Somatic, gain-of-function mutations in the PIK3CA gene can result in a range of vascular malformations (VMs). These rare disorders include lymphatic anomalies and PIK3CA-related overgrowth spectrum (PROS). Inhibition of wild-type PI3Kα results in significant toxicity, including hyperglycemia, diarrhea and rash. RLY-2608 is a novel, allosteric, pan-mutant and isoform-selective oral PI3Kα inhibitor designed to have higher potency and improved tolerability. In a PIK3CA H1047R HUVEC xenograft mouse model, RLY-2608 demonstrated greater lesion regression and less insulin induction across clinically relevant dose levels than alpelisib. ReInspire (NCT06789913) is an ongoing global, 3-part study (n=277) in patients ≥2 years with PIK3CA-driven VMs to assess the safety, tolerability, pharmacokinetics, recommended adult and pediatric dosing, and efficacy of RLY-2608 based on target lesion volume by blinded independent central review and age-appropriate clinical outcome assessments. The trial includes open-label dose selection (Part 1), open-label dose expansion (Part 2), and a double-blinded, placebo-controlled, 2:1 randomized study (Part 3). The majority of patients must have a documented activating PIK3CA mutation per local assessment of lesional tissue and/or cell-free DNA from the lesion or blood, and severe, symptomatic, and/or progressive disease. Patients ≥12 years are now enrolling in Part 1. For more information, contact clinicaltrials@relaytx.com.

Pyogenic granulomas (PGs) are benign vascular tumors that present as rapidly growing, friable papules that often bleed and cause cosmetic disfigurement. PGs generally respond well to treatments such as excision, laser, cryotherapy, topical imiquimod, and topical timolol, but agminated PGs can be distressing to patients and challenging to treat. Topical sirolimus, an mTOR inhibitor, is used in the treatment of other vascular anomalies but has not been previously investigated for use in PGs. We report two patients with agminated PGs who demonstrated improvement in size, color, and bleeding following treatment with topical sirolimus.

Patients with vascular anomalies (VAs) require expert multidisciplinary care. No prior studies have characterized the sociodemographic characteristics across multiple VA centers. We collected data on 5783 patients receiving care at 20 VA centers between July 1, 2020 through December 31, 2022. Male patients were underrepresented compared to the state-level census data at 17/20 centers. Black and Asian patients were underrepresented at 14/20 and 12/20 centers, respectively. The median distance to the hospital was 48 miles, and median age was 12.0 years. These data suggest that race, sex, age, and distance from the hospital could impede the ability to access expert VA care.

Many pediatric patients with leukemia undergo lumbar punctures (LP) for intrathecal (IT) chemotherapy. Patients who experience post-LP headaches may be suffering from intracranial hypotension due to persistent leakage of cerebrospinal fluid through the meninges. The purpose of this study was to analyze clinical features of intracranial hypotension secondary to LP. This IRB-approved retrospective, single-center study included patients aged of 5-21 with an oncologic condition who experienced a neurologic complication secondary to LP. Five patients were identified with a diagnosis of intracranial hypotension in the setting of a recent LP. Patients reported postural headache on average 3.8 days after receiving IT methotrexate. Brain magnetic resonance imaging confirmed diagnosis. Three of the five patients received an epidural blood patch with resolution. The additional two patients were treated with intravenous caffeine and dihydroergotamine. Many patients showed resolution of symptoms with treatment. Future studies would investigate optimal management strategies for pediatric patients with persistent symptoms.

BACKGROUND:Lung disease is a major cause of morbidity and mortality in children with sickle cell disease (SCD), a condition that is more common in individuals of African American descent. Spirometry is utilized in monitoring lung health. Recently, the American Thoracic Society recommended the use of race-neutral predictive equations. We aimed to evaluate how the use of race-neutral equations may affect spirometry results and interpretation in children with SCD. METHODS:This retrospective study included children aged 5-21 years with SCD followed at Arkansas Children's Hospital (01/01/2000-06/30/2023) who had completed at least one spirometry. Percent predictive (pp) and z-score values were calculated using race-adjusted and race-neutral predictive equations. Absolute and relative differences were calculated. Percent of subjects with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) with z-score <-1.645 and pp < 80%, and FEV1/FVC z-score < -1.645 were compared. Severity of impairment based on z-score was compared. RESULTS:One hundred children completed 460 spirometries. Transitioning from race-adjusted to race-neutral equations resulted in [mean (SD)]: a decrease in ppFEV1 [-9.497% (2.8344)], FEV1 z-score [-0.723 (0.2286)], ppFVC [-10.08% (3.3440)], FVC z-score [-0.750 (0.2757)], FEV1/FVC z-score [-0.057 (0.05461)], and an increase in ppFEV1/FVC [0.2785 (0.3921)]. Transitioning from race-adjusted to race-neutral equations resulted in an increase of impairment for FVC and FEV1 and a threefold increase in subjects with abnormal values. CONCLUSIONS:Adoption of race-neutral reference equations resulted in a decrease in FEV1 and FVC values (z-scores and percent predicted) and an increase in severity of impairment.

Importance:Adverse childhood experiences (ACEs) are associated with poor health care use. In African American communities, where ACEs are more prevalent, it is critical to understand the association of ACEs with chronic illnesses, such as sickle cell disease (SCD), in children to expand trauma-informed care and improve outcomes. Objective:To examine the association between parental ACEs and health care use in pediatric patients with SCD, accounting for factors that may influence this association. Design, Setting, and Participants:This unblinded cross-sectional study was conducted from January 1, 2020, to December 31, 2023, at Arkansas Children's Hospital. Seventy-two of 77 approached caregivers (93.5%) participated. All resided within the Arkansas Children's Hospital catchment area. Exposure:Parental ACEs and resiliency were assessed using the Adverse Childhood Experiences Questionnaire (ACE-Q) and the Brief Resiliency Scale, respectively. Neighborhood deprivation was assessed using the Area Deprivation Index (ADI). Main Outcomes and Measures:Primary outcomes included number of visits to the emergency department (ED), number of missed clinic visits, and medication adherence (categorical outcomes). Independent variables included parental ACEs, parental resilience, and neighborhood ADI. Coefficients were derived from mixed regression models. Results:The final sample included 79 observations (mean [SD] patient age, 9.73 [4.88] years; 44 [55.7%] female) from 72 caregivers (6 reporting for >1 child), with 70 (88.6%) of ACE-Q respondents being mothers. The ACE risk was low in 32 caregivers (40.5%), intermediate in 33 (41.8%), and high in 14 (17.7%). Patients whose caregivers were at high risk had significantly more ED visits and admissions compared with those whose caregivers were at low risk (regression coefficient = 7.35; 95% CI, 1.77-12.94). Likewise, the number of ED visits and admissions was higher among patients whose caregivers had lower resiliency compared with those with more resilient caregivers (regression coefficient = 5.69; 95% CI, 0.13-11.26). ADI was not significantly associated with ED visits and admissions (regression coefficient = -0.02; 95% CI, -0.12 to 0.08). Parental ACEs were not significantly associated with other metrics of health care use. Conclusions and Relevance:This cross-sectional study of ACEs and resiliency in parents of children with SCD found that higher levels of parental ACE scores and lower resiliency were associated with visits to the ED. These findings support the importance of screening caregivers for ACEs and resilience to enhance trauma-informed care, particularly in marginalized populations.

A State of the Art lecture titled "Anticoagulation and Vascular Anomalies" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2023. Vascular anomalies have been classified by the International Society for the Study of Vascular Anomalies into vascular tumors and vascular malformations. Although some vascular tumors, such as tufted angioma and kaposiform hemangioendothelioma, and other vascular malformations can present with coagulation aberrancies, these are not generally managed with anticoagulation. A subclassification of vascular malformations includes slow-flow vascular malformations. It is this subgroup specifically that has a high risk of venous thromboembolism (VTE) and morbidity associated with coagulopathy that may be present. In these select cases, anticoagulation may be indicated to reduce the risk of VTE, treat VTE, or manage localized thrombosis in the malformation that causes significant pain and reduced quality of life. There are established risk factors for VTE in these patients that will be reviewed. Finally, we summarize relevant new data on this topic presented during the 2023 ISTH Congress.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

Introduction: Kidney transplant has been shown to be the best treatment for children with end-stage kidney disease. Graft thrombosis is a well-recognized complication following kidney transplant and is one of the leading causes of early graft loss. Hypercoagulability has been implicated as a risk factor leading to graft thrombosis. Pre-transplant hypercoagulability evaluation can guide prophylactic strategies to mitigate thrombotic events and early graft loss, yet utility of universal screening for hypercoagulability in the pre-transplant population remains controversial. We report a single center experience of standardized pre-transplant thrombophilia screening and corresponding antithrombotic prophylaxis regimens that were implemented to predict and prevent thrombosis in pediatric kidney transplant (PKT) recipients. Methods: This is an IRB-exempt, single institution, quality improvement study of PKT recipients who underwent pre-transplant hypercoagulable evaluations to assess thrombotic risk at 6 months post-kidney transplant between 2017-2024. Data collected included personal and family history of thrombosis and laboratory tests for thrombophilia, including lipoprotein(a), serum homocysteine, factor VIII activity, protein C functional activity, protein S functional activity and free antigen, antithrombin III, antiphospholipid antibody panel, factor V Leiden and prothrombin gene mutation. Risk level for hypercoagulability concern was assessed based on history and laboratory results. Hematology recommendations were as follows: no antithrombotic therapy following transplant (Category 1: no history of thrombosis or laboratory abnormalities), prophylaxis with low-dose aspirin (LDA) post-transplant (Category 2: no history of thrombosis and 1-2 minor risk factors), or prophylaxis with heparin/Lovenox post-transplant (Category 3: personal history of thrombosis, major laboratory risk factor or >2 minor laboratory risk factors). Postoperative outcomes were focused on bleeding and clotting complications. Results: Among the 44 patients, the median age was 7 years (range: 1-18), with approximately 80% being male. Congenital anomalies of the kidney and urinary tract were present in 29 patients (65%). Eighteen patients fell into Category 1, with 10 of them initiated on LDA and one on clopidogrel despite hematology recommendations of no antithrombotic therapy. Category 2 included 20 patients, with 17 who received prophylaxis with LDA, one with clopidogrel, and two with no thromboprophylaxis. Category 3 comprised 6 patients (4 with a prior history of thrombosis), with 5 on Lovenox and one on LDA. Two patients experienced both bleeding and thrombosis and one patient with thrombosis only. All 3 patients received LDA due to their risk factor categorization. Patient #1 initially received heparin due to an intra-operative renal artery clot and was later transitioned to Lovenox before being switched to LDA prior to discharge. Around one month post-op, the patient developed bleeding around his central line, at which time LDA was discontinued. Patient #2 had focal segmental glomerulosclerosis (FSGS) with nephrotic range proteinuria at the time of transplantation and underwent kidney biopsy, which confirmed recurrence of FSGS. Her post-op course was further complicated by hematoma around the biopsy site, requiring surgical evacuation and eventually embolization. A superficial vein thrombus was simultaneously found during evacuation of the hematoma. Additionally, she required numerous blood product transfusions during this time. Patient #3 developed a portal vein thrombus less than one month post-transplant and was transitioned to Lovenox. Of note, two of the above patients with thrombotic events had elevated lipoprotein(a). Fortunately, there were 15 other patients in our study with elevated Lp(a), in whom thrombosis was successfully prevented with the use of antithrombotic therapy. Conclusion: Our findings highlight the critical role of pre-transplant hypercoagulability evaluation in predicting and managing thrombosis risk in pediatric kidney transplant recipients. There were few bleeding and thrombotic complications, and these did not compromise transplant outcomes. Effective pre-transplant assessment and tailored prophylactic strategies are essential in reducing thrombotic risks and optimizing kidney transplant outcomes.

BACKGROUND:There are very few large population-based studies studying mental health in persons with von Willebrand disease (PwVWD). OBJECTIVES:We aim to assess prevalence of depression and anxiety in PwVWD over a period of 20 years and identify bleeding symptoms that may be more likely associated with depression and anxiety in PwVWD. METHODS:This is a retrospective cohort study using a deidentified national dataset from 1118 hospitals with 176 million patients. Cases were defined as patients aged 0-110 years, both male and female, with von Willebrand disease (VWD), without hemophilia. Controls were defined as patients aged 0-110 years, both male and female, without VWD or hemophilia. We compared rates of depression and anxiety in cases and controls and by type of bleeding symptoms. RESULTS:We identified 66 367 PwVWD and 183 890 766 controls. The prevalence of depression (23.12% vs 8.62%; p ≤ .00093; relative risk = 2.68) and anxiety (32.90% vs 12.29%; p ≤ .00093; relative risk = 2.68) was higher in PwVWD. Most of the bleeding symptoms were associated with higher rates of depression and anxiety in PwVWD with the highest rates with abnormal uterine bleeding, hematemesis, hemoptysis, hematuria, and melena. CONCLUSION:Our study shows that mental health disorders in PwVWD are a significant health burden, and that burden is increased with documented bleeding symptoms. It is important that primary care physicians and hematologists caring for this population recognize this increased risk and appropriately screen and refer to mental health professionals.