is also visible in the right pulmonary artery (arrowhead). 

World Health Organization. WHO Coronavirus Disease (COVID-19)

The Role of chest imaging in patient management during the COVID-19 pandemic: a multinational consensus statement from the Fleischner Society

COVID-19: gastrointestinal manifestations and potential fecal-oral transmission

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

Endothelial cell infection and endotheliitis in COVID-19

Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels

Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT angiography

Right ventricular heart failure from pulmonary embolism: key distinctions from chronic pulmonary hypertension

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Brain MRI findings in patients in the intensive care unit with COVID-19 infection

Acral cutaneous lesions in the time of COVID-19

A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East

Abdominal imaging findings in COVID-19: preliminary observations

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review

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

CT pulmonary angiogram of a 72-year-old woman with D-dimer level >20,000 ng/ml on admission to the emergency department reveals a thrombus (arrow) in the main pulmonary artery at the saddle extending across the origin of both the right and left pulmonary arteries. (b,c) A 72-year-old woman with D-dimer level >2,000 ng/ml. (b) CT pulmonary angiogram on admission shows a pulmonary thrombus (arrow) in the right main pulmonary artery, subsegmental thrombi in the left, bilateral pleural effusion with atelectasis. (c) CT pulmonary angiogram at 1-week follow-up for