View clinical trials related to Inherited Platelet Disorder.
Filter by:This project seeks to perform whole genome sequence (WGS) and whole transcriptome sequence (WTS) analysis on 350 patients with suspected inherited bone marrow failure syndromes and related disorder (IBMFS-RD) in order to increase the genomic diagnostic rate in IBMFS.
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.
Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by a reduced number of blood platelets and a consequent bleeding tendency that ranges from mild to life-threatening. Thrombocytopenia is caused by genetic mutations and therefore is present throughout life and can be transmitted to the progeny. Some patients with severely reduced platelet count present spontaneous bleeding, which represents a major clinical problem: in fact, bleeding diathesis exposes these subjects to the risk of severe hemorrhages, affects their quality of life and often requires hospitalization and/or transfusions. Conversely, other patients with ITs have absent or mild spontaneous bleeding tendency. However, even these patients are at risk of major bleeding on the occasion of surgery or other invasive procedures. Therefore, the potential for hemorrhages on the occasion of invasive procedures represent a clinical problem for all patients affected by ITs. Eltrombopag is a drug, available in tablets, which stimulates the production of platelets by the bone marrow. A previous study demonstrated that a short course of eltrombopag was effective in increasing platelet count in most patients with the MYH9-related disease (MYH9-RD), the most frequent form of IT. Eltrombopag was given for 3 to 6 weeks to 12 patients with MYH9-RD and platelet counts lower than 50 x10e9/L. Eleven patients responded to the drug and 8 of them obtained platelet counts higher than 100 x10e9/L or three times the baseline value. Remission of spontaneous bleeding was achieved by 8 of 10 patients and treatment was well tolerated in all the cases. Based on these findings, short-term eltrombopag courses have been successfully used for preparing for major surgery two patients with MYH9-RD and less than 20 x10e9 platelets/L. The present study has two main objectives. - To verify if eltrombopag is effective in transiently increasing platelet count over 100 x 10e9/L and abolishing bleeding tendency in patients with different forms of IT. To this end, eltrombopag will be given for 3-6 weeks to patients with different forms of IT. Eltrombopag will be administered at the dose of 50 mg/day for 3 weeks. After 3 weeks of treatment, the patients who will obtain a platelet count higher than 100 x10e9/L and complete remission of bleeding tendency will stop therapy. In the other cases, patients will be treated with eltrombopag at a higher dose (75 mg/day) for 3 additional weeks. This treatment schedule is called "Phase 1" of the study. If the study will achieve this goal, short-term eltrombopag could be potentially used in the future to prepare these patients for surgery or other invasive procedures - To verify if eltrombopag can be used to stably reduce spontaneous bleeding tendency for long periods of time in patients with clinically significant spontaneous hemorrhages. To this end, patients with clinically significant spontaneous bleedings at baseline and who had their bleeding tendency reduced during the Phase 1 of the study without severe side effects, will be admitted to the "Phase 2" of the study. During the Phase 2, patients will be treated with eltrombopag for 16 weeks. In order to determine the lowest dose of eltrombopag that is able to reduce or abolish their bleeding tendency, patients will start treatment with eltrombopag 25 mg/day for 4 weeks. Then, every 4 weeks, patients will be re-evaluated and the dosage of eltrombopag will be adjusted according to bleeding tendency and platelet count. The dosages of eltrombopag that can be used in the Phase 2 range from 12.5 to 75 mg/day. Other objectives of the study are: - to evaluate safety and tolerability of Eltrombopag in patients affected with ITs. - to identify the dosages of Eltrombopag required for achieving the primary endpoints of Phases 1 and 2. - to study the effects of Phase 2 treatment on patients' health-related quality of life (HR-QoL); - to study the effects of treatment on some laboratory parameters related to platelet production and function. All patients will be undergo a follow-up visit 30 days after completion of treatment. Patients will be treated as outpatients. The evaluation of patients at enrollment and at each subsequent on-treatment and post-treatment visits includes: medical history; physical examination; evaluation of bleeding tendency according to WHO bleeding scale; CBC and differential; platelet count by phase-contrast microscopy; peripheral blood smear examination; plasma transaminases, bilirubin, and creatinine; urine analysis; ophthalmic assessment (only at some visits); measurement of serum thrombopoietin level; evaluation of HR-QoL (only at baseline and during Phase 2); evaluation of in vitro platelet aggregation in response to ADP, collagen and ristocetin whenever platelet count is over 100 x 10e9/L.