key: cord-0943159-gnvs5bdl
authors: Collett, Luke Wallace; Gluck, Samuel; Michael, Richard; Reddi, Benjamin John
title: Evaluation of coagulation status using viscoelastic testing in Intensive Care patients with COVID-19: An observational point prevalence cohort study
date: 2020-07-21
journal: Aust Crit Care
DOI: 10.1016/j.aucc.2020.07.003
sha: 10c35fc1999274e4b65ab30b8f6d5bb755c2908e
doc_id: 943159
cord_uid: gnvs5bdl

BACKGROUND: Coronavirus-19 (COVID-19) is associated with a high rate of thrombosis, the pathophysiology of which is not well defined. Viscoelastic testing may identify and characterise hypercoagulable states which are not apparent using conventional coagulation assays OBJECTIVES: To undertake viscoelastic evaluation of the coagulation state in critically ill adults with COVID-19 associated respiratory failure METHODS: Single centre observational point prevalence cohort study of adults requiring respiratory support in the intensive care unit with COVID-19 associated respiratory failure. Coagulation status was evaluated using rotational thromboelastometry in conjunction with laboratory markers of coagulation. RESULTS: Six patients fulfilled inclusion criteria. Each patient had one ROTEM performed. All patients had supra-normal clot amplitude at 10 minutes (A10) and supra-normal clot firmness (MCF) measured in at least one ROTEM pathway, and 5 were supra-normal on all pathways. Minimal clot lysis was present on all analyses. Fibrinogen and d-dimer were elevated and routine markers of coagulation within normal ranges in all patients. CONCLUSION: Patients admitted to ICU with COVID-19 associated respiratory failure exhibit a hyper-coagulable state which is not appreciable on conventional tests of coagulation. Supra-normal clot firmness, minimal fibrinolysis and hyperfibrinogenaemia are key findings. Further research is required into the pathophysiology of this hypercoagulable state, as well as the harms and benefits of different anticoagulation strategies.

Abstract Background:

Coronavirus-19 is associated with a high rate of thrombosis, the pathophysiology of which is not well defined. Viscoelastic testing may identify and characterise hypercoagulable states which are not apparent using conventional coagulation assays

To undertake viscoelastic evaluation of the coagulation state in critically ill adults with COVID-19 associated respiratory failure

Single centre observational point prevalence cohort study of adults requiring respiratory support in the intensive care unit with COVID-19 associated respiratory failure. Coagulation status was evaluated using rotational thromboelastometry in conjunction with laboratory markers of coagulation.

Six patients fulfilled inclusion criteria. Each patient had one ROTEM performed. All patients had supra-normal clot amplitude at 10 minutes (A10) and supra-normal clot firmness (MCF) measured in at least one ROTEM pathway, and 5 were supra-normal on all pathways. Minimal clot lysis was present on all analyses. Fibrinogen and d-dimer were elevated and routine markers of coagulation within normal ranges in all patients.

Patients admitted to ICU with COVID-19 associated respiratory failure exhibit a hyper-coagulable state which is not appreciable on conventional tests of coagulation. Supra-normal clot firmness, minimal fibrinolysis and hyperfibrinogenaemia are key findings. Further research is required into the pathophysiology of this hypercoagulable state, as well as the harms and benefits of different anticoagulation strategies.

Our understanding of the mechanisms by which the novel SARS-coronavirus-2, the virus causing COVID-19, causes organ failure and death continue to evolve. Several lines of investigation implicate a pro-coagulant tendency associated with COVID-19 which leads to micro and macro vascular thrombosis. Clinical reports of disproportionate rates of venous and arterial thromboembolism 1 are corroborated by histological evidence of thrombotic microangiopathy in post-mortem studies of patients dying from COVID-19 2 . Intravascular thromboses can lead to local ischemia, microhemorrhage and inflammation which, in the lung, is consistent with the observations that a subset of patients exhibit profound hypoxia with relatively preserved lung compliance 3 .

Furthermore, thrombotic microangiopathy could underlie the acute kidney injury which affects up to 25.2% of patients admitted to intensive care units with COVID-19 4 .

Rotational thromboelastometry (ROTEM) and thromboelastography (TEG) are viscoelastic point of care tests which provide functional analysis of clot development and fibrinolytic function. In addition to their role in bleeding 5 , they are able to identify a variety of patient populations at increased risk of thromboembolic events 6 . We undertook an observational cohort study to evaluate the coagulation state, as defined by viscoelastic testing, in patients admitted to the intensive care unit requiring respiratory support for COVID-19 associated lung disease. Our objective was to identify whether these patients exhibited a pro-coagulant state.

We undertook a single-centre observational point prevalence cohort study in the xx bed Intensive Care Unit of the xxxxxxxxxxx, a metropolitan tertiary centre and xxxxxxx hospital for xxxxxxxx in April 2020. Local ethics approval was granted and waiver of consent obtained. (xxxxxxxxx Human Research Ethics Committee, Reg 13102). All patients >18yrs old admitted to the intensive care unit with COVID-19 associated respiratory failure were identified using our electronic medical record (xxxxx, xxxxx, USA) from which demographic and clinical data were derived. Diagnosis of SARS-CoV-2 was performed with RT-PCR from throat or nasal swab. SOFA score was calculated as previously 

Six patients met the study inclusion criteria during the study period. Demographic and clinical information are summarized in Table 1 . Renal dialysis was provided through prolonged intermittent renal replacement therapy, with sessions complete for > 6 hours prior to blood sampling. 3 patients were treated with prone positioning for respiratory failure, no patients received pulmonary vasodilator therapy or extra-corporeal membrane oxygenation. All patients were receiving thromboprophylaxis with 40mg enoxaparin administered subcutaneously daily. Each patient had one ROTEM performed. ROTEM and laboratory results are presented in Table 2 . A representative ROTEM from our cohort is presented in Figure 1 .

The most salient findings are the supra-normal clot amplitude at 10 minutes and supra-normal clot firmness in all analyses. In addition, the INTEM clot formation time was significantly reduced. Clot lysis was minimal (median <2%) in all analyses. In contrast traditional coagulation parameters (PT, Endogenous anticoagulant proteins (Antithrombin III, Protein C and Protein S) were within normal range.

No patient had known arterial or venous thrombosis at the time of the study. Two patients later developed venous thromboembolism, one with pulmonary embolism, who underwent no DVT screening, and one with catheter-associated jugular vein thrombus. Both survived. A third patient died in the intensive care unit, with venous thromboembolism not clinically suspected. The other three patients were discharged from our hospital alive without identified thromboembolic disease, including one with a negative dedicated computed tomography pulmonary arteriography scan prior to hospital discharge.

Our data indicate that patients admitted to the intensive care units with COVID-19 exhibit a prothrombotic tendency as evaluated by viscoelastic testing of clot formation. These data are consistent with both the clinical observation that thromboembolic disease is over-represented in patients with COVID-19 and histological evidence of thrombotic microangiopathy in non-survivors of COVID-19. In patients with COVID-19 there is early limited evidence of a pro-coagulant pattern on ROTEM 9, 10 and TEG 11, 12 that appears to be persistent beyond admission. This pro-coagulant pattern is not commonly found in other groups of critically ill patients [13] [14] [15] .

Our cohort had been admitted to the intensive care unit for a median of 14 days at time of testing. This is the first study to evaluate for a prothrombotic state this late in intensive care admission and our findings suggest that thromboembolic complications should be considered as a cause of clinical deterioration throughout the ICU admission and potentially beyond.

Syndrome-1 and Middle Eastern Respiratory Syndrome coronavirus infections 16 although mechanisms remain unclear. Viral endotheliitis has been postulated but the ROTEM evaluation indicates that the pro-coagulant state is not dependent on an activated endothelial surface. COVID-19 has been associated with a hyper-inflammatory state 17 , which may directly contribute to hypercoagulability.

Depression of fibrinolysis, identified by failure of clot lysis at 30 minutes on thromboelastography, has been described in selected patients with severe COVID-19 infection in a single centre study, with strong correlation to thromboembolic events and renal injury 18 . Our study identified similar results in unselected ICU patients, demonstrating that a persistent reduction in fibrinolysis and elevation in D-dimer was present throughout a small general COVID-19 ICU cohort, adding weight to this mechanism contributing to the increased thrombotic state of COVID-19.

Traditional clotting parameters were normal, consistent with findings from other studies 10 . We did not measure factor 8 levels but it has been previously shown that these are elevated in COVID-19 infected ICU patients 12 . Importantly, endogenous anti-thrombotic proteins such as antithrombin III, Proteins C and S were not significantly altered. To our knowledge, this is the first paper where these endogenous proteins have been measured in COVID-19 and suggests that deficiencies in these counter-regulatory proteins do not underlie the clotting tendency identified in these patients.

Positive lupus anticoagulant (LAC) has previously been described 19, 20 in a high proportion of patients.

In contrast, antiphospholipid antibodies were absent in the five patients assayed in our cohort. It is unclear whether this is due to the small numbers in our study, differences in assays, or differences in timing of test performance. Of note, our tests were performed relatively late in the hospital presentation, and LAC can be transiently positive in acute viral infection 21 .

Our study has several limitations. Ours is a small, single centre study and findings can only be considered hypothesis generating, requiring validation in a larger multicentre cohort. The absence of a control group limits interpretation of our results; potential confounders include prolonged critical illness, immobility and comorbidity. Our rate of thromboembolic disease was 33%, lower than reported in some other studies 1, 19 . Routine imaging surveillance for deep vein thrombosis was not undertaken, in keeping with our standard practice prior to the COVID-19 pandemic and also in light of the potential risks of HCW exposure to patients with COVID-19, potentially explaining why the detected incidence appears low. 

Patients admitted to ICU with COVID-19 associated respiratory failure have a high prevalence of a hypercoaguable state which is not appreciable on conventional tests of coagulation. This is not explained by alterations in endogenous anticoagulant proteins or lupus anticoagulant. Supra-normal clot firmness, minimal fibrinolysis and hyperfibrinogenaemia are key findings, and further research is required into the drivers of these markers, as well as the influence of anticoagulant therapies on the prothrombotic state and patient outcomes. 

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