When and How to Start Prophylaxis in Children with Hemophilia

Authors: Martin Olivieri, Christoph Königs

Abstract

Background

Hemophilia A and B are X-linked inherited bleeding disorders resulting from factor VIII or IX deficiency and are associated with substantial morbidity beginning in early childhood. Recurrent musculoskeletal bleeding can lead to hemophilic arthropathy and long-term disability. Intracranial hemorrhage, especially in early infancy, remains a life-threatening complication with high risks of mortality and neurological sequelae. As treatment decisions in early life decisively influence lifetime outcomes, the optimal timing and mode of prophylaxis are central aspects of pediatric hemophilia care.

Summary

This review summarizes the current evidence and expert opinions regarding the initiation of prophylaxis in children with hemophilia, focusing on early diagnosis, perinatal management, the timing of and indications for prophylaxis, therapeutic options, inhibitor development, and psychosocial aspects. Prophylaxis is recommended as early as possible in children with severe hemophilia and in those with moderate disease and a severe bleeding phenotype, ideally before the first joint bleed, to prevent future bleeds and microbleeds and to therefore preserve joint health. The choice of therapy (nonfactor replacement therapy, factor concentrate) should be individualized on the basis of the type and severity of hemophilia, patient age, venous access, risk of inhibitor development, clinical presentation, and family circumstances. For hemophilia A, the early use of nonfactor therapy (emicizumab) in newborns and toddlers represents an efficacious and safe therapeutic option. Data on FVIII inhibitor development in children on nonfactor prophylaxis with infrequent exposure to FVIII are still lacking. In the course of life with improved venous access, switching to FVIII prophylaxis may be beneficial in cases of bleeding despite prophylaxis with nonfactor therapy in daily life or based on parental choice. The psychosocial impact on patients and their families, especially related to treatment burden and venous access, highlights the need for shared decision-making and multidisciplinary care.

Key Message

Early individualized prophylaxis is the cornerstone of modern pediatric hemophilia management. For children with hemophilia, prompt initiation after diagnosis, tailored therapeutic approaches, and close interdisciplinary support are essential for preventing life-threatening bleeding, preserving musculoskeletal and neurodevelopmental health, and ensuring a normal quality of life and participation in daily activities.

Introduction

Hemophilia A (HA) and hemophilia B (HB) are complex chronic disorders and are among the most common bleeding disorders caused by factor VIII (HA) or IX (HB) deficiency due to X-linked mutations in F8 or F9. The prevalence of HA in males has been estimated at one in 5,000 live births, whereas that of HB has been estimated to be one in 30,000 live births [1, 2]. According to global annual surveys conducted by the World Federation of Hemophilia, 1,125,000 persons worldwide are living with hemophilia including an estimated number of 418,000 severe ones, but with a majority of undiagnosed patients [3].

The bleeding phenotype in hemophilia correlates with the measured residual factor concentration and is classified as mild (>5–40%), moderate (1–5%), or severe (<1%). Recurrent bleeding into the joints and muscles can causes long-term musculoskeletal impairment, leading to chronic pain, hemophilic arthropathy, and disability. Soft tissue and intracranial bleeding are rare but can also cause permanent damage and may be life-threatening [1, 2]. People living with a more severe phenotype are more affected than those living with a mild phenotype.

Because therapy in childhood is critical and reduces the extent of impairment in adulthood, the treatment goals of hemophilia treatment in childhood include early bleeding prevention, avoidance of adverse events, preservation of quality of life, and full participation in daily activities; thus, achieving the goal of normal development is not limited by hemophilia. However, more than 1/3 of affected children are undiagnosed prior to a bleeding episode, particularly because of a de novo mutation without any family history [4]. Muscle and joint bleeding is rare in early infancy. Subcutaneous hematomas occur with increasing mobility, but the perinatal period is associated with a markedly increased risk of intracranial hemorrhage (ICH). The reported incidence of ICH in children with hemophilia ranges from 1.5% to 8.2%, with approximately 80% of cases occurring within the first 12 months of life [5, 6]. The risk factors for ICH include severe hemophilia, genetic predispositions such as null mutations, perinatal complications (especially operative vaginal deliveries with vacuum extraction or forceps), lack of prophylactic therapy, and trauma during infancy [7–11]. Intracranial hemorrhage is associated with a mortality rate of up to 30%, and long-term neurological sequelae are common among survivors [10, 12].

These data emphasize the need for early diagnosis and rapid initiation of prophylactic therapy following birth or diagnosis. This review aimed to provide an overview of data and opinions on when and how to start prophylaxis in children with hemophilia, identifying difficulties and obstacles.

Early Diagnosis and Perinatal Management

Worldwide, most patients living with the disease remain undiagnosed; however, in any country, approximately 30% of patients have a spontaneous mutation. Although a family history of hemophilia should, in principle, be present in the remaining 70% of patients, the carrier status or a positive family history is frequently unknown at the time of birth. The diagnosis of and care for carriers represents a key component in the comprehensive management of hemophilia, as it enables precise genetic risk assessment and informed reproductive counseling. The identification of female carriers allows for the clarification of transmission risk to offspring, facilitates cascade testing within affected families, and supports early diagnostic evaluation of potentially affected children and therapeutic intervention. Beyond reproductive implications, carrier status is also clinically relevant, as a subset of carriers exhibit reduced factor levels and an increased bleeding tendency, warranting individualized hemostatic assessment and periprocedural management. Accordingly, the systematic implementation of carrier diagnostics contributes to improved patient counseling, anticipatory guidance, and long-term care planning within multidisciplinary hemophilia management programs. If the carrier status of the mother is unknown at birth, early prophylaxis cannot be offered to all newborns, and diagnosis typically occurs later, most often upon the appearance of subcutaneous hematomas or the first joint bleed [13]. Additionally, early prophylaxis is not feasible in all patients because of difficult peripheral venous access, particularly in HB, as no subcutaneous therapy has been approved thus far for infants and young children. According to registry data, the median age at diagnosis ranges from 3.7 to 11.9 months [14]. For infants with a known carrier status or prenatal diagnosis, perinatal management should be coordinated with a hemophilia treatment center. Delivery must be atraumatic, regardless of whether it is a vaginal or cesarean delivery, to decrease the risk of bleeding complications. Forceps and vacuum extraction during vaginal delivery as well as invasive procedures involving the fetus, such as fetal scalp blood sampling and internal fetal scalp electrodes, should be avoided, and the indication for cesarean section should be considered liberally to avoid invasive procedures. Perinatal management should include early cerebral ultrasound to monitor for ICH, factor level measurements to confirm the diagnosis, and the availability of factor VIII or IX concentrates to treat potentially arising bleeding episodes [3, 7, 15–17]. This can only be planned and performed if a family history is known prior to birth [18].

Timing and Indications for Prophylaxis

Prophylaxis in children is indicated to prevent bleeding episodes including life-threatening bleeding and to preserve joint health, thereby allowing normal participation and development. In patients with severe and moderate hemophilia with factor levels <3%, prophylaxis should be initiated as early as possible, ideally before the first joint bleed, targeting factor levels above 3–5%. To prevent arthropathy due to microbleeds, prophylaxis is also indicated in patients with severe bleeding phenotypes, despite mild or moderate hemophilia [3, 19–21]. Available and licensed treatment options in Germany for previously untreated patients/infants (PUPs) are listed summarized in Figure 1. Emicizumab is licensed in the European Medicine Agency (EMA) region for severe hemophilia A and moderate (<5% factor VIII) hemophilia A with a severe bleeding phenotype. The timing and mode of prophylaxis depend on the Type of hemophiliaSeverity of hemophiliaPresence of acute bleedingPatient ageVenous accessRisk of inhibitor developmentCaregivers’ choiceFamily situation

Considering these influences and focusing on patients with severe or moderate hemophilia, 4 patient categories can be distinguished. The decision tree for patients with HA is shown in Figure 2.1.Children with hemophilia B.2.Neonates with prenatal known hemophilia A.3.Children initially diagnosed hemophilia A due to mild bleeding symptoms such as subcutaneous hematomas.4.Children with hemophilia A and an acute bleeding in need of treatment.

Children with Hemophilia B

For hemophilia B, extended half-life (EHL) factor IX products can be regarded as the current standard of care in children. Plasma-derived or standard half-life recombinant products play only minor roles. Given that there are no available licensed nonfactor replacement therapies for hemophilia B in children younger than 12 years of age, intravenous factor substitution remains the only option. The type of product should be selected after the family is consulted as part of a shared decision process, considering the advantages and disadvantages of SHL and EHL preparations [21–24]. In infants with a known diagnosis, prophylaxes should start before the first joint bleed approximately between 6 and 12 months of age when they start moving. The start of prophylaxis is limited only by venous access and the risk of inhibitor development (up to 10%) because of early start, age, family history, and genetics [3, 25–28]. Inhibitor development is associated with significant morbidity, attributable not only to the increased risk of bleeding but also to the frequent occurrence of allergic or anaphylactic reactions and the development of nephrotic syndrome. Owing to the relative rarity of this complication, available data on the risk factors, underlying pathophysiological mechanisms, and clinical characteristics of inhibitor formation in hemophilia B patients remain limited [21, 27]. Extravasation in the context of difficult venipuncture with frequent failed punctures has been discussed, but since yet there is no evidence to support this. A central venous line should be avoided [3, 21]. In case of venous puncture difficulties, an individualized prophylactic approach can be applied every 10–14 days. In Germany, professional home care/i.v. services with expertise in venous puncture in infants and toddlers can help manage prophylaxis and support the families.

Neonates with Prenatal Known/Expected Hemophilia A

As part of both planned delivery management and interdisciplinary care, especially in cases of severe hemophilia A, pediatric hemophilia experts should advise families about post-birth treatment options during pregnancy to reduce the risk of cerebral hemorrhage after birth [8, 9, 18, 19]. According to different guidelines and expert opinions concerning the use of emicizumab, which is administered subcutaneously, patients with severe hemophilia A can begin treatment immediately or soon after birth to potentially prevent the occurrence of intracranial hemorrhage during the first months of life [18, 19, 29, 30]. Data from the HAVEN 7 study revealed that the use of emicizumab in this patient group was efficacious and well tolerated without severe adverse events. A model-based ABR for treated bleeds was reported to be 0.4 (95% confidence interval, 0.30–0.63); 54.5% of participants (n = 30) had zero treated bleeds, and all 42 treated bleeds among 25 participants (45.5%) were traumatic. Two of 55 patients developed an FVIII inhibitor after the concomitant use of factor VIII concentrate during the bleeding episodes [31]. Nevertheless, the family should be provided with factor VIII concentrate for the cases of bleeding episodes and should receive supervised training in intravenous cannulation. Additionally, the expert panel from the French Society of Thrombosis and Hemostasis recommends regular clinical monitoring up to every 3 months until 3 years of age [21]. The proposed inhibitor testing every 5 exposure days has its limitations, as emicizumab prophylaxis delays the factor VIII exposure. It may take several years to reach these milestones of exposure days. Thus, regular testing after FVIII exposure is warranted. Currently, it remains still unclear whether delayed and less frequent exposure to FVIII might reduce the risk associated with inhibitor development or, conversely, whether the administration of FVIII concentrates for the management of acute bleeding episodes or perioperative prophylaxis may be associated with increased immunogenicity. In addition, until now, there are no data that indicates whether concomitant regular, low-dose factor VIII substitutions are beneficial or harmful for FVIII tolerance.

If caregivers refuse this early prophylaxis, standardized prophylaxis with emicizumab or a factor VIII concentrate should be initiated at the latest before the first joint bleed, approximately between 6 and 12 months of age when the infant starts moving.

Children with Diagnosed Hemophilia A due to Mild Bleeding Symptoms Such as Subcutaneous Hematomas

In this patient group, the time to diagnosis was usually between 3.7 and 11.9 months after birth, mostly because of the sudden appearance of large hematomas or other mild bleeding symptoms [14]. Advanced age is often associated with improved venous access and opens up for various treatment options. Therapeutic approaches are individualized within a shared decision-making framework after parental counseling. Treatment decisions depends on the child’s age, clinical characteristics, bleeding tendency, venous access status, family history, history of inhibitor development, and the psychosocial situation of the family. The time frame for counseling is usually much shorter than that in the first group, which has a known family history. Factor concentrates are generally approved for all age groups and severities of hemophilia (with the exception of PEGylated EHL products), whereas emicizumab is approved for prophylaxis in patients with severe HA or a moderate form with a severe clinical bleeding phenotype [18–20, 23, 31]. Pfrepper et al. [20] proposed a general definition for the severe bleeding phenotype in patients with nonsevere hemophilia. Although pediatricians are involved in the development process, certain difficulties remain, particularly since prophylaxis should only begin after severe bleeding has occurred, and larger hematomas may only appear once sufficient mobility is achieved. It may be necessary to place greater emphasis on family history, especially in younger children, to prevent bleeding and sequelae in a timely manner [20, 32]. Comparison of the various therapeutic agents revealed no evidence of a significant superiority of any single product with respect to bleeding rates or joint outcomes [13]. In patients treated with emicizumab, additional administration of factor concentrates is necessary in cases of breakthrough bleeding or during surgical procedures. When factor concentrates were used, an age-dependent markedly reduced half-life was observed in younger children. This must be considered when determining the dose and frequency. Venipuncture as a factor replacement also significantly contributes to the psychosocial burden on both the children and their families. The use of EHL products or subcutaneous therapy administered mainly once weekly results in a significant reduction of this burden [33, 34]. Nevertheless, some centers continue to use plasma-derived concentrates as proposed by the International Society on Thrombosis and Hemostasis (ISTH) guideline because of a potentially lower risk of inhibitor development, even if recent data could not consistently confirm this theory and discuss a center influence [35–38]. This ISTH recommendation to preferentially use a plasma-derived factor concentrate for the initiation of prophylaxis in order to reduce the risk of inhibitor development has generated considerable controversy among various organizations and experts. This is particularly because the recommendation is largely based on the findings of the SIPPET study, while a number of new and EHL products have since become available on the market [37, 39–41].

Children with Hemophilia A and an Acute Bleeding with the Need for Treatment

In cases of acute bleeding leading to initial diagnosis of hemophilia, immediate substitution of intravenous factor VIII is necessary. The product type depends on local availability. The use of EHL products or a sustained half-life factor VIII product may be advantageous in that fewer infusions are needed for bleeding control. After bleeding occurs, regular prophylaxis should be initiated (see points 2 and 3). Data on inhibitor development with novel concentrates are rare or lacking. Routine inhibitor testing should be performed after factor substitution according to current recommendations and local standards [3, 21].

Immunological Considerations

The development of inhibitors for pediatric hemophilia management remains a major challenge. The average incidence is 30% in PUPs with HA and up to 10% in patients with HB, ranging between 16% and 45%, with a peak during the first 20 days of exposure [25–27, 35, 36, 40, 42]. Inhibitor development in hemophilia A is multifactorial with an increased risk in patients with large deletions, peak treatment moments in bleeding situations or during surgical interventions, a positive family history or mutations in genes related to the immune response, while available data on risk factors, underlying pathophysiological mechanisms, and clinical characteristics in hemophilia B patients are limited [40]. Compared with intermittent high-dose therapy, regular low-dose prophylaxis appears to reduce the risk of inhibitors development [43]. In contrast to published data by Peyvandi et al. [37], who suggested a higher risk of inhibitor development in patients treated with recombinant factor concentrates, more recent cohort studies revealed no difference between plasma-derived factor concentrates, recombinant factor concentrates, and EHL factor concentrates [35, 36]. Data on inhibitor development using recently licensed highly sustained factor VIII concentrates are not available until now. Since large prospective studies on hemophilia treatment are lacking, data on inhibitor development using individual concentrates became available only several years after approval. Registries with sufficient data allow for comparisons of classes and products.

When nonfactor replacement therapies are used, factor VIII is required only in the context of bleeding episodes or surgical procedures. Consequently, it took considerably longer to reach the corresponding number of exposure days. However, whether the current exposure day milestones associated with inhibitor risk development are still valid and how this delay in reaching exposure days until an older age affects the risk of inhibitor development remains unclear. Data on the lifelong impact of sporadic factor VIII exposure during prophylactic nonfactor replacement therapy on the risk of inhibitor development are lacking. In the HAVEN 7 study, 2 patients out of 55 developed an inhibitor after factor VIII substitution [31]. Further studies are needed to address this question. In clinical practice, testing for FVIII inhibitors appears crucial after FVIII exposure in children on nonfactor replacement therapies.

Psychosocial Aspects and Family Burden

The new diagnosis of a severe, complex, chronic, and lifelong disease is a major psychosocial burden for both the patients and their families, with the burden of treatment being the greatest [33]. The use of EHL products or subcutaneous therapies administered once a week may significantly reduce this burden [22]. Counseling, shared decision-making, early education in home therapy, emergency management, and bleeding control are essential. Interdisciplinary and multimodal care, comprehensive training programs, and psychosocial support should be integrated into care, particularly during the early years of life [2, 33].

Discussion

The therapeutic landscape of pediatric hemophilia has evolved substantially over the past decade, resulting in improved bleeding control but also in increased complexity of treatment decisions. While early prophylaxis is widely accepted as the standard of care in children with severe hemophilia, several clinically relevant questions remain unresolved.

One major open issue concerns the role of concomitant FVIII administration in patients receiving primary prophylaxis with nonfactor replacement therapies [18, 19, 44]. In patients with hemophilia A, subcutaneous prophylaxis with emicizumab has enabled effective bleeding prevention from early infancy without the need for regular intravenous access. However, this approach markedly reduces early FVIII exposure, thereby delaying the accumulation of exposure days traditionally associated with peak inhibitor development risk. It remains unclear whether delayed and sporadic FVIII exposure reduces, shifts, or potentially alters the immunological risk profile for inhibitor development. Furthermore, the question of whether structured, low-dose concomitant FVIII administration is beneficial or harmful for immune tolerance induction in this setting is unanswered. Currently available data are limited and do not allow definitive conclusions regarding optimal strategies for balancing bleeding protection and immunological safety [19, 44].

In addition, gaps in knowledge persist regarding inhibitor development in patients who begin nonfactor prophylaxis immediately after birth. Existing exposure day-based risk models were established for cohorts treated with regular FVIII replacement and may not be directly transferable to children with minimal or intermittent FVIII exposure [42]. Whether age at first substantial FVIII exposure, immune system maturation, or inflammatory “danger signals” during breakthrough bleeds influence inhibitor formation in this new treatment paradigm requires prospective investigation. Long-term registry data will be essential for clarifying the cumulative lifetime risk of inhibitor development under these evolving strategies.

Another relevant clinical consideration is the question of switching treatment modalities over time. With increasing age, improved peripheral venous access, and the ability to self-infuse intravenously, some patients may benefit from transitioning from nonfactor prophylaxis to FVIII-based regimens, particularly when higher peak and trough levels are needed for better bleeding protection or to optimize joint protection. Conversely, others may prefer to maintain subcutaneous therapy because of the lower treatment burden and effective control of bleeding. Evidence guiding the optimal timing, immunological implications, and clinical outcomes of such switching strategies remains limited. Careful monitoring of the status of inhibitor development and bleeding phenotype during and after transitions between therapeutic approaches is therefore warranted.

Future treatment strategies may further reshape early management concepts. Highly sustained factor VIII products, rebalancing agents, and emerging gene therapy approaches have the potential to alter prophylactic paradigms [19, 45]. In particular, the possibility of achieving stable endogenous factor expression through gene-based therapies raises questions about the optimal sequencing of treatments across childhood and adolescence. Moreover, personalized prophylaxis guided by choice or therapeutic concepts, pharmacokinetic modeling, bleeding phenotype, genetic risk factors, and biomarkers of immune activation may allow a more refined risk stratification and individualized approaches.

Conclusion

Prophylaxis in pediatric hemophilia is the cornerstone of modern care. Early initiation after diagnosis, individualized shared treatment decisions, and interdisciplinary, multimodal coordination are crucial for preventing life-threatening hemorrhage and maintaining musculoskeletal and neurodevelopmental health, as well as guaranteeing a normal life expectancy, a good quality of life, and participation in daily activities. The timing and mode of prophylaxis not only depend on the form and severity of hemophilia, the presence of an acute bleeding situation, patient age, feasibility of venous access, and risk of inhibitor development but also on the caregivers’ choice and the family’s social situation. Modern treatment options and increasing experience have made treatment decisions more complex but have improved the situation for children living with hemophilia and their families. Uncertainties remain regarding immunological consequences, optimal integration of factor and nonfactor therapies, and long-term treatment sequencing. Addressing these questions through prospective studies, international registry studies, and collaborative research networks will be crucial for improving lifetime outcomes in this vulnerable population.

Conflict of Interest Statement

M.O. received grants/support from Bayer, Bristol Meyers Squibb, BioMarin, Takeda, CSL Behring, Octapharma, Pfizer, Shire, Roche, Sanofi, Stago, and Swedish Orphan Biovitrum and received consultancy and speaker fees from Bayer, BioMarin, Novo Nordisk, Takeda, CLS Behring, Pfizer, Roche, and Swedish Orphan Biovitrum. C.K.: the institution has received grants for clinical trials from Bayer, Biotest, CSL Behring, Interzero, Novo Nordisk, Pfizer, Roche/Chugai, Takeda, Sobi/Sanofi, EU H2020 ITN, State of Hesse, and FUSE e.V. and has received speaker or consultation fees from Bayer, CSL Behring, Florio, Novo Nordisk, Pfizer, Roche/Chugai, Sobi/Sanofi, and Takeda.

Funding Sources

This study was not supported by any sponsor or funding.

Author Contributions

M.O. and C.K. conceived and drafted the manuscript. Both critically revised and approved the final version of the manuscript.