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Hemophilia A is an X-linked disorder characterized by quantitative deficiency of coagulation factor VIII (FVIII) caused by pathogenic variants in the factor 8 (F8) gene. Our study's primary objective was to identify genetic variants within the exonic region of F8 in 50 Colombian male participants with severe hemophilia A (HA). Whole-exome sequencing and bioinformatics analyses were performed, and bivariate analysis was used to evaluate the relationship between identified variants, disease severity, and inhibitor risk formation. Out of the 50 participants, 21 were found to have 17 different pathogenic F8 variants (var). It was found that 70% (var = 12) of them were premature truncation variants (nonsense, frameshift), 17.6% (var = 3) were missense mutations, and 11.7% (var = 2) were splice-site variants. Interestingly, 35% (var = 6) of the identified variants have not been previously reported in the literature. All patients with a history of positive inhibitors (n = 4) were found to have high-impact genetic variants (nonsense and frameshift). When investigating the relationship between variant location (heavy versus light chain) and specific inhibitor risk, 75% (n = 3) of the inhibitor participants were found to have variants located in the F8 light chain (p = 0.075), suggesting that conserved domains are associated with higher inhibitor risk. In summary, we identified genetic variants within the F8 that can possibly influence inhibitor development in Colombian patients with severe HA. Our results provide a basis for future studies and the development of further personalized treatment strategies in this population.

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Anemia is the most common hematologic abnormality identified in children and represents a major global health problem. A delay in diagnosis and treatment might place patients with anemia at risk for the development of rare but serious complications, including chronic and irreversible cognitive impairment. Identified risk factors contributing to the development of anemia in children include the presence of nutritional deficiencies, environmental factors, chronic comorbidities, and congenital disorders of hemoglobin or red blood cells. Pediatricians, especially those in the primary care setting, serve a particularly critical role in the identification and care of those children affected by anemia. Prompt recognition of these risk factors is crucial for developing appropriate and timely therapeutic interventions and prevention strategies.

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OBJECTIVES: We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates. METHODS: Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. RESULTS: A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%. CONCLUSIONS: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less.

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Coagulation factor VII (FVII) deficiency is a congenital disorder with heterogeneous clinical phenotypes ranging from asymptomatic to life-threatening bleeding and/or thrombotic events. We present the case of an adolescent male who developed acute deep and superficial venous thromboses of the upper extremities in the setting of multiple peripheral venous line insertions and shortly after receiving his second coronavirus disease of 2019 immunization dose. A hemostatic work-up revealed low FVII activity levels associated with 4 different FVII genetic variants. We highlight the need to better understand the pathophysiologic mechanisms behind FVII deficiency-associated prothrombotic risk and the role that specific FVII genetic variants may play in the clinical presentation of these patients.

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Background: Before the official US Food and Drug Administration approval in 2021, pediatric hematologists across the United States have used direct oral anticoagulants (DOACs) "off-label" and based on extrapolation from labeling for adults with venous thromboembolism (VTE) and interim results of pediatric-specific DOAC clinical studies. Objectives: The American Thrombosis and Hemostasis Network 15 (ATHN 15) study aimed to characterize the use of DOACs from 2015 to 2021 at 15 specialized pediatric hemostasis centers in the United States, with emphasis on safety and effectiveness. Methods: Eligible participants were those aged 0 to 21 years who had a DOAC included as part of their anticoagulation regimen for the treatment of acute VTE or secondary prevention of VTE. Data were collected for up to 6 months after initiation of the DOAC. Results: A total of 233 participants were enrolled, with a mean age of 16.5 years. Rivaroxaban was the most commonly prescribed DOAC (59.1%) followed by apixaban (38.8%). Thirty-one (13.8%) participants reported bleeding complications while on a DOAC. Major or clinically relevant nonmajor bleeding events occurred in 1 (0.4%) and 5 (2.2%) participants, respectively. Worsening menstrual bleeding was reported in 35.7% of females aged >12 years and occurred more frequently in those using rivaroxaban (45.6%) compared with apixaban (18.9%). The recurrent thrombosis rate was 4%. Conclusion: Pediatric hematologists at specialized hemostasis centers in the United States have been using DOACs for the treatment and prevention of VTEs, primarily in adolescents and young adults. Reported DOAC use showed adequate safety and effectiveness rates.

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Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative deficiencies in von Willebrand factor (VWF). People with VWD may experience excessive, recurrent or prolonged bleeding, particularly during menstruation, childbirth, surgery or following trauma. However, many VWD patients are undiagnosed, and therefore inadequately treated. Reasons for the underdiagnosis of VWD include its relatively mild symptoms, complex diagnosis, lack of awareness among non-specialist healthcare providers and the general population, and a lack of prioritisation of disorders disproportionately affecting females. The vwdtest.com platform was launched as part of a global initiative to raise awareness and improve diagnosis of VWD. Besides providing VWD-specific educational resources, the website includes an online bleeding self-assessment tool and offers diagnostic support for individuals, and their providers, who have a score suggestive of a bleeding disorder. vwdtest.com helps to address these unmet needs, especially in regions with limited access to educational and diagnostic resources.

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STUDY OBJECTIVE: To examine the clinical characteristics and prevalence of congenital bleeding disorders (CBDs), with emphasis on congenital factor VII (FVII) deficiency and other rare bleeding disorders, in adolescent and young adult females referred to a hemophilia treatment center (HTC) for evaluation and management of heavy menstrual bleeding (HMB) and iron deficiency anemia (IDA) DESIGN: In this single-center retrospective study, we reviewed the clinical characteristics and prevalence of CBDs in postmenarchal females, younger than 22 years of age, referred to an HTC from 2015 to 2021 for evaluation of HMB with or without IDA. RESULTS: One hundred females, with a mean age of 15 years (range 9-20 years), met initial study criteria, and 95 were included in the final analysis. Forty-five (47%) females were ultimately diagnosed with a CBD. The most prevalent diagnoses were FVII deficiency and type 1 von Willebrand disease (VWD) (42.3%, n = 19 each). Forty-two percent of patients with FVII deficiency had a low-for-age FVII activity level, 21.1% were only positive for the FVII R353Q variant associated with borderline FVII levels, whereas 36.8% had both a low-for-age FVII activity level and a positive R353Q variant. Eighty percent of patients with a CBD were found to have relatives with abnormal bleeding symptoms. CONCLUSION: Congenital FVII deficiency is prevalent among female adolescents experiencing HMB with or without IDA. In addition to VWD, evaluation for this specific factor deficiency should be considered as part of the initial CBD workup. Presence of abnormal bleeding history in the family could also help to predict presence of a CBD.

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INTRODUCTION: The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018. AIM: The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. RESULTS AND DISCUSSION: The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non-haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.

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Retinoblastoma (RB) is the most common intraocular pediatric malignancy. Advancements in intra-arterial chemotherapy (IAC) for treatment of RB have resulted in dramatic improvement in eye salvage rates. Data regarding IAC outcomes and associated hematologic toxicities are limited. The objective of this retrospective study was to analyze baseline characteristics, efficacy, and hematologic complications associated with IAC treatment in children with RB at a single international referral institution. Ninety-five sessions of IAC were performed in 28 patients. Mean age at RB diagnosis was 12.5 months (SD, 9.2 mo). Fourteen patients had bilateral RB. IAC agents included melphalan, carboplatin, and topotecan. The most common regimens were triple-agent IAC and single-agent melphalan (66.3% and 15.8%, respectively). Median number of IAC sessions was 3 (mean: 3.39, range: 1 to 9). Eye salvage rate was 83.7% with an overall survival rate of 100% at a median follow-up of 29 months (mean: 29.8 mo, range: 1 to 63 mo). A total of 26 patients (92.9%) experienced at least 1 hematologic toxicity during their treatment course Prevalence of neutropenia, anemia, and thrombocytopenia were 89.3%, 85.7%, and 25%, respectively. While IAC is effective in salvaging most eyes with advanced intraocular RB, over half of patients experienced clinically significant neutropenia and anemia. Clinicians should be vigilant in monitoring patients for IAC-related complications.

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Leukopenia, thrombocytopenia, elevated D-dimer, and prolonged prothrombin time are considered poor prognostic factors in adults with acute Coronavirus Disease 2019. The prognostic significance of these abnormalities among pediatric patients remains underreported in the literature. This retrospective cohort study evaluates the prognostic implications of hematologic and hemostatic derangements in patients younger than 22-years-of-age who were admitted to a tertiary-care referral institution for management of acute Coronavirus Disease 2019 infection. Leukopenia and thrombocytopenia were identified as independent prognostic factors of disease severity. Although the majority of children, with available results, had elevated D-dimer or prolonged prothrombin time upon initial presentation, these markers were not found to be associated with the development of severe clinical complications.

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Fibrinogen replacement therapy is a treatment mainstay for patients with afibrinogenemia and significant bleeding. A male infant with congenital afibrinogenemia and several spontaneous hemarthroses commenced cryoprecipitate prophylaxis but developed severe urticarial reactions. He transitioned to a human fibrinogen concentrate (HFC) (RiaSTAP® , CSL Behring; 70 mg/kg biweekly) but continued experiencing hemarthroses (estimated annualized bleeding rate [ABR]: 5-6) and severe anaphylactic reactions, despite pre- and postinfusion medications. Following switching to a new HFC (Fibryga® , Octapharma; 50 mg/kg biweekly), ABR was 0-1 with no further infusion reactions. Aged 9 years, because of limited quality of life, development of obesity and fatty liver disease, he underwent orthotopic liver transplant (OLT) under HFC coverage. Pharmacokinetic analysis guided presurgical fibrinogen levels > 150 mg/dL. No intraoperative HFC infusions were required. Coagulation profile and fibrinogen levels remained within normal limits during and posttransplant. To our knowledge, this is the first pediatric report of afibrinogenemia successfully treated with OLT.

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BACKGROUND AND OBJECTIVE: Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design. METHODS: Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date. RESULTS: The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations. CONCLUSIONS: The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.

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HBL is the most common malignant liver neoplasm in children. The etiology of HBL is largely unknown but there are certain syndromes, such as Beckwith-Wiedemann syndrome, that have been clearly associated with an increased incidence of this malignancy. EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions. Despite an improvement on the survival rates of patients with advanced-stage HBL, the presence of concomitant end-stage renal disease that occurs in patients with EBS constitutes a therapeutic challenge for the clinician not only due to the use of nephrotoxic chemotherapy but also due to the potential need for multi-organ transplant. We report case of a 2-year-old male patient with EBS diagnosed with stage IV, metastatic HBL successfully treated with multi-agent chemotherapy while on dialysis whom then underwent a simultaneous liver-kidney transplant followed by adjuvant chemotherapy. Ultimately, the patient achieved cancer remission with normalization of his renal function. Our report emphasizes that patients with HBL in the setting of EBS will not only require careful kidney function monitoring while receiving chemotherapy, but they might also need to undergo multi-organ transplantation in order to achieve adequate cancer control and also normalization of their kidney function. Awareness of this unusual association calls for further investigation to potentially establish a genetic association between these two disease processes.

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Improved life expectancy in hemophilia has led to a greater interest in age-related disorders. Hypertension (HTN) as well as cardiovascular disease have been increasingly reported in hemophilic adults but there is currently very limited data in the pediatric population. We conducted a cross-sectional study using data from the 2012 National Health Cost and Utilization Project database to determine the prevalence of HTN and associated cardiovascular risk factors in a hospitalized pediatric hemophilia population, between the ages of 0 to 21 years, in comparison with the general pediatric population. The prevalence of HTN was significantly higher in children with hemophilia (CWH) in comparison with the general pediatric population (1.71% vs. 1.02%, P-value=0.005). When adjusting the analysis for sex, the prevalence of HTN in the hemophilia cohort remained higher, although not statistically significant (1.52% vs. 1.22%, P-value=0.2568). When examining the concomitant presence of ≥1 cardiovascular risk factors in the hypertensive subgroups, CWH had a higher prevalence of obesity (2.64% vs. 1.32%, P-value <0.0001). Interestingly, diabetes mellitus was more prevalent in nonhemophilic children (1.47% vs. 0.56%, P-value=0.0015). These data suggest that cardiovascular risk factors need to be closely monitored in CWH, and a better preventive strategy is likely needed to identify those hemophilic patients at higher risk of developing cardiovascular disease in adulthood.

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BACKGROUND: Pericardial effusion (PE) is a known complication after hematopoietic stem cell transplant (HSCT). Limited data is currently available regarding the incidence and outcomes of PE in pediatric HSCT. METHODS: We conducted a retrospective study on a cohort of patients who underwent HSCT between 2004 and 2015. Risk factors associated with development of PE were evaluated. RESULTS: In 111 HSCT, stem cell source was bone marrow in 37 (33.3%), peripheral blood-42 (37.8%) and cord blood-32 (28.8%). Incidence of PE after HSCT was 37.8%. Insignificant effusion (trivial or small) was noted in 30 (27.0%) transplants, and significant (moderate or large) PE in 12 (10.8%). There were no associations between incidence of effusion and stem cell source, graft versus host disease or CMV infection. Risk factors associated with development of PE included systemic hypertension (P<0.05), total body irradiation (P<0.05), and sinusoidal obstruction syndrome formerly known as venoocclusive disease (P=0.03). Overall mortality was 22.5% after HSCT, but 38.1% among those with effusion (P<0.05). None of these deaths were attributed to primary cardiac etiologies. CONCLUSIONS: The incidence of PE in this cohort of pediatric HSCT recipients is high and associated with higher morbidity and mortality.

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