key: cord-322259-khknne8s
authors: de Roquetaillade, C.; Chousterman, B.G.; Tomasoni, D.; Zeitouni, M.; Houdart, E.; Guedon, A.; Reiner, P.; Bordier, R.; Gayat, E.; Montalescot, G.; Metra, M.; Mebazaa, A.
title: Unusual arterial thrombotic events in Covid-19 patients
date: 2020-09-10
journal: Int J Cardiol
DOI: 10.1016/j.ijcard.2020.08.103
sha: 
doc_id: 322259
cord_uid: khknne8s

INTRODUCTION: COVID-19 infection is commonly complicated with pro-thrombotic state and endothelial dysfunction. While several studies reported a high incidence of venous thromboembolic events. The occurrence of arterial thromboses are yet rarely described and could be underestimated. OBJECTIVES: To describe the clinical and biological characteristics of COVID-19 patients presenting with an associated arterial thromboembolic event. MATERIAL AND METHODS: We performed a retrospective multicentric study in 3 centers between France and Italy. All patients with a confirmed SARS-CoV-2 infection and arterial thromboembolic events were included in the analysis. RESULTS: From March 8th to April 25th 2020, we identified 20 patients (24 events) with arterial thromboembolic events over 209 admitted patients (9.6%) with severe COVID-19 infection. Arterial thrombotic events included acute coronary occlusions (n = 9), stroke (n = 6), limb ischemia (n = 3), splenic infarcts (n = 3), aortic thrombosis (n = 2) and occlusive mesenteric ischemia (n = 1). At the time of the event, 10/20 (50%) of patients received thromboprohylaxis, 2/20 (10%) were receiving treatment dose anticoagulation and 5/20 (25%) were receiving antiplatelet therapy. CONCLUSION: Our observations suggest that serious arterial thrombotic events might occur in Covid-19 patients. However, the exact incidence of such events and the best way to prevent them yet remains to be investigated.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is commonly complicated with pro-thrombotic state and endothelial dysfunction 1 . Excess of venous thromboembolic events (deep vein thrombosis (DVT), pulmonary embolism (PE)) have been described among patients suffering from coronavirus disease 2019 2 . However, arterial thrombosis are yet rarely described in this setting and could be underestimated 3 . Here we report our multicentric experience with patients suffering from arterial thromboembolic events during the first months of the Covid-19 outbreak in Western Europe.

During a six weeks period (March 8th to April 25th 2020) we performed a retrospective study in three critical care departments. Patients with a confirmed SARS-CoV-2 infection (rt-PCR) and arterial thromboembolic events were included in the analysis. Baseline characteristics, biological findings and imaging were extracted from medical records. For most patients, antithrombotic prophylaxis was made of 4000 ui per day of enoxaparine administered subcutaneously, the dose was increased (6000UI/day or 8000UI/day) in case of obesity (BMI > 30 kg/m2). In patient treated with therapeutic dose anticoagulant, the therapeutic objectives followed international recommendations (AntiXa activity 0.3-0.6 for unfractionated heparin (UFH), and no systematic AntiXa monitoring for low-molecular-weight heparin (LMWH) treatment except for patient at risk of altered renal function or obese or unstable patients, for those the AntiXa was monitored and the LMWH doses were adapted for an AntiXa activity between 0.5-1.2 UI/mL). For the descriptive analysis, continuous variables were expressed as median (interquartile range) and categorical variables as numbers (percentages). This study was approved by our local committee (Institutional Review Board -IRB 00006477-of HUPNVS, Paris 7 University, AP-HP).

J o u r n a l P r e -p r o o f Journal Pre-proof

We report a total of 20 patients out of a total of 209 patients (9.6%) observed of COVID-19 patients suffering from arterial thromboses. Among them 4 patients had multiple arterial thrombotic events, accounting for a total of 24 events (Table) . A total of 5/20 (25%) patients had ischemia-related symptoms (sudden neurologic deficit or acute coronary syndrome) at the time of presentation and the other 15/20 patients developed ischemia during hospitalization.

Reported arterial thrombotic events were acute coronary occlusions (n=9), stroke (n=6), limb ischemia (n=3), splenic infarcts (n=3), aortic thrombosis (n=2) activity tested in 2 patients was normal. A total of 4 patients (20%) died in the hospital, all from complications due to ischemia (extended aortic thrombosis (n=1) (Figure) , mesenteric ischemia (n=1), fatal cardiogenic shock (n=1) and devastating brain injury (n=1)).

In this multicentric serie of patients, severe SARS-CoV-2 infection was complicated with atypical severe arterial thrombotic events including acute coronary infarction, stroke, and limb ischemia not prevented by thromboprophylaxis. Thromboses we observed occurred mainly on non-atherosclerotic vessels. Patients were of relatively young age and available CT-scans and angiography revealed no prior major atherosclerosis. Our observations suggest that a significative proportion of arterial thromboses in Covid-19 patients might occur over non diseased or mildly diseased vessels 4 . A prothrombotic state might be triggered by various mechanisms such as inflammation, endothelial injury or vascular injury 5 . Taken together, our observations suggest that serious arterial thrombotic events occur in Covid-19 patients who exhibit high inflammation and sometimes unusual localisation of these thrombotic events.

Those arterial thromboses might be reason for admission but can also occur during hospitalisation of patients with Covid-19. Several recommandations were emitted by several groups regarding VTE prevention and management 6 same as ACS occuring among Covid-19 J o u r n a l P r e -p r o o f patients 7 . However, the best prevention and management of arterial thromboses in the Covid-19 context remains to be elucidated.

This statement is to certify that all authors have seen and approved the manuscript being submitted, have contributed significantly to the work, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission to the International Journal of Cardiology.

We attest that the article is the Authors' original work, has not received prior publication and is not under consideration for publication elsewhere. We adhere to the statement of ethical publishing as appears in the International of Cardiology (citable as: Shewan On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. Any changes to the list of authors, including changes in order, additions or removals will require the submission of a new author agreement form approved and signed by all the original and added submitting authors. A 74 years old patient was admitted in ICU for respiratory failure. Nasal swab confirmed the suspected COVID-19. Doppler ultrasound revealed no deep venous thrombosis despite Ddimers >20 000UI/L. The patient received prophylactic enoxaparin (4000UI/12h). On the 6 th day, the patient presented lower limb ischemia and abdominal occlusion syndrome. Subsequent Arterial-TDM revealed de novo multifocal and circumferential aortic thrombi of suprarenal and subrenal localization, with up to 50% occlusion on the infra-renal portion. There were no associated deep vein thrombosis nor pulmonary embolism. 

The versatile heparin in COVID-19

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

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

ST-Elevation Myocardial Infarction in Patients with COVID-19: Clinical and Angiographic Outcomes. Circulation. Epub ahead of print

Endothelial cell infection and endotheliitis in P/F ratio 200

The authors report no relationships that could be construed as a conflict of interest.

CdR designed the study, collected data and wrote the manuscript. DT, MZ, AG, PR, RB, TM collected data, images and wrote the manuscript. BGC, EH, EG, MM, GM and AM designed the study and wrote the manuscript.

Patient under mechanical ventilation, n (%) 5 (25) 1 (11) 2 (33) 2 (40) Tocilizumab or other anti IL6, n (%) 1 (5) 0 (0) 1 (17) 0 (0)

Time from symptom onset, days 11 (7-13) 8 (4-10) 9 (7-12) 14 ( 

 SARS-CoV-2 infection is commonly complicated with pro-thrombotic state and endothelial dysfunction.  High rate of venous thromboembolic events have been described among patients suffering from Covid-19. However, arterial thromboses are yet rarely described in this setting.  We report a total of 20 cases of COVID-19 patients suffering from arterial thromboses.  Our observations suggest that arterial thrombotic events might occur in patients and could be underestimated.