Clinical trial NCT05233384: Genomics of Fibrin Clot Structure in Patients With Constitutional Dysfibrinogenemia
Official title: Genomics of Fibrin Clot Structure in Patients With Constitutional Dysfibrinogenemia
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Hereditary Dysfibrinogenemia
Keywords: Hereditary Dysfibrinogenemia
Fibrin clot
Polymorphism
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2022-02-10
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: Patient with confirmed hereditary dysfibrinogenemia

Brief summary: Hereditary dysfibrinogenemia results from monoallelic mutation in one of the fibrinogen genes (FGA, FGB, FGG). The spectrum of molecular abnormalities is broad, leading to several subtypes of coagulation disorders with specific biological and clinical features. The correlation between the genotype and the phenotype is poor, and the clinical course of patients, from major bleeding to recurrent thromboses, is unpredictable. Fibrin clot structure is a determinant of the risk of thrombosis in cardiovascular diseases. In all individuals, fibrin networks define the propensity of clot to be more resistant to removal or, on the contrary, susceptible to fragmentation leading to bleeding complications. Besides fibrinogen variants, other relatively common genetic polymorphisms in coagulation and fibrinolytic pathways may affect the fibrin clot structure and therefore act as modifiers of the blood clot function.

In this proposal, the investigators will analyze properties (polymerization, fibrinolysis, viscoelastic properties, permeation) and ultrastructure (size, number, packaging, architecture of fibrin fiber by confocal microscopy and scanning electron microscopy) of plasma-based clots in relation to the presence of genetic modifiers (polymorphisms). Polymorphisms will be detected using a whole exome sequencing (WES) in a selected panel of genes of the coagulation and fibrinolytic pathways. The gene panel of 28 genes will include the three fibrinogen genes plus 25 potential modifier genes including F5, F2, PAI-1, PROCR and MTHFR. The overall clot phenotype will be correlated to the presence of prothrombotic polymorphisms and to the patient's clinical phenotype. The investigators plan to include about 100 patients with dysfibrinogenemia. The combination of integrative hemostasis models with genetic dataset will provide a global view of the patient's individual hemostatic profile. This may allow to better predict the clinical outcome and help provide a more personalized therapeutic strategy and precision medicine. In addition, the development of models allowing a reliable global assessment of fibrin clot architecture will be the basis for further research in other acquired diseases involving thrombotic or bleeding events.


Eligibility criteria: Inclusion Criteria:

* Patient with confirmed hereditary dysfibrinogenemia
* Able to give his/her informed consent to participate
* Affiliated to the French Health insurance

Exclusion Criteria:

* Refusal to participate
* pregnant and breastfeeding women,
* protected adults (individuals under guardianship by court order),
* adults deprived of their liberty

Primary outcomes:
measure: relation between the genetic polymorphisms and the main parameters of each different tools evaluating the ultrastructure of fibrin clot
timeFrame: at the end of the inclusion period
Secondary outcomes:
measure: relation between the genetic polymorphisms and the clinical phenotype of patients with dysfibrinogenemia (thrombotic and/or bleeding phenotype)
timeFrame: at the end of the inclusion period
measure: relation between the main parameters of ultrastructure of fibrin clot properties and the clinical phenotype of patients with dysfibrinogenemia
timeFrame: at the end of the inclusion period
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU clermont-ferrand
city: Dijon
country: France
facility: CHU Dijon
city: Lille
country: France
facility: CHU de Lille
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHu Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Aurélien LEBRETON
role: PRINCIPAL_INVESTIGATOR
References: