Analysis of the Coagulopathy Developed by COVID-19 Infected Patients (COVID-TGT)

Analysis of the Coagulopathy Developed by COVID-19 Infected Patients: Thrombin Generation Potential in COVID-19 Infected Patients

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Sepsis; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Thrombin
• Intervention / Treatment: Other: Thrombin generation test assay; Other: Fibrin generation markers assays

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 Type: Observational
• Enrollment (Actual): 175

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • CHU de Bordeaux
  • Limoges, France
    • chu de Limoges
  • Montpellier, France
    • CHU de Montpellier
  • Nîmes, France
    • CHU de Nîmes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Consecutive patients hospitalized for SARS-CoV-2 infection with symptomatology / severity requiring hospital treatment.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Investigators: Principal Investigator: Jean-Christophe Gris, CHU Nimes

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2020
• Primary Completion (Actual): February 14, 2022
• Study Completion (Actual): June 2, 2022

Study Registration Dates

• First Submitted: April 16, 2020
• First Submitted That Met QC Criteria: April 20, 2020
• First Posted (Actual): April 22, 2020

Study Record Updates

• Last Update Posted (Actual): October 3, 2022
• Last Update Submitted That Met QC Criteria: September 30, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: survival; coagulation; thrombin generation test
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Hematologic Diseases; Hemorrhagic Disorders; Thrombophilia; COVID-19; Hemostatic Disorders; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemostatics; Coagulants; Thrombin
• Other Study ID Numbers: PHRC-I/2020/JCG-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No