Characterization of New Candidate Genes in Cases of Human Inherited Thrombocytopenia (CATCH)

NCT04272970 | Completed

• 2 other identifiers: C19-082019-A01351-56
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

Circulating blood platelets are small cellular elements that help to control bleeding (a process called hemostasis) and to avoid hemorrhage when blood vessels are injured. Platelets originate from cells in the bone marrow, the megakaryocytes (MKs), following a complex process of morphological transformation and maturation, which finally leads to the production of blood platelets. Multiple genes are implicated in this process. Constitutive thrombocytopenia (CT) are rare hematological diseases characterized by a decreased number of circulating platelets that are often larger than normal, that may lead to more or less severe hemorrhagic events. However, CT can be difficult to diagnose and differentiate from various forms of acquired thrombocytopenia. The ultimate diagnosis for CT is thus based on the molecular diagnosis, obtained by identifying and characterizing the abnormal gene and protein. About 40 genes / proteins have been identified so far as causal in CT, however, in about half of the patients suspected to have CT, genomic analysis does not detect a variant in one of these genes, and etiology of CT thus remains unknown. But insuring the diagnosis of CT is important: it will avoid misdiagnosis and inefficient or deleterious therapeutic interventions, while allowing a proposal of an adapted curative/preventive medical action. At the Resource and Competence Center for Constitutional Hemorrhagic Diseases (CRCMHC) (University Hospital Robert Debré, Paris, France), the investigating team has evidenced in unrelated patients presenting with familial forms of thrombocytopenia and no known molecular diagnosis, variants of genes not yet described as formally implicated in the occurrence of CT. Molecular genetic evidence must be completed by functional studies. Such functional studies are conducted in a research laboratory from the National Institute for Health and Medical Research (Inserm), "Innovative Therapies in Haemostasis (IThEM)" (Faculty of Medical Sciences, University of Paris, Paris, France), and include:

• an evaluation of how blood progenitor cells mature into MKs, by comparing cells obtained from patients to those of members free of the disease (the latter taken as normal control subjects);
• an evaluation of platelet functionalities, such as ability to form a blood clot similar to what happens during hemostasis, with the aim to detect not only quantitative (number and size) but also any qualitative (functions) defects;
• an evaluation of the ultrastructure (the structure of intracellular components) and biochemistry of MKs and platelets, focusing on the molecular pathways the variant protein is implicated in. This clinical trial is aimed to precisely delineate the mechanism of action of newly identified CT genetic variants, and will fulfill the aims of (1) offering the patient(s) a formal molecular diagnosis of CT, (2) ameliorating patients' medical support, both for diagnosis and therapy, (3) providing patients and family members with a pertinent genetic counseling, and (4) expanding the validated panel of genes implicated in CT to be explored in new suspected cases of CT. It will also help in extending the basic knowledge of the process of MK and platelet formation.

Conditions

Thrombocytopenia; Inherited Platelet Disorder

Keywords

Familial thrombocytopenia; Molecular etiology

Outcome Measures

Primary Outcomes (1)

• Validation of new genes potentially involved in the occurrence of CT by determination of the amount of the protein produced and its effect on the megakaryocytes producing platelets aspect in culture

  Functional study of variants altering these new genes, identified in patients and their family members presenting a CT. This study will include the determination of the amount of the protein produced by the new identified gene variants (qualitative and quantitative) and its effect on the platelet production by megakaryocytes in culture.

  6 months

Secondary Outcomes (2)

• Description of the phenotype of these new CT entities

  6 months

• Search of a potentially platelet dysfunction

  6 months

Study Arms (2)

New gene / protein variant functional study

ACTIVE COMPARATOR

Morphological and functional studies of circulating blood platelets and hematopoietic progenitor cells, in order to prove the pathogenicity of variants of new genes potentially involved in constitutional familial thrombocytopenia.

Diagnostic Test: Validation of a new gene / protein variant implicated in familial CT

Normal gene / protein variant functional study

SHAM COMPARATOR

Morphological and functional studies of circulating blood platelets and hematopoietic progenitor cells, in order to provide control observations / analyses / measures for the "Active Comparator" arm

Diagnostic Test: Validation of a new gene / protein variant implicated in familial CT

Interventions

Validation of a new gene / protein variant implicated in familial CT DIAGNOSTIC_TEST

Realize a blood sample to perform functional studies of circulating blood platelets and hematopoietic progenitor cells, in order to prove the pathogenicity of variants of new genes potentially involved in constitutional thrombocytopenia.

New gene / protein variant functional study; Normal gene / protein variant functional study

Eligibility Criteria

• Age: 11 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• platelet count \< 150.000/µl for at least 6 months
• thrombocytopenia in at least one family member
• weight \> 35 kg
• no pathogenic variant (already reported or suspected) in genes causative for inherited CT
• harboring a variant potentially pathogenic in a gene potentially implicated in the megakaryopoiesis or platelet production, this variant being harbored also by the affected family members, and not by the non-affected family members .

You may not qualify if:

• Pregnant woman
• Subject with an anemia: Hb \< 8g/dl
• Subject with a behavior disorder
• Subject with a hemostasis disease added (Willebrand disease, hemophilia, ...)
• Subject with another suspected cause of thrombopenia (drug, infection, ...)
• Subject taking a drug interfering on the platelet production
• Subject protected by a legal measure
• Subject participating to another program research, leading to larger blood volume than authorized

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead

Study Sites (2)

Resource and Competence Center for Constitutional Hemorrhagic Diseases (CRCMHC), University Hospital Robert Debré

Paris, 75019, France

Location

Resource and Competence Center for Constitutional Hemorrhagic Diseases (CRCMHC), University Hospital Pontchaillou

Rennes, 35000, France

Location

Related Publications (4)

• Vincenot A, Saultier P, Kunishima S, Poggi M, Hurtaud-Roux MF, Roussel A, Actn Study Coinvestigators, Schlegel N, Alessi MC. Novel ACTN1 variants in cases of thrombocytopenia. Hum Mutat. 2019 Dec;40(12):2258-2269. doi: 10.1002/humu.23840. Epub 2019 Nov 6.

  PMID: 31237726 BACKGROUND

• Boutroux H, David B, Gueguen P, Frange P, Vincenot A, Leverger G, Favier R. ACTN1-related Macrothrombocytopenia: A Novel Entity in the Progressing Field of Pediatric Thrombocytopenia. J Pediatr Hematol Oncol. 2017 Nov;39(8):e515-e518. doi: 10.1097/MPH.0000000000000885.

  PMID: 28562514 BACKGROUND

• Guillet B, Bayart S, Pillois X, Nurden P, Caen JP, Nurden AT. A Glanzmann thrombasthenia family associated with a TUBB1-related macrothrombocytopenia. J Thromb Haemost. 2019 Dec;17(12):2211-2215. doi: 10.1111/jth.14622. Epub 2019 Sep 29.

  PMID: 31565851 BACKGROUND

• Balduini CL, Melazzini F, Pecci A. Inherited thrombocytopenias-recent advances in clinical and molecular aspects. Platelets. 2017 Jan;28(1):3-13. doi: 10.3109/09537104.2016.1171835. Epub 2016 May 9.

  PMID: 27161842 BACKGROUND

Related Links

• Website of the Inserm U1140 laboratory "Innovative Therapeutics in Hemostasis"
• Website of the rare diseases health chain "Mhemo" (meaning haemorrhagic diseases), which includes the CRCMHC

MeSH Terms

Conditions

Thrombocytopenia

Condition Hierarchy (Ancestors)

Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Study Officials

• Marie-Françoise Hurtaud-Roux, MD

  Assistance Publique - Hôpitaux de Paris (AP-HP)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Each participant will receive at the time of recruitment a normalized code number that will remain confidential for the investigators, and which will hide his / her full identity
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: Within each family that will be studied for functional studies of platelets and MKs, subjects both harboring a variant gene / protein and presenting with CT will be compared to non CT family members with a normal gene / protein (control subjects) in parallel investigation ; when family control subject(s) will not be available, a subject external to the family with no evidence for CT will be recruited as a control subject

Study Record Dates

• First Submitted: January 21, 2020
• First Posted: February 17, 2020
• Study Start: July 7, 2020
• Primary Completion: March 21, 2024
• Study Completion: March 21, 2024
• Last Updated: July 30, 2024

Record last verified: 2024-07

Locations

FR (2)