Protein S antibody as an adjunct therapy for hemophilia B.

ABSTRACT: Hemophilia B (HB) is caused by an inherited deficiency of plasma coagulation factor IX (FIX). Approximately 60% of pediatric patients with HB possess a severe form of FIX deficiency (<1% FIX activity). Treatment typically requires replacement therapy through the administration of FIX. However, exogenous FIX has a limited functional half-life, and the natural anticoagulant protein S (PS) inhibits activated FIX (FIXa). PS ultimately limits thrombin formation, which limits plasma coagulation. This regulation of FIXa activity by PS led us to test whether inhibiting PS would extend the functional half-life of FIX and thereby prolong FIX-based HB therapy. We assayed clotting times and thrombin generation to measure the efficacy of a PS antibody for increasing FIX activity in commercially obtained plasma and plasma from pediatric patients with HB. We included 11 pediatric patients who lacked additional comorbidities and coagulopathies. In vivo, we assessed thrombus formation in HB mice in the presence of the FIXa ± PS antibody. We found an accelerated rate of clotting in the presence of PS antibody. Similarly, the peak thrombin formed was significantly greater in the presence of the PS antibody, even in plasma from patients with severe HB. Furthermore, HB mice injected with PS antibody and FIX had a 4.5-fold higher accumulation of fibrin at the thrombus induction site compared with mice injected with FIX alone. Our findings imply that a PS antibody would be a valuable adjunct to increase the effectiveness of FIX replacement therapy in pediatric patients who have mild, moderate, and severe HB.

Corrigendum to ' Recurrent venous thromboembolism in hospitalized children with a history of prior venous thromboembolism: a report from the Children's Hospital-Acquired Thrombosis Consortium' [Research and Practice in Thrombosis and Haemostasis Volume 7, Issue 5, July 2023, 102139].

[This corrects the article DOI: 10.1016/j.rpth.2023.102139.].

Diagnosis and management of isolated neutropenia: A survey of pediatric hematologist oncologists.

BACKGROUND: Isolated neutropenia is a common referral to pediatric hematology oncology (PHO) physicians. There are no established consensus guidelines in the diagnosis and management of patients with isolated, asymptomatic, and incidentally discovered neutropenia. METHODS: A survey was distributed to PHO physicians on the American Society of Pediatric Hematology Oncology member discussion page to determine the common diagnostic and management decisions regarding patients with isolated neutropenia and to explore beliefs regarding the term "benign ethnic neutropenia." RESULTS: One hundred twenty-six PHO attending physicians completed the survey. The most common tests reportedly ordered for this patient population included complete blood cell count (CBC) (98%), peripheral smear (75%), antineutrophil antibody testing (29%), and immunoglobulins (24%). Providers were more likely to order an antineutrophil antibody in toddlers (p = .0085), and antinuclear antibody (ANA) panels in adolescents (p < .001). Half of providers do not request additional CBCs prior to their initial consultation, and most suggest referring patients with mild neutropenia after confirming a declining absolute neutrophil count (ANC) (51%). The three most important factors influencing ongoing follow-up included: history of recurrent/severe infections (98%), family history of blood disorders (98%), and more severe/progressively worsening neutropenia (97%). Seventy percent of respondents have diagnosed patients with "benign ethnic neutropenia," and 75% support replacement of the term to "typical neutrophil count with Fy(a-/b-) status," if confirmed with red cell phenotyping. CONCLUSION: We identified practice patterns of PHO physicians for the diagnosis and management of patients referred for asymptomatic and isolated neutropenia. These data provide the framework to conduct cost-effectiveness studies.

Enoxaparin Thromboprophylaxis in Children Hospitalized for COVID-19: A Phase 2 Trial.

BACKGROUND: Evidence regarding the safety and efficacy of anticoagulant thromboprophylaxis among pediatric patients hospitalized for coronavirus disease 2019 (COVID-19) is limited. We sought to evaluate safety, dose-finding, and preliminary efficacy of twice-daily enoxaparin as primary thromboprophylaxis among children hospitalized for symptomatic COVID-19, including primary respiratory infection and multisystem inflammatory syndrome in children (MISC). METHODS: We performed a phase 2, multicenter, prospective, open-label, single-arm clinical trial of twice-daily enoxaparin (initial dose: 0.5mg/kg per dose; max: 60mg; target anti-Xa activity: 0.20-0.49IU/mL) as primary thromboprophylaxis for children <18 years of age hospitalized for symptomatic COVID-19. Study endpoints included: cumulative incidence of International Society of Thrombosis and Haemostasis-defined clinically relevant bleeding; enoxaparin dose-requirements; and cumulative incidence of venous thromboembolism within 30-days of hospital discharge. Descriptive statistics summarized endpoint estimates that were further evaluated by participant age (±12 years) and clinical presentation. RESULTS: Forty children were enrolled and 38 met analyses criteria. None experienced clinically relevant bleeding. Median (interquartile range) dose to achieve target anti-Xa levels was 0.5 mg/kg (0.48-0.54). Dose-requirement did not differ by age (0.5 [0.46-0.52] mg/kg for age ≥12 years versus 0.52 [0.49-0.55] mg/kg for age <12 years, P = .51) but was greater for participants with MISC (0.52 [0.5-0.61] mg/kg) as compared with primary COVID-19 (0.48 [0.39-0.51] mg/kg, P = .010). Two children (5.3%) developed central-venous catheter-related venous thromboembolism. No serious adverse events were related to trial intervention. CONCLUSIONS: Among children hospitalized for COVID-19, thromboprophylaxis with twice-daily enoxaparin appears safe and warrants further investigation to assess efficacy.

Secondary thrombosis prevention practice patterns in pediatrics: Results of an international survey.

Background: Pediatric venous thromboembolism (VTE) rates continue to increase. Although most children present with transient provoking factors, some have persistent prothrombotic risks beyond the initial treatment period warranting secondary anticoagulation. Current pediatric VTE guidelines provide limited recommendations in this regard. Objectives: Our primary objective was to identify key influences on pediatric thrombosis physicians' decisions to initiate secondary anticoagulation. Methods: We targeted pediatric hematologists/oncologists internationally using Duration of Therapy for Thrombosis in Children, Children's Hospital Acquired Thrombosis consortium, and Venous Thromboembolism Network US pediatric subgroup membership rosters, who self-identified as primary outpatient thrombosis providers. Of 124 total surveys distributed, 61 complete surveys were evaluable. We defined secondary anticoagulation as anticoagulant use beyond the initial treatment period, on a daily basis (extended) or limited to periods of superimposed clinical risk factors (episodic). Results: Pediatric thrombosis physicians surveyed indicated that they prescribe secondary anticoagulation in <25% of children despite persistent risks. Among those who indicated use of secondary anticoagulation, the preferred modality was extended anticoagulation in children with a history of recurrent unprovoked VTE (98%), chronic central venous catheter (74%), and potent thrombophilia (73%). Episodic anticoagulation was preferred in children with a history of mild thrombophilia (54%). Respondents were more likely to prescribe secondary anticoagulation for adolescents as opposed to children <12 years old. Conclusions: Among pediatric thrombosis physicians surveyed, they perceived the prevalence of persistent prothrombotic risks to be high in children who have completed a course of anticoagulation for provoked VTE; however, estimated use of secondary anticoagulation was low. Studies involving real-world data are needed to further evaluate use of secondary anticoagulation in this setting.

Outcomes of Isolated Neutropenia Referred to Pediatric Hematology-Oncology Clinic.

BACKGROUND: Children with isolated neutropenia (absolute neutrophil count [ANC] <1500/µL) are frequently referred to pediatric hematology and oncology clinics for further diagnostic evaluation. Scant literature exists on interventions and outcomes for isolated neutropenia. We hypothesized that children will have resolution of their neutropenia without the need for intervention(s) by a pediatric hematologist and oncologist. METHODS: We performed a 5.5-year institutional review board-approved retrospective chart review of children referred to our pediatric hematology and oncology clinics for isolated neutropenia. Neutropenia was categorized as mild (ANC of 1001-1500/µL), moderate (ANC of 500-1000 µL), severe (ANC of 201-500/µL), or very severe (ANC of ≤200/µL). RESULTS: Among 155 children referred with isolated neutropenia, 45 (29%) had mild neutropenia, 65 (42%) had moderate neutropenia, 30 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia. Only 29 (19%) children changed to an ANC category lower than their initial referral category. At a median follow-up of 12 months, 101 children had resolution of neutropenia, 40 children had mild neutropenia, 10 children had moderate neutropenia, 3 children had severe neutropenia, and 1 patient had very severe neutropenia. A specific diagnosis was not identified in most (54%) children. The most common etiologies were viral suppression (16%), autoimmune neutropenia (14%), and drug-induced neutropenia (8%). Black children had a 3.5 higher odds of having persistent mild neutropenia. Six (4%) children received granulocyte colony-stimulating factor therapy. CONCLUSIONS: Most children referred for isolated neutropenia do not progress in severity and do not require subspecialty interventions or hospitalizations.