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Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

ABSTRACT: Immune thrombocytopenia (ITP) is the consequence of a complex, still incompletely understood immunological dysregulation. Proposed mechanisms include autoantibody-induced platelet destruction, impaired platelet production as well as abnormalities in T-cell immunity, such as T helper cells (Th1) polarization, a high proportion of Th17 cells, and a reduced number of regulatory T cells. Although the etiology of ITP is incompletely understood and considered multifactorial in most cases, genetic variants are thought to play a key role in susceptibility to ITP, especially in persistent or chronic ITP. Efforts are currently underway to uncover possible predisposing genetic factors for the development of ITP. Single-nucleotide polymorphisms and copy number variations have been identified in several immune-related genes, such as cytokine genes, Fcγ receptor genes or T-cell costimulation genes, and have been associated with patients' susceptibility to ITP. However, because of the clinical heterogeneity and low incidence of ITP it remains challenging to perform genetic analyses with sufficiently large sample size within informative patient populations, highlighting the need for collection of well-annotated biomaterials in clinical trials or registry projects. Another significant challenge is to go beyond performing association studies alone and to establish genotype-phenotype associations, thus proving causality between a genetic alteration and ITP pathogenesis. This review summarizes our current knowledge on genetic alterations identified as potential predisposing factors for the development of ITP in adults, thereby addressing signaling pathways considered critical for ITP pathogenesis.

SUBMITTER: Georgi JA

PROVIDER: S-EPMC10368779 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

Georgi Julia-Annabell JA Middeke Jan Moritz JM Bornhäuser Martin M Matzdorff Axel A Trautmann-Grill Karolin K

Blood advances 20230701 14

Immune thrombocytopenia (ITP) is the consequence of a complex, still incompletely understood immunological dysregulation. Proposed mechanisms include autoantibody-induced platelet destruction, impaired platelet production as well as abnormalities in T-cell immunity, such as T helper cells (Th1) polarization, a high proportion of Th17 cells, and a reduced number of regulatory T cells. Although the etiology of ITP is incompletely understood and considered multifactorial in most cases, genetic vari ...[more]

PMID: 37042947

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Project description:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia caused by increased platelet destruction and impaired platelet production. First-line therapies include corticosteroids, intravenous immunoglobulin, and anti-D immunoglobulin. For patients who are refractory to these therapies, those who become corticosteroid dependent, or relapse following treatment with corticosteroid, options include splenectomy, rituximab, and thrombopoietin-receptor agonists, alongside a variety of additional immunosuppressive and experimental therapies. Despite recent advances in the management of ITP, many areas need further research. Although it is recognized that an assessment of patient-reported outcomes in ITP is valuable to understand and guide treatment, these measures are not routinely measured in the clinical setting. Consequently, although corticosteroids are first-line therapies for both children and adults, there are no data to suggest that corticosteroids improve health-related quality of life or other patient-related outcomes in either children or adults. In fact, long courses of corticosteroids, in either children or adults, may have a negative impact on a patient's health-related quality of life, secondary to the impact on sleep disturbance, weight gain, and mental health. In adults, additional therapies may be needed to treat overt hemorrhage, but unfortunately the results are transient for the majority of patients. Therefore, there is a need to recognize the limitations of current existing therapies and evaluate new approaches, such as individualized treatment based on the probability of response and the size of effect on the patient's most bothersome symptoms and risk of adverse effects or complications. Finally, a validated screening tool that identifies clinically significant patient-reported outcomes in routine clinical practice would help both patients and physicians to effectively follow a patient's health beyond simply treating the laboratory findings and physical symptoms of ITP. The goal of this narrative review is to discuss management of newly diagnosed and refractory patients with ITP, with a focus on the limitations of current therapies from the patient's perspective.

Dataset Information

Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

Publications

Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

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