Objective

There have been five focus areas determined which are explored to provide insight into the pathogenesis of COVID-19 associated thrombosis. These five focus areas are antiphospholipid antibodies, fibrinolysis, coagulation and anticoagulants, thrombus composition and identify molecular players and possible biomarkers by using proteomic and genetic analysis. For each of these focus areas, multi-center expert teams are in place to investigate the underlying mechanisms. We will be using residual plasma samples and tissue specimens collected in several biobanks to achieve these aims.

To fully understand the coagulopathy seen in COVID-19 patients and test potential interventions in vitro models, studying both the virus and the host response, are essential. This work package will focus on these in-vitro models studying SARS-CoV-2 kinetics and dynamics and their effect on endothelial cells and co-culture models. In this way, we can differentiate between the direct effects of SARS-CoV-2 infection on endothelial cell function and other known causes of “endothelitis” that might contribute to the pathogenesis of COVID-19 associated thrombosis. There have been four specifics aims identified to study the effects of SARS-CoV-2 infection on pulmonary microvascular bed specific endothelial cell function and its role in COVID-19 coagulopathy. First, the role of respiratory epithelial cells and activated monocytes in inducing a procoagulant state in pulmonary microvascular endothelial cells will be studied. Furthermore, the possible effect of non-neutralising antibodies on the rate of infection of respiratory endothelial cells, epithelial cells and monocytes will be determined. Finally, the collected data will be linked to the pathology observations in autopsies.

This work package, combined with work package 4 and 5, comprise the clinical cohort studies. In work package 3, clinical data of the participating Dutch Hospitals will be combined with data from established registries as well as data from the targeted data collection by participating centers. One of the key questions addresses the efficacy of different regimes of thromboprophylaxis, taking into account variation in time and variation between hospitals. Main outcomes are major bleeding, venous thromboembolism and death. Furthermore, the consortium will coordinate and facilitate the participation of Dutch hospitals in international RCT’s, in particular the REMAP-CAP study, to establish whether therapeutic-dose anticoagulation is superior compared to standard thromboprophylaxis. Additionally, we will investigate the efficacy and safety of venous thromboembolism treatment. All COVID-19 infected patients that develop venous thromboembolism during the hospital stay will be followed. These patients will be compared with data from known ongoing cohorts of patients with venous thromboembolic events without COVID-19 infection. In this way, we can study the efficacy and safety of anticoagulant treatment. Finally, we will also investigate the influence of anticoagulation on coagulopathy by performing anti-Xa, thrombin generation and ROTEM/TEG measurements. Additionally, the outcome of patients with COVID-19 who were already anticoagulants for other reasons (e. g. prevention of stroke in atrial fibrillation) will be compared to patients infected with COVID-19 who are not using anticoagulants, to determine a possible protective effect against dying from COVID-19 infection

This work package has the aim to predict the risk of VTE in admitted patients with COVID-19. We will collect data on all admitted patients with COVID-19 in the participating centers. This data will be supplemented with routine laboratory parameters, as well as data from imaging and post-mortem studies. A dynamic prediction model will be developed and developed to estimate the individual risk of venous thromboembolism. Afterwards, separate models will be created for patients admitted to the wards vs ICU’s and for different venous thromboembolic phenotypes. Eventually, dynamic prediction models will be developed that enable prediction of risk of venous thromboembolism at specific days during and after admission to the hospital.

In this work package, the impact and long-term consequences of COVID-19 associated thrombosis will be assessed. In the participating hospitals, a clinical care pathway, as recommended by the Dutch guidelines, has been established. This follow-up involves exercise testing, pulmonary function tests, and assessment of patient-reported outcome measures (PROMS). At the follow-up visit, all patients with objective venous thromboembolism will be identified. Based on these numbers, incidence rated and cumulative incidences can be calculated for the post-discharge period. In addition, all COVID-19 patient with venous thromboembolism will be subjected to follow-up procedures in which, depending on the phenotype of the venous thromboembolism, several questionnaires, scores, and tests will be conducted. The Villalta scores will be calculated at three and six months, and a compression ultrasound will be conducted in patients with a deep vein thrombosis. With these data, the rate of thrombus resolution can be established. In patients with pulmonary embolism, an ECG will be conducted, and NT-proBNP levels will be measured when patients have a high pre-test probability of chronic thromboembolic pulmonary hypertension. If abnormal, further diagnostic tests such as echocardiography, ventilation-perfusion scintigraphy and CPET can be conducted. We will be able to calculate the prevalence, severity and impact of the persisting abnormalities. These results will be compared with the results of two cohorts to determine the additional impact of VTE in covid-19 patients.