Clonal Hematopoiesis and NETs Formation in Venous Thrombosis (CLODETTE)

Sponsor

University Hospital, Bordeaux (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05711173

Collaborator

(none)

Enrollment

Locations

Anticipated Duration (Months)

6.3

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Thrombo-embolic venous diseases are represented by deep venous thrombosis and/or pulmonary embolism. In some patients with repeated thrombosis or occurrence of thrombosis in unusual sites, the etiological workup remains negative, which represents a problem for the management of the anticoagulant treatments. Recently, two factors have been identified as important in the physiopathology of hemostasis and coagulation: the presence of clonal hematopoiesis of indetermined potential (CHIP) and the formation of neutrophil extracellular traps (NETs). In this study, these two factors will be studied in patients with repeated venous thrombosis or thrombosis occurring in unusual site.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboses Thromboembolic Disease Neutrophil Extracellular Trap Formation Clonal Hematopoiesis of Indeterminate Potential	Biological: Additional blood sampling	N/A

Detailed Description

It has recently been shown that some patients clonal have mutations at a low level in hematopoietic cells (this phenomenon is named clonal hematopoiesis of indetermined potential (CHIP)) and that the presence of a clonal hematopoiesis is associated with an increased cardiovascular risk. However, few data exist about the implication of CHIP in venous thrombosis. Neutrophils extracellular traps are involved in the activation of hemostasis and coagulation. Murine models have highlighted the crucial role of NETs in the physiopathology of venous thrombosis. In patients, studies have demonstrated that NETs markers were present in arteries lesions as coronary plaques. However, few studies have analyzed the NETosis in the setting of venous thrombosis.

The study hypothesis is that patients with venous thrombosis may have an increased prevalence of CHIP and/or an increased NETosis formation, which may represent a predisposition for the occurrence of venous thrombosis. We also speculate that patients with CHIP may have an increased NETosis, due to the presence of activating clonal mutations in neutrophils.

Patients included will be : younger than 50-years-old with repeated thrombosis or thrombosis of unusual sites (cerebral venous thrombosis, splanchnic thrombosis) with a negative etiological workup and notably the absence of constitutional or acquired venous thrombosis risk factors. In this population, we will analyze the prevalence of CHIP and the NETosis via the study of 4 different NETosis plasmatic markers.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Role of Clonal Hematopoiesis and NETs Formation in Unusual Venous Thrombosis (CLODETTE)

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Feb 1, 2024

Outcome Measures

Primary Outcome Measures

Presence of clonal hematopoiesis [At baseline]
The existence of clonal hematopoiesis will be defined as the demonstration of at least one mutation in the blood cells of an apparently healthy subject (without obvious hematological pathology). DNA will be extracted from circulating leukocytes to search for mutations in a panel of 59 genes

Secondary Outcome Measures

Presence of one or more increased NETosis markers and/or a decreased NETosis-inhibiting marker (DNAse level) compared to a control population. [At baseline]
Analysis of the following markers: MPO-DNA complex, Histone 3-DNA complex, citrullinated histone 3, DNAse
Correlation (correlation coefficient values) between the presence of a CHIP and the formation of NETs [During final analysis]
Correlation analysis will be performed between each NETosis marker and CHIP evaluation (presence or absence, number of mutations, variant allele frequency for each mutation)
Allele frequency [At baseline]
Variant allele frequency of each detected mutation will be determined using NGS analysis
Number of clonal mutations [At baseline]
The number of clonal mutations for each patient will be determined using NGS analysis
C-reactive protein (CRP) level as a marker of inflammation [At baseline]
C-reactive protein concentration will be determined for each patient, as a marker of inflammation
Site(s) of thrombosis [At baseline]
Site(s) of thrombosis will be determined during examination of the patient
Number of thrombosis [At baseline]
The number of thrombosis will be determined during examination of the patient

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients (male or female) less than 50 y.o with :
Splanchnic venous territory thrombosis or
Cerebral venous thrombosis or
Venous thrombosis of the upper limb or
Pulmonary embolism (1st episode if male, 2nd episode if female) unprovoked or
1 episode of deep vein thrombosis + 1 episode of arterial thrombosis

Exclusion Criteria:

Presence of a major or minor transient venous thrombosis risk factor:
Surgery within the last 3 months preceding the qualifying thrombotic episode
Lower limb fracture with immobilization > 3 days in the last 3 months preceding the qualifying thrombotic episode
Presence of estro-progestational contraception
Pregnancy
Immobilization for acute medical reasons within the last 3 months preceding the qualifying thrombotic episode
Air or car travel > 6 hours
Presence of a major or minor persistent risk factor for venous thrombosis:
Presence of active cancer (solid cancer or hematologic malignancy)
Chronic inflammatory digestive or joint diseases
Ongoing treatment with heparin (low molecular weight heparin (LMWH) or unfractionated heparin (UFH))
Presence of an abnormality on the thrombophilia test among the following abnormalities
Protein C deficiency
Protein S deficiency
Anti-thrombin deficiency
Heterozygous or homozygous factor II mutation
Heterozygous or homozygous factor V mutation
Presence of anti-phospholipid syndrome
Presence of myeloproliferative neoplasia
Presence of paroxysmal nocturnal hemoglobinuria

Contacts and Locations

Locations

	Site	City	Country
1	CHU de Bordeaux, Service de Neurologie	Bordeaux	France
2	CHU de Bordeaux, Service Gastro-Entérologie	Bordeaux	France
3	CHU de Bordeaux, Service Hématologie Biologique	Bordeaux	France
4	CHU de Bordeaux, Service Médecine Interne et Immunologie Clinique	Bordeaux	France
5	CHU de Bordeaux, Service Médecine Interne et Maladies Infectieuses	Bordeaux	France
6	CHU de Bordeaux, Service Médecine Interne	Bordeaux	France
7	CHU de Bordeaux, Service Médecine Vasculaire	Bordeaux	France
8	CHU de Bordeaux, Unité ambulatoire de Médecine Vasculaire	Bordeaux	France