Data on efficacy and safety of Emicizumab in children, especially in young children < 3 years and PUPs is still scarce. Between 2019–2021 several publications have reported the use of Emicizumab in children, including about 40 children under the age of 3 years , , –. All studies showed similar results regarding reduction of ABR, safety and laboratory results as adult cohorts. But especially PUPs demand special attention, because avoiding FVlll exposure might impose a higher risk of inhibitor development on these patients in case of breakthrough bleeding or surgery  .
This current study provides additional evidence on efficacy and safety of Emicizumab in 5 children < the age of 3 years, 2 PUPs and 3 MTPs. Our data show that the ABR significantly reduced under Emicizumab, regardless of age and inhibitor status. There were no spontaneous breakthrough bleeds during the long follow up-time of 24 months in our study. Other studies presented data of up to 50% breakthrough bleeds on Emicizumab .
Regarding PUPs, there is still no standardized recommendation regarding primary prophylaxis with Emicizumab in very young children. In 2020, the Society for Thrombosis und Hemostasis (GTH) published a guidance regarding the use of Emicizumab that stated a 92% agreement rate to the statement that “The decision to use Emicizumab in small children, especially PUPs, has to be made on an individual base” . Published studies of pediatric patients on Emicizumab included three PUPs and one minimally treated patient in a total cohort of 52 individuals  and one PUP in the HOHOEMI study . Both studies reported no other safety profiles or differences in efficacy compared to the other pediatric studies.
Therefore, our study adds to the data that, although haemostasis may still be developing in young children and FlX -activities may be low during the first months of life, efficacy in terms of reduction of ABR of Emicizumab is nevertheless comparable to adults. In addition, the same dosing can reach stable levels of Emicizumab. We were able to confirm this finding in children under the age of 3 years. We also report on two PUPs and three MTPs that experienced no complications while being treated with Emicizumab. This was independent of whether Emicizumab was the initial treatment, initiated upon occurrence of inhibitors or administered in combination with FVlll.
Although this current study provides crucial information about treatment of PUPs, future studies, e.g. the FREE-study, on PUPs, will provide more extensive data on this particular group and add valuable insight.
Currently, there is still an ongoing debate on eradication of inhibitors in the era of Emicizumab. Most experts argue that inhibitor eradication by ITI should be initiated to be able to use FVlll products in case of breakthrough bleeds or surgery. Others argue that Emicizumab is efficient to prevent bleeding and therefore, ITI is not mandatory –. The German expert panel of the GTH recommended that one treatment trial with ITI should be offered to patients on Emicizumab . Our cohort consisted of four high-titre inhibitor patients of whom three had already received several years of ITI long before transition to Emicizumab. One patient was transitioned to Emicizumab and additional ITI according to the Atlanta-Protocol (3 x 100/IE/kg bw weekly) immediately after diagnosis of high-titre inhibitors. Due to very difficult venous access and parental decision, ITI was terminated in this patient after a total of 2,5 years on ITI. Overall, none of our patients had a breakthrough bleed and according to patients and parents perspective, quality of life improved significantly.
In our cohort injection site reactions including minor skin reddening resembled previous reports . We used a skin prick test to exclude acute allergic reaction to Emicizumab. Deeper deposition of the Emicizumab (still on the subcutaneous level) led to no more local side reaction in this patient. No other safety issues occurred during the study period.
We show that minor surgery in patients receiving Emicizumab prophylaxis is safe and that no bleeding or thrombosis occurred, even if few doses of rFVlla were administered additionally . Nevertheless, treatment strategies in case of major trauma or other major surgery should still be investigated in further studies.
Lastly, we demonstrate that efficient Emicizumab levels were reached already after 3 doses of 3 mg/kg bw and were stable at follow-ups in most patients. This went along with the already well documented effect of shortening the aPTT , .
This study has some limitations, especially due to its retrospective design and limited number of patients. This makes statistical analysis vulnerable for outliers and generalization of results must be considered carefully. One example is patient no 1, who experienced two bleeds in 6 months and therefore has an ABR of 4, which is very high compared to our cohort in total.
In conclusion, we report longitudinal data on a small pediatric cohort including two PUPs and three MTPs that were treated safely and efficiently with Emicizumab. The debate on ITI and treatment decision making on PUPs/MTPs in the era of Emicizumab must be validated by larger cohorts.