Author(s): Ady Correa, MD, Rosalynn Conic, MD, PhD
Originally published: September 9, 2015 Last updated: July 13, 2023
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Disease/ Disorder

Definition

Hemophilia is an inherited coagulation disorder most commonly caused by deficiency of clotting factors VIII (Hemophilia A) or IX (Hemophilia B) that leads to lifelong recurrent bleeding episodes into joints (hemarthrosis), muscles, and closed spaces, either spontaneously or following an injury.1 There are three categories of hemophilia: mild, moderate, and severe determined by serum factor level.2 Mild is defined as factor levels 5-40% of normal, moderate 1-5%, and severe less than 1% of normal serum levels. The term “target joint” describes one particular joint that has had three or more episodes of bleeding in a six-month period and chronic inflammatory changes occur.3 Hemophilic arthropathy refers to persistent joint disease caused by multiple bleeds within one or more joints leading to decreased function, chronic pain, and worsened quality of life.4,5,6

Epidemiology including risk factors

Hemophilia A and B are X-linked recessive disorders with an overall prevalence of 29.6 cases per 100,000 males.7 Hemophilia A occurs more frequently than Hemophilia B with an almost five-fold increase in prevalence. Hemophilia does not have a significant predilection for any particular race, ethnicity or geographic area. The median age at first joint hemorrhage is two years of age.8 In males less than two years of age, joint hemorrhage accounted for 28% of bleeding events.8 Hemorrhagic arthropathy is the most common site of bleeding in severe hemophiliacs.3 The most common joints affected are the knee, ankle, elbow and shoulder joint. Approximately one-quarter of all patients with severe disease have at least one target joint. Non-Hispanic Caucasians with severe hemophilia have greater function over time than those of other races or ethnicities, perhaps due to access to health care.10 Elevated BMI is associated with decreased function over time.

Pathophysiology                             

Hemarthroses predominantly occurs in large synovial joints. Inflammatory cytokines, chemokines, and neoangiogenesis cause the early manifestations of synovitis and synovial hypertrophy, a process that can start within four days of blood contact with cartilage.3,4 Recurrent deposition of iron and hemoglobin triggers inflammatory interleukin-1 beta and interleukin-6 which have been implicated in cartilage destruction. Neoangiogenesis occurs due to a relatively hypoxic environment leading to upregulation of vascular endothelial growth factor. The combination of the hypertrophic synovium with fragile blood vessels makes the joint more susceptible to recurrent bleeding episodes. Subchondral bone damage leading to joint destruction may be associated with high levels of receptor activator of nuclear factor kappa-beta and ligand (RANK/RANKL) in the synovium which may lead to pathological bone remodeling, and peri-articular osteoporosis.

Disease progression

Prevention of joint bleeds and subsequent hemophilic arthropathy is the main objective of using prophylactic clotting factor replacement therapy (CFR). Early initiation of prophylaxis with CFR at a younger age and after fewer joint bleeds is associated with a decreased progression in joint disease.8-12 There is an inverse correlation between range-of-motion (ROM) and number of joint bleeds.10 Even with prophylaxis started prior to a first bleed in children, joint damage may occur, albeit at a slower rate than if prophylaxis was delayed.13 ROM decreased asymmetrically, most notably among those with severe hemophilia.10 Knees, elbows, and ankles were most frequently affected 6. Elevated BMI was associated with worse ROM over time.10,12 Synovitis was seen in children from six to sixteen years of age but was less common in adults.11 Adults with current synovitis or a history of synovitis as a child or adolescent were more likely to have decreased ROM and joint damage.11,12 The development of alloantibodies to coagulation plasma proteins, clinically termed inhibitors, is currently the major complication of hemophilia treatment. The presence and serum level of inhibitors made abnormal joints and destruction of joints more likely.11 Prognosis was improved with early initiation of prophylaxis.12,14 However, the optimum time for starting prophylaxis in young children with hemophilia has not yet been established. Untreated joint bleeding can lead to complete destruction of the joint by early adulthood.3

Specific secondary or associated conditions and complications 15

  • Chronic hemophilic synovitis
  • Articular irregularities, such as angular deformities
  • Subchondral cysts, and osteophytes
  • Advanced hemophilic arthropathy
  • Septic arthritis
  • Muscle atrophy
  • Flexion contractures
  • Synovial fibrosis
  • Joint ankylosis
  • Osteonecrosis of the femoral head
  • Muscle hematomas: The deltoid and forearm flexors are the most affected in the upper extremity and the quadriceps, psoas, and gastrocnemius-soleus complex muscles in the lower extremity. Complication includes compartment syndrome.
  • Pseudotumors: Rare complication; results from progressive subperiosteal hemorrhage and occur in 1% to 2% of patients. They present as firm, fixed, painless masses that slowly expand. They cause pressure necrosis of bone, muscle, and other nearby structures. If untreated, proximal pseudotumors lead to vascular or neurological changes and destroy soft tissues and erode bone.

Essentials of Assessment

History

Personal history: Documentation should include diagnosis/suspected diagnosis, laboratory testing which was performed, including genetic testing, age at first bleeding episode, history of spontaneous bleeding into joints, muscles or soft tissues, bleeding record (number of hemarthroses episodes and treatment given).16

Current symptoms: In an acute joint bleed, the patient may complain of acute decrease in range of motion with pain, paresthesia, and/or tightness, swelling, and warmth. With repeated bleeding, the toxic effects of blood products lead to synovial hypertrophy, fibrosis, and impaired joint movement. Despite these internal joint changes, pain is not prominent at this time. Repeated attacks or persistent hemorrhage for more than six months leads to chronic disabling arthropathy.15

Treatment history: Documentation should include what prophylactic treatment was initiated, age when prophylaxis was initiated, was it prior to or after a first joint bleed, what prophylaxis was used, other treatments which were attempted, and current treatment regimen.

Family history: Documentation should include number of affected siblings and family members, their diagnosis and genetics if known.

Physical examination

A complete musculoskeletal assessment should be performed in any patient with hemophilia with an evaluation of the joints conducted every six months in children and at least, every year in adults.17

An acute joint bleed will manifest with any of the following at the affected joint: swelling, warmth, tenderness to palpation, pain with passive or active range of motion, especially extension, limited range of motion, and muscle spasms. In the subacute and chronic stages, the joint appears swollen but not particularly painful. As the swelling continues to increase, muscle atrophy and loss of motion will be more evident.14

Clinical functional assessment18

An annual assessment of bleeding frequency over the past twelve months, the annual bleeding record (ABR) and annual joint bleed record (AJBR), should be documented. This subjective assessment relies on the patient’s recollection of bleeding episodes since most events are treated at home.

One of the first clinical assessment tools was The World Federation of Hemophilia Physical Examination Score, also known as the Gilbert score, assesses joint health in the domain of body structure and function (i.e., impairment) of the joints most commonly affected by bleeding. It is a self-assessment tool completed by patients; however, takes 30-45 minutes to administer (available at https://www1.wfh.org/docs/en/Publications/Assessment_Tools/Gilbert_Score.pdf).

In clinical practice, the Hemophilia Joint Health Score (HJHS), has been studied the most.19 It detects early signs of joint damage and allows for monitoring of joint changes over time as well as assessment of treatment efficacy. The first version was an 11-item measure administered by a physical therapist, which has been validated in boys aged 14-17.20Objective findings assessed include the presence or absence of joint swelling, preservation or loss of flexion and extension and gait changes.6

The most recent version is the Hemophilia Joint Health Score 2.1 (HJHS 2.1), which similarly examines six joints and scores swelling, pain, strength, flexion/extension, muscle atrophy and gait changes.21 The maximum score for each joint is 20, and the maximum gait score is 4, with higher scores indicating worse joint health (available on http://ipsg.ca/hjhs‐portal). It has been validated to identify mild to moderate bleeds in children on prophylaxis as well as joint bleeds in adults.

The Functional Independence Score in Hemophilia (FISH) provides a performance-based score for the assessment of activities of daily living.22It assesses eight activities of daily living: eating, grooming, dressing, chair transfer, squatting, walking, step climbing, and running. Each activity is graded according to the amount of assistance required to perform it (available at https://wfh.org/wp-content/uploads/2021/12/WBDR-FISH-scoring-sheet.pdf). The level of independence for each activity is clearly defined to reduce inter-observer variance.

The Hemophilia Activities List (HAL) and the pediatric version, ped-HAL assesses activity limitations. It is a disease-specific, self-rated questionnaire based on the International Classification of Functioning, Disability, and Health (ICF) classification. There are 42 questions across seven domains (lying down/sitting/sitting/kneeling/standing, leg and arm function, use of transportation, self-care, household tasks, leisure activities and sports.23

Laboratory studies

Platelet count, bleeding time (BT), PT, and APTT are used to screen and potentially categorize bleeding disorders. A factor assay (Factor VIII or Factor IX) is then performed to determine diagnosis, severity and to monitor treatment.

Imaging

X-rays were traditionally used for staging hemophilic arthropathy, as they are more sensitive for late changes – such as osteonecrosis, joint space narrowing, and ankylosis – as opposed to acute joint changes. The Pettersson score is the most widely used instrument based on x-ray films of joints and it is used to quantify the severity of hemophilic arthropathy. This score has high interrater reliability and can be improved by using a consensus atlas.24Soft tissue changes, such as subtle changes of synovium and cartilage which are poorly detected on X-ray, are not included in the Pettersson score, and require utilization of ultrasound or MRI.2,18

Musculoskeletal ultrasound is rapidly gaining popularity as it is a rapid, cheap, method of evaluating early pathology such as joint effusion and synovitis and can be used in a point-of-care setting. 2 It can also be used to monitor resolution of hemarthrosis or inflammation.25 A scoring protocol called Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) can be used for rapid, standardized joint evaluation in children and adults which is useful in both early and later stages of joint disease.26 It correlates well with HJHS scores, and their combined use assists in detecting relevant physical and functional changes.27-29 One of the major limitations in use of ultrasound is that it is operator dependent and has a steep learning curve; however, most physical medicine and rehabilitation physicians receive significant training.

MRI is similarly effective in detecting early pathology; however, requires contrast, more expensive, and requires children to be sedated to obtain reliable imaging, and time required to scan multiple joints.

CT is not typically used in evaluation or management but is overall better than conventional radiography in detecting subchondral cysts and erosions.

Radiologically, five stages of hemophilic arthropathy are recognized44

  • Stage 1: Soft tissue swelling of the joint and adjacent tissues.
  • Stage 2: Osteoporosis due to inflammatory hyperemia, especially in knee and elbow.
  • Stage 3: Joint disorganization due to osseous lesions. The articular cartilage remains intact.
  • Stage 4: Cartilage destruction and secondary joint space narrowing.
  • Stage 5: Complete loss of cartilage spaces with bony erosion.

Table 1: Assessment of Hemophilia/Hemophilic Arthropathy

Hemophilia-and-Hemorrhagic-Arthropathy-Table-1-1Download

Early predictors of outcomes

The severity of disease is the primary predictor of outcome and is determined by the level of Factor VIII (hemophilia A) or Factor IX (hemophilia B) present on factor assay testing. People with severe hemophilia experience bleeding into joints/muscles in absence of identifiable insults whereas those with mild to moderate hemophilia experience bleeding into joints typically only with direct trauma.30 Studies today are investigating the utility of various biomarkers as potential predictors of outcomes, such as serum Coll2-1, COL-18N, COMP, C2M, MIF, plasma sVCAM-1, serum CS846 and urinary CTX-II which in combination are associated with radiographic joint damage progression.31-32However, the vast majority of these tests are not regularly performed and may not be commercially available. Additionally, imaging studies might have a predictive value. In a recent study, synovial hypertrophy findings on MRI showed to be predictive for joint bleeding in hemophilic patients 5 year later.33

Environmental

Adaptations to the home, school, or work environment can be made to allow participation in community activities and employment and to facilitate activities of daily living. For children, it is essential to educate school staff about appropriate activities for the student, urgent care when suspecting a bleed, and activity modification that may be required post-bleed.

Professional issues

N/A

Rehabilitation Management and Treatments

Available or current treatment guidelines

The primary initial management is prevention of hemarthroses and subsequent arthropathy through intravenous CFR. Ideally, replacement therapy should be initiated early, before or soon after the first joint bleed (before joint damage occurs). However, HA cannot be prevented through CFR alone as evidenced by ~30-50% of patients in industrialized countries developing hemarthroses despite CFR prophylaxis since childhood.30

More recently, in 2018, Emicizumab, a bispecific monoclonal antibody was approved for hemophilia A.34 It is gradually becoming the standard of care treatment for adults and children with inhibitor and non-inhibitor hemophilia A. Emicizumab use is associated with significant improvement in quality of life, decreased work disruption, and leads to resolution of joint symptoms in almost all patients; however, cost remains a major barrier. Additionally,

As with most musculoskeletal conditions, it is beneficial to start with the most conservative management first and progress to more invasive strategies as needed.

For acute hemarthroses, after hemostasis is achieved either through CFR or other means, patients should be placed on one day bed rest followed by three to four days of weight bearing avoidance (i.e., crutches for lower extremity involvement and splinting for upper extremity involvement).20 Swelling and pain can be reduced with ice or cryotherapy particularly in the first 24-48 hours. Supplemental analgesia with medications should follow a stepwise progression starting with Tylenol. While aspirin & non-selective NSAIDs should be avoided due to increased risk of GI bleed, COX-2 inhibitors are safe and effective for HA.20 Opioids should be held as a last resort but can be used for moderate to severe or refractory pain. Joint aspiration may be useful for pain relief in tense hemarthroses but is not routinely recommended unless there is concern for potential septic arthritis. This is both due to the risk of introducing infection and iatrogenic bleeding. Surgical intervention is typically not indicated after an episode of acute hemarthrosis.36,37,38,39,41

Acute to chronic hemarthroses benefit from exercise which is an important component of treatment in order to restore ROM, preserve strength as well as to maintain a healthy body weight and decrease stress on joints. To date there are no specific guidelines as to which exercises or programs are most beneficial and safe. ROM exercises should be performed after an initial rest period in acute HA to prevent formation of contracture.35

Various options are available for chronic hemarthroses. Synoviorthesis also known as radionuclide synovium ablation or radiation synovectomy can be considered when other conservative measures fail. This procedure is particularly useful in inhibitor patients or those who are not surgical candidates. Surgical synovectomy can also be considered. Arthroscopic synovectomy is the gold standard when compared to open synovectomy given decreased complication rates and earlier joint mobilization. If a patient continues to experience joint destruction after trial of the above, joint replacement should be discussed.3,36,37

Coordination of care15

A multidisciplinary team that addresses the wide-ranging needs of people with hemophilia/hemophilic arthropathy should be included for comprehensive care. In the United States, the Hemophilia Treatment Centers (HTCs) have been established for more than 40 years to address the needs of patients with hemophilia following a multidisciplinary approach. In the last years, these centers have made possible evaluation of diverse population, including adult patients and increased number of female patients.38

The multidisciplinary team of professionals treating patients with hemophilia includes

  • A pediatric and/ or adult hematologist particularly those who specialize in hemophilia management.
  • A musculoskeletal expert (physiatrist, orthopedist, rheumatologist) to address musculoskeletal concerns and address HA prevention/treatment strategies.
  • A physical/occupational therapist to address therapy needs and provide input on functional status.
  • A social worker or case manager to provide counseling, assess psychosocial needs.

Patient & family education

To facilitate appropriate management in emergency situations, all patients should carry easily accessible identification indicating the diagnosis, severity of the bleeding disorder, inhibitor status, type of treatment product used, initial dosage for treatment of severe, moderate, and mild bleeding, and contact information of the treating physician/clinic.15

Cutting Edge/ Emerging and Unique Concepts and Practice

Multiple, potential targets are available for disease modifying therapy considering the many processes involved in the pathophysiology of HA. Treatment such as iron chelators, anti-inflammatory therapy, antifibrinolytics and bone remodeling agents have shown beneficial effects in the pre-clinical setting. Identifying a universal outcome measure to assess efficacy of treatment and determining optimal route and timing would be beneficial for the prevention and treatment of HA in hemophilic patients.40,42,43

Gaps in the Evidence-Based Knowledge

Preventative strategies such as prophylaxis with CFR, extended half-life recombinant drugs, non-replacement therapies and procedures such as synovectomy have provided good results but may be insufficient in preventing HA or joint destruction.41 There is a need to explore biomarkers that can help monitor joint disease initiation and progression. These biomarkers then can dictate the timings of interventions such as prophylaxis and synovectomy.24

In addition, there is insufficient evidence in the literature to comment on the safety of various exercise regimens and it is unclear specifically what exercises or exercise regimens are most beneficial.35

References

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Original Version of the Topic

Jaspreet Singh, MD, Navdeep Singh Jassal, MD, Ritika Oberoi-Jassal, MD. Hemophilia and hemorrhagic arthropathy. 9/9/2015

Previous Revision(s) of the Topic

Julio Vazquez-Galliano, MD, Deborah Pacik, MD MPH and Bari Madureira, DO MPH. Hemophilia and hemorrhagic arthropathy. 7/22/2020

Author Disclosure

Ady Correa, MD
Nothing to Disclose

Rosalynn Conic, MD, PhD
Nothing to Disclose