Faculty Bibliography

Immune thrombocytopenia (ITP) is an acquired bleeding disorder caused by complex immune dysregulation. ITP is a rare disorder with significant morbidity; patients can suffer from bleeding symptoms and reduced quality of life. The pathogenesis of ITP can be observed at several levels: the mechanisms of thrombocytopenia, the loss of tolerance mechanisms, and underlying factors that drive its occurrence. Several mechanisms of platelet destruction and impaired platelet production are recognized as driving the disease. These mechanisms range from autoantibody-mediated platelet destruction, T cell-mediated cytotoxicity, complement-mediated destruction, and platelet desialylation leading to platelet clearance, to thrombopoietin consumption. These alterations are driven by a loss of tolerance with impaired T regulatory and myeloid derived suppressor cell surveillance. Several underlying factors may contribute to ITP pathogenesis by promoting this loss of tolerance, including genetic susceptibility, infections, the gut microbiome, and environmental influences. The numerous alterations described may be heterogeneous across patients with ITP, contributing to disease heterogeneity. Many patients will require treatment of ITP, which may target one or more of these mechanisms, with new therapies being developed to focus on specific pathways. Ultimately, identifying the main mechanism(s) driving ITP in a patient may allow individualized management. This review will highlight the major mechanisms of ITP immunopathology to deepen understanding of important pathways and therapies modulating these pathways.

Practice variation exists in the management of newly diagnosed pediatric immune thrombocytopenia (ITP) despite availability of evidence-based treatment guidelines. The American Society of Hematology (ASH) ITP guidelines recommend that initial treatment of children should be based on assessment of clinical symptoms rather than the degree of thrombocytopenia and that short courses of corticosteroids should be prescribed to children requiring initial medication treatment. Retrospective review evaluating treatment of newly diagnosed children with ITP has demonstrated that management continues to be based on the platelet count with high use of intravenous immunoglobulin, which results in overuse of medications and high rates of inpatient hospitalizations and medical visits for administration and management of side effects. To improve adherence to ASH guidelines, the ITP Consortium of North America implemented a clinical care pathway as a multicenter quality improvement initiative. Retrospective data (11 centers, n=284) were collected prior to implementation and compared to post-implementation data (12 centers, n=266). With implementation of the clinical pathway, documentation of a bleeding score for children at diagnosis increased from 1% (3/284) to 95% (253/266). At diagnosis, initial treatment with ITP-directed medications decreased in children with no or mild bleeding symptoms (62% (177/284) vs. 31% (83/266), p<0.0001). Intravenous immunoglobulin use reduced from 51% (145/284) to 15% (41/266), p<0.0001. With implementation of the pathway, clinical outcomes were comparable with no increase in inpatient hospitalizations or bleeding events. Implementation of a clinical care pathway for a rare condition increases adherence to evidence-based guidelines and is feasible to implement across multiple centers.

Immune thrombocytopenia (ITP) is associated with a variable and unpredictable clinical course in children, including a spectrum of bleeding and systemic symptoms in the months following diagnosis. Although many children will have spontaneous resolution of disease prior to 1 year, up to 30% will go on to develop chronic disease. Known predictors for developing chronic ITP are limited, making clinical management and guidance during this early course of disease very challenging. Additionally, the pathophysiology of immune dysregulation in ITP is complex, with multiple variables likely contributing to the development of chronic disease. We aimed to create a statistical model to predict development of chronic ITP. Utilizing a retrospective training cohort of 611 children with ITP from two institutions and two validation cohorts comprised of 161 children, we developed and validated a multivariable logistic regression model and found that age, sex, IgG, IgA, IgM, presenting platelet count, presenting lymphocyte count, known secondary cause at diagnosis, and DAT positivity were useful in predicting chronic ITP. The external validations demonstrated consistent discriminative performance and clinical utility. The model is available for use at https://opal.shinyapps.io/citp-rm/. A chronicity prediction tool to use at the time of ITP diagnosis will better equip hematologists to counsel patients and families and engage in appropriate treatment strategies for individual patients earlier in their course.

BACKGROUND:Evans syndrome (ES) is a rare immune-mediated disorder involving two or more cytopenias, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia, and/or immune neutropenia. ES may occur secondary to another condition or be idiopathic. While consensus recommendations exist for adults, there is no standardized diagnostic approach for pediatric Evans syndrome (pES). This study aimed to describe typical diagnostic evaluations conducted by clinicians caring for pES patients. METHODS:A cross-sectional survey of the Pediatric ITP Consortium of North America (ICON) assessed typical diagnostic workup for pES, the influence of clinical features on testing, evaluation for underlying disorders, including immune defects and autoimmune disease, subspecialty involvement, and genetic testing practices. RESULTS:Sixty percent (28/47) of respondents reported performing the same evaluation for all pES patients. There was no consensus on specific diagnostic tests. Providers consistently evaluated for autoimmune conditions, but varied in testing for inborn errors of immunity (IEI). Rheumatology and immunology were most often consulted. Most respondents (85%, n = 40) obtained genetic testing through commercial laboratories, frequently encountering insurance-related barriers. CONCLUSIONS:Even among experts, diagnostic approaches to pES vary widely. Standardized frameworks are needed to guide comprehensive evaluation for this complex disorder.

Patients with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) deficiency exhibit profound humoral immune dysfunction, yet the basis for the B-cell defect is not known. We observed a marked reduction in transitional-to-follicular (FO) B-cell development in patients with CTLA4 deficiency, correlating with decreased CTLA4 function in regulatory T cells, increased CD40L levels in effector CD4+ T cells, and increased mammalian target of rapamycin complex 1 (mTORC1) signaling in transitional B cells (TrBs). Treatment of TrBs with CD40L was sufficient to induce mTORC1 signaling and inhibit FO B-cell maturation in vitro. Frequent cell-to-cell contacts between CD40L+ T cells and immunoglobulin D-positive CD27- B cells were observed in patient lymph nodes. FO B-cell maturation in patients with CTLA4 deficiency was partially rescued after CTLA4 replacement therapy in vivo. We conclude that functional regulatory T cells and the containment of excessive T-cell activation may be required for human TrBs to mature and attain metabolic quiescence at the FO B-cell stage.

There are no agreed upon terminology to define "refractory" pediatric immune thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease-modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group.

Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2-year-old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants. IKZF1 variants could potentially lead to aberrant neutrophil chemotaxis and development of neutrophilic dermatoses. Long-term surveillance is required to monitor the development of hematologic malignancy, autoimmunity, immunodeficiency, and infection in patients with pathogenic IKZF1 germline variants.

Lupus anti-coagulant hypoprothrombinemia syndrome (LAHPS) is a rare condition that can be difficult to treat. It increases the risk of thrombosis and bleeding due to the presence of lupus anti-coagulant and factor II deficiency, respectively. There are a limited number of cases described in the literature. Herein we describe a case of LAHPS with bleeding symptoms as a first clinical manifestation of systemic lupus erythematosus (SLE) in an 8-year-old female. She has had multiple recurrences of her bleeding symptoms, requiring treatment with steroids, cyclophosphamide, mycophenolate mofetil, and rituximab. Her course was later complicated by development of arthritis and lupus nephritis. Her complicated course provides a new perspective on the clinical course and treatment of LAHPS. We also present a comprehensive literature review which demonstrates the difficulty in treating patients with LAHPS with underlying SLE and the variability of the clinical course and management of LAHPS depending on the age at presentation.