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 or 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” is used to describe one particular joint that has had recurrent bleeding episodes and chronic inflammatory changes occur. 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 3,4,5.
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 6. 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 7. 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 2. 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 9. Elevated BMI is associated with decreased function over time.
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 2,3. 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. Subcondral 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.
Prevention of joint bleeds and subsequent hemophilic arthropathy is the main objective of using prophylactic clotting factor replacement therapy (CRF). Early initiation of prophylaxis with CFR at a younger age and after fewer joint bleeds is associated with a decreased progression in joint disease7,9-11. There is an inverse correlation between range-of-motion (ROM) and number of joint bleeds 9. 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 12. ROM decreased asymmetrically, most notably among those with severe hemophilia 9. Knees, elbows, and ankles were most frequently affected 6. Elevated BMI was associated with worse ROM over time 9.11. Synovitis was seen in children from six to sixteen years of age but was less common in adults 10. Adults with current synovitis or a history of synovitis as a child or adolescent were more likely to have decreased ROM and joint damage 10,11. 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 10. Prognosis was improved with early initiation of prophylaxis11,13. 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 2.
Specific Secondary or Associated Conditions and Complications 14
- 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
Documentation should include family history with the number of affected siblings and family members, diagnosis and genetics if known, inhibitors if present, history of spontaneous bleeding into joints, muscles or soft tissues, bleeding record (number of hemarthroses episodes and treatment given), and age at the first bleeding episode 15. Document the age when prophylaxis was initiated and if it was prior or after the first joint bleed, and current replacement therapy regimen. 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 14.
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 16.
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 evident14.
Clinical Functional Assessment 17
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.
The Haemophilia Joint Health Score 2.1 (HJHS 2.1), is a validated instrument that identify mild to moderate bleeds in children on prophylaxis as well as joint bleeds in adults. The HJHS 2.1 has eight questions and a global gait score.
One tool developed specifically to evaluate the functional wellbeing of hemophilia patients is the Hemophilia Joint Health Score (HJHS), an 11-item measure administered by a physical therapist, which has been validated in boys. Objective findings assessed include the presence or absence of joint swelling, preservation or loss of flexion and extension and gain changes 6. World Federation of Hemophilia recommends the HJHS, which picks up the early signs of joint damage. It monitors joint changes over time for assessing efficacy of treatment.
The Petterson 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. The Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) is a protocol developed for ultrasound images.
The Functional Independence Score in Haemophilia (FISH) provides a performance-based score for assessment of activities of daily living. It assesses eight activities: 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. 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. 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.
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.
X-rays have long been used for staging hemophilic arthropathy. X-rays are more sensitive for late changes – such as osteonecrosis, joint space narrowing, and ankylosis – as opposed to acute joint changes. The Petterson score is an additive scale that is frequently used to classify HA stage. This score has high interrater reliability. Soft tissue changes, which are poorly detected on X-ray, are not included in the Petterson score2,18. Soft tissue changes, such as subtle changes of synovium and cartilage, can be detected with utilization of other imaging modalities such as ultrasound or MRI.
Ultrasound and MRI are equally effective in detecting early pathology such as joint effusion and synovitis. The addition of power doppler to ultrasound allows differentiation between joint fluid and active synovitis. Contrast must be used to detect the same in MRI. Limitations of MRI include its higher cost, necessity to sedate children to obtain reliable imaging and inability to frequently scan multiple joints. Limitations of ultrasound include operator dependency and years of experience of radiologist. Joints may be more easily monitored with serial point of care US performed in the office 2.
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 recognized:26
- 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.
Early Predictions 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 19.
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-bleeds.
REHABILITATION MANAGEMENT & TREATMENTS SECTION
Available or Current Treatment Guidelines
The most important 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 18.
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 (ie. 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 hemarthoses 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 20,21,22,25.
Acute to chronic hemarthoses benefits 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 19.
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 2,20,21.
Coordination of Care 14
A multidisciplinary team that addresses the wide-ranging needs of people with hemophilia/hemophilic arthropathy should be included for comprehensive care. This team may include:
- 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.
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 14.
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 23.
GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Preventative strategies such as prophylaxis with CFR and procedures such as synovectomy have provided good results but may be insufficient in preventing HA or joint destruction. 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 19.
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- 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. September 2019. doi:10.7326/M19-1208.
- Nijdam A, Foppen W, van der Schouw YT, Mauser-Bunschoten EP, Schutgens REG, Fischer K. Long-term effects of joint bleeding before starting prophylaxis in severe haemophilia. Haemophilia. 2016;22(6):852-858.
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- Soucie JM, Cianfrini C, Janco RL, et al. Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors. Blood. 2004;103(7):2467-2473.
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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
Julio Vazquez-Galliano, MD
Nothing to Disclose
Deborah Pacik, MD MPH
Nothing to Disclose
Bari Madureira, DO MPH
Nothing to Disclose