Prevalence of Thrombotic Complications in ICU-Treated Patients With Coronavirus Disease 2019 Detected With Systematic CT Scanning

Saeed Mirsadraee, MD, PhD, FRCR, FRCPE; Diana A. Gorog, MD, PhD, FRCP; Ciara F. Mahon, BCh, BAO, MSc, MRCP; Bhavin Rawal, MBBS, FRCR; Thomas R. Semple, FRCR; Edward D. Nicol, MD, FRCP, FRCR; Deepa R. J. Arachchillage, MD, MRCP, FRCPath; Anand Devaraj, MD, FRCR; Susanna Price, PhD, FRCP; Sujal R. Desai, MD, FRCR, FRCP; Carole A. Ridge, FFRRCSI; Suveer Singh, MD, PHD; Simon P. G. Padley, MBBS, FRCR

Disclosures

Crit Care Med. 2021;49(5):804-815. 

In This Article

Discussion

This study confirmed a relatively high prevalence of thrombotic (arterial and venous) complications in patients admitted with severe COVID-19. Our study is unique for two reasons. To the best of our knowledge, this represents the first report of thrombotic complications in high-risk ICU patients, in whom regular systematic whole-body CT scanning was undertaken. Second, we report on the prevalence of thrombotic complications in relatively large number of patients with severe COVID-19 receiving ECMO.

In this cohort, pulmonary artery thromboses were present in 47%. To put this into context, a review of the CT imaging data from a group of patients with infectious pneumonia-related ARDS (many due to viral pneumonitis) on routine thromboprophylaxis, admitted to our ICU for respiratory support in 2018, demonstrated a prevalence of pulmonary thromboembolism that was less than half of that seen in patients with COVID-19 (14/64, 22%; male:female = 34:30; mean age 47 ± 15 yr; 75% on ECMO) (unpublished data).

Prevalence of Thrombosis and Importance of Systematic Imaging

Our study reports a much higher rate of thrombotic complications than previously reported. The recent report from three articles on a combined total of 441 ICU-treated patients with COVID-19 receiving standard anticoagulant prophylaxis revealed a pooled 16% rate of pulmonary thrombotic complications[7,11,14] and a 3.7% arterial thrombotic event rate.[7] The main difference in these studies, compared with ours, is that their assessment with CT, or ultrasonography, was only performed for clinical indications, without routine systematic evaluation, and may therefore not have captured all thrombotic complications. There has only been one prior report of routine ultrasound imaging in a small case series of 26 patients at admission to ICU who received anticoagulant thromboprophylaxis. Venous thrombosis was observed in 69%, 100% of the patients developed thrombosis while on prophylactic dose anticoagulation but only in 56% of those on therapeutic anticoagulation. This study highlights the importance of systematic screening.[15]

A further report on 198 hospitalized patients with COVID-19 (75 on ICU) receiving thromboprophylaxis showed the prevalence of thrombotic complications increased over time and was linked to increased mortality.[16] Autopsy findings in 12 consecutive COVID-19 deaths revealed deep vein thrombosis in seven patients in whom thromboembolism was not suspected antemortem, with pulmonary embolism being the direct cause of death in four patients.[17]

Our data highlights a number of important issues; first, the prevalence of thrombotic complications is very high in COVID-19 patients on ICU, despite chemical thromboprophylaxis; second, clinicians cannot rely on clinical features to determine thromboembolic disease; and third, biomarkers do not appear to be predictive of thrombotic complications in this cohort. Although ultrasound can be used at the bedside to exclude peripheral venous thrombosis, it has limited application in these patients as it cannot map systemic and pulmonary artery thrombosis. We would recommend that systematic imaging should be considered in all COVID-19 ICU-treated patients to adequately guide treatment decisions. We feel that the additional radiation and contrast burden is justified in this cohort to enable diagnosis and treatment of thrombotic complications that adversely impact on outcome. This would understandably limit the use of a dedicated scanner to reduce infection risks to staff and other patients. We acknowledge that the routine imaging of these patients may not be possible in all settings due to the availability of CT scanners and safety concerns pertaining to transfer of infected patients. It may be therefore necessary to work closely with infection control teams and carefully risk assess each patient and consider institutional logistics.

Clinical Relevance of Identifying Thrombotic Complications

As with previous publications, we demonstrate that the presence of thrombotic complications in patients with COVID-19 is related to adverse outcome. The benefits of anticoagulant thromboprophylaxis in hospitalized COVID-19 patients are now well recognized. The International Society on Thrombosis and Haemostasis and the American Society of Hematology recommends that all hospitalized COVID-19 patients should receive prophylactic dose LMWH unless contraindicated.[20] More recently, a report on 3,000 patients with COVID-19 in New York reported that anticoagulation improved survival (not the thrombosis risk), particularly in patients on mechanical ventilation, in whom inhospital mortality fell from 62.7% to 29.1%, and the median survival jumped from 9 to 21 days.[21] Bleeding was similar in both groups.

Usefulness of Biomarkers in Predicting or Diagnosing Thrombotic Complications on the ICU

One of the emerging hallmarks of severe COVID-19 is a coagulopathy that is detectable through markers of coagulation and inflammation in peripheral blood. In the original Wuhan cohort of 919 patients, lymphopenia, leukocytosis, and elevated alanine aminotransferase, lactate dehydrogenase, D-dimer, and PT were reported and related to increased mortality.[1] Since then, severe coagulation abnormalities have been reported in some 20% of COVID-19 patients and in almost all patients with very severe disease.[22,23]

It has been suggested that D-dimer should be used as a guide to indicate pulmonary embolism (e.g., ≥ 500 mg/L, or ≥ 1,000 mg/L when no clinical for pulmonary embolism are present.[18,19] However, estimation of D-dimer levels for predicting thrombosis risk is generally not helpful, given the significant baseline elevations in ICU-treated COVID-19 patients.[24] In our study, D-dimer levels did not discriminate patients with or without thrombosis as the D-dimer levels (even after age-adjustment) were highly elevated in most patients. This does not exclude the screening role of D-dimer (with or without age-adjustment) in earlier stages of the disease.

The finding that coagulation and inflammatory markers on ICU admission did not correlate with thrombotic complications should be interpreted with caution as we only analyzed the admission results in a limited number of patients. The main message is that in this setting, the biomarkers did not discriminate patients with thrombosis.

Pathologic Mechanism of Thrombotic Complications

While significant disturbances in coagulation markers were seen in our cohort, these did not correlate with the occurrence of thrombosis. This could suggest that the pathologic mechanism in these patients may be more complex than a simple procoagulant state, with inflammation and endothelial dysfunction playing important roles, particularly in some vascular beds.[25–27] The finding that 77% of patients in our cohort had CT evidence of pulmonary thrombosis without evidence of venous thrombosis is similar to that reported by Poissy et al[11] and may suggest that in some cases, the pulmonary arterial filling defect represents in situ thrombosis.

Limitations

As a large observational study of COVID-19 patients, some patients remain in hospital, so the prevalence of thrombotic complications and its relationship to mortality may be under-estimated. In addition, it was difficult to assess when exactly patients developed the thrombosis and these were likely present prior to admission to ICU. This might have affected the predictive value of blood biomarkers as shown in this study.

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