Thrombomodulin-modified Thrombin Generation Assay (TGA-TM) in Patients With Critical Infections

Study Overview
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Brief Summary
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Inflammation and abnormalities in laboratory coagulation tests are inseparably tied. For example, coagulation abnormalities are nearly universal in septic patients. Coagulation disorders have also been reported in many patients with severe courses of Coronavirus disease 2019 (Covid-19). But it is difficult to assess these changes. Global coagulation tests have been shown to incorrectly assess in vivo coagulation in patients admitted to intensive care units. But other tests are available. Thrombin generation assay (TGA) is a laboratory test which allows the assessment of an individual's potential to generate thrombin. But also in conventional TGA the protein C system is hardly activated because of the absence of endothelial cells (containing natural thrombomodulin) in the plasma sample. Therefore the investigators add recombinant human thrombomodulin to a conventional TGA. Thereby the investigators hope to be able to depict in vivo coagulation more closely than global coagulation tests do.

Official Title
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Coagulation Assays in the Critically Ill Patient: a New Approach Using the Thrombomodulin-modified Thrombin Generation Assay (TGA-TM)

Conditions
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Disseminated Intravascular Coagulation, Critical Illness, Sars-CoV2, Viral Infection, Coagulation Disorder, Blood, Covid19

Intervention / Treatment
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* Diagnostic Test: Thrombin Generation Assay (TGA)
* Diagnostic Test: Thrombomodulin Modified Thrombin Generation Assay (TGA-TM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admission to ICU Clinical signs of infection with SARS-CoV-2 or already diagnosed infection with SARS-CoV-2 Neutrophil-Lymphocyte Ratio (NLR) >3 Exclusion Criteria: Intake of oral anticoagulants or any kind of parenteral therapeutic anticoagulation prior to ICU admission Congenital coagulation disorder Treatment with Prothrombin complex concentrate (F. II, VII, IX, X) or activated Prothrombin complex within past 48 hours Treatment with recombinant factor VIIa (e.g. eptacog alfa) within past 48 hours Treatment with recombinant protein C within past 48 hours Active bleeding Acute myocardial infarction HIV infection Chronic pancreatitis Liver cirrhosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Critical infection<br>Patients with signs of infection with SARS-CoV-2 or already diagnosed infection with SARS-CoV-2 admitted to the ICU | Diagnostic Test: Thrombin Generation Assay (TGA)<br>* TGA via a fluorimetric module. Coagulation cascade is activated upon addition of different concentrations of tissue factor and phospholipids. The fluorogenic substrate Z-Gly-Gly-Arg-AMC (ZGGR-AMC) is cleaved by formed thrombin over time. By plotting the changes in fluorescence as a function of time (cnt/min), it depicts the Thrombin Generation Curve (thrombin generated - plotted against time). The area under the thrombin curve is defined as the endogenous thrombin potential (ETP).<br>Diagnostic Test: Thrombomodulin Modified Thrombin Generation Assay (TGA-TM)<br>* Recombinant Human Thrombomodulin (TM) is added to the conventional TGA. When recombinant TM is added, the protein C system is fully activated and therefore the ETP obtained reflects both the anti- and procoagulant factors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ETP (AUC) without rhThrombomodulin (rhTM) | nM; | 6 months | 
| ETP (AUC) with rhThrombomodulin (rhTM) | nM; | 6 months | 
| ETP-ratio | Ratio of endogenous thrombin potential (ETP) with rhTM to ETP without rhTM | 6 months | 
| ETP-Normalisation | Comparison of ETP-ratios from ICU patients and ETP-ratios from citrated plasma samples from healthy donors | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TGA, thrombin generation, Sars-CoV2, ROTEM, rotational thromboelastometry, viscoelastic assay, thrombomodulin