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Table 1.  Clinical Characteristics and Laboratory Findings Among 34 Patients at Admission
Clinical Characteristics and Laboratory Findings Among 34 Patients at Admission
Table 2.  Rate of Deep Vein Thrombosis at Admission and at 48 Hours
Rate of Deep Vein Thrombosis at Admission and at 48 Hours
1.
Yang  X, Yu  Y, Xu  J,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. 2020;2600(20):1-7. doi:10.1016/S2213-2600(20)30079-5PubMedGoogle Scholar
2.
Chen  T, Wu  D, Chen  H,  et al.  Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.   BMJ. 2020;368(March):m1091. doi:10.1136/bmj.m1091PubMedGoogle ScholarCrossref
3.
Tang  N, Li  D, Wang  X, Sun  Z.  Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.   J Thromb Haemost. 2020;18(4):844-847. doi:10.1111/jth.14768PubMedGoogle ScholarCrossref
4.
Klok  FA, Kruip  MJHA, van der Meer  NJM,  et al.  Incidence of thrombotic complications in critically ill ICU patients with COVID-19.   Thromb Res. Published online April 10, 2020. doi:10.1016/j.thromres.2020.04.013PubMedGoogle Scholar
5.
Llitjos  J-F, Leclerc  M, Chochois  C,  et al.  High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.   J Thromb Haemost. Published online April 22, 2020. doi:10.1111/jth.14869PubMedGoogle Scholar
6.
Bhatraju  PK, Ghassemieh  BJ, Nichols  M,  et al.  COVID-19 in critically ill patients in the Seattle region: case series.   N Engl J Med. 2020;(Mar). doi:10.1056/NEJMoa2004500PubMedGoogle Scholar
2 Comments for this article
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Coagulopathy in CoVID19 patients
Camilo Colaco, PhD | ImmunoBiology Ltd
The normal range for D-Dimer is 0.21 to 0.32mg/L on some assays. In your study, the D-dimer levels were 3.3mg/L in patients without DVT and 5.4mg/L in those with DVT. As clotting is a cascade, it should be expected that some patients with elevated D-dimer levels may progress to develop DVT. Have you looked if there is a difference in blood markers (including D-dimer) in the 15% who develop DVT compared to those that don't?
Pragmatically, should we start treating with anticoagulant therapy before admission to ICU, as lung microthrombi could manifest as breathing difficulties?
CONFLICT OF INTEREST: None Reported
Author reply to Dr. Colaco
Tristan Morichau-Beauchant, MD | Centre Cardiologique du Nord
Thank you for your interest in our article.
Comparing biological markers and in particular D-Dimer levels in the group who develops DVT 48h after ICU admission and the group who does not develop DVT brings no significant difference, but the sample sizes are small.
Current guidelines regarding anticoagulant prophylaxis for patients with COVID-19 pneumonia are heterogenous. Intermediate doses and full dose anticoagulant therapy have been recommended in some guidelines for more severe patients or patients with high levels of D-Dimers based on retrospective data. While waiting for more solid proof, it seems reasonable in my opinion to use at
least intermediate doses of anticoagulant therapy for patients with COVID-19 and high levels of inflammatory markers and D-Dimer.
CONFLICT OF INTEREST: None Reported
READ MORE
Research Letter
Critical Care Medicine
May 29, 2020

Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19)

Author Affiliations
  • 1Intensive Care Unit, Centre Cardiologique du Nord, Saint-Denis, France
  • 2Ultrasound and Vascular Lab, Centre Cardiologique du Nord, Saint-Denis, France
JAMA Netw Open. 2020;3(5):e2010478. doi:10.1001/jamanetworkopen.2020.10478
Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) was identified as a new coronavirus causing pneumonia and acute respiratory distress syndrome. It has become a pandemic, spreading particularly quickly across Europe and the US. Most deaths are related to severe acute respiratory distress syndrome, but other organ failures, such as acute kidney failure and acute cardiac injury, seem also related to the disease.1 Inflammatory response is highly increased in coronavirus disease 2019 (COVID-19) infection, and inflammation is known to favor thrombosis. High dimerized plasmin fragment D (D-dimer) levels and procoagulant changes in coagulation pathways were reported among patients with severe COVID-19.2,3 An elevated rate of venous and arterial thrombotic events associated with COVID-19 infection has also been reported.4,5 This case series reports a systematic assessment of deep vein thrombosis among patients in an intensive care unit (ICU) in France with severe COVID-19.

Methods

This case series was approved by the ethical committee of the Centre Cardiologique du Nord, which granted a waiver of consent because the research presented no risk of harm and required no procedures for which consent is normally required outside a research context. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Patients with severe COVID-19 pneumonia were admitted to our ICU located in the suburban Paris area from mid-March 2020 to the beginning of April 2020. All patients had acute respiratory distress syndrome according to the Berlin definition and required mechanical ventilation.

We prospectively performed a venous ultrasonogram of the inferior limbs for all patients at admission to our ICU, considering previous data that showed increased levels of inflammatory markers, preliminary reports from the intensive care community signaling frequent events of deep vein thrombosis in ICU patients with COVID-19 at the time we received our first patients, and the high rate of deep vein thrombosis found among the first patients with COVID-19 admitted to our unit. Considering the high prevalence of venous thrombosis at admission, we systematically repeated venous ultrasonography after 48 hours if the first examination returned normal results. As recommended, all patients received anticoagulant prophylaxis at hospital admission. Statistical analyses were conducted in Prism version 5.0 (GraphPad) and Excel 365 (Microsoft Corp). Statistical significance was set at P < .05, and all tests were 2-tailed.

Results

A total of 34 consecutive patients were included in this study. COVID-19 diagnosis was confirmed with polymerase chain reaction on nasopharyngeal swabs of 26 patients (76%); 8 patients (24%) had a negative result on polymerase chain reaction but had a typical pattern of COVID-19 pneumonia on chest computed tomography scan. Mean (SD) age was 62.2 (8.6) years, and 25 patients (78%) were men. Major comorbidities were diabetes (15 [44%]), hypertension (13 [38%]), and obesity (mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 31.4 [9.0]). Overall, 26 patients (76%) required norepinephrine at admission, 16 (47%) required prone positioning, and 4 (12%) required venovenous extracorporeal membrane oxygenation (Table 1). Only 1 patient (3%) received anticoagulant therapy before hospitalization.

Deep vein thrombosis was found in 22 patients (65%) at admission and in 27 patients (79%) when the venous ultrasonograms performed 48 hours after ICU admission were included (Table 2). Eighteen patients (53%) had bilateral thrombosis, and 9 patients (26%) had proximal thrombosis. Comparable with previously published data,2,3 our population had high levels of D-dimer (mean [SD], 5.1 μg/mL [to convert to nanomoles per liter, multiply by 5.476]), fibrinogen (mean [SD], 760 [170] mg/dL [to convert to grams per liter, multiply by 0.01]) and C-reactive protein (mean [SD], 22.8 [12.9] mg/dL [to convert to milligrams per liter, multiply by 10]). Prothrombin activity (mean [SD], 85% [11.4%]) and platelet count (mean [SD], 256 [107] × 103/μL) were normal (Table 1).

Discussion

Mortality of patients with COVID-19 admitted to ICUs has been reported to be high, at 50%.6 Frequent venous and arterial thrombotic events have been reported, with rates from 27% to 69% of peripheral venous thromboembolism and up to 23% of pulmonary embolism.4,5 The occurrence of pulmonary embolism might be favored by deep vein thrombosis. The main limitations of this study were its monocentric nature and the relatively small size of our cohort. In view of the high rate (ie, 79%) of deep vein thrombosis reported in this study, prognosis might be improved with early detection and a prompt start of anticoagulant therapy. Despite anticoagulant prophylaxis, 15% of our patients developed deep vein thrombosis only 2 days after ICU admission. Systematic anticoagulant therapy for all ICU patients with COVID-19 should be assessed.

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Article Information

Accepted for Publication: May 3, 2020.

Published: May 29, 2020. doi:10.1001/jamanetworkopen.2020.10478

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Nahum J et al. JAMA Network Open.

Corresponding Author: Tristan Morichau-Beauchant, MD, Intensive Care Unit, Centre Cardiologique du Nord, 32-36 rue des Moulins-Gémeaux, 93200 Saint-Denis, France (t.morichau-beauchant@ccn.fr).

Author Contributions: Drs Nahum and Morichau-Beauchant had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nahum, Morichau-Beauchant, and Daviaud contributed equally to this work.

Concept and design: Nahum, Morichau-Beauchant, Daviaud, Maillet.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Nahum, Morichau-Beauchant, Daviaud, Echegut, Maillet.

Critical revision of the manuscript for important intellectual content: Nahum, Morichau-Beauchant, Daviaud, Fichet, Maillet, Thierry.

Statistical analysis: Nahum, Daviaud, Maillet.

Obtained funding: Nahum, Thierry.

Administrative, technical, or material support: Nahum, Echegut, Fichet, Thierry.

Supervision: Nahum, Morichau-Beauchant, Daviaud, Fichet, Thierry.

Conflict of Interest Disclosures: None reported.

References
1.
Yang  X, Yu  Y, Xu  J,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. 2020;2600(20):1-7. doi:10.1016/S2213-2600(20)30079-5PubMedGoogle Scholar
2.
Chen  T, Wu  D, Chen  H,  et al.  Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study.   BMJ. 2020;368(March):m1091. doi:10.1136/bmj.m1091PubMedGoogle ScholarCrossref
3.
Tang  N, Li  D, Wang  X, Sun  Z.  Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.   J Thromb Haemost. 2020;18(4):844-847. doi:10.1111/jth.14768PubMedGoogle ScholarCrossref
4.
Klok  FA, Kruip  MJHA, van der Meer  NJM,  et al.  Incidence of thrombotic complications in critically ill ICU patients with COVID-19.   Thromb Res. Published online April 10, 2020. doi:10.1016/j.thromres.2020.04.013PubMedGoogle Scholar
5.
Llitjos  J-F, Leclerc  M, Chochois  C,  et al.  High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients.   J Thromb Haemost. Published online April 22, 2020. doi:10.1111/jth.14869PubMedGoogle Scholar
6.
Bhatraju  PK, Ghassemieh  BJ, Nichols  M,  et al.  COVID-19 in critically ill patients in the Seattle region: case series.   N Engl J Med. 2020;(Mar). doi:10.1056/NEJMoa2004500PubMedGoogle Scholar
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