Primary Raynaud's phenomenon in an infant: a case report and review of literature

Raynaud's phenomenon (RP) is an extremely unusual finding in early infancy. In the present report we describe a one-month-old previously healthy male infant who presented with unilateral acrocyanosis. Although infantile acrocyanosis is known to be a benign and self-resolving condition, it is generally bilateral and symmetric. The unilateral nature of the acrocyanosis was an atypical finding in this infant. Consequently, he was closely monitored to evaluate the progression of his acrocyanosis. Based on his benign clinical course and failure to demonstrate other etiologies contributing to his acrocyanosis, he was diagnosed to have primary RP. Due to the rarity of RP in children, we review the progress in understanding the pathophysiology, epidemiology and management of RP and additionally discuss the differential diagnosis of unilateral and bilateral acrocyanosis in infants

Congenital Neutropenia with Specific Granulocyte Deficiency Caused by Novel Double Heterozygous SMARCD2 Mutations

SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) is critical for myelopoiesis. Recently, bi-allelic SMARCD2 mutations have been reported in five children, causing autosomal recessive congenital neutropenia with specific granulocytes deficiency (CN-SGD); a syndrome resulting in G-CSF resistant neutropenia, recurrent infections, and dysplastic myelopoiesis. We report a new case with CN-SGD caused by two novel heterozygous pathogenic variants in the SMARCD2 gene (c.1081del (p.Gln361Argfs*15)), and (c.217C>T (p.Arg73*)). Treatment with the weekly dosing of thrombopoietin receptor agonist, Romiplostim, along with daily G-CSF transformed her clinical course, implying potential synergism. This report advances the understanding of CN-SGD caused by SMARCD2 mutations

Successful medical management of a neonate with spontaneous splenic rupture and severe hemophilia A

Splenic rupture in neonates is a rare event, usually occurring in the setting of underlying predisposing conditions. Here, we present the case of a term neonate who presented with worsening anemia in the setting of known hemolytic disease during the newborn period and was later found to have a spontaneous splenic rupture. He was subsequently diagnosed with severe hemophilia A, and was managed medically with recombinant factor VIII replacement therapy without any surgical intervention. This is the first reported case of a neonate who had spontaneous splenic rupture and severe hemophilia A, and underwent successful medical treatment without any surgical intervention. Keywords: Factor VIII deficiency, Hemophilia A, Neonate, Splenic ruptur

Antiphospholipid Syndrome: Clinical Characteristics of Patients and Affected Family Members From Multiplex Families

Abstract Abstract 2972 Poster Board II-950 Background: Antiphospholipid syndrome (APS) is characterized by venous and/or arterial thromboembolic events, recurrent fetal loss, and persistently elevated antiphospholipid antibody (aPL) levels. Familial clustering of individuals with elevated aPL levels occurs, and up to 37% of patients with APS have one or more relatives with at least one clinical feature of APS. Individuals with elevated aPL levels or APS are also frequently identified in families with other autoimmune (AI) disorders, such as lupus or rheumatoid arthritis. Individuals with different autoimmune disorders appear to share common susceptibility loci, suggesting that a common set of susceptibility genes may contribute to clinically distinct autoimmune disorders. To investigate the heritability of APS, we are enrolling patients with APS who have one or more family members affected by APS (multiplex APS) or by other, non-APS, autoimmune disorders (multiplex AI). This study summarizes clinical characteristics of probands and family members enrolled to date in these two groups. Methods: Probands meeting clinical and laboratory criteria for APS (Miyakis, et al. J.Thromb.Haemost, 2006;4: 295-306) who had at least one clinically affected relative positive for either APS or another autoimmune disorder (e.g., lupus, rheumatoid arthritis) were recruited and enrolled into the study. A detailed personal and family history was obtained and relevant family members were also approached to participate in the study. Blood specimens were collected for genetic, serologic, and coagulation testing. Results: Review of more than 200 potential participants identified 13 probands with multiplex APS families and 49 with multiplex AI families. Probands from both groups more frequently had primary rather than secondary APS, and thromboembolic events were the most common clinical manifestation. Catastrophic APS was reported in 1 multiplex APS proband and 4 multiplex AI probands. Proband characteristics are summarized in the Table. In the multiplex APS families, 1 to 3 family members had APS, and the most common clinical manifestation was thromboembolism. In addition, 8 multiplex APS families also had one or more family members who were affected with other autoimmune disorders, most commonly lupus and rheumatoid arthritis. In the multiplex AI families, 1 to 8 family members were affected by a variety of autoimmune disorders, including lupus, Hashimoto's disease, Sjögren's syndrome, rheumatoid arthritis, myasthenia gravis, type I diabetes mellitus, and other diseases. Affected family members most commonly included siblings and/or parents of the probands. Conclusions: In the participants enrolled to date, probands with APS who belonged to multiplex APS or multiplex AI families most commonly had primary APS, and thromboembolic complications were the most common clinical manifestation. Families that were multiplex AI were more common than families that included more than one family member affected with APS, and families that were multiplex APS frequently included members that had other autoimmune disorders. Disclosures: No relevant conflicts of interest to declare

Development and Validation of a Population-Pharmacokinetic Model for Rurioctacog Alfa Pegol (Adynovate ® ): A Report on Behalf of the WAPPS-Hemo Investigators Ad Hoc Subgroup

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. 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. 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. 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

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

BACKGROUND: Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism. METHODS: DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to \u3c18 \u3eyears, 2 to \u3c12 \u3eyears, and birth to \u3c2 \u3eyears) via interactive response technology. The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent venous thromboembolism and venous thromboembolism-related death. A non-inferiority margin of absolute differences of 20% was used. Secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]), and pharmacokinetic-pharmacodynamic relationships (descriptive analyses). This trial is registered with ClinicalTrials.gov, NCT01895777 and is completed. FINDINGS: 328 children were enrolled between Feb 18, 2014, and Nov 14, 2019. 267 were randomly assigned (90 [34%] to standard of care and 177 [66%] to dabigatran) and included in the analyses. Median exposure to standard of care was 85·0 days (IQR 80·0-90·0) and to dabigatran was 84·5 days (78·0-89·0). Similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs 81 [46%] of 177; Mantel-Haenszel weighted difference, -0·04; 90% CI -0·14 to 0·07; p INTERPRETATION: An age-adjusted and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to less than 18 years with venous thromboembolism. Dabigatran was non-inferior to standard of care in terms of efficacy, with similar pharmacokinetic-pharmacodynamic relationships as those seen in adults, and might be a suitable alternative to standard of care. FUNDING: Boehringer Ingelheim