key: cord-0767915-ovwiqmmj
authors: Marone, Enrico M.; Bonalumi, Giovanni; Curci, Ruggiero; Arzini, Aldo; Chierico, Simona; Marazzi, Giulia; Diaco, Domenico A.; Rossini, Rosa; Boschini, Stefano; Rinaldi, Luigi F.
title: Characteristics of venous thromboembolism in COVID-19 patients: a multicenter experience from Northern Italy.
date: 2020-07-14
journal: Ann Vasc Surg
DOI: 10.1016/j.avsg.2020.07.007
sha: 2441b391e9def85bdab81ecb7b96eea6b5abd0a9
doc_id: 767915
cord_uid: ovwiqmmj

OBJECTIVE: The liability of patients affected by novel coronavirus disease (COVID-19) to develop venous thromboembolic events (VTE) is widely acknowledged. However, many particulars of the interactions between the two diseases are still unknown. This study aims to outline the main characteristics of deep venous thrombosis (DVT) and pulmonary embolism (PE) in COVID-19 patients, based on experience of four high-volume COVID-19 hospitals in Northern Italy. METHODS: All cases of COVID-19 in-hospital patients undergoing duplex ultrasound (DUS) for clinically suspected DVT between March 1(st) and April 25(th) 2020 were reviewed. Demographics and clinical data of all patients with confirmed DVT were recorded. Computed Tomography Pulmonary Angiographies of the same population were also examined looking for signs of PE. RESULTS: of 101 DUS performed, 42 were positive for DVT, 7 for superficial thrombophlebitis and 24 for PE, 8 of which associated with a DVT. Most had a moderate (43.9%) or mild (16.9%) pneumonia. All venous districts were involved. Time of onset varied greatly, but diagnosis was more frequent in the first two weeks since in-hospital acceptance (73.8%). Most PEs involved the most distal pulmonary vessels, and two thirds occurred in absence of a recognizable deep vein thrombosis. CONCLUSIONS: DVT, thrombophlebitis and PE are different aspects of COVID-19 procoagulant activity and they can arise regardless of severity of respiratory impairment. All venous districts can be involved, including the pulmonary arteries, where the high number and distribution of the thrombotic lesions without signs of DVT could hint a primitive thrombosis rather than embolism.

Novel Coronavirus pneumonia (COVID-19) has rapidly spread worldwide, affecting more than three million people and killing almost 200000 [1] . Although several reports and reviews have been 48 published so far concerning its pathogenic activity and related morbidity and mortality, much still 49 remains unknown, especially regarding its effects on the vascular system. In fact, like in other 50 respiratory infections, important alterations in the hemostatic functions, namely a procoagulant 51 effect, have been described in critically ill COVID-19 patients, yielding to an increased incidence of 52 venous thromboembolism (VTE) that has been estimated between 25% and 29% among those 53 hospitalized in Intensive Care Unit (ICU) [2-3]. However, although the higher liability of COVID-54 19 patients to develop VTE is widely acknowledged, many aspects of this frequent and worrisome 55 complication have not been investigated yet: the most pressing questions that need to be addressed 56 concern its time of onset, if and how it relates with the severity and progression of the pneumonia, 57 and whether it affects in particular some venous districts. 58

The present study conducted across four high volume hospitals for COVID-19 patients in 59

Lombardy, the Italian region that was affected the most by the pandemics, aims to offer a 60 contribution to address those questions. The severity assessment was based on c-reactive protein (CRP) levels, stratified as shown in Table  72 1, which has been demonstrated a valuable marker of the extent of pulmonary involvement [4] . recognize and treat promptly this dangerous and frequent complication, but also because VTE is 120 probably associated with poor prognosis and is said to predict systemic disseminated intravascular 121 coagulation (DIC) [5] . Most evidence reporting on the incidence of DVT in COVID-19 patients 122 focusses on critically ill ICU patients, although some reports have involved also non-ICU cases 123 with mild or moderate pneumonia [5] [6] [7] . This case series clearly shows that VTE can affect in-124 hospital COVID-19 patients regardless of grade and extent of their disease or other risk factors. In 125 fact, the distribution of VTE events showed no predilection for critical and severe patients, as 126 expected, but 46% of patients that were positive for DVT had a moderate pulmonary involvement, 127 as shown by the CRP levels. This consideration is also supported by the fact that the majority of 128 patients were not under mechanical ventilation with orotracheal tube, but were ventilated with C-129 PAP, so their respiratory impairment was only partial. The predilection of VTE events for male sex 130 and age groups ranging between 50 and 80 years reflects the characteristics of the population 131 examined. The fact that only 11 patients were hospitalized in ICU and 15 had a severe or critical 132 illness is probably due to the fact that most of ICU patients receive anticoagulant therapy from the 133 beginning, as a result of the existing evidence, whereas heparin is not routinely administered to non-134 critical, non-ICU hospitalized patients. Therefore, the first conclusion that can be drawn from these 135 data is that administration of anticoagulant or at least prophylactic doses of LMWH should be 136 considered also for non-ICU patients. Moreover, a discussion on whether a DUS screening program 137 should be organized or not in all COVID-19 in-hospital patients, as suggested for ICU patients, 138

should be started, based on the evidence available so far [3, 5] . 139

The second consideration regards the timing of onset of DVT: it has been claimed that DVT is an 140 early complication of COVID-19 pneumonia and that it can often be diagnosed directly at the time 141

of hospitalization. This study shows conflicting findings on the matter, as displayed in table 2: it is  142 true, in fact, that 16 cases out of 42 (38%) were found on the first week since hospital admission, 143 six of whom at first medical contact, on the first day, but, on the other hand, almost as many 144 patients showed the first symptoms only the following weeks, and a lesser, but considerable, 145 number of cases were diagnosed even later, on the third and fourth week, which should lead to 146 conclude that DVTs can arise in any phase of COVID-19, although there seems to be some 147 predilection towards the early phase, when the first respiratory symptoms appear. The limits of this study include its retrospective nature and the lack of incidence and prevalence 171 data of DVT in COVID-19 patients, since it is only based on those cases that were referred to the 172 vascular surgeons for suspected DVT, and cannot offer a whole panorama of the whole population 173 of COVID-19 in-hospital patients. Therefore, it is possible that silent, undiagnosed, DVT makes the 174 total number of in-hospital COVID-19 patients with DVT considerably larger than that examined 175 here, and the same can be said for PE, since the CTPAs analyzed were also limited to the same 176 sample of patients: having shown that most cases are negative for DVT, the number of PE among 177 in-hospital COVID-19 patients is expected to be even higher than those of DVTs. However, this is 178 not a prevalence study, and its aim is to describe the most important and most peculiar 179 characteristics of VTE in COVID-19, which is already acknowledged as a common and severe 180 complication of this disease. In this respect, the observations made above should be useful in 181 learning how to manage it, both in terms of early recognition and treatment, even in its most 182 insidious forms and presentations, namely primitive PE. The lack of a control group to compare the 183 results reported is also an important shortcoming, but to conduct a full controlled study in the 184 present situation of health emergency would have delayed the publication of these results too much, 185 and we think it in the best interest of the readers to be provided with the present data, albeit partial, 186 as soon as possible. Another limit is the lack of information regarding the general prognosis and 187 disease progression, which require a longer follow-up period to be available. Once they are 188 collected and reviewed, they will provide a more complete picture of the course of VTE in COVID-189 19, especially concerning its response to anticoagulation, which still needs further explanation, as 190 suggested by the cases, reported here and by Llitjos 

timing of onset is variable, ranging from the first day of hospitalization to the fifth week, 200 although early onset seems slightly more frequent

Authors' contribution: 205 Conception and study design: EMM, GB, RG, AA 206 Data collection and analysis: SC, GM, DAD, RR, SB, LFR 207 Article writing: LFR, GM, SC 208 Critical revision: EMM

World Health Organization

Prevalence of venous thromboembolism in 215 patients with severe novel coronavirus pneumonia

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

-reactive protein levels in the early stage of COVID-19 Med Mal Infect