Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.
In any investigation of the role of genetics in immune thrombocytopenia (ITP), it is important to distinguish between immune thrombocytopenia and inherited thrombocytopenia.
Inherited thrombocytopenia describes a group of hereditary disorders in which low platelet counts are a characteristic feature. In inherited thrombocytopenia, causative mutations occur in the genes involved in megakaryocyte differentiation and/or platelet formation and clearance.1
ITP is an autoimmune condition in which the immune system produces antiplatelet antibodies.2 The antiplatelet antibodies attack surface membrane proteins (usually glycoprotein IIb/IIIa), causing the premature destruction of normal platelets.2,3 ITP also decreases the ability of megakaryocytes to compensate for low platelet levels by increasing platelet production.2
Primary ITP occurs in the absence of underlying conditions, whereas secondary ITP is triggered by bacterial or viral infections, underlying autoimmune conditions, or underlying malignancies, especially hematologic malignancies.
The Genetics of ITP
Familial inheritance of ITP is exceptionally rare, so ITP is not considered a genetic condition.4 Although unusual, it is possible for ITP to run in families with an unknown inheritance pattern. People who have first-degree relatives (parents or siblings) with ITP are at increased risk for the condition. Genetic mutations have been discovered in certain genes of people with ITP. This may increase the risk of disease development, but the full effect is still unclear.2
Read more about ITP etiology
CTLA4 Gene Mutations
Acquired single-nucleotide polymorphisms (SNPs) in several genes associated with T-cell activation of the immune system have been identified in patients with ITP.2,5 CTLA4 gene mutations occurred more frequently in patients with primary ITP, secondary ITP, or a combination of the two.5
Mutations in CTLA4 result in T-cell overactivation, which promotes autoimmunity. CTLA4 has a greater impact on the pathway of T-cell activation. It differentiates follicular helper T-cells with the help of CD28, which modulates the activation of cytotoxic T-cells. Previous ITP-related studies show that SNPs of CTLA4 are related to the mRNA transcription level, and CTLA4 gene polymorphism can affect the severity of thrombocytopenia.5
INFG Gene Mutations
Researchers reviewed literature from 2000 to 2016 for evidence of genetic links to ITP. They discovered that most of the abnormalities occurred within immune system genes, including the interferon gamma (IFNG) gene. Alterations in genes such as IFNG cause immune system dysfunction and the production of antiplatelet antibodies targeting surface glycoproteins, including glycoproteins IIb/IIIa. In addition, interleukin-3 (IL-3), stem cell factor, and IFNG are involved in megakaryopoiesis, megakaryocyte differentiation, and platelet formation and release.6
The level of functionality of these cytokines and factors is related to the severity of ITP. While IFNG is a factor related to thrombocytopenia and inflammation, the coexistence of this cytokine along with thrombopoietin, IL-3, and stem cell factor can increase platelet counts and effectively reduce the severity of ITP.6
Read more about ITP risk factors
Genetics in Chronic Refractory ITP
From March 2016 to March 2019, researchers in China compared the genetic characteristics of 51 children who had chronic refractory ITP with those of 103 children who did not have abnormal mutations. Pathogenic variations occurred within immune-related genes in the children with refractory ITP, including TNFRSF13B, CARD11, RAG2, and CBL — all of which are associated with primary immunodeficiencies.7
In terms of clinical characteristics, the children with immune-related genetic variants presented with episodes of severe bleeding, increased expression of systemic lupus erythematosus biomarkers, and abnormal immunological indices. The abnormal immunological indices included thyroid autoantibody, insulin autoantibody, antinuclear antibody, alexin, anti-double-stranded DNA antibody, anti-ENA antibody, lupus anticoagulant, anti-β2 glycoprotein antibody, erythrocyte sedimentation rate, rheumatoid factor, and anticardiolipin antibody. Additionally, a higher number of T and B lymphocytes were observed in the peripheral serum samples of the children with immune-related genetic variants.7
Of the 51 children with refractory ITP, 9 presented with probable pathogenic mutations in 4 genes: TNFRSF13B, CARD11, RAG2, and CBL. The remaining 42 children (82.4%) presented with variants of uncertain significance in 23 genes, including AIRE, C1R, CARD11, CASP10, CBL, CD40LG, CTLA4, FASLG, GATA2, IFIH1, IL2KG, JAK2, LAT, LRBA, LZTR1, NHEJ1, NLRP1, NLRP2, NLRP12, PIK3CD, PIK3R1, PLCG2, and TNFRSF13B.7
When analyzing the type of mutation (spontaneous or familial), the researchers discovered that 2 mutations, found in the CARD11 and CBL genes, were spontaneous. Familial inheritance of ITP was determined in 14 children, 9 of whom inherited mutations in TNFRSF13B, FASLG, GATA2, IL2KG, JAK2, and PLCG2 from their mothers and 5 of whom inherited mutations in TNFRSF13B, CASP10, CBL, and CTLA4 from their fathers. None of the parents exhibited any autoimmune or immunodeficiency conditions.7
Read more about ITP prognosis
- Almazni I, Stapley R, Morgan NV. Inherited thrombocytopenia: update on genes and genetic variants which may be associated with bleeding. Front Cardiovasc Med. 2019;6. doi:10.3389/fcvm/2019/00080
- Immune thrombocytopenia. Medline Plus. Accessed October 29, 2022.
- Kessler CM. Immune thrombocytopenia (ITP): etiology. Medscape. Updated January 7, 2021. Accessed October 29, 2022.
- Immune thrombocytopenia. Orphanet. Accessed October 29, 2022.
- Chen DP, Lin WT, Wen YH, Wang WT. Investigation of the correlation between immune thrombocytopenia and T cell activity-regulated gene polymorphism using functional study. Sci Rep. 2022;12:6601. doi:10.1038/s41598-022-10631-z
- Rezaeeyan H, Jaseb K, Alghasi A, Asnafi AA, Saki N. Association between gene polymorphisms and clinical features in idiopathic thrombocytopenic purpura patients. Blood Coagul Fibrinolysis. 2017;28(8):617-622. doi:10.1097/MBC.0000000000000646
- Zhao S, Ma J, Zhu X, Zhang J, Wu R. Chronic refractory immune thrombocytopenia is associated with variants in immune genes. Clin Appl Thromb Hemost. 2021;27:10760296211059812. doi:10.1177/10760296211059813
Reviewed by Debjyoti Talukdar, MD, on 10/31/2022.