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. 2025 Sep 29;26:74. doi: 10.1186/s12865-025-00761-0

Thrombocytopenia in patients with inborn errors of immunity

Saba Fekrvand 1,2, Maryam Mohtashami 1,3, Negin Sanadgol 1,4, Helia Salehi 1, Najmeh Nameh Goshay Fard 5, Ehsan Khoshnezhad Afkham 6, Zahra Chavoshzadeh 7, Nima Parvaneh 8, Seyed Alireza Mahdaviani 9,10,11, Samin Sharafian 7, Sahar Barzamini 1, Hamid Ahanchian 12, Arash Kalantari 13, Alireza Shafiei 14, Marzieh Tavakol 15, Farhad Abolnezhadian 16, Mina Kianmanesh Rad 1, Gholamreza Hassanpour 17, Taher Cheraghi 18, Amir Salehi Farid 1, Samaneh Delavari 1,2, Hassan Abolhassani 1,2,19, Nima Rezaei 1,2, Reza Yazdani 1,2,✉
PMCID: PMC12482213  PMID: 41023781

Abstract

Background

Inborn errors of immunity (IEI) are inherited defects of innate or adaptive immune system. Thrombocytopenia is a significant multifactorial complication in IEI patients leading to severe clinical consequences including coagulative disorders and vasculopathies.

Methods

In the present study, we assessed frequency of thrombocytopenia in the most common IEI including combined immunodeficiency (CID), common variable immunodeficiency (CVID), selective immunoglobulin A deficiency (SIgAD), agammaglobulinemia (AGA), hyper immunoglobulin M (HIGM) syndrome, chronic granulomatous disease (CGD) and congenital neutropenia (CN). Also, we compared demographic, clinical and laboratory data between IEI patients with and without thrombocytopenia.

Results

A total of 890 patients (37% female) were included in this study. The frequency of thrombocytopenia in total IEI was 26.6%. Patients with CID and SIgAD had the highest and lowest frequency of thrombocytopenia (50.9% and 8.7%), respectively. Although rare, thrombocytopenia was more severe (< 50000/ul) among patients with AGA compared to other IEI entities. Notably hepatosplenomegaly and autoimmunity were significantly associated with thrombocytopenia and higher mortality in patients with humoral immunodeficiencies.

Conclusion

The significant association between thrombocytopenia with lymphoproliferation and autoimmunity emphasizes the importance of paying attention to these clinical features for suspecting IEI disorders. Understanding the pathophysiology of thrombocytopenia in various genetic defects associated with IEI is required for the development of proper diagnostic and therapeutic techniques as well as improved quality of life of these patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12865-025-00761-0.

Keywords: Inborn errors of immunity, Primary immunodeficiency, Thrombocytopenia, Lymphoproliferation, Autoimmunity

Introduction

Inborn errors of immunity (IEI), also known as primary immunodeficiencies, refer to a heterogeneous group of congenital disorders characterized by impaired innate or adaptive immune system components. IEIs present a wide spectrum of clinical manifestations including recurrent infections, lymphoproliferation, malignancies and autoimmunity [1]. Hematological complications such as thrombocytopenia are also observed in some IEI patients [2]. Thrombocytopenia is one of the most important and common complications among IEI patients, contributing to a dysregulated immune system, as well as coagulopathy and vascular disorders [2–8].

Thrombocytopenia is defined as platelet count less than 150,000/microliter and is generally divided into two categories, including congenital and acquired thrombocytopenia. Underlying pathogeneses are multifactorial and include decreased platelet production, increased platelet destruction, and platelet sequestration [9]. Inherited defects in thrombopoiesis and megakaryopoiesis have been reported in several IEI-related genetic defects including actinopathies (WAS, WIPF1, ARPC1B, ACTB, MKL1, DIAPH1 deficiencies), bone marrow failure (Fanconi Anemia, MECOM deficiency), calcium channel defects (ORAI1 and STIM1 deficiencies), and other functional platelet defects (LYST, RAB27A, CDC42, TWEAK, ZIP7, ITPKB deficiencies). Accordingly, defects in late stages of megakaryocyte differentiation may lead to thrombocytopenia and have been reported in some IEI, including DiGeorge syndrome, ataxia-telangiectasia (AT), glucose-6-phosphatase dehydrogenase (G6PD) deficiency class I, chronic granulomatous disease (CGD), and Goods syndrome [2, 10–26].

On the other hand, secondary thrombocytopenia in IEI patients may be caused by inappropriate immune responses to megakaryocytic precursors or glycoprotein (GP)Ibα, GPIIb/IIIa, and GPIa/IIa complexes on platelets, auto-antibody production, and its removal in the context of autoimmune diseases (e.g. immune thrombocytopenic purpura and Evans syndrome), infectious conditions (e.g. EBV and CMV viral infection, bacterial endocarditis or sepsis), platelet sequestration (e.g. hepatosplenomegaly due to lymphoproliferation or EBV complications), nutritional defects (e.g. abnormal folate metabolism in SLC46A1 and MTHFD1 deficiencies), microangiopathic complications (e.g. complement deficiencies associated with the hemolytic-uremic syndrome and disseminated intravascular coagulation), malignancy (e.g. IEI with lymphoma and leukemia infiltrating bone marrow) or certain medications (e.g. vancomycin, NSAID) [27–31]. Based on the underlying cause of thrombocytopenia in IEI patients, various treatments including platelet transfusion, intravenous immunoglobulin (IVIg), immunosuppressants, and splenectomy may be considered as first-line management of thrombocytopenia, along with hematopoietic stem cell transplantation (HSCT) or gene therapy as the cornerstone of therapy for the specific underlying IEI [32].

In the current study, for the first time, we evaluated the frequency of thrombocytopenia in Iranian IEI patients to provide a comprehensive picture of thrombocytopenia as an important complication in IEI patients.

Materials and methods

Study population

Patients registered in the national IEI registry [33, 34] with selective immunoglobulin A deficiency (SIgAD), agammaglobulinemia (AGA), combined immunodeficiency (CID), common variable immunodeficiency (CVID), hyper immunoglobulin M (HIGM) syndrome, chronic granulomatous disease (CGD) and congenital neutropenia (CN) were enrolled in the present study. The clinical diagnosis of IEI was made based on the Middle East and North Africa Diagnosis and Management Guidelines for Inborn Errors of Immunity [35]. All included patients were followed up at Children’s Medical Center (Pediatrics Center of Excellence affiliated to Tehran University of Medical Sciences, Tehran, Iran). Only IEI patients with a complete medical record were included in this study and those with missing clinical or laboratory data were excluded. The Ethics Committee of the Tehran University of Medical Sciences approved this study and written consent forms were obtained from all patients and/or their legal guardians.

Data collection

A questionnaire was designed to retrospectively obtain detailed demographic information, clinical manifestation history, and laboratory data by reviewing the medical history (Supplementary File 1). The collected data included current age, gender, age at onset of IEI symptoms, age of IEI diagnosis, delay in diagnosis, vital status, clinical manifestations and immunological data at the time of disease diagnosis. Platelet count data was obtained at two different times: at the time of IEI diagnosis, and the latest visit of the patient.

Classification of the patients

IEI patients were categorized into two groups, including patients with thrombocytopenia and those without thrombocytopenia. Thrombocytopenia was defined as a platelet count below 150,000/mm3 and was considered mild in case of 100,000/mm3 < platelet count < 150,000/mm3, moderate in case of 50,000/mm3 < platelet count < 100,000/mm3 and severe in case of platelet count < 50,000/mm3.

Statistical analysis

Statistical analysis was accomplished using SPSS (version 24) software (SPSS Inc., Chicago, IL, USA). The Kolmogorov–Smirnov and Shapiro-Wilk tests were used to evaluate the normality of data. According to normality test results, data analytics was performed using the T-test or Mann-Whitney test for quantitative variables. Chi-square or Fisher exact tests were used for qualitative data. P-value < 0.05 was considered statistically significant.

Results

Demographic characteristics

A total of 890 patients (male to female ratio, 1.7:1) fulfilled the inclusion criteria and were surveyed in the current study: CVID was the most frequent group with 283 patients, followed by CID (N = 159 patients), CGD (N = 142 patients), CN (N = 87 patients), AGA (N = 80 patients), HIGM syndrome (N = 70 patients) and symptomatic SIgAD (N = 69 patients). The mean ± standard deviation (SD) age at the time of study was 202.9 ± 160.5 months. The mean ± SD age at the onset of IEI-related clinical symptoms and the mean ± SD age at IEI diagnosis for total studied patients were 40.9 ± 83.9 and 85.7 ± 119.9 months, respectively. 465 cases (52.2%) had parental consanguinity.

Frequency of thrombocytopenia and its severity

The detailed data on the frequency and severity of thrombocytopenia among total IEI patients and 7 IEI groups is presented in Table 1. Thrombocytopenia was found in 26.6% of total patients (237 out of 890 cases). Most of the thrombocytopenic patients presented severe thrombocytopenia (87 cases, 36.7%). When we compared the frequency and severity of thrombocytopenia among seven IEI groups, we found a significant difference between groups (P-value < 0.001 and P-value = 0.01, respectively, Table 1). CID patients presented the predominant frequency of thrombocytopenia (81 cases, 50.9%), while the lowest frequency was observed in SIgAD patients (6 cases, 8.7%) (Table 1). Regarding severity, we noticed that a higher proportion of severe thrombocytopenia is predominantly found in AGA patients (7 cases, 53.8%), while mild type is mostly observed in CN patients (12 cases, 60%).

Table 1.

The frequency and severity of thrombocytopenia among total and different groups of IEI patients

IEI groups Thrombocytopenia
N (%)		 Thrombocytopenia severity
N (%)
Mild Moderate Severe
Total IEI (N = 890) 237 (26.6) 80 (33.7) 70 (29.5) 87 (36.7)
CGD (N = 142) 13 (9.1) 3 (23.1) 5 (38.5) 5 (38.5)
CN (N = 87) 20 (23) 12 (60) 0 (0) 8 (40)
CVID (N = 283) 85 (30) 36 (42.3) 28 (32.9) 21 (24.7)
CID (N = 159) 81 (50.9) 18 (22.2) 23 (28.4) 40 (49.4)
SIgAD (N = 69) 6 (8.7) 1 (16.7) 3 (50) 2 (33.3)
HIGM (N = 70) 19 (27.1) 6 (31.6) 9 (47.4) 4 (21)
AGA (N = 80) 13 (16.25) 4 (30.8) 2 (15.4) 7 (53.8)
P -value < 0.001* 0.01*
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IEI inborn errors of immunity, N number, CGD chronic granulomatous disease, CN congenital neutropenia, CVID common variable immunodeficiency disease, CID combined immunodeficiency, SIgAD selective IgA deficiency, HIGM hyper immunoglobulin M syndrome, AGA agammaglobulinemia

*P- value < 0.05 is statistically significant

Clinical manifestations

Table S1-S7 represents precise data on clinical manifestations in each of the 7 studied IEI groups as well as their comparison between thrombocytopenic and non-thrombocytopenic patients in each group. Among the comparative analyses of clinical manifestations in IEI patients, the interesting finding was the higher frequency of lymphoproliferative signs (hepatomegaly or splenomegaly) in thrombocytopenic patients in comparison to non-thrombocytopenic patients. In this regard, hepatomegaly was more common in the thrombocytopenic group than in the non-thrombocytopenic group among patients with CGD (30.8% vs. 13.2%), CN (25% vs. 4.5%), CVID (38.8% vs. 18.7%), CID (25.9% vs. 23.1%), HIGM syndrome (57.9% vs. 13.7%) and AGA (30.8% vs. 9%), and this difference was statistically significant in CN, CVID, HIGM syndrome and AGA (P < 0.05).

As mentioned, splenomegaly was more frequent in the thrombocytopenic group compared with the non-thrombocytopenic group among patients with CGD (30.8% vs. 15.5%), CN (25% vs. 7.5%), CVID (52.9% vs. 26.3%), CID (32.1% vs. 16.7%), HIGM syndrome (68.4% vs. 19.6%) and AGA (7.7% vs. 6%), and the difference was significant in CN, CVID, CID and HIGM syndrome (P < 0.05). The distribution of hepatomegaly, splenomegaly, and their link with lymphadenopathy among lymphoproliferative manifestations within thrombocytopenic patients of studied IEI groups is shown in Fig. 1. Furthermore, we found higher frequency of autoimmunity in the thrombocytopenic group than in the non-thrombocytopenic group in CVID (57.6% vs. 40.4%), SIgAD (33.3% vs. 11.1%), HIGM syndrome (47.4% vs. 19.6%) and AGA (23.1% vs. 16.4%), and this difference was significant in CVID and HIGM syndrome (P < 0.05).

Fig. 1.

Fig. 1

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Frequency of lymphoproliferative disorders among thrombocytopenic patients. A Total thrombocytopenic IEI patients; B Various IEI groups with thrombocytopenia. CGD, chronic granulomatous disease; CN, congenital neutropenia; CVID, common variable immunodeficiency disease; CID, combined immunodeficiency; SIgAD, selective IgA deficiency; HIGM, hyper immunoglobulin M syndrome; AGA, agammaglobulinemia

In Fig. 2 we have demonstrated the main clinical features across major IEI groups including splenomegaly, hepatomegaly, lymphadenopathy and autoimmunity.

Fig. 2.

Fig. 2

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Frequency of lymphoproliferation, autoimmunity, thrombocytopenia, and mortality across major IEI groups CGD, chronic granulomatous disease; CN, congenital neutropenia; CVID, common variable immunodeficiency disease; CID, combined immunodeficiency; SIgAD, selective IgA deficiency; HIGM, hyper immunoglobulin M syndrome; AGA, agammaglobulinemia

Laboratory findings

Immunologic data was compared between thrombocytopenic and non-thrombocytopenic patients in each of the seven IEI groups (Tables S1-S7). Regarding immune cells, the frequency of B cells was significantly higher in the thrombocytopenic patients with CGD (mean: 33.1% vs. 19.3%, P = 0.038), while the thrombocytopenic patients with CID had a significantly higher residual T cells (mean: 32% vs. 18.6%, P = 0.019) when compared to those with the non-thrombocytopenic patients in their respective groups. The thrombocytopenic patients with AGA also had a significantly lower frequency of T cells compared with the non-thrombocytopenic patients with AGA (mean: 72.7% vs. 83.8%, P = 0.016). The thrombocytopenic patients with SIgAD exhibited a remarkably lower frequency of total lymphocytes compared with the non-thrombocytopenic patients with SIgAD (mean: 24.1% vs. 44.7%, P = 0.002). Other comparative analyses of laboratory data are provided in Tables S1-S7.

Genetic findings

A total number of 41 thrombocytopenic patiets were genetically evaluated. Figure 3 manifests the distribution of mutated genes among these patients. Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and CD40 ligand (CD40L) had the highest frequency followed by Bruton’s tyrosine kinase (BTK). Among the total genetically studied thrombocytopenic patients, 17 patients had mild thrombocytopenia, while 13 and 11 patients had moderate and severe thrombocytopenia, respectively. Figure 4 manifests the distribution of thrombocytopenia severity among found genetic mutations. Table S8 represents the detailed results of whole exom-sequencing (WES), the severity of thrombocytopenia and clinical manifestations in these patients.

Fig. 3.

Fig. 3

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Frequency of mutated genes found among thrombocytopenic patients. ADA, adenosine deaminase; BAFFR, B cell-activating factor receptor; BTK, Bruton’s tyrosine kinase; CD3D, Cluster of Differentiation 3 Delta; CD3E, Cluster of Differentiation 3 Epsilon; CD40L, CD40 ligand; DCLRE1C, DNA cross-link repair 1C; IL2RG, interleukin 2 receptor subunit gamma; JACK3, Janus kinase 3; LRBA, Lipopolysaccharide-responsive and beige-like anchor protein; MSN, Moesin; NFKB1, nuclear factor kappa B subunit 1; NHEJ1, non-homologous end-joining factor 1; WES, Whole exome sequencing; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PMS2, postmeiotic segregation increased 2; RAC2, Ras-related C3 botulinum toxin substrate 2; RAG1, Recombination activating gene 1; RFXANK, regulatory factor X associated ankyrin containing protein

Fig. 4.

Fig. 4

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Distribution of thrombocytopenia severity among found genetic defects ADA, adenosine deaminase; BAFFR, B cell-activating factor receptor; BTK, Bruton’s tyrosine kinase; CD3D, Cluster of Differentiation 3 Delta; CD3E, Cluster of Differentiation 3 Epsilon; CD40L, CD40 ligand; DCLRE1C, DNA cross-link repair 1 C; IL2RG, interleukin 2 receptor subunit gamma; JACK3, Janus kinase 3; LRBA, Lipopolysaccharide-responsive and beige-like anchor protein; MSN, Moesin; NFKB1, nuclear factor kappa B subunit 1; NHEJ1, non-homologous end-joining factor 1; WES, Whole exome sequencing; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PMS2, postmeiotic segregation increased 2; RAC2, Ras-related C3 botulinum toxin substrate 2; RAG1, Recombination activating gene 1; RFXANK, regulatory factor X associated ankyrin containing protein

Outcome and mortality

At the time of study, 474 patients (53.3%) were alive, while 190 patients (21.3%) were dead and vital status of 226 cases (25.4%) were unknown (data not shown). There was a significant association between mortality and thrombocytopenia (frequency of death: 49.5% in total thrombocytopenic patients vs. 19.3% in total non-thrombocytopenic patients, P < 0.001). Also, frequency of death was remarkably higher in thrombocytopenic patients than non-thrombocytopenic ones in patients with CVID (43.4% vs. 20.3%, P-value < 0.001), CID (61.7% vs. 33.3%, P < 0.001), HIGM syndrome (55.6% vs. 17.4%, P = 0.002) and AGA (41.7% vs. 13.2%, P = 0.022).

Discussion

Thrombocytopenia is one of the common complications among IEI patients. To the best of our knowledge, our study is the first one to exclusively evaluate the frequency of thrombocytopenia in various IEI. We observed that thrombocytopenia manifested in 26.6% of our study population, with the highest frequency in patients with CID. Interestingly, we found a significant association between thrombocytopenia and lymphoproliferation and autoimmunity in most of our studied IEI.

Pathogenesis of cytopenias in IEI is multifactorial. In this regard, dysfunction and/or dysregulation of humoral and cellular immunity, autoinflammation, hemophagocytosis, bone marrow diseases like primary bone marrow failure, infection-induced myelosuppression, myelofibrosis or malignancy, recent immunizations or transfusions, transplantation, cytotoxic drugs, cytoskeletal and megakaryocyte dysfunction as well as splenic platelet destruction secondary to lymphoproliferation have been reported as contributing factors to thrombocytopenia in IEI [36–41]. In our study, patients with CID and CVID had the highest frequency of thrombocytopenia (50.9% and 30%, respectively). The frequency of thrombocytopenia in our CVID patients is higher (30%) than in other studies reporting a frequency of 7% in Sweden and 20% in France [42, 43]. This might be due to higher awareness of IEI in European countries, earlier diagnosis, prophylaxis and management of these patients. In addition to the aforementioned IEI with primary cytopenias, IEI with underlying immune dysregulation such as hemophagocytosis and oligoclonal or polyclonal lymphoproliferation could lead to secondary cytopenias [36, 44]. The mechanism of cytopenias in IEI with lymphoproliferation could be attributed to the sequestration of blood cells [36]. Interestingly, we found a significant association between thrombocytopenia and lymphoproliferation (hepatomegaly, splenomegaly and/or lymphadenopathy) among patients with CN, CVID, CID, HIGM syndrome and AGA. In line with our findings, a study has reported a synergic correlation between AICs and splenomegaly in CVID [42]. Although we did not observe a an association between pulmonary manifestations of thrombocytopenic patients and non-thrombocytopenic ones, except for a significantly higher frequency of sinusitis and otitis media in thrombocytopenic SIgAD patients in comparison to non-thrombocytopenic SIgAD patients, a recent study has reported an association between granulomatous–lymphocytic interstitial lung disease (GLILD) and cytopenias and immune dysregulation in form of hepatosplenomegaly in CVID paients [45]. This highlights the need for further imaging or histological work-up in patients with overlapping pulmonary and hematologic features.

IEI with intrinsic B cell defects or those with disturbed regulation or interaction between T and B cells contribute to auto-antibody production [36, 46, 47], while IEI with intrinsic T-effector cell defects may develop cellular autoimmunity [36, 48, 49]. AICs are the most prevalent autoimmune manifestations in IEI patients, with an approximate prevalence of 10.2–84.1% [50–52]. Several studies have demonstrated that a significant number of cases with AICs may have an underlying IEI, particularly in the co-occurrence of lymphoproliferation, highlighting the importance of multidisciplinary collaboration between hematologists and immunologists in the evaluation and management of AICs [37, 53–56]. AICs in IEI patients often fail to respond to first-line therapies for cytopenias including IVIg and/or corticosteroids, thus a prompt diagnosis of the underlying etiology for cytopenias is pivotal for definitive treatment of them [53–55, 57]. Our findings and others suggest that the manifestation of lymphoproliferation and AICs can be considered a key diagnostic point for earlier diagnosis of an underlying IEI [57]. Early diagnosis is pivotal in targeted therapies or definitive treatments such as HSCT or gene therapy [57].

A recent study on IEI patients with cytopenias at presentation in South Africa reported remarkable shorter overall survival in those with thrombocytopenia and other cytopenias at presentation [55]. Similarly, thrombocytopenic patients in our study had significantly higher mortality compared to non-thrombocytopenic patients. Physicians should be aware of the consequences of chronic, relapsing or refractory thrombocytopenia and other cytopenias in IEI and regularly follow up IEI patients for possible cytopenias, their mechanism and timely appropriate treatment based on the underlying IEI type.

While our study provides valuable insights into the frequency of thrombocytopenia in a large cohot of patients with IEI, it is important to acknowledge several limitations. First, due to the retrospective design and variability in available clinical documentation, we were unable to stratify thrombocytopenia cases into immune versus non-immune categories. Therefore, our findings reflect the overall prevalence of thrombocytopenia in patients with IEI, without distinction regarding underlying mechanisms. Furthermore, data on treatment strategies, lines of therapy, and patient responses were not consistently available across cases, preventing us from analyzing the therapeutic approaches and outcomes. These limitations underscore the need for prospective, standardized data collection in future studies to better characterize the nature and management of thrombocytopenia in the context of IEI.

Conclusion

Understanding the distribution of thrombocytopenia in IEI patients enlightens physicians for earlier diagnosis of an underlying IEI. The significant association between thrombocytopenia and lymphoproliferation as well as autoimmunity highlights the importance of paying attention to these clinical features for suspecting IEI disorders as well as multidisciplinary care and early genetic screening in managing cytopenic complications of IEI patients. Implementation of further studies to clarify the pathophysiology of thrombocytopenia in various genetic defects associated with IEI could lead to the development of proper diagnostic and therapeutic techniques as well as improved quality of life of these patients.

Supplementary Information

Supplementary Material 1 (181KB, xlsx)
Supplementary Material 2 (70.6KB, docx)

Acknowledgements

NA.

Authors’ contributions

SF: Conceptualization, investigation, formal analysis, writing–original draft. MM: Conceptualization, investigation, writing–original draft. NS: Investigation, data collection. HS: Investigation, data collection. NNGF: Investigation, data collection. EKA: Validation, review and editing. ZC: Validation, review and editing. NP: Validation, review and editing. SAM: Validation, review and editing. SS: Validation, review and editing. SB: Investigation, data collection. HA: Validation, review and editing. AK: Validation, review and editing. AS: Validation, review and editing. MT: Validation, review and editing. FA: Validation, review and editing. MKR: Investigation, data collection. GH: Validation, review and editing. TC: Validation, review and editing. ASF: Investigation, data collection. SD: Investigation, data collection. HA: Conceptualization, investigation, validation, review and editing. NR: Conceptualization, investigation, validation, review and editing. RY: Conceptualization, investigation, software, supervision, validation, writing–review and editing. The final version of the manuscript has been accepted by all of the authors.

Funding

This study was supported by a grant (No. 49980) from the Tehran University of Medical Sciences.

Data availability

The data belong to the Iranian national registry of primary immunodeficiency, and the data used for this study can be available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This project was conducted in accordance with the guidelines of the Helsinki Declaration, and approved by the Tehran University of Medical Sciences Committee for Ethics with the code IR.TUMS.CHMC.REC.1399.142. Consent forms were obtained from all patients and/or their legal guardians.

Consent for publication

All authors approve the content of this manuscript and consent to publication.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Yazdani R, Abolhassani H, Asgardoon MH, Shaghaghi M, Modaresi M, Azizi G, et al. Infectious and noninfectious pulmonary complications in patients with primary immunodeficiency disorders. J Investig Allergol Clin Immunol. 2017;27(4):213–24. [DOI] [PubMed] [Google Scholar]
  • 2.Mohtashami M, Razavi A, Abolhassani H, Aghamohammadi A, Yazdani R. Primary immunodeficiency and thrombocytopenia. Int Rev Immunol. 2022;41(2):135–59. [DOI] [PubMed] [Google Scholar]
  • 3.Park HK, Lee SH. Ischemic stroke associated with immune thrombocytopenia: lesion patterns and characteristics. Neurol Sci. 2014;35(11):1801–6. [DOI] [PubMed] [Google Scholar]
  • 4.AlKhater SA. CNS vasculitis and stroke as a complication of DOCK8 deficiency: a case report. BMC Neurol. 2016;16:1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Seyoum M, Enawgaw B, Melku M. Human blood platelets and viruses: defense mechanism and role in the removal of viral pathogens. Thromb J. 2018;16:16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lam FW, Vijayan KV, Rumbaut RE. Platelets and their interactions with other immune cells. Compr Physiol. 2015;5(3):1265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.de Stoppelaar SF, van ‘t Veer C, Claushuis TA, Albersen BJ, Roelofs JJ, van der Poll T. Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. Blood. 2014;124(25):3781–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Ghasemzadeh M, Hosseini E. Platelet-leukocyte crosstalk: linking proinflammatory responses to procoagulant state. Thromb Res. 2013;131(3):191–7. [DOI] [PubMed] [Google Scholar]
  • 9.Walter JE, Farmer JR, Foldvari Z, Torgerson TR, Cooper MA. Mechanism-based strategies for the management of autoimmunity and immune dysregulation in primary immunodeficiencies. The Journal of Allergy and Clinical Immunology: In Practice. 2016;4(6):1089–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Chen M, Yan R, Zhou K, Li X, Zhang Y, Liu C, et al. Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia. Proc Natl Acad Sci U S A. 2018;115(45):E10682-91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Quach ME, Chen W, Li R. Mechanisms of platelet clearance and translation to improve platelet storage. Blood. 2018;131(14):1512–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Cranmer SL, Ashworth KJ, Yao Y, Berndt MC, Ruggeri ZM, Andrews RK, et al. High shear-dependent loss of membrane integrity and defective platelet adhesion following disruption of the GPIbalpha-filamin interaction. Blood. 2011;117(9):2718–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Priel DL, et al. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood. 2016;128(17):2135–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ji Y, Ferracci G, Warley A, Ward M, Leung K-Y, Samsuddin S, et al. β-actin regulates platelet nitric oxide synthase 3 activity through interaction with heat shock protein 90. Proc Natl Acad Sci U S A. 2007;104(21):8839–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol. 2010;30(12):2357–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Gkaliagkousi E, Corrigall V, Becker S, de Winter P, Shah A, Zamboulis C, et al. Decreased platelet nitric oxide contributes to increased Circulating monocyte-platelet aggregates in hypertension. Eur Heart J. 2009;30(24):3048–54. [DOI] [PubMed] [Google Scholar]
  • 18.Dinauer MC. Disorders of neutrophil function: an overview. Methods Mol Biol. 2007;412:489–504. [DOI] [PubMed] [Google Scholar]
  • 19.Maugeri N, Rovere-Querini P, Evangelista V, Covino C, Capobianco A, Bertilaccio MT, et al. Neutrophils phagocytose activated platelets in vivo: a phosphatidylserine, P-selectin, and β2 integrin–dependent cell clearance program. Blood. 2009;113(21):5254–65. [DOI] [PubMed] [Google Scholar]
  • 20.Ghalloussi D, Dhenge A, Bergmeier W. New insights into cytoskeletal remodeling during platelet production. J Thromb Haemost. 2019;17(9):1430–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chen S, Su Y, Wang J. ROS-mediated platelet generation: a microenvironment-dependent manner for megakaryocyte proliferation, differentiation, and maturation. Cell Death Dis. 2013;4(7):e722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Arnold DE, Heimall JR. A review of chronic granulomatous disease. Adv Ther. 2017;34(12):2543–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Chou JY, Jun HS, Mansfield BC. Glycogen storage disease type I and G6Pase-beta deficiency: etiology and therapy. Nat Rev Endocrinol. 2010;6(12):676–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Melchinger H, Jain K, Tyagi T, Hwa J. Role of platelet mitochondria: life in a nucleus-free zone. Front Cardiovasc Med. 2019;6:153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Pang L, Weiss MJ, Poncz M. Megakaryocyte biology and related disorders. J Clin Invest. 2005;115(12):3332–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Malphettes M, Gerard L, Galicier L, Boutboul D, Asli B, Szalat R, et al. Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications. Clin Infect Dis. 2015;61(2):e13–9. [DOI] [PubMed] [Google Scholar]
  • 27.Izak M, Bussel JB. Management of thrombocytopenia. F1000Prime Rep. 2014;6:45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Kistangari G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495–520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Grodzicky T, Bussel J, Elkon K. Anti-platelet antibodies associated with the Canale–Smith syndrome bind to the same platelet glycoprotein complexes as those of idiopathic thrombocytopenic purpura patients. Clin Exp Immunol. 2002;127(2):289–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Smock KJ, Perkins SL. Thrombocytopenia: an update. Int J Lab Hematol. 2014;36(3):269–78. [DOI] [PubMed] [Google Scholar]
  • 31.Swinkels M, Rijkers M, Voorberg J, Vidarsson G, Leebeek FWG, Jansen AJG. Emerging concepts in immune thrombocytopenia. Front Immunol. 2018;9:880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Razavi AS, Mohtashami M, Razi S, Rezaei N. TGF-β signaling and the interaction between platelets and T-cells in tumor microenvironment: foes or friends? Cytokine. 2022;150:155772. [DOI] [PubMed] [Google Scholar]
  • 33.Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth update on the Iranian National registry of primary immunodeficiencies: integration of molecular diagnosis. J Clin Immunol. 2018;38(7):816–32. [DOI] [PubMed] [Google Scholar]
  • 34.Aghamohammadi A, Rezaei N, Yazdani R, Delavari S, Kutukculer N, Topyildiz E, et al. Consensus middle East and North Africa registry on inborn errors of immunity. J Clin Immunol. 2021;41(6):1339–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Baris S, Abolhassani H, Massaad MJ, Al-Nesf M, Chavoshzadeh Z, Keles S, et al. The middle East and North Africa diagnosis and management guidelines for inborn errors of immunity. J Allergy Clin Immunol Pract. 2023;11(1):158–e8011. [DOI] [PubMed] [Google Scholar]
  • 36.Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood. 2014;124(15):2337–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Zama D, Conti F, Moratti M, Cantarini ME, Facchini E, Rivalta B, et al. Immune cytopenias as a continuum in inborn errors of immunity: an in-depth clinical and immunological exploration. Immunity Inflamm Dis. 2021;9(2):583–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Sánchez-Ramón S, Bermúdez A, González-Granado LI, Rodríguez-Gallego C, Sastre A, Soler-Palacín P, et al. Primary and secondary immunodeficiency diseases in oncohaematology: warning signs, diagnosis, and management. Front Immunol. 2019;10:586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Mortaz E, Tabarsi P, Mansouri D, Khosravi A, Garssen J, Velayati A, et al. Cancers related to immunodeficiencies: update and perspectives. Front Immunol. 2016;7:365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Oliveira JB, Fleisher TA. Laboratory evaluation of primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2):S297–305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277–86. [DOI] [PubMed] [Google Scholar]
  • 43.Michel M, Chanet V, Galicier L, Ruivard M, Levy Y, Hermine O, et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine. 2004;83(4):254–63. [DOI] [PubMed] [Google Scholar]
  • 44.Janka GE, Lehmberg K. Hemophagocytic syndromes—an update. Blood Rev. 2014;28(4):135–42. [DOI] [PubMed] [Google Scholar]
  • 45.Moratti M, Schifino G, Baccelli F, Ferrari S, Magrini E, Bassi M, et al. Granulomatous lymphocytic interstitial lung disease in common variable immune deficiency: an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection. Front Immunol. 2025;16–1589052. [DOI] [PMC free article] [PubMed]
  • 46.Von Boehmer H, Melchers F. Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol. 2010;11(1):14–20. [DOI] [PubMed] [Google Scholar]
  • 47.Meffre E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann N Y Acad Sci. 2011;1246(1):1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Davies EG, Thrasher AJ. Update on the hyper Immunoglobulin M syndromes. Br J Haematol. 2010;149(2):167–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022;42(7):1508–20. [DOI] [PubMed] [Google Scholar]
  • 50.Feuille EJ, Anooshiravani N, Sullivan KE, Fuleihan RL, Cunningham-Rundles C. Autoimmune cytopenias and associated conditions in CVID: a report from the USIDNET registry. J Clin Immunol. 2018;38:28–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Farmer JR, Foldvari Z, Ujhazi B, De Ravin SS, Chen K, Bleesing JJ, et al. Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency. J Allergy Clin Immunology: Pract. 2019;7(6):1970–85. e4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Fischer A, Provot J, Jais J-P, Alcais A, Mahlaoui N, Adoue D, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388–93. e8. [DOI] [PubMed] [Google Scholar]
  • 53.Schiavo E, Martini B, Attardi E, Consonni F, Ciullini Mannurita S, Coniglio ML, et al. Autoimmune cytopenias and dysregulated immunophenotype act as warning signs of inborn errors of immunity: results from a prospective study. Front Immunol. 2022;12:790455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Taskin RB, Topyıldız E, Edeer Karaca N, Aksu G, Yılmaz Karapınar D, Kutukculer N. Autoimmune cytopenias are highly associated with inborn errors of immunity and they may be the initial presentations in cases without severe infections. Int Arch Allergy Immunol. 2024;185(4):392–401. [DOI] [PubMed] [Google Scholar]
  • 55.Cornelissen HM, Musekwa EM, Glashoff RH, Esser M, Zunza M, Abraham DR, et al. Peripheral-blood cytopenia, an early indicator of inborn errors of immunity. Br J Haematol. 2022;198(5):875–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Beatrice JM, Liphaus BL, Kamioka PE, Matsumoto LC, Correa-Silva S, Carneiro-Sampaio MM, et al. Inborn errors of immunity in children and adolescents with immune thrombocytopenia. 2022. 10.21203/rs.3.rs-1625733/v1.
  • 57.Cortesi M, Soresina A, Dotta L, Gorio C, Cattalini M, Lougaris V, et al. Pathogenesis of autoimmune cytopenias in inborn errors of immunity revealing novel therapeutic targets. Front Immunol. 2022;13:846660. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1 (181KB, xlsx)
Supplementary Material 2 (70.6KB, docx)

Data Availability Statement

The data belong to the Iranian national registry of primary immunodeficiency, and the data used for this study can be available from the corresponding author upon reasonable request.

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