Hemophilia: A Clinical Overview

Written by Margaret Anne Rockwood | Last updated August 4th, 2026
Medically reviewed by Shannon Walker, MD

Hemophilia is an inherited bleeding disorder caused by deficiency or dysfunction of a coagulation factor: Factor VIII in hemophilia A and Factor IX in hemophilia B. Both are X-linked disorders, so they predominantly affect males, although symptomatic female carriers are increasingly recognized, especially when factor levels are low due to skewed X-inactivation (lyonization).

Clinically, the phenotype ranges from mild disease, with bleeding mainly after trauma or procedures, to severe disease, with spontaneous joint and muscle bleeding often beginning in infancy or early childhood.

Its prevalence tends to be underestimated, primarily due to some people leading normal lives or due to under- or missed diagnoses. Yet recognition of milder cases that can fall under the radar can be most critical, inviting potential complications from trauma or surgery in individuals who are not under ongoing monitoring and medication.

Epidemiology

Hemophilia A accounts for about 80% to 85% of hemophilia cases, while hemophilia B accounts for about 15% to 20%.

A major international meta-analysis estimated that hemophilia A prevalence is about 17.1 per 100,000 males for all severities, and 6.0 per 100,000 males for severe disease. Hemophilia B is less common – about 3.8 per 100,000 males for all severities and 1.1 per 100,000 males for severe disease. The US Centers for Disease Control and Prevention (CDC) estimate is lower: about 12 per 100,000 males for hemophilia A and 3.7 per 100,000 males for hemophilia B.

However, prevalence at birth is significantly higher, with estimates of roughly 24.6 per 100,000 males are born with hemophilia A and 5.0 per 100,000 with hemophilia B.

Globally, approximately 1.1 million males are living with hemophilia, including about 418,000 with severe disease. In lower-resource settings, many remain undiagnosed or undertreated.  Many individuals with hemophilia are underdiagnosed and die after infancy, some from bleeding complications or, in some parts of the world, from infection with HIV or hepatitis C in contaminated blood products.

The dangers of untreated hemophilia go beyond uncontrolled bleeding to include preventable disability, reduced educational and work opportunities, and avoidable early death. Even in well-resourced settings, hemophilia still carries a life-expectancy disadvantage, though the gap has narrowed substantially in the past 50 years.

The “Royal Disease” – A Brief History of Hemophilia

Historically, hemophilia proved to be a devastating disease. Before effective replacement therapy, recurrent hemarthroses (bleeds into the joints) led to chronic arthropathy, disability, pain, and shortened survival. The disorder carries a memorable social history, with Queen Victoria’s descendants who had hemophilia B as the leading example. The most famous royal case was Tsarevich Alexei, the son of Czar Nicholas II and Empress Alexandra, granddaughter of Queen Victoria and a carrier of FIX deficiency. Alexei’s hemophilia and the family’s efforts to manage it helped raise awareness and contributed to  hemophilia’s label as “the royal disease.”

The outlook for people with hemophilia turned a corner in the late 1950s with the introduction of fresh frozen plasma (FPP), a donated blood product that contains all clotting factors, and, most notably, with cryoprecipitate, a concentrate that made factor VIII replacement possible with less volume, in the early 1960s.  In the 1970s, manufacturers began producing lyophilized (freeze-dried) plasma-derived factor VIII concentrates from pools of thousands of plasma donations, transforming care by enabling home treatment.

The concentrates from large pools had a dark side, however, as viral contamination led to many tragic incidents of HIV and hepatitis C transmission through contaminated blood products. This devastated the hemophilia community, yet it also accelerated demands for safer manufacturing, donor screening, viral inactivation, and eventually recombinant factor products.

Starting in the 1990s, pharmacologic advances shifted the care paradigm from treatment of bleeds to prevention, which can markedly reduce bleeding events and protect joints from damage due to repeated bleeds. Prophylactic measures were further boosted by the introduction of recombinant factor VIII and IX, extended half-life products, individualized pharmacokinetic dosing, and home infusion.

An Evolving Treatment Paradigm

Approximately 25% to 30% of patients with severe hemophilia A and 1 to 5% of patients with hemophilia B develop neutralizing antibodies against clotting factors, making some treatments less effective and complicating bleeding management. These inhibitors have been among the most challenging complications of hemophilia management,  particularly in severe hemophilia A.

Today, bypassing agents – which can generate thrombin through alternative pathways to the coagulation cascade – are able to partially compensate for the neutralizing effect of the inhibitors in many patients but require frequent dosing. Immune tolerance induction can be used to induce tolerance to factor products so they can be again used for bleed management, although complete resolution is not always achieved.

In 2017, emicizumab (Hemlibra, Genentech), a non-factor bispecific antibody that is dosed subcutaneously, provided an effective coagulation workaround for hemophilia A patients with inhibitors. It has been a major advance for patients and is now used for hemophilia A patients with and without inhibitors. The drug does not eliminate the need for factor or bypassing agents in all situations, as major bleeding, surgery, and laboratory interpretation still require additional treatment, but it has reduced spontaneous bleeding, bleeding from minor trauma, and the frequency of intravenous (IV) infusions.

Gene therapy is the latest chapter in the fight to control hemophilia. Adeno-associated viral vector (AAV) approaches for hemophilia A and B were FDA-approved in recent years. Currently available FDA-approved AAV therapies include valoctocogene roxaparvovec-rvox (Roctavian, Biomarin) for hemophilia A and etranacogene dezaparvovec-drlb (Hemgenix, CSL Behring) for hemophilia B. AAVs have proven to enable hepatocytes to produce clotting factor to approximately 20-40% of normal levels and reduce clotting factor concentrate use by up 95% to 99%.

While clinical trials have shown major reductions in bleeding and factor use for many adults, durability, variability of factor expression, liver enzyme elevations, eligibility limitations, and cost remain real considerations.

On the Horizon

Thanks to medical advances, hemophilia is generally no longer a bleeding disorder to be managed at moments of crisis. It is a longitudinal condition that calls for early diagnosis which allows for multidisciplinary management, including genetic counseling, pharmacologic prophylaxis, joint surveillance, inhibitor screening, physical therapy, vaccination and procedure planning, and psychosocial support.

The overall trajectory is remarkable. A child born with severe hemophilia today, particularly in a setting with access to modern prophylaxis, has a very different future than a child born in the middle of the 20th century. Bleeding can often be prevented. Arthropathy can often be delayed or avoided. Families can think beyond survival and disability toward participation in many types of athletics, and normal or near-normal mobility, education, work, and aging.

Sources

• Centers for Disease Control and Prevention. Data and statistics on hemophilia. Updated 2024. Accessed July 13, 2026. https://www.cdc.gov/hemophilia/data/index.html
• Callaghan MU, Negrier C, Paz-Priel I, et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1–4 studies. Blood. 2021;137(16):2231-2242. doi:10.1182/blood.2020009217
• Guelcher CJ. Evolution of the treatments for hemophilia. J Infus Nurs. 2016;39(4):218-224. doi:10.1097/NAN.0000000000000175
• Iorio A, Stonebraker JS, Chambost H, et al. Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries. Ann Intern Med. 2019;171(8):540-546. doi:10.7326/M19-1208
• Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544. doi:10.1056/NEJMoa067659
• Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379(9):811-822. doi:10.1056/NEJMoa1803550
• Mahlangu J, Pipe SW, Ragni MV, et al. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N Engl J Med. 2023;388(8):694-705. doi:10.1056/NEJMoa2211067
• Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377(9):809-818. doi:10.1056/NEJMoa1703068
• Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022;386(11):1013-1025. doi:10.1056/NEJMoa2113708
• Pipe SW, Leebeek FWG, Ferreira V, et al. Etranacogene dezaparvovec gene therapy for hemophilia B. N Engl J Med. 2023;388(8):706-718. doi:10.1056/NEJMoa2211644
• World Federation of Hemophilia. WFH Guidelines for the Management of Hemophilia. 3rd ed. World Federation of Hemophilia; 2020. 
• U.S. Food and Drug Administration. FDA approves first gene therapy for adults with severe hemophilia A. Published June 29, 2023. Accessed July 13, 2026.