key: cord-1051436-sci331nm
authors: Criel, Maarten; falter, Maarten; Jaeken, Jasmien; Van Kerrebroeck, Margaretha; Lefere, Isabelle; Meylaerts, Liesbeth; Mesotten, Dieter; vander Laenen, Margot; Fivez, Tom; Thomeer, Michiel; David, Ruttens
title: Venous thromboembolism in SARS-CoV-2 patients: only a problem in ventilated ICU patients, or is there more to it?
date: 2020-05-14
journal: Eur Respir J
DOI: 10.1183/13993003.01201-2020
sha: 749944f2fd8088aeaec4104ae575e608930778ae
doc_id: 1051436
cord_uid: sci331nm

The insidious VTE seems mainly a problem in the ICU ventilated patients, while patients in the general ward, treated with thromboprophylaxis (0.5 mg/kg), had a low incidence of insidious VTE.

Venous thromboembolism (VTE) is a well-known complication in hospitalized patients (1) (2) (3) (4) (5) . Risk factors include older age, obesity, immobilization, active malignancy, systemic inflammatory response syndrome (SIRS), (major) surgery, thrombophilia, and a history of thromboembolism (2, 5) . Rudolph Virchow first described in 1884 its underlying pathophysiological mechanism and consists of endothelial cell dysfunction/inflammation, low blood flow, and blood hypercoagulability. Current guidelines recommend the use of thromboprophylaxis in acutely ill medical patients who are at high risk for VTE (Padua score ≥ 4, IMPROVE score ≥ 2) (6). However, in medical practice, less than half of the patients at risk receive adequate thromboprophylaxis (4) . In light of the current worldwide SARS-CoV-2 outbreak, medical wards are confronted with increased numbers of acute severely ill patients.

It is estimated that one in five SARS-CoV-2 infected patients require hospitalization with a median stay of 11 days (7). Together with older age (> 65 yrs) and higher SOFA-score (> 4), elevated D-dimer levels (> 1 µg/mL) are associated with in-hospital death (7) . D-dimer levels are a well-known but nonspecific biomarker for VTE, and they could indicate hypercoagulability. Elevated D-dimer levels also indicate inflammation. D-dimer levels are elevated in many other conditions than VTE, and its specificity for VTE diagnosis is low (7)". Among hospitalized SARS-CoV-2 patients, 68% had D-dimer levels above the upper limit of normal, suggesting hypercoagulability in these patients (7) . Up to now, there is no clear association between SARS-CoV-2 infection and the presence of VTE besides a few case reports (9,10). Nevertheless, it seems that these patients are at increased risk for VTE. Firstly, elevated levels of pro-inflammatory cytokines are found in patients infected with SARS-CoV-2 leading to a highly inflammatory state in these patients (7) . Secondly, similar to the previous SARScoronavirus epidemic, angiotensin receptor 2 has been identified as a receptor SARS-CoV-2 uses for cellular entry (11) . This receptor is highly expressed on the membrane of endothelial cells, and this could lead to endothelial cell-specific inflammation/dysfunction due to viral replication in these cells (12) .

We assessed all patients hospitalized in the intensive care unit (ICU) and non-ICU ward of our center the April 3rd, 2020. At that time in Belgium, 7297 patients were hospitalized due to SARS-CoV-2, the province Limburg had the highest incidence, 2607 infected patients, corresponding with 3 infected patients per 1000 inhabitants. Patients in a palliative phase and/or not contributive, mostly due to agitation or impaired mental status, were excluded. Insidious VTE was investigated using a doppler echography of the upper and lower limbs. ICU patients daily received 2x 40 mg enoxaparin. Patients above 100kg received 2x 60mg enoxaparin. In the non-ICU population, patients daily received 1x 40mg enoxaparin. Patients above 100kg received 1x60mg enoxaparin. None of the patients was on unfractionated heparin. For the statistical analysis, where appropriate, Mann-Whitney or Chisquared test was used for the analysis of patient's characteristics using GraphPad Prism version 5.0.

In total 82 patients were screened, 52 in the general ward, and 30 in ICU. In ICU, 21 out of 30 patients were ventilated, none was on extracorporeal membrane oxygenation(ECMO) ; the other 9 patients received nasal high flow oxygen (Optiflow™). In total 6 patients (7.3%) had an insidious VTE (flowchart).

Flowchart: population IN the ICU, four patients had insidious VTE; all of these patients were ventilated. Among the 52 patients from the general ward, two patients had an insidious VTE, of which 1 had a risk factor (active stage IV cancer). If we consider the 49 patients (out of the 52) who benefit of prophylaxis, only 1 of them develop VTE (1/49= 2%), compared to the incidence of VTE of 4/30(13%) in ICU ward. None of the patients who accidentally (n=2) did not receive thromboprophylaxis, developed a VTE.

The patient demographics were comparable between the ICU and non-ICU (table) . In both groups, overweight seems a clinically relevant issue in hospitalization SARS-CoV-2. Patients in ICU had lower renal clearance at admission. No difference in D-dimer levels and cardiac enzymes were observed between both groups. Hypertension and diabetes were more prevalent in the cohort, without a difference between both groups. Mortality in the ICU group was until 22th April 4 out of 30 patients (13%) and in the non-ICU ward 5 out of 52(9.6%). History of diabetes (n-%) 9(17%) 5(17%) 0.94

The current observation confirms a possible problem of thromboembolic events in SARS-CoV-2 critically ill ventilated patients. The insidious VTE seems mainly a problem in the ICU ventilated patients, while patients in the general ward, treated with thromboprophylaxis, had a low incidence of insidious VTE. In our cohort, two patients had an insidious VTE in the non-ICU population, and both had an apparent predisposing risk factor. One other patient had a tiny clot in the left internal jugular vein. This is also described in another viral disease like influenza A (13) , although in this case, without any findings of thrombosis in neither one of the lower limbs. Cultures were negative, no sciences of sepsis. Control after 3 days was negative for any VTE.

VTE with adequate thromboprophylaxis is prevalent in 5 to 15% of critically ill patients in an ICU (14) .

In this cohort, we describe 13%, in line with previous data. Thromboprophylaxis failure (n=5) in our cohort (ICU and non-ICU) was 6.1%, comparable with landmark studies MEDODOX (15) for noncritical ill patients and PROTECT (16) for critically ill patients were thromboprophylaxis failure of 5-6% is reported. In the ventilated SARS-CoV-2 population, 4/21(19%) developed VTE. Until now, no clear correlation with the underlying disease is found. These results were somewhat lower than previously published studies. In the Cui et al study, authors reported and incidence of VTE in 25% of the patients, while they did not receive thromboprophylaxis (17) . In the Klok et al. study, authors reported that 27% developed VTE, with inclusion of pulmonary embolism (18) . As remark should we address that the incidence in our study of VTE is possibly underestimated since we only looked at VTE in the lower and upper limbs. Due to practical reasons and disease severity, no CTscan was performed in al patients. As so, pulmonary embolism was not included in this study. D-dimer levels at presentation seem to be no clear marker for the development of insidious VTE or outcome in our cohort, probably due to the evaluated levels that we detect in our whole SARS CoV-2 population. The VTE cohort (n=6) is too small to do adequate analysis and draw a conclusion on the patients with VTE and the predictive value of d-dimer levels. Further, as previously described in other cohorts, overweight, hypertension, and diabetes are risk factors for hospitalization due to SARS-CoV-2 (19) .

In conclusion, we believe these single-center data could be relevant as preliminary data on a hot topic as thromboprophylaxis in the SARS-Cov-2 population. Further data and follow-up data are needed to confirm if SARS-CoV-2, as a risk factor for thromboembolic events.

Predictive and Associative Models to Identify Hospitalized Medical Patients at Risk for VTE. CHEST. The American College of Chest Physicians

Risk Factors for Venous Thromboembolism

Venous Thromboembolism Prophylaxis in Acutely Ill Hospitalized Medical Patients

Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. The Lancet

VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock

American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients

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

Arteriosclerosis, Thrombosis, and Vascular Biology

Acute pulmonary embolism and COVID-19 pneumonia: a random association?

COVID-19 Complicated by Acute Pulmonary Embolism. Radiology: Cardiothoracic Imaging

The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Runel-Belliard C. Lemierre syndrome and influenza A (H1N1)

Deep Vein Thrombosis in Intensive Care

A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group

Dalteparin versus unfractionated heparin in critically ill patients. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

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

COVID-19 Pandemic, Corona Viruses, and Diabetes Mellitus