Author(s): Yuxi Chen, MD, Michelle Nunez Garcia, MD, Jordan Schnoll, MD, Keri Morgan, MD
Originally published: September 15, 2015 Last updated: September 18, 2025
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Disease/Disorder

Definition

Hemophilia is a congenital bleeding disorder characterized by low or absent coagulation factors. The most common types are Hemophilia A (classic hemophilia), caused by decreased factor VIII, accounting for about 80% to 85% of all hemophilia cases, and Hemophilia B (Christmas disease) caused by decreased factor IX.1 Hemophilia C is due to factor XI deficiency.

Etiology

Hemophilia A and B are caused by defects in the genes for factor VIII and factor IX respectively, which are transmitted as X-linked recessive.1 Sporadic cases are common and are responsible for up to 50% of cases of hemophilia A and 40 % of hemophilia B.2 Hemophilia C is most inherited through an autosomal recessive pattern.

Epidemiology including risk factors and primary prevention

Hemophilia occurs most commonly in patients with family history of hemophilia with male predominance (due to its X-linked recessive inheritance). Hemophilia A is about four time more common than hemophilia B. The estimated prevalence of hemophilia A and B at birth is 24.6 and 5.0 cases per 100 000 males, respectively.1 In the U.S. average incidence for hemophilia A is 1 per 5,617 live male births while hemophilia B occurs 1 per 19,283 live male births. Approximately 30,000 to 33,000 males with hemophilia live in the US.3,4 The strongest risk factor for the disease is an inherited mutation on the X chromosome, typically passed down from mother to son. Severity is determined by the specific genes affected and resulting factor activity level.

Among female carriers, approximately 30% have lower than 40% factor VIII or IX clotting activity and may have abnormal bleeding.5 Rarely, they can be severely affected in cases such as homozygosity of extreme X-inactivation.6

Patho-anatomy/physiology

Hemophilia results in abnormalities in the clotting cascade.  Factor VIII and IX respectively are involved in the initiation and propagation of the hemostatic mechanism. This mechanism involves the interaction of platelets with the exposed thrombogenic endothelium mediated by collagen, which serves an adhesive function for platelets in the subendothelium, and the coagulation proteins to dock on activated platelets, resulting in fibrin generating concentrations of thrombin.7 Any resulting dysfunction in coagulation factors VIII and IX disrupt two processes: the formation of fibrin, which help stabilize the clot, and fibrinolysis inhibitor, which helps prevent clot breakdown.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The natural history of hemophilia varies with severity of the condition. Severity is classified into mild, moderate, and severe with plasma levels of factor VIII or factor IX of between 5-40%, 1-5%, and <1% respectively.8 Patients with severe hemophilia are more likely to have spontaneous bleeding as early as birth. If left untreated, spontaneous bleeding episodes can occur two to five times per month.

Initial sites of bleeding may change with age.9

  • Infants- intracranial or extracranial bleeding, affecting about 3-5% of patients at birth.  Prolonged bleeding during circumcision or phlebotomy are common. Most patients with severe hemophilia (90%) will present with symptoms during the first year.
  • Children (6 m to 11 year)- Bruising, forehead hematomas, hemarthrosis, other musculoskeletal bleeding, or young toddlers with frenulum and oral injuries are common. Children in this age group generally have mild or moderate disease.
  • Older children and adults –joints, muscle, CNS, and oral or gastrointestinal tract bleeding are common.

Specific secondary or associated conditions and complications

Recurrent hemarthrosis may cause joint arthropathy, muscle atrophy, soft tissue contractures, bone mineral density loss, chronic pain, and functional disability. Life threatening bleeds, such as intracranial hemorrhage, can occur at any age and are the leading cause of mortality in this condition.

Frequent infusions increase the risk of infections and may also lead to the development of antibodies to infused factors (factor inhibitors). Formation of factor inhibitors occurs in 30-35% of patients with severe hemophilia A, and 5-15% of patients with severe hemophilia B.10

Essentials of Assessment

History

A detailed history is essential. It should include the patient’s age, sex, past medical history, birth history, bleeding history, family history, recent trauma or surgery. A detailed timeline of bleeding symptoms from infancy is helpful. Findings include excessive bruising, gum bleeding, and prolonged bleeding with circumcision or minor procedures such as immunizations.7,11 Bleeding in utero or during forceps delivery can occur since Factor VIII or IX does not cross the placenta. A bleeding history should specify whether episodes involve joints or other sites, whether they are associated with arthropathy, if they occurred spontaneously or after trauma, and the exact locations affected.

Physical examination

Physical examination requires comprehensive thorough musculoskeletal evaluation of all limbs, including inspection, palpation, range of motion and strength. Inspection should be focused on evaluating for pallor, joint effusions, bruising, leg length discrepancy, joint deformity and limb/joint asymmetry. Posture of the limb can suggest muscle hematoma – for example, in the case of iliopsoas hematoma, it may present as vague groin pain in a flexed and internally rotated hip, with difficulty on hip extension. 12

During palpation, assess for tenderness in the joint (commonly elbows, knees and ankles) or muscle (most commonly the quadriceps, hamstrings, iliopsoas, biceps and triceps) and possible effusion. Consider hemarthrosis in the presence of limited ROM, stiffness, swelling, pain and warm tingling sensation, or irritability and unwillingness to use the limb in infants.11

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Patients with severe arthropathy and/or joint deformity can have issues affecting functional mobility and basic (ADL’s) and may require assistive devices.

Cognitive state is usually not affected in the child-adolescent stage, but adults may present with mild cognitive dysfunction as the result of asymptomatic cerebral microbleeds.12

Laboratory studies

  • Prothrombin time (PT), platelet count and bleeding time – Normal
  • Activated partial thromboplastin time (aPTT) – Prolonged
    • If prolonged, mixing study is performed.
    • Despite a negative family history and a noncarrier mother, this highly suggests the diagnosis.
  • Factor activity level (Factor VIII- Hemophilia A; Factor IX – Hemophilia B) provides a definite diagnosis
    • Mild: > 5%-40%, where bleeds commonly occurring in joints and soft tissue, are caused by major surgery and trauma.11
    • Moderate: 1-5%, where bleeds are caused by minor trauma, may also lead to neonatal intracranial hemorrhage.
    • Severe: <1%, where bleeds occur spontaneously
  • Von Willebrand Factor antigen and activity level – Normal but tested as some variants of deficiency can present like Hemophilia.

It is recommended that for children with moderate to severe disease, inhibitor (antibody) screens should be completed every 6 to 12 months.14

Imaging

  • Musculoskeletal Ultrasonography (MSKUS): Point-of-care MSKUS is a fast, efficient, safe, and cost-effective imaging modality in early detection and management of hemarthrosis.15 It can detect bleeding in joints, synovial hypertrophy, cartilage damage, muscle hematoma, and evaluate periarticular structures (tendons, ligaments, muscles).POC-MSKUS has become the preferred imaging test in the acute and subacute setting, with similar diagnostic accuracy to MRI.
  • Radiographs: Useful for adults with advanced joint disease. Several classifications have been developed based on radiographic findings (Arnold-Hilgartner, Petterson score). It identifies irregularity of joint space, joint effusion and epiphyseal overgrowth. It is insensitive to early changes and unreliable for cartilage or soft tissue evaluation.
  • CT: Non-contrast head CT is the study of choice to rule out intracranial bleeding in a hemophilia child, however you must not delay an immediate infusion of factor concentrate for imaging.11 Compared to radiographs, CT scans are better able to demonstrate erosions and cysts.16
  • MRI: High resolution for assessing hemarthrosis, synovial hypertrophy, deposits of hemosiderin, focal cartilage damage, bony destruction, subchondral bone and cysts, osseous pseudotumors and muscle bruising. MRI can be used for common complications such as for iliopsoas or quadricep bleeds.16

Supplemental assessment tools

Genetic testing is offered at no cost to individuals in the US with hemophilia through participating Hemophilia Treatment Centers (HTCs), currently up to 140 centers. This helps predict the risk of factor inhibitor formation and facilitates carrier identification in female family members. In suspected carriers, genetic testing is considered first line evaluation. Confirming or excluding carrier status is important, both for managing the carrier herself and the offspring.6 Although family history can prove enlightening, approximately 30-50% will be de novo mutations.11

Early prediction of outcomes

Children with recurrent hemarthrosis are at high risk of developing severe arthropathy and joint contractures later in life. Neuromuscular dysfunction can precede radiologic pathology of the affected joint.

Environmental

Complete assessment of home and school environment for possible injury hazards at discharge planning.

Evaluation of sports activity and the use of sports safety equipment such as knee pads, elbow pads and helmets.

Social role and social support system

All those involved in the care of a child with hemophilia should be informed about the diseases. The child’s caregivers, daycare providers, teachers, other school staff, and coaches should be prepared to contact parents and emergency services in case of injury. Patients are encouraged to seek care at a Hemophilia Treatment Center (HTC) as it decreases the likelihood of dying from a hemophilia-related complication by 40%.17 Children with disabilities face interpersonal challenges; anticipatory guidance and supportive strategies help promote social adaptation and appropriate integration.18

Professional issues

Bleeding history, physical exam and diagnostic testing should be consistent with the child’s development and level of activity. If suspected, physical abuse should be reported to the proper authorities for further investigation.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Current treatment aims to prevent musculoskeletal injuries and maintain the locomotor apparatus in optimal condition through rehabilitation and clotting factor replacement therapy. Rehabilitation requires a clinical evaluation of the patient’s physical state in order to develop a customized therapeutic program. Treatment objectives include alleviate pain, improve joint range of motion and proprioception, prevent muscle atrophy or joint damage, improve muscle power, recover balance and coordination, improve the functional capacity and gait as well as decrease fear of movement, and ultimately reduce the frequency of joint bleeds and improve quality of life and activity participation.11,15,19

At different disease stages

Pre-Bleed/Preventative Management

  • Hemarthrosis emerges with motor activity; without treatment, it may recur or worsen, highlighting the importance of prophylaxis and rehabilitation in early childhood.19
  • Early prophylaxis with factor concentrates is the best method for preventing or reducing the risk of recurrent joint bleeds and arthropathy, and is typically administered for severely affected patients two to three times per week.15, 20 Even one hemarthrosis induces synovial angiogenesis and recurrent bleeding; early continuous prophylaxis is superior to episodic therapy for joint preservation.15
  • Due to cost, potential adherence challenges amongst adolescents, as well as the development of neutralizing autoantibodies (inhibitors) to FVIII/IX, new alternative therapies have become available that allow for subcutaneous administration and longer half-life, which reduces the required number of injections, further improving patients’ quality of life and treatment adherence.15 This includes humanized antibody mimicking FVIIIa function, small interfering RNAs, and gene therapy.15,21
  • Ancillary treatments include vasopressin (DDAVP) and fibrinolysis inhibitors. DDAVP increases FVIII levels by 2-3 fold and can be used for hemorrhagic episodes in mild hemophilia A patients or before minor procedures. Antifibrinolytic drugs can be used prior to dental procedures and epistaxis, oral hemorrhage, or menorrhagia.22
  • In patients receiving adequate prophylaxis, high-impact sports or strenuous activity show no increased risk of bleeding or adverse joint outcomes.23 However, the National Hemophilia Foundation recommends that patients engage in activities that it has stratified as “safe” or “moderate”, such as aerobics, swimming, frisbee, and more while avoiding those that are “dangerous” such as football, lacrosse, and hockey, or those that involve high contact.24 Each patient and sport should be evaluated prior to participation in addition to adequate adult supervision and prophylaxis.

Acute Hemarthrosis

  • First line treatment is clotting factor replacement therapy. Rapid administration has shown to reduce the severity of the bleeding episode.15, 20
  • Arthrocentesis should be avoided in the absence of factor therapy, though it can be considered in painful joints after failure of conservative therapy. Joint aspiration can reduce inflammation in acute hemarthrosis, but evidence does not confirm that benefits surpass procedural risks.15
  • Compressive bandage, static orthotics for joint immobilization, elevation, and avoidance of weight-bearing should be implemented for up to 7 days.25
  • Proper analgesia with NSAIDs, preferably COX-2 inhibitors are indicated. Ice also reduces pain, but it can delay healing, thus is indicated only within the first 6 hours of an acute bleed. Electrical stimulation can also reduce pain.25,26 Isometric exercises and stretching with the goal to restore joint function can be started shortly after joint bleeding to overcome the arthrogenic inhibition and accelerated atrophy that may occur.15
  • Chronic Hemarthrosis: characterized by destructive synovitis, joint destruction, osteophyte formation, and ultimately hemophiliac arthropathy. When tolerated, a supervised physiotherapy program aiming to preserve muscle strength and functionality to pre-bleeding level should be initiated.1,20 Patients should progress to active range of motion (AROM) or very careful assisted active range of motion (AAROM) and avoid passive range of motion (PROM) to prevent further hemarthrosis. Balance, coordination, and proprioceptive exercises are beneficial, and hydrotherapy may be more effective than land exercises for pain relief. Dynamic orthotics can support pain management and functional restoration.
  • Chronic hemophilic synovitis is unresponsive to factor replacement alone; TNF-α blockade shows promise, but clinical efficacy remains unproven.15
  • Pulsed high-intensity or neodymium-doped yttrium aluminum garnet (Nd:YAG) laser therapy have been found to significantly reduce pain, improve function and postural stability compared to placebo laser in children with mild to moderate hemophiliac arthropathy.19,27
  • Non-invasive synovectomy using radiation or chemical agents is indicated in refractory synovitis.15,20 It does not require major coverage with coagulation factors.
  • Surgical synovectomy can be performed either by open or arthroscopic approach with complete excision of the hypertrophic synovial membrane. The procedure requires more use of coagulation factors.
  • Joint arthroplasty of the hip and knee or arthrodesis of the ankle can be considered in cases of severe deformity.

Coordination of care

A multidisciplinary approach is recommended in these patients. A primary care physician, hematologist, physiatrist, genetic counselor, physical and occupational therapist, and orthopedic surgeon should be involved in the treatment. The physiatrist’s input is important to the patient from the point of diagnosis throughout their lifespan, and should be involved in the assessment, education and treatment of the condition.1

Patient & family education

Parents and family must learn how to recognize signs of bleeding and be prepared for bleeding episodes, know the location of nearest certified HTC, and be oriented about national and international support organizations.

The patient should wear a medical ID bracelet or necklace to alert any care providers about their hemophilia.

Measurement of treatment outcomes including those that are impairment-based, activity participation-based and environmentally-based

  • Annualized Bleeding Rate (ABR) and Annualized Joint Bleeding Rate (AJBR) measure bleeding and joint bleeding outcomes in hemophilia, serving as important indicators of therapeutic efficacy.28
  • Hemophilia Joint Health Score (HJHS and HJHS 2.1) – is a physical examination tool to measure the impact of bleeding in the joint and is appropriate for monitoring joint change over time or assessing efficacy of treatment regimens. It is useful as an outcome measure of orthopedic or physiotherapy interventions.28,29
  • Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) – is a simplified ultrasound scoring system (0–8) assessing synovitis, cartilage, and subchondral bone to monitor hemophilic joint degeneration and treatment efficacy.28
  • Functional Independence Score in Hemophilia (FISH) – a performance-based assessment tool to objectively measure an individual’s functional ability.
  • Hemophilia Activities List (HAL/PedHAL) – measures the impact of hemophilia on self-perceived functional abilities in patients.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Children with hemophilia are particularly vulnerable to loss of physical conditioning and becoming overweight or obese as a result of restrictions on their activity.9 Regular exercise to stimulate normal psychomotor development should be encouraged to promote toned  muscles and healthy bone mineral density, develop balance and coordination, and improve fitness.1 The role of an exercise program for the child and adult following episodes of bleeding is best discussed before the child has a joint bleed.1 Education improves compliance and patient-provider communication. Prophylactic hematological treatment makes it possible to advise patients to take part in a sport, provided that certain basic safety conditions are obeyed. Virtual physical therapy programs, telemedicine, and mobile health applications are available now, but there are indications that in-person therapy may lead to better outcomes.30

Cutting Edge/Emerging and Unique Concepts and Practice

The next-generation FVIII-mimetic bispecific antibodies such as Emicizumab can restore the function of factor VIII but has no structural relationship to factor VIII. Emicizumab is FDA approved for use as a prophylaxis in hemophilia A patients with or without factor inhibitors.31 Gene therapy is another major advancement. It uses adeno-associated viral vectors to deliver factor VIII or IX genes to the liver, enabling endogenous production. This may reduce or eliminate factor replacement, though durability, efficacy, and long-term liver safety remain uncertain. 32

Gaps in the Evidence-Based Knowledge

Despite the multitude of scientific advancements, challenges persist in managing patients with hemophilia. Some treatments are associated with the development of Factor VIII or IX inhibitor formation when used on specific genetic mutations. Overcoming these complications is another obstacle that grows in research.11

There are still gaps in the evidence-based knowledge regarding the patient selection, dosage and duration of treatment, therefore recommendations for prophylaxis still needs to be tailored to each individual case.1 In addition, the long-term safety, durability, and accessibility of newer modalities like gene therapy are not yet fully established. Concerns remain regarding affordability and fair access to these advanced treatments.

References

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  13. Zanon, Ezio, Renzo Manara, Marta Milan, Barbara Brandolin, Daniela Mapelli, Rodica Mardari, Sandra Rosini, and Piero Amodio. “Cognitive Dysfunctions and Cerebral Microbleeds in Adult Patients with Haemophilia A: A Clinical and MRI Pilot-study.” Thrombosis Research4 (2014): 851-55. Print.
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Original Version of the Topic

Edwardo Ramos, MD, Juan Galloza, MD, Juan Perez, MD, Isabel Rutzen, MD, Natalia Betances, MD. Hemophilia in Children. 9/15/2015.

Previous Revision(s) of the Topic

Yuxi Chen, MD, Monika Desai, MD, Dara Jones, MD. Hemophilia in Children. 10/22/2019

Yuxi Chen, MD, Christopher Lu, MD, Michael Hagen, MD, Fernando Martinez, MD. Hemophilia in Children. 12/14/2022

Author Disclosure

Yuxi Chen, MD
Ipsen; Research Grants, Principal Investigator

Michelle Nunez Garcia, MD
Nothing to Disclose

Jordan Schnoll, MD
Nothing to Disclose

Keri Morgan, MD
Nothing to Disclose