Substudy of CADRE: for People With Extreme Phenotype: BIOCADRE

Study Overview
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Brief Summary
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BIOCADRE is a CADRE substudy and aims to characterize more precisely the sickle cell patients with extreme phenotype.

Detailed Description
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Sickle cell disease (SCD) is the most frequent monogenic disease in the world, due to a unique mutation on the β-globin gene. Most affected individuals live in sub-Saharan Africa, yet, the natural history of the disease in Africa remains largely unknown. SCD usually presents in childhood and is characterized by the association of a chronic hemolytic anemia with episodes of acute vaso-occlusive events and progressive vascular organ damage. SCD is now widely recognized as a vascular disease with marked endothelial dysfunction. Hemolysis probably plays a key role by reducing NO bioavailability, but other involved mechanisms are not fully understood. The project aims at better understanding SCD chronic vascular complications and in particular to explore extensively the different mechanisms associated with hemolysis. This will be addressed through both an epidemiological approach and a hypotheses-driven pathophysiological approach. On the one hand, a descriptive and analytic epidemiological study will isolate clusters of clinical, functional and usual biological phenotypes in SCD patients and look for new mechanistic and biological markers predictive of chronic vascular complications in SCD with SS phenotype. Investigators will specifically investigate i) microcirculation functions using peripheral arterial tonometry, ii) blood and plasma viscosities, iii) level of plasma blood cell derived microparticles, free hemoglobin, and the free heme content of erythrocytes-derived microparticles and expression of Duffy erythrocyte antigen, the unique erythroid receptor for chemokines. One the other hand, investigators will test novel markers and modifiers of hemolysis and heme metabolism and assess their relationship with inflammation and vascular phenotypes.These different biomarkers will be compared between the selected subgroups of patients with extreme vascular phenotype. Methods: The project involves a transversal case control study, nested in the CADRE cohort, recently built up by Partner 1 and African collaborators. CADRE is the largest ongoing epidemiological cohort, including 4,300 SCD patients and 1,000 controls in five west and central African countries, in which various chronic complications of SCD have already been registered. The present second phase study will be conducted in the centres of Dakar and Bamako. Patients' selection will be performed in the existing database to obtain 6 subgroups of 40 SS patients with one of the main vascular chronic complications or none of them, for a total of 240 patients. Selected patients will be recalled during one year in parallel in the 2 recruiting centres. Clinical phenotyping, usual biology, functional microvascular functions (peripheral arterial tonometry), and blood/plasma viscosities analyses will be performed in the African recruiting centres after training of technicians, PhD and MD students by the French partners. Plasma samples, microparticles and extracellular DNA, will be prepared and frozen for further analyses in the partner's laboratories. DNA will be collected for each subject. A principal component analysis will isolate clusters of clinical complications, functional and biological markers and a multivariate logistic regression will quantify the effect of these markers on the risk of vasculopathy, with adjustment on all known SCD modifying factors. Expected results: 1) The identification of high risk SCD patients for chronic vascular complications using new biomarkers, 2) A better understanding of chronic vascular disease process at the mechanistic and biological (viscosity, hemolysis, erythrocyte derived microparticles, inflammatory cytokines and receptors) levels, 3) The identification of endophenotypes and constitution of DNA bank for further genetic studies.

Official Title
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A Substudy of the CADRE Study: Determination of Clinical Markers in Patients With Extreme Sickle Cell Disease Phenotype

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Biological: biological analysis
* Other: peripheral arterial tonometry


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: sickle cell patients with extreme phenotypes: SS-hemoglobin Exclusion Criteria: transfusion in the previous 2 months vaso-occlusive crisis in the previous 15 days infection in the previous 8 days

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| osteonecrosis<br>Sickle cell patients with osteonecrosis as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|
| leg ulcer<br>Sickle cell patients with leg ulcer as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|
| microalbuminuria<br>Sickle cell patients with microalbuminuria as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|
| pulmonary hypertension<br>Sickle cell patients with pulmonary hypertension as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|
| stroke<br>Sickle cell patients with strocke as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|
| priapism<br>Sickle cell patients with priapism as a vascular main complication | Biological: biological analysis<br>* biological analysis will be performed in the 6 groups of patients<br>Other: peripheral arterial tonometry<br>* peripheral arterial tonometry will be performed in the 6 groups of patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Description of microcirculation by peripheral arterial tonometry | EndoPAT2000®, Itamar Medical Ltd, | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of blood viscosities | In whole blood by viscosimeter | 1 year | 
| Dosage of microparticles | In plasma: microparticles of erythrocytic, platelet, monocytic, neutrophilic and endothelial origin by flow cytometry | 1 year | 
| Determination of free hemoglobin | In plasma | 1 year | 
| Measurement of neutrophil extracellular trap (NET) | In plasma | 1 year | 
| Measurement of proinflammatory cytokines by ELISA | In plasma by ELISA | 1 year | 
| Genotyping of the alpha-globin gene associated with persistence of fetal hemoglobin | In saliva DNA | 1 year | 
| Genotyping of the polymorphisms associated with persistence of fetal hemoglobin | In saliva DNA | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell disease, anemia, Africa