Analysis of the Coagulopathy Developed by COVID-19 Infected Patients

Completed

• Conditions: Blood Coagulation Disorders; Thrombin; Disseminated Intravascular Coagulation; COVID-19; Sepsis

• Registration Number: NCT04356950
• Lead Sponsor: Centre Hospitalier Universitaire de Nīmes

Brief Summary

Increased D-dimers at admission of COVID-19 infected patients entering hospital due to a severe disease is a risk factor for death. Understanding this acquired coagulopathy is a prerequisite before specific interventional studies. The study investigators aim to apply a normalized and automated thrombin generation test (TGT), developed for testing the thrombotic risk (triggered by 5 pM Tissue Factor, with a purified thrombomodulin (TM) challenge) and to study its association with survival.

Detailed Description

Accumulating data describe, in COVID-19 severely infected patients necessitating hospitalized medical support, the development of an acquired coagulopathy, from a sepsis-induced coagulopathy to an overt-DIC, which is a strong risk factor for death. Understanding this coagulopathy is a prerequisite before specific interventional studies. Conventional coagulation tests, like prothrombin time PT and aPTT, only reflect 5% of the total thrombin generation and are insensitive to the patients' natural anticoagulants. The investigators thus wish to analyze the coagulopathy of SARS-CoV-2 using a global analytical test reflecting the full complexity of thrombin generation then inhibition, the thrombin generation test (TGT), in its version designed to analyze the thrombotic risk (initiation by an intermediate concentration of human Tissue: 5 pM), in its fully automated and standardized technical version. This test analyzes not only the generation of thrombin and its various informative phases (initiation phase, propagation phase culminating at the peak of formation, inhibition phase with natural anticoagulants) but also the capacity for an exogenous addition of purified thrombomodulin (TM), which quantifies the anticoagulant activity of the patient's protein C activated by thrombin, to inhibit this generation of thrombin.

The aim is to assay this TGT version in a centralized way, on the patients' plasma obtained at hospital admission, just after checking the positive COVID-19 testing , together with the traditional blood tests including platelet counts, PT, D-dimers (DDi) and soluble fibrin monomers (FMs). The various quantitative biological parameters describing the results of the TGT assay, together with relevant covariates, will be tested using multivariate analysis for their capacity to be risk factors for clinically-relevant qualitative outcomes.

Study Timeline

• Study First Submitted: 2020-04-16
• Study First Submitted QC: 2020-04-20
• Study First Posted: 2020-04-22
• Study Start: 2020-04-28
• Primary Completion: 2022-02-14
• Study Completion: 2022-06-02
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-30
• Last Update Posted: 2022-10-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 175

Inclusion Criteria

• Patient with SARS-CoV-2 infection entering hospitalization with or without resuscitation
• The patient (or their carer) must have given their free and informed consent and signed the consent form
• The patient must be a member or beneficiary of a health insurance plan

Exclusion Criteria

• Pregnant or breastfeeding patient
• It is impossible to give the subject informed information
• The patient is under safeguard of justice or state guardianship
• Thrombotic events during treatment: flare-up of venous thromboembolism, flare-up of atherothrombosis.
• Long-term anticoagulant treatment (anti-vitamin K, direct oral anticoagulant).
• Chronic anti-aggregation treatment.
• Pre-existing constitutive or acquired known coagulation pathology: hemorrhagic diseases (thrombocytopenia, thrombocytopathy, hemophilia, von Willebrand's disease, hemorrhagiparous factor deficiency), and for thrombophilia (deficits in antithrombin, protein C or S , Factor V Leiden or Prothrombin 20201A mutation).

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Absolute thrombin generation test latent period	Day 0	Seconds; without (TM-) and with (TM+) purified thrombomodulin
Absolute thrombin generation test peak thrombin	Day 0	nmol/L; without (TM-) and with (TM+) purified thrombomodulin
Absolute thrombin generation test peak thrombin time	Day 0	Seconds; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test total thrombin generation time compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
28-day survival rate	1 month	Death yes/no during hopstilization, 28 days after admittence
Absolute thrombin generation test initial velocity	Day 0	nmol/s; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test latent period compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test initial velocity compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test peak thrombin compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test peak thrombin time compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
Absolute thrombin generation test total thrombin generation time	Day 0	seconds; without (TM-) and with (TM+) purified thrombomodulin
Relative thrombin generation test endogenous thrombin potential compared to reference plasma	Day 0	%; without (TM-) and with (TM+) purified thrombomodulin
Absolute thrombin generation test endogenous thrombin potential	Day 0	Seconds; without (TM-) and with (TM+) purified thrombomodulin

Secondary Outcome Measures

Name	Time	Method
3-month survival rate	3 months	Death yes/no
Transfer to intensive care unit during hospitalization	3 months	Yes/no
Thrombotic complication during hospitalization	3 months	Yes/no (deep vein thrombosis, pulmonary embolism, atherothrombosis flare, arterial thrombosis)
Plasma concentrations of D-dimers	Day 0	µg / L, assayed by automated enzyme linked fluorescent assay (Vidas® D-dimers Exclusion ™ II)
Plasma concentrations of soluble fibrin monomers	Day 0	mg / L, measured by automated immunoagglutination (STA®-Liatest® FM)

Trial Locations

Locations (4)

CHU de Bordeaux; 🇫🇷 Bordeaux, France

CHU de Limoges; 🇫🇷 Limoges, France

CHU de Montpellier; 🇫🇷 Montpellier, France

CHU de Nimes; 🇫🇷 Nîmes, France