Hemophilia in Children
1. Abdullah Alim Khan
2. Osmonova Gulnaz Zhenishbaevna
(1. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic
2. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
Abstract
Hemophilia is an X-linked recessive bleeding disorder caused by deficiency of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). It remains one of the most important inherited hematologic conditions of childhood, affecting approximately 1 in 5,000 male births for hemophilia A and 1 in 30,000 for hemophilia B. Severity is defined by residual factor activity: severe (<1 percent), moderate (1–5 percent), and mild (5–40 percent). Children with severe disease typically present in the first years of life with spontaneous joint and muscle bleeds, while milder forms may declare themselves only after trauma or surgery. Early diagnosis, ideally through family history, neonatal screening, or prompt laboratory evaluation after abnormal bleeding, allows timely initiation of prophylaxis, which has transformed outcomes. Contemporary management has moved well beyond episodic factor replacement. Standard and extended half-life factor concentrates, subcutaneous non-factor therapies such as emicizumab, rebalancing agents (fitusiran, concizumab, marstacimab), and, for selected adolescents and adults, gene therapy have markedly reduced bleeding rates, preserved joint health, and improved quality of life. Inhibitor development remains the most serious treatment-related complication, occurring in up to 30 percent of severe hemophilia A. Comprehensive care delivered through specialized hemophilia treatment centers, attention to psychosocial needs, safe physical activity, and transition planning into adulthood form the foundation of modern pediatric practice. This review synthesizes current understanding of epidemiology, pathophysiology, clinical presentation, diagnosis, and evolving therapeutic strategies for hemophilia in children, emphasizing evidence-based prophylaxis and the human dimensions of living with a chronic bleeding disorder.
Introduction
For generations, the diagnosis of hemophilia carried a heavy burden of repeated joint hemorrhages, progressive arthropathy, and restricted life expectancy. Today the outlook for a child born with hemophilia is profoundly different. Advances in clotting-factor technology, the introduction of non-factor therapies that can be given subcutaneously, and the early promise of gene therapy have shifted the therapeutic goal from merely treating bleeds to preventing them almost entirely. Yet the condition still demands lifelong vigilance, specialized expertise, and a partnership between families and multidisciplinary care teams.
Hemophilia A accounts for roughly 80–85 percent of cases and results from mutations in the F8 gene on the X chromosome; hemophilia B arises from mutations in the F9 gene. Because the disorders are X-linked, they predominantly affect males, although females can be symptomatic carriers or, rarely, have clinically significant disease through skewed X-inactivation or other mechanisms. Global prevalence estimates from the World Federation of Hemophilia indicate more than one million people living with hemophilia worldwide, many still undiagnosed in resource-limited settings. In high-income countries nearly all severe cases are identified in early childhood.
The clinical severity correlates closely with residual factor activity. Children with severe hemophilia experience spontaneous bleeding into joints (hemarthroses) and muscles, often beginning when they start to crawl or walk. Moderate disease produces less frequent spontaneous bleeds but marked hemorrhage after trauma. Mild disease may go unrecognized until a surgical or dental procedure precipitates prolonged bleeding. Intracranial hemorrhage remains a feared complication in infants and young children, particularly before prophylaxis is established.
Diagnosis rests on a careful family and personal history, prolonged activated partial thromboplastin time, and specific factor assays. Genetic testing confirms the mutation and facilitates carrier detection and prenatal counseling. Once the diagnosis is secured, the central therapeutic decision is whether and when to begin prophylaxis. Strong evidence and international guidelines now favor early, regular prophylactic treatment over episodic (on-demand) therapy for severe and moderately severe disease, because prophylaxis dramatically reduces bleeding frequency, protects joints, and improves long-term function and quality of life.
Treatment options have expanded rapidly. Standard half-life factor concentrates require frequent intravenous infusions. Extended half-life products allow longer dosing intervals. Emicizumab, a bispecific monoclonal antibody that mimics the cofactor function of factor VIII, can be given subcutaneously every one to four weeks and is effective regardless of inhibitor status. Newer rebalancing agents that inhibit natural anticoagulants (antithrombin or tissue-factor pathway inhibitor) further broaden the armamentarium. Gene therapy has achieved sustained factor expression in adults and is being studied in carefully selected older children and adolescents, although durability, safety, and accessibility remain active areas of investigation.
Despite these advances, challenges persist. Inhibitor formation continues to complicate management, especially in previously untreated patients with severe hemophilia A. Access to specialized care and newer therapies is uneven across the globe. Children still face the psychosocial impact of a chronic condition, the need for venous access, school and activity restrictions, and the transition to adult care. This article reviews the current state of knowledge on hemophilia in children within an IMRAD framework, drawing on recent guidelines, clinical trials, and observational studies to provide a comprehensive, clinically oriented overview.
Methods
This narrative review was prepared by synthesizing peer-reviewed literature on congenital hemophilia A and B in the pediatric population, with emphasis on publications from 2018 through 2026. Primary sources included the 2024 International Society on Thrombosis and Haemostasis (ISTH) clinical practice guideline based on GRADE methodology, World Federation of Hemophilia recommendations, American and European hematology society statements, pivotal clinical trials of extended half-life factors, emicizumab, rebalancing agents, and gene therapy, as well as large observational cohorts and real-world studies. Search strategies employed combinations of the terms “hemophilia,” “children,” “pediatric,” “prophylaxis,” “inhibitors,” “emicizumab,” “gene therapy,” “extended half-life,” and related keywords in PubMed, major hematology journals, and guideline repositories. Preference was given to pediatric-specific data, randomized evidence when available, and consensus recommendations. Quantitative estimates of incidence, bleeding rates, and treatment outcomes are presented as ranges reflecting geographic and methodological variation. The review aims to integrate scientific detail with the practical and human aspects of caring for children and families living with hemophilia.
Results
Hemophilia A occurs in approximately 1 in 5,000 live male births and hemophilia B in 1 in 30,000. Roughly 60–70 percent of cases are severe. Spontaneous mutations account for about one-third of severe hemophilia A diagnoses, so the absence of a positive family history does not exclude the condition. Early diagnosis is strongly associated with earlier initiation of prophylaxis and lower subsequent treatment intensity. Children without a known family history are often diagnosed later (median around 8–10 months) after a first significant bleed, whereas those with a family history are frequently identified at birth or in the neonatal period.
Clinical presentation varies with severity and age. In severe disease the first bleeds commonly involve soft tissues or joints once mobility increases. Recurrent hemarthroses, if untreated, lead to synovitis, cartilage damage, and ultimately chronic arthropathy. Muscle hematomas can cause compartment syndromes or nerve compression. Intracranial hemorrhage, although less frequent under modern prophylaxis, remains a leading cause of early mortality when it occurs. Mild and moderate disease more often manifests as prolonged bleeding after circumcision, dental extraction, trauma, or surgery.
Laboratory diagnosis begins with a prolonged activated partial thromboplastin time that corrects on mixing studies, followed by specific factor VIII or IX assays. Genetic analysis identifies the causative mutation, informs inhibitor risk (large deletions and nonsense mutations carry higher risk), and enables family counseling. Prenatal diagnosis and pre-implantation genetic testing are available for known familial mutations.
The cornerstone of modern management is prophylaxis. The ISTH guideline issues a strong recommendation for prophylactic over episodic treatment in severe and moderately severe hemophilia A and B, supported by moderate-certainty evidence from randomized trials and observational data showing marked reductions in annualized bleeding rates and joint damage. Primary prophylaxis, begun before the second joint bleed and ideally before age three, offers the greatest protection of joint health. Secondary prophylaxis, started after joint disease has already appeared, still reduces further bleeding and slows progression of arthropathy.
Factor replacement remains foundational. Standard half-life recombinant products require infusions two to three times weekly for factor VIII and once or twice weekly for factor IX. Extended half-life concentrates, achieved through Fc fusion, albumin fusion, or PEGylation, extend dosing intervals and improve trough levels. Real-world pediatric data demonstrate lower annualized bleeding rates, fewer infusions, and improved adherence with extended half-life products compared with standard half-life regimens.
Non-factor therapies have changed the daily experience of many families. Emicizumab, a bispecific antibody that bridges activated factor IX and factor X, is administered subcutaneously and maintains steady hemostatic coverage. Studies in young children, including those under one year of age and those with inhibitors, show substantial reductions in annualized bleeding rates (often to less than 1) and improved quality of life. Low-dose regimens have also proved effective in some settings. Rebalancing agents that reduce antithrombin (fitusiran) or inhibit tissue-factor pathway inhibitor (concizumab, marstacimab) further expand options, particularly for patients with inhibitors or those who prefer infrequent subcutaneous dosing. Recent regulatory expansions have made certain agents available to children as young as six years, including those with inhibitors.
Inhibitor development occurs in approximately 25–30 percent of previously untreated patients with severe hemophilia A and less frequently in hemophilia B. High-titer inhibitors render standard factor replacement ineffective. Management includes immune tolerance induction with intensive factor exposure, use of bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrates) for acute bleeds, and prophylaxis with emicizumab or other non-factor agents. Success rates of immune tolerance induction have improved, and concurrent emicizumab does not preclude attempts at tolerance.
Gene therapy using adeno-associated viral vectors has produced sustained factor expression in adults with severe hemophilia A and B, often converting the phenotype to mild disease and allowing many patients to discontinue routine prophylaxis. Long-term follow-up data extending to five years show durable reductions in bleeding rates for a majority of recipients, although variability in expression levels, potential loss of response over time, and the requirement for intact liver function and absence of neutralizing antibodies to the vector limit current eligibility. Pediatric trials are ongoing or planned, but gene therapy is not yet standard care for young children.
Supportive care is essential. Children are encouraged to participate in age-appropriate physical activity and sports under prophylaxis, because muscle strength and proprioception protect joints. Vaccinations are given subcutaneously when possible. Dental care requires coordination with the hemophilia center. Psychosocial support addresses anxiety, school absences, sibling dynamics, and the emotional weight carried by parents who must administer infusions or injections. Transition programs help adolescents assume responsibility for their own care and navigate adult services.
Outcomes under contemporary regimens are markedly better than historical experience. Annualized bleeding rates on effective prophylaxis commonly fall below one to two events per year, and many children experience zero spontaneous bleeds. Joint scores remain near normal when primary prophylaxis is instituted early. Life expectancy approaches that of the general population in settings with access to comprehensive care. Cognitive and behavioral development is generally comparable to peers, although attention to school performance and mental health remains important.
Discussion
The transformation of pediatric hemophilia care over the past two decades illustrates how scientific progress, when coupled with organized comprehensive care, can alter the natural history of a once-devastating disease. Prophylaxis is no longer optional for severe disease; it is the expected standard, supported by strong guideline recommendations and clear evidence of reduced bleeding and preserved joint integrity. The shift from frequent intravenous factor infusions to subcutaneous non-factor therapies has lightened the treatment burden for many families, improving adherence and allowing children greater freedom in daily activities and sports.
Yet progress is uneven. Inhibitor formation continues to pose a serious clinical and economic challenge. Although non-factor agents provide effective prophylaxis for inhibitor patients, the long-term goal of restoring immune tolerance remains important, especially for those who may later require surgery or experience trauma. Gene therapy offers the prospect of a functional cure for some individuals, but its current restriction to older adolescents and adults, the variability of response, and uncertainties about durability and rare long-term risks mean that most children will continue to rely on exogenous therapies for years to come.
Access remains a critical equity issue. High-cost novel agents and specialized laboratory monitoring are available primarily in well-resourced settings. Global initiatives by the World Federation of Hemophilia and national programs seek to expand diagnosis and treatment capacity, yet many children worldwide still receive only episodic care or no treatment at all. Even in high-income countries, disparities related to geography, insurance, and social determinants of health affect outcomes.
The human dimension of hemophilia care deserves equal attention. Parents often describe the early years as a period of intense hypervigilance, interrupted sleep for infusions, and anxiety about every bruise or limp. As children grow, the focus shifts to fostering independence, negotiating risk in sports and social activities, and preparing for adult life. Multidisciplinary teams that include hematologists, nurses, physiotherapists, social workers, and psychologists are uniquely positioned to support these transitions. Open communication about treatment choices, including the option of newer agents or eventual gene therapy, empowers families and builds trust.
Future research priorities include pediatric-specific trials of emerging rebalancing agents and gene therapies, biomarkers that better predict inhibitor risk and treatment response, and strategies to optimize joint health and physical function across the lifespan. Real-world evidence and patient-reported outcomes will be essential to refine guidelines and ensure that therapeutic advances translate into meaningful improvements in daily life.
In summary, a child diagnosed with hemophilia today can reasonably expect a near-normal life expectancy, preserved joint function, and the opportunity to pursue education, sports, and careers with far fewer limitations than previous generations faced. Realizing this potential requires early diagnosis, commitment to prophylaxis, access to the full range of modern therapies, and sustained, compassionate comprehensive care. The scientific and clinical community has made remarkable strides; the remaining task is to ensure that every child, regardless of geography or circumstance, benefits from them.
References
Chowdary P, et al. Haemophilia. Lancet. 2025;405(10480):736-750.
International Society on Thrombosis and Haemostasis. Clinical practice guideline for treatment of congenital hemophilia A and B based on GRADE methodology. J Thromb Haemost. 2024.
World Federation of Hemophilia. Guidelines for the management of haemophilia, including AAV gene therapy updates. 2025–2026.
Iorio A, et al. Data and Demographics Committee of the World Federation of Hemophilia. Prevalence estimates.
Srivastava A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition and subsequent updates.
Clinical trial and real-world data on emicizumab (Hemlibra) in pediatric patients, including low-dose regimens.
FDA and regulatory approvals and expansions for fitusiran (Qfitlia), concizumab (Alhemo), and marstacimab (Hympavzi) in pediatric and inhibitor populations.
Long-term follow-up data from gene therapy trials (valoctocogene roxaparvovec, etranacogene dezaparvovec, fidanacogene elaparvovec).
Studies on extended half-life factor VIII and factor IX products in children, including bleeding rates and infusion frequency.
Nordic Hemophilia Council and other regional guidelines on inhibitor management and immune tolerance induction.
Observational cohorts examining timing of diagnosis, family history, and impact on treatment burden.
Reviews of joint outcomes under primary versus secondary prophylaxis.
Literature on physical activity, sports participation, and psychosocial outcomes in children with hemophilia.
Chinese and other national pediatric hemophilia diagnosis and treatment guidelines (2025 updates).
Additional supporting publications on epidemiology, inhibitor epidemiology, comprehensive care models, and emerging therapies cited throughout the text.