Mental health in persons with von Willebrand disease in the United States - a large national database study.

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.

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

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.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Barriers to Genetic Testing in Vascular Malformations.

Importance: Vascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options. Objectives: To examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM. Design, Setting, and Participants: This survey study invited members of the Pediatric Hematology-Oncology Vascular Anomalies Interest Group, representing 81 vascular anomaly centers (VACs) serving individuals up to 18 years of age, to complete an electronic survey. Respondents were mostly pediatric hematologists-oncologists (PHOs) but included geneticists, genetic counselors, clinic administrators, and nurse practitioners. Responses that were received between March 1 and September 30, 2022, were analyzed with descriptive methods. Requirements for genetic testing by several genetics laboratories were also reviewed. Results were stratified by size of the VAC. Main Outcomes and Measures: Vascular anomaly center and associated clinician characteristics and practice patterns for ordering and obtaining insurance approval for genetic testing for VMs were collected. Results: Responses were received from 55 of 81 clinicians, for a response rate of 67.9%. Most respondents were PHOs (50 [90.9%]). Most respondents (32 of 55 respondents [58.2%]) replied that they order genetic testing on 5 to 50 patients per year and reported a genetic testing volume increase of 2- to 10-fold over the past 3 years (38 of 53 respondents [71.7%]). Most testing was ordered by PHOs (35 of 53 respondents [66.0%]), followed by geneticists (28 [52.8%]) and genetic counselors (24 [45.3%]). In-house clinical testing was more common at large and medium-sized VACs. Small VACs were more likely to use oncology-based platforms, which potentially miss low-frequency allelic variants in VM. Logistics and barriers varied by size of the VAC. Obtaining prior authorization was the duty shared among PHOs, nurses, and administrative staff, but the burden of insurance denials and appeals were on PHOs (35 of 53 respondents [66.0%]). Lack of administrative support; unclear institutional, insurance, and laboratory requirements; and lack of clinician education were barriers to genetic testing at VACs of all sizes. The effort to obtain genetic testing for patients with VM, compared with patients with cancer, was perceived as excessive, despite genetic testing being considered standard of care for this population. Conclusions and Relevance: Results of this survey study showed the barriers to genetic testing for VM across VACs, described differences between VACs based on size, and proposed multiple interventions to support clinicians ordering genetic testing for VM. The results and recommendations should have broader application to clinicians caring for patients for whom molecular diagnosis is important to medical management.

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

Pupil Size and Reactivity in Pediatric Patients With Sickle Cell Disease.

Pupil size and reactivity have been studied to objectively measure pain utilizing pupillometry measurements. Given the challenges associated with treating vaso-occlusive pain in pediatric patients with sickle cell disease, better assessment tools are needed. The objective of this study is to establish normative values for pupil size and reactivity in pediatric patients with sickle cell disease with the hope that pupillometry can be used as a tool to objectively measure pain and response to treatment with analgesic medications. Readings were performed using a NeurOptics PLR-2000 pupillometer. Forty-four males and 38 females, all black, were studied. Their median age was 11 years (range: 2 to 21). When comparing our participants with white participants in a previously published pediatric study, there was a significant difference in maximum constriction velocity ( t =3.45, P =0.009), maximum pupil size ( t =-5.57 mm, P <0.0001), and minimum pupil size ( t =-3.24, P =0.002). There was no significant difference in pupil size and reactivity between patients with sickle cell disease and black patients without the disease when compared with the previously published study. Therefore, further investigation of pupillometry within the black population during vaso-occlusive crisis and in the "well state" is warranted in pediatric patients with sickle cell disease.

How we approach coagulopathy with vascular anomalies.

Some vascular anomalies can present with challenging hematologic aberrations. Kaposiform hemangioendothelioma (KHE) may be complicated with Kasabach-Merritt phenomenon (KMP) and stagnant blood flow in slow-flow malformations can promote activation and consumption of coagulation factors, which results in bleeding and clotting known as localized intravascular coagulopathy (LIC). These patients can experience significant morbidity secondary to pain due to thrombosis and are at higher risk of hematologic complications during surgical procedures. No standard of care has been established to prevent or manage these complications. This review focuses on the management of coagulopathy in children and adults with vascular anomalies.

Pharmacokinetics of bleomycin sclerotherapy in patients with vascular malformations.

Bleomycin, a chemotherapy agent that inhibits synthesis of DNA, has been increasingly utilized in sclerotherapy for patients with vascular malformations. A serious long-term risk of intravenous bleomycin is dose-dependent interstitial pneumonitis. Little is known about absorption and circulating levels of bleomycin when used in sclerotherapy for patients with vascular malformations. This is an Institutional Review Board (IRB)-approved prospective study on patients receiving bleomycin sclerotherapy in the management of vascular malformations. Depending on the type of vascular malformation, bleomycin was administered either in the lumen or interstitial space of the involved lesion. A bleomycin assay measured serum bleomycin plasma concentrations versus time at seven intervals following treatment. Pharmacokinetic parameters were obtained for each participant and included peak plasma concentration (Cmax ), time to reach peak plasma concentration (Tmax ), volume of distribution (Vd ), elimination half-life (t1/2 ), the volume of plasma cleared of the drug per unit time (CL), and total systemic exposure area under the curve (AUC). Fifteen patients were enrolled (5: lymphatic, 4: venous, 6: arteriovenous malformations). Bleomycin was administered interstitially (IS) in 11 patients and intraluminal (IL) in four; median age of 13 years (range: 2-67). Pharmacokinetic analysis revealed terminal elimination half-life (t1/2λz ) of 88.51 (±23.09) and 111.61 (±37.75) minutes for the IS and IL groups, respectively. Vd was 4.86 L (±6.74) and 1.55 L (±0.54) for the IS and IL groups, respectively. AUC was 53.9 (±23.45) and 129.17 (±93.57) mg min/L for the IS and IL groups, respectively. There were no statistically significant differences in t1/2λz , Vd , or AUC parameters between groups. Bleomycin is absorbed systemically when used as a sclerosant for vascular malformations when injected either IS or IL.

Analyzing coagulation dynamics during treatment of vascular malformations with thromboelastography.

BACKGROUND/OBJECTIVES: Slow-flow vascular malformations are abnormal vessels that can lead to activation and consumption of coagulation factors and thrombosis, known as localized intravascular coagulopathy (LIC). Most clinical and research evidence of vascular malformation hemostasis relies on conventional coagulation studies, which may not provide a complete picture. Thromboelastograpy (TEG) is a tool that can provide real-time assessment of a patient's coagulation dynamics, and may allow for a more individualized treatment approach. We hypothesized that patients with slow-flow vascular malformations will have changes in TEG parameters peri-procedure that will help predict blood product or medication administration. DESIGN/METHODS: Institutional Review Board approved prospective study of patients with slow-flow vascular malformations undergoing a sedated, minor procedure. TEG and conventional coagulation studies were obtained preprocedure, 15 min, and when possible, at 30 min after the start of the procedure. RESULTS: Twenty-five patients were enrolled. Median age was 15 years (range 3-47 years). Procedures included laser and/or sclerotherapy. There were no changes in TEG parameters from baseline to 15 min or 30 min. The following decreased from baseline to 15 min: fibrinogen 313 to 287 mg/dL (P = .001), D-dimer 1.3 to 1.1 mg/L (P = .02), hemoglobin 12.8 to 11.8 g/dL (P = .001), and platelet count 272 000 to 256 000 (P = .006). No patient had a bleeding/thrombotic complication during or within 1 week postprocedure. CONCLUSION: We saw no change in TEG parameters or bleeding or clotting complications despite significant numerical changes in conventional coagulation profiles, suggesting that conventional studies may not be as useful in determining risks of bleeding or thrombotic complications peri-procedure for minor procedures.

Effect of sirolimus on coagulopathy of slow-flow vascular malformations.

BACKGROUND/OBJECTIVES: Stagnant blood flow present in slow-flow vascular malformations can lead to localized intravascular coagulopathy (LIC), measured by elevated D-dimer levels, low fibrinogen, and/or thrombocytopenia. LIC can lead to localized thrombosis and/or bleeding, resulting in pain, swelling, and functional limitations. Patients with complex vascular malformations treated with sirolimus show clinical improvement in these symptoms. We hypothesized that the clinical benefits of sirolimus may correlate with improvements in coexisting LIC. DESIGN/METHODS: A retrospective chart review was performed, including D-dimer, fibrinogen, and platelet count, in patients with slow-flow vascular malformations treated with sirolimus. Laboratory values were assessed at three time points (presirolimus, 1-3 months postsirolimus, and last clinic visit). Clinical response, as defined by decreased pain and swelling, was extracted from the record. RESULTS: Thirty-five patients at our vascular anomalies center had been prescribed sirolimus between 2014 and 2017. Fifteen patients (12 combined slow-flow vascular malformations and three pure venous malformations) remained after excluding patients that did not have adequate records or a venous component to their vascular malformation. Patients who did not adhere to the treatment were also excluded. All 15 had elevated D-dimer levels prior to treatment and there was a statistically significant decrease in D-dimer levels following treatment with sirolimus. Symptomatic improvement of pain and swelling was reported after 3 months of starting sirolimus in 13/15 patients. CONCLUSION: This study suggests that sirolimus improves coagulopathy in slow-flow vascular malformations, as evidenced by reduced D-dimer levels. Improvement in LIC symptoms also correlates with sirolimus-corrected coagulopathy.

Cancer Risk in Klippel-Trenaunay Syndrome.

Background: Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome defined by capillary/venous/lymphatic malformations (CVLM) with soft tissue and/or bone hypertrophy. Whether KTS predisposes to cancer is not clear. Methods and Results: We surveyed members of the K-T Support Group (KTSG) and reviewed PubMed for "Klippel Trenaunay Syndrome" or "CVLM" and "cancer." Individuals with cancer were reviewed for confirmation of KTS, tumor type, location, and age at presentation. Of 223 KTSG respondents, 24 (10.8%) reported 26 malignancies or benign brain tumors (diagnosed from 6 months to 68 years of age, median 41 years), including 3 who were younger than 18 years (2 with Wilms tumor). Nine of twenty-six cancers were basal cell carcinomas (4% of respondents). From 475 articles, we identified 11 cancers or brain tumors in 10 individuals with KTS. Four of these were in children (Wilms tumor n = 2; rhabdomyosarcoma n = 1; serous borderline tumor n = 1). Tumors in adults included basal cell carcinoma (n = 1), squamous cell carcinoma of skin (n = 2), and angiosarcoma, Hodgkin disease, glioblastoma, malignant hemangiopericytoma in one patient each. Ulceration or lymphedema associated with VLM or capillary malformations were associated with some basal cell or squamous cell carcinomas and angiosarcomas. Conclusions: The risk of embryonal cancer other than Wilms tumor in children with KTS does not appear to be higher than in the general population. Wilms tumor incidence is under 5%, and routine surveillance is not indicated. In adults, particular attention should be paid to skin in the area of malformations. These conclusions may not apply to all overgrowth syndromes with vascular malformations.

Second-line treatments in children with immune thrombocytopenia: Effect on platelet count and patient-centered outcomes.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and hemorrhagic risk. While many children with ITP can be safely observed, treatments are often needed for various reasons, including to decrease bleeding, or to improve health related quality of life (HRQoL). There are a number of available second-line treatments, including rituximab, thrombopoietin-receptor agonists, oral immunosuppressive agents, and splenectomy, but data comparing treatment outcomes are lacking. ICON1 is a prospective, multi-center, observational study of 120 children starting second-line treatments for ITP designed to compare treatment outcomes including platelet count, bleeding, and HRQoL utilizing the Kids ITP Tool (KIT). While all treatments resulted in increased platelet counts, romiplostim had the most pronounced effect at 6 months (P = .04). Only patients on romiplostim and rituximab had a significant reduction in both skin-related (84% to 48%, P = .01 and 81% to 43%, P = .004) and non-skin-related bleeding symptoms (58% to 14%, P = .0001 and 54% to 17%, P = .0006) after 1 month of treatment. HRQoL significantly improved on all treatments. However, only patients treated with eltrombopag had a median improvement in KIT scores at 1 month that met the minimal important difference (MID). Bleeding, platelet count, and HRQoL improved in each treatment group, but the extent and timing of the effect varied among treatments. These results are hypothesis generating and help to improve our understanding of the effect of each treatment on specific patient outcomes. Combined with future randomized trials, these findings will help clinicians select the optimal second-line treatment for an individual child with ITP.

Multiple Autoimmune Disorders in Aicardi-Goutières Syndrome.

BACKGROUND: Aicardi-Goutières syndrome is an early-onset encephalopathy with presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. It is a model disease to study systemic autoimmunity, and there are many clinical, genetic, and basic science considerations that underline a possible overlap between Aicardi-Goutières syndrome and systemic lupus erythematosus. RESULTS: We describe a 15-year-old girl with Aicardi-Goutières syndrome due to compound heterozygous pathogenic variants in SAMHD1 (sterile alpha motif domain and HD domain-containing protein 1). Over time, she developed multiple autoimmune diseases (vitiligo, alopecia areata, immune thrombocytopenia, positive antithyroglobulin antibodies) without positive antinuclear antibody or features of systemic lupus erythematosus. Her thrombocytopenia was refractory to treatment with corticosteroids and intravenous immunoglobulin but responded to a standard course of rituximab. CONCLUSION: This is the first report of a multiple autoimmune syndrome in a patient with molecularly proven Aicardi-Goutières syndrome. This study illustrates an emerging pattern of the natural history of Aicardi-Goutières syndrome characterized by early encephalopathic presentation followed by symptoms of systemic autoimmunity.

Physician decision making in selection of second-line treatments in immune thrombocytopenia in children.

Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P = .003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P < .001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P < .001). Physicians chose rituximab in patients with lower expected adherence (P = .017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.

Effectiveness and Safety of Treatment with Direct Oral Anticoagulant Rivaroxaban in Patients with Slow-Flow Vascular Malformations: A Case Series.

BACKGROUND: Slow-flow vascular malformations (VM) can be associated with localized intravascular coagulopathy (LIC) that is characterized by elevated D-Dimer levels and low fibrinogen and platelets. This can lead to bleeding and clotting tendencies, which can give rise to functional limitations such as pain and swelling and even progress to disseminated intravascular coagulopathy. METHODS AND RESULTS: We conducted a chart review of four patients with evidence of LIC who were started on rivaroxaban. We found an improvement of D-Dimer and/or fibrinogen levels in all four patients. They also had an improvement of pain and functionality. CONCLUSIONS: We report on four patients in whom anticoagulation with a direct oral anticoagulant, rivaroxaban, was effective in controlling signs and symptoms of consumptive coagulopathy with no evidence of bleeding from the use of rivaroxaban.

Short-term side effects and patient-reported outcomes of bleomycin sclerotherapy in vascular malformations.

BACKGROUND: Vascular malformations (VM) are congenital lesions that can be debilitating and cause significant aesthetic and functional limitations. The chemotherapeutic agent bleomycin has been utilized as a sclerosant, directly injected percutaneously into the VM. Unfortunately, little is known about the benefits and short-term side effects of bleomycin with intralesional injections. PROCEDURE: An IRB approved, retrospective chart review was performed on patients with VM who had been treated with intralesional bleomycin. Data included type of VM, number of treatments, total bleomycin dose per m², and adverse effects. A questionnaire was administered to available patients to assess subjective outcomes and side effects. RESULTS: Forty-six patients were treated with 141 procedures of bleomycin sclerotherapy for VM. Patient ages ranged from 1 to 20 years (median age 10 years). The median cumulative bleomycin dose was 16.3 units/m²/person (range of 1.7-97.0 units/m²/person). Sixty-three percent of patients were reached for a questionnaire to assess short-term side effects. Ninety percent of patients surveyed were satisfied to very satisfied with the results from the procedure. About 24% of patients experienced transient nausea, vomiting and/or local hyperpigmentation. CONCLUSION: Bleomycin sclerotherapy can be an effective treatment of VM with repeat exposure with minor risk of short-term side effects, however, long-term risks are of great concern. Further studies are required to assess systemic absorption and long-term risks.

Autoimmune Lymphoproliferative Syndrome Masquerading as Posttransplant Lymphoproliferative Disorder.

We present a case of a 2-year-old female presenting with diffuse lymphadenopathy 2 years following orthotopic heart transplant. Initially, she was diagnosed with posttransplant lymphoproliferative disease based on clinical presentation and pathology and she was treated accordingly. Because of persistent lymphadenopathy following the completion of chemotherapy and new onset of autoimmune cytopenias, repeat flow of the lymph node showed an elevated double negative T-cell population prompting evaluation for autoimmune lymphoproliferative syndrome (ALPS). A complete workup was confirmative of a germline Fas mutation consistent with ALPS-FAS. This case emphasizes the importance of considering ALPS-FAS in a patient with lymphadenopathy of unknown cause.

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSßspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.

Hematologic outcomes after total splenectomy and partial splenectomy for congenital hemolytic anemia.

PURPOSE: The purpose of this study was to define the hematologic response to total splenectomy (TS) or partial splenectomy (PS) in children with hereditary spherocytosis (HS) or sickle cell disease (SCD). METHODS: The Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium registry collected hematologic outcomes of children with CHA undergoing TS or PS to 1 year after surgery. Using random effects mixed modeling, we evaluated the association of operative type with change in hemoglobin, reticulocyte counts, and bilirubin. We also compared laparoscopic to open splenectomy. RESULTS: The analysis included 130 children, with 62.3% (n=81) undergoing TS. For children with HS, all hematologic measures improved after TS, including a 4.1g/dl increase in hemoglobin. Hematologic parameters also improved after PS, although the response was less robust (hemoglobin increase 2.4 g/dl, p<0.001). For children with SCD, there was no change in hemoglobin. Laparoscopy was not associated with differences in hematologic outcomes compared to open. TS and laparoscopy were associated with shorter length of stay. CONCLUSION: Children with HS have an excellent hematologic response after TS or PS, although the hematologic response is more robust following TS. Children with SCD have smaller changes in their hematologic parameters. These data offer guidance to families and clinicians considering TS or PS.