key: cord-0803709-64r0usny authors: Dujardin, Romein W.G.; Hilderink, Bashar N.; Haksteen, Wolmet E.; Middeldorp, S.; Vlaar, Alexander P.J.; Thachil, J.; Müller, Marcella C.A.; Juffermans, Nicole P. title: Biomarkers for the prediction of venous thromboembolism in critically ill COVID-19 patients date: 2020-09-15 journal: Thromb Res DOI: 10.1016/j.thromres.2020.09.017 sha: 44fa7af99e5d52f582c2d57dd7e89426390c8bc8 doc_id: 803709 cord_uid: 64r0usny BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in critically ill patients with coronavirus disease 2019 (COVID-19) and is associated with mortality. Early diagnosis and treatment of VTE is warranted. OBJECTIVE: To develop a prediction model for VTE in critically ill COVID-19 patients. PATIENTS AND METHODS: In this retrospective cohort study, 127 adult patients with confirmed COVID-19 infection admitted to the intensive care unit of two teaching hospitals were included. VTE was diagnosed with either ultrasound or computed tomography scan. Univariate receiver operating characteristic (ROC) curves were constructed for Positive End Expiratory Pressure, PaO(2)/FiO(2) ratio, platelet count, international normalized ratio, activated partial thromboplastin time as well as levels of fibrinogen, antithrombin, D-dimer and C-reactive protein (CRP). Multivariate analysis was done using binary linear regression. RESULTS: Variables associated with VTE in both univariate and multivariate analysis were D-dimer and CRP with an area under the curve (AUC) of 0.64, P = 0.023 and 0.75, P = 0.045, respectively. Variables indicating hypoxemia were not predictive. The ROC curve of D-dimer and CRP combined had an AUC of 0.83, P < 0.05. Categorized values of D-dimer and CRP were used to compute a mean absolute risk for the combination of these variables with a high positive predictive value. The predicted probability of VTE with a D-dimer > 15 in combination with a CRP > 280 was 98%. The negative predictive value of D-dimer was low. CONCLUSION: Elevated CRP and D-dimer have a high positive predictive value for VTE in critically ill COVID-19 patients. We developed a prediction table with these biomarkers that can aid clinicians in the timing of imaging in patients with suspected VTE. . Furthermore, the development of thrombosis is associated with increased mortality (2) , whereas the use of heparin is associated with a decrease in mortality in observational studies in critically ill COVID-19 patients (3) . This indicates that early diagnosis and treatment of thrombotic complications is of paramount importance. The diagnosis of VTE can be challenging in critically ill patients with COVID-19. DVT can be difficult to recognise in sedated and often obese patients. Moreover, PE is also challenging to diagnose as worsening hypoxemia can be attributed to concomitant pneumonia or acute respiratory distress syndrome (ARDS), leading to underdiagnoses. Also, optimal timing of imaging is a challenge, as it was shown that when computed tomography (CT) scanning for a suspected PE is performed in COVID-19 patients, 75% of the scans are negative(4). Transportation of a patient to perform a CT scan while on mechanical ventilation with high pressures is a logistic challenge with risks for the patient as well as risks of contamination. Thereby, the use of a prediction model with the ability to differentiate between patients with high and low risk for VTE is likely to improve diagnostic efficiency and early commencement of anticoagulant therapy. The use of biomarkers in the prognosis of COVID-19 has already been described. A markedly elevated D-dimer was shown to be a predictor of mortality(5, 6). Other deranged coagulation tests in patients with COVID-19 are slightly decreased platelet counts and prolongation of the prothrombin time (PT) (7) . Monitoring of these biomarkers in patients with COVID-19 is recommended by the International Society of Thrombosis and Haemostasis, as an increase may justify more aggressive critical care support (8) . In addition, although pathophysiology of COVID-19 induced coagulopathy remains unclear, it is suggested that thrombosis is inflammatory driven (7, 9) . Thereby, acute phase reactant proteins could also be a useful tool in the diagnosis of VTE. Daily blood examinations consisted of complete blood count, platelets, international normalized ratio (INR), activated Partial Thromboplastin Time (aPTT), serum biochemical tests for liver and kidney function, electrolytes and C-reactive protein (CRP). Journal Pre-proof D-dimer, fibrinogen and antithrombin were measured twice a week. Oxygenation parameters included the level of PEEP, which is the positive pressure at the end of expiration given to prevent the alveoli form collapsing, and PaO 2 /FiO 2 ratio, which is a clinical indicator of hypoxaemia. The laboratory and ventilation values measured most recently prior to imaging (ultrasound or CT-scan) that confirmed VTE were used for the prediction model. Based on normality, data is either presented as mean with standard deviation or median with interquartile ranges and differences between groups was analysed with either the student t- Journal Pre-proof One-hundred and twenty-seven patients were enrolled in the study. patients who had no proven VTE (no-VTE). Error bars show the upper limit of the IQR for the group with the highest median and lower limit of the IQR for the group with the lowest median. In the univariate analysis, D-dimer and CRP showed statistically significant AUCs Therefore, D-dimer is generally used to detect an active thrombus with a high sensitivity but low specificity(11). In clinical practice, a D-dimer of less than 0.5 µg/ml is used to rule out VTE (12, 13) . A recently published study on D-dimer in Asian COVID-19 patients reported a negative predicting value (NPV) for VTE of 92.5% using a D-dimer cut off value of 3.0 µg/ml (14) . In contrast, the ability of a D-dimer level of < 3.0 µg/ml to rule out VTE in this study was only 67%. An explanation may be the larger sample size in this study. Alternatively, the different patient population characteristics can be an explanation. There are genetic differences between Asians and Caucasians with regard to the coagulation system (15) , which may have led to different predictive values of D-dimer. However, a high Ddimer level has a high positive predictive value for VTE. Thereby, in contrast to non-COVID-19 patients, D-dimer levels in COVID-19 appear not useful to rule out VTE, but could be useful in timing of imaging in COVID-19 patients suspected of VTE. High CRP levels had the best performance to predict VTE. It has already been suggested that rises in CRP reflect physiologic complications of COVID-19(16). Furthermore, this underlines the current hypothesis that inflammation is the driving force behind the development of thrombosis in COVID-19 patients (7, 9) . The implication of our finding is that an increase in CRP should not only raise suspicion of ongoing viremia or a nosocomial infection, but also of the occurrence of VTE. Of note, we did not find fibrinogen levels to be predictive for VTE in COVID-19 patients. This is remarkable, as fibrinogen is also an acute phase reactant and high levels of fibrinogen have been reported to be a prominent feature of COVID-19 induced coagulopathy (17 (7), which may not be visible on CT imaging. This could also be an explanation for loss of significance. Alternatively, the sub analysis was done in a small sample size, which could also have accounted for loss of significance. A limitation of this study is the fact that CT imaging was performed upon clinical suspicion and not as standard of care, possibly causing underdiagnosis of PE. Another limitation is the retrospective design and that, as a result, some parameters used in our model were collected three days prior to imaging. This may have caused a decrease in sensitivity. Also, data collection commenced at ICU admission and not from onset of symptoms. In conclusion, we constructed a prediction model based on D-dimer and CRP, which are widely available biomarkers that can help to differentiate between patients with a high and a low risk for VTE. It can be used to increase awareness of the possibility of VTE as well as optimize timing of imaging for critically ill patients with COVID-19 suspected for VTE. All authors contributed substantially to the study design and interpretation of the data. W. Haksteen and B. Hilderink collected data from electronic patient records. B. Hilderink and R. Dujardin analysed data, univariate ROC and multivariate models were computed by B. Hilderink. The first version of the manuscript was written by R. Dujardin, B. Hilderink and N. Juffermans. All authors revised the manuscript critically and approved the final version. 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