Lower dose emicizumab prophylaxis in children with hemophilia A: Real - world outcomes, hemostatic profiles and cost- effectiveness from a resource limited setting

Abstract

Abstract Background: Although Emicizumab has transformed prophylaxis in Hemophilia A management, standard-dose therapy remains inaccessible for most in resource-limited settings. Evidence on lower dose Emicizumab in real-world pediatric cohorts is limited. Objective: To assess clinical outcomes, thromboelastography (TEG) profiles, and cost-effectiveness in children receiving lower dose Emicizumab compared to prior treatment regimens. Methods: This was a hybrid observational study comprising a retrospective clinical audit and a prospectively designed laboratory substudy, conducted at a single tertiary care center in India of children with severe Hemophilia A who initiated lower-dose Emicizumab prophylaxis between June 2019 and May 2024. Eighteen pediatric patients were included: 15 without inhibitors (on low- to intermediate-dose clotting factor concentrate [CFC] prophylaxis) and 3 with inhibitors (previously on FEIBA on demand). Clinical Outcomes: Annualized bleed rates (ABR) and school absenteeism (days/year) were recorded for one year pre- and post-Emicizumab. Data were verified using clinical documentation and parental recall. Laboratory Evaluation: All 18 children underwent TEG while on Emicizumab. Parameters—R time, K time, α-angle, and maximum amplitude (MA)—were compared with age-matched Hemophilia A controls not on Emicizumab. Correlations with clinical bleeding outcomes were explored. Plasma Emicizumab concentrations were measured in a subset (n=9) using a modified ELISA assay. Cost-Effectiveness Analysis: A detailed healthcare system cost analysis compared treatment expenditures before and after Emicizumab initiation. Costs included prophylactic and episodic factor use, hospitalization, emergency transport, and Emicizumab acquisition. Cost per bleed avoided and cost per school day gained were calculated. Statistical Analysis: Paired t-tests or Wilcoxon signed-rank tests were used for continuous variables; chi-square test for categorical data. A p-value <0.05 was considered statistically significant. SPSS v25.0 was used for all analyses. Results: Mean age was 8.1 years (range 2–17). Three children (16.6%) were inhibitor-positive, previously managed with FEIBA. The mean monthly Emicizumab dose was 2.8 mg/kg (Range: 1.3-5.8 mg/kg/month, SD 1.45), yielding a mean plasma level of 25.16 µg/mL (Range: 6.01-48.42, SD 16). Prior to switching, average FVIII usage was 30 IU/kg/week (7.4 - 77.7 IU/kg/week).ABR dropped significantly from 6 (Range: 0-28, SD 8) to 0.6 (Range 0-2, SD 0.7) post-Emicizumab (p < 0.01). All 10 post-treatment bleeds were minor and trauma-related. No major bleeds occurred. The proportion with zero bleeds increased from 16.6% on FVIII to 44.4% on Emicizumab (p = 0.03).School absenteeism declined from a median of ~30 days/year to <10 days/year (p = 0.03), indicating improved quality of life.Plasma Emicizumab levels correlated strongly with administered dose (p < 0.01), confirming predictable pharmacokinetics at lower doses.TEG demonstrated significant improvements in global hemostasis: median R-time (5 vs 22 min, p < 0.001), K-time (1.3 vs 4.3 min, p < 0.001), α-angle (70° vs 45°, p < 0.001), MA (79 vs 66 mm, p < 0.001), coagulation index (4 vs –11, p < 0.001), and thrombin generation (950 vs 812, p < 0.001). However, TEG parameters did not predict individual bleeding phenotypes.Mean annual treatment cost increased from USD 5,790 (Range: 401 - 39279, SD 8,791) to USD 20,115 (Range: 8047.4 - 40220, SD 12,039). The incremental cost-effectiveness ratio (ICER) for avoiding one bleed per year was USD 7,308 (95% CI: 3,604–12,085), within accepted thresholds based on a willingness-to-pay of two times per capita GDP, per Health Technology Assessment (HTA) guidelines. Conclusion: Lower dose Emicizumab significantly reduces bleeding and school absenteeism in children with Hemophilia A, including those on prior low/intermediate-dose FVIII prophylaxis or bypassing agents. Despite higher costs, the clinical and functional benefits support its cost-effectiveness in resource-limited settings. TEG parameters improved post-therapy but did not correlate with bleeding phenotype. These findings support adoption of tailored, lower-dose Emicizumab regimens as a viable and sustainable prophylaxis option in low- and middle-income countries.