Evidence Based Strategies: Primary Care, Lifelong Impact: Pediatricians’ Role in the Diagnosis of Hemophilia

Hemophilia is a common inherited bleeding disorder caused by the deficiency or absence of clotting factors. Hemophilia can be further broken down into hemophilia A, B and C. Factor VIII deficiency is known as hemophilia A, factor IX deficiency is known as hemophilia B, and factor XI deficiency is known as hemophilia C. Annual incidence of hemophilia A and B in the United States is 1 in 5,000 and 1 in 30,000 male births, respectively.¹ Severe bleeding can be life-threatening, making early recognition and intervention extremely important. Primary care pediatricians are often the first point of contact for these patients and will follow them closely through childhood, serving an essential role in reducing their complications and improving their quality of life.

As primary care pediatricians, it is important to recognize historical details, signs and symptoms that could be consistent with hemophilia. While obtaining a detailed family history is essential, a negative family history should not be reassuring if there are other concerns for hemophilia. In a retrospective study of patients diagnosed with hemophilia A, 54.1% (654/1208) had a negative family history. Lack of family history of hemophilia was associated with longer time to diagnosis and initiation of treatment.²

Clinical manifestations of hemophilia can vary based on the severity of the factor deficiency. Severe hemophilia is described as <1% of factor present, with moderate and mild hemophilia defined as factor levels 1%-5% and 5%-40%, respectively.³ Those with severe deficiencies usually present as neonates with severe, early-onset bleeding such as intraventricular hemorrhage.⁴ Other common clinical manifestations of bleeding include spontaneous hemarthroses, soft tissue hematomas, and excessive bleeding following minor trauma or procedures.³ Red flag signs that warrant further evaluation include bruising in non-mobile infants, unexplained swelling in joints or muscles, prolonged bleeding after dental procedures or circumcision, or family history of excessive bleeding.

If hemophilia is suspected, initial evaluation should include a complete blood count, prothrombin time (PT)/international normalized ratio, activated partial thromboplastin time (aPTT), mixing studies, fibrinogen level, von Willebrand factor (VWF) antigen, and VWF activity level.³ Hemophilia is characterized by a normal platelet count, PT and fibrinogen for age, but prolonged aPTT. Definitive diagnosis is made with factor assays. Due to lower normal ranges of factor IX levels at birth, diagnosis of mild hemophilia in neonates by factor assay can be challenging and repeat testing may be needed at 6 to 12 months of age.⁴ If lab results are concerning or there is a strong clinical suspicion for hemophilia, the best next step is prompt referral to a pediatric hematologist and/or a regional hemophilia treatment center.

Traditionally, factor replacement (prophylactically vs. on-demand) has been standard of care for management of hemophilia. However, new therapies, such as emicizumab (monoclonal antibody that bridges activated factor IV and factor X to replace function of missing factor VIII), have been introduced and are making a positive impact on patients with hemophilia. Gene therapy is still being explored in this patient population and represents an exciting advancement in the treatment of hemophilia.⁵

Despite common misconception, females can also be affected by hemophilia and warrant special consideration. Hemophilia A and B are inherited as sex-linked recessive, but females can be asymptomatic carriers or display disease phenotypes similar to males due to skewed X chromosome inactivation. There are an estimated 2 to 5 female carriers for every male with hemophilia. These patients have factor levels ranging from normal to those low enough to be consistent with the diagnosis of hemophilia.⁶ The prevalence of disease in females is likely underestimated due to missed or delayed diagnosis. Females have a significantly longer delay between their first abnormal bleeding event and diagnosis compared to males, even after adjusting for the severity of bleeding phenotype. Compared to males, diagnosis in females occurs an average of 12 years later for mild disease, often presenting as heavy menstrual bleeding. Diagnosis occurs an average of 39 months later than in males for moderate disease, and six months later for severe disease.⁶

Earlier diagnosis of both symptomatic females and asymptomatic carriers has far-reaching implications for their health and that of their future children. Nearly half of infants diagnosed with severe hemophilia were born to mothers not known to be carriers.⁷ These infants’ risks of severe bleeding, such as intracranial hemorrhage, can be mitigated with improved awareness, reproductive counseling and peripartum care.

Primary care pediatricians play an integral role in recognizing signs and symptoms that may be concerning for hemophilia. Their prompt identification and early referral to specialists allows for swift diagnosis, treatment and education. Even after patients with hemophilia are undergoing proper management by their hematologist, community pediatricians continue to manage essential care, including provision of recommended vaccinations, guidance on proper nutrition, screening for development concerns, discussing importance of dental care, and monitoring for mental health concerns.⁸ Primary care pediatricians are a crucial link between patients, families and subspecialists, providing comprehensive management to improve the outcomes and quality of life of patients with hemophilia.

References:

1. About hemophilia. Hemophilia. Centers for Disease Control and Prevention. May 16, 2024. https://www.cdc.gov/hemophilia/about/index.html
2. Mendoza A, Rivas I, Hidalgo OB, et al. Impact of family history of haemophilia on diagnosis, management and outcomes in severe haemophilia. Haemophilia. 2025;31(4):679-686. doi:10.1111/hae.70018
3. Carcao M, Gomez K, Matino D, Pierce GF. Hemophilia A and B. In: Hoffman R, Benz EJ, Silberstein LE, et al, eds. Hematology: Basic Principles and Practice. 8th ed. Elsevier; 2023:2095-2124.
4. Saxonhouse MA, Hinson AP. Evaluation of bleeding disorders in the newborn. Pediatr Clin North Am. 2025;72(4):773-791. doi:10.1016/j.pcl.2025.03.004
5. Matuk-Villazon O, Roberts JC, Corrales-Medina FF. Hemophilia: the past, the present, and the future. Pediatr Rev. 2021;42(12):672-683. doi:10.1542/pir.2020-004143
6. Wright TS, Cygan PH. Closing the diagnostic gap in adolescents and young adult women with bleeding disorders: missed opportunities. Obstet Gynecol. 2023;142(2):251-256. doi:10.1097/AOG.0000000000005262
7. Han JH, Dupervil B, Mahajerin A, Kulkarni R, Manco-Johnson M, Thornburg C. Clinical and treatment characteristics of infants and toddlers less than 2 years of age with hemophilia. Blood Adv. 2024;8(11):2707-2717. doi:10.1182/bloodadvances.2023012486
8. Nomura S. Current status and challenges in delivering comprehensive care for patients with hemophilia. J Blood Med. 2023;14:629-637. doi:10.2147/JBM.S446204