Faculty Bibliography

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 Guidelines are therefore limited to arbitrary and outdated definitions.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.

Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.

Despite availability of epidemiologic studies and national guidelines for the management of newly diagnosed pediatric immune thrombocytopenia (ITP), practice variation exists among and within hematology practices. We previously described the development of an ITP pathway guiding management based on bleeding symptoms. Over an 8-year period, integration of this iterative ITP pathway into management of newly diagnosed ITP increased observation rates in children with no or mild bleeding symptoms and improved consistency of laboratory evaluation and treatment strategies without increasing adverse outcomes. This quality improvement initiative has been sustainable, acceptable to providers, and increased adherence to guidelines.

BACKGROUND:Venous thromboembolism is a significant cause of postoperative death and morbidity. While prophylactic and treatment regimens exist, they usually come with some risk of clinically relevant bleeding and, thus, must be considered carefully for each individual patient. METHODS:This special topic article represents a review of current evidence regarding venous thromboembolism risk, biology, and prevention in plastic surgery patients. The specific types and duration of available prophylaxis are also reviewed. The balance of venous thromboembolism risk must be weighed against the risk of hemorrhage. RESULTS:Though alternatives exist, the most validated risk assessment tool is the 2005 modification of the Caprini Risk Assessment Model. Controversies remain regarding recommendations for outpatient and low risk cosmetic patients. The authors additionally make recommendations for high-risk patients regarding the use of tranexamic acid, estrogen therapy, anesthesia, and prophylaxis regimens. CONCLUSION/CONCLUSIONS:The authors have made great strides in understanding the science behind venous thromboembolism, risk stratification for patients, and prophylactic regimens; yet, continued studies and definitive data are needed.