Hemophilia and hemorrhagic arthropathy

Author(s): Jaspreet Singh, MD , Navdeep Singh Jassal, MD, Ritika Oberoi-Jassal, MD

Originally published:09/09/2015

Last updated:09/09/2015

1. DISEASE/DISORDER

Definition

Hemophilia is an inherited disorder of clotting factor XIII or IX deficiency resulting in musculoskeletal bleeding, including hemarthroses. Hemophilic arthropathy refers to persistent joint disease caused by multiple hemarthrosis within a target joint. This is defined by the United States Centers for Disease Control and Prevention as four episodes of hemarthroses in a 6-month interval, or 20 joint hemorrhages over the lifetime of a joint.

Etiology

Multifactorial mechanism includes chronic or episodic synovitis, with loss of cartilage, subchondral cyst formation, bone cysts, erosion, and joint space narrowing. Iron deposition adds to synovial inflammation, and fibrosis of the joint can cause pain, contractures and restricted range of motion

Epidemiology including risk factors and primary prevention

Hemophilia is an X-linked recessive disorder with an incidence of approximately 1 in 10,000 (factor VIII) and 1 in 30,000 (factor IX) live male births. Hemophilia does not have a significant predilection for any particular ethnicity and geographic areas.1 The median age at first joint hemorrhage ranges from 17 months to 2.2 years. 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.

Patho-anatomy/physiology                             

Hemarthroses predominantly occurs in large synovial joints, which comprise two connected bones enclosed by a capsule composed on ligaments and synovial tissue within. Synovial tissue has a lining and a sublining layer. The sublining layer has fibrous and fatty tissue with blood vessels and capillaries, which serve as a source of joint bleeds. Articular cartilage covers bone ends and is not lined by synovial tissue and hence is avascular.2

Any perturbation from blood or trauma can cause collagen to release excessive proteoglycan contributing to long lasting cartilage damage. Synovial tissue also removes blood and its components after hemarthroses, which also triggers the synovial cells to proliferate and hypertrophy with the release of hydrolytic enzymes. Prolonged exposure of cartilage to blood can lead to apoptosis of the chondrocyte. As chondrocytes rarely proliferate, apoptosis leads to long lasting and irreversible damage to the cartilage matrix, or permanent cartilage loss.2

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

Three forms of hemarthrosis are recognized:

  1. Acute: The affected joint is painful, swollen, and warm, and range of motion is reduced. The clinical presentation differs according to age. Infants present with irritability and decreased use of the affected limb as early signs of bleeding. Older children and adults report prodromal stiffness and sometimes a distinguishing warm sensation followed by acute pain and swelling. Typically, one joint is affected at a time, but multiple bleeding sites may be present as well. However, these symptoms quickly respond to treatment with plasma and factor replacement, and mobility returns as the effusion is reabsorbed.
  2. Subacute: In this stage, an untreated hemorrhage can lead to intraarticular damage. In this stage, 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.
  3. Chronic: Repeated attacks or persistent hemorrhage for more than six months leads to chronic disabling arthropathy.

Radiologically, five stages of hemophilic arthropathy are recognized:

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 boney erosion.

Specific Secondary or Associated Conditions and Complications

  1. Chronic Hemophilic Synovitis
  2. Articular deformities
  3. Subchondral cysts, and osteophytes
  4. Advanced hemophilic arthropathy
  5. Septic Arthritis
  6. Flexion contractures
  7. Osteonecrosis of the femoral head
  8. Muscle hematomas: The deltoid and forearm flexors are most commonly affected in the upper extremity and the quadriceps, psoas, and grastrocnemius-soleus complex muscles in the lower extremity. Complication includes compartment syndrome.
  9. 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.

2. ESSENTIALS OF ASSESSMENT

History

Documentation should include any history of spontaneous bleeding into joints, muscles or soft tissues, bleeding record (number of hemarthroses episodes and treatment given), age at the first bleeding episode, and having prolonged bleeding after a cut, tooth removal or any surgery. There should be a focus on childhood history, number of joints affected and duration of joint issues.

Physical Examination

A complete musculoskeletal assessment of joint and muscle should be performed in any patient with hemophilia with an evaluation of the joints conducted every 6 months in children and at least, every year in adults. 2

Clinical Functional Assessment

The Functional Independence Score in Haemophilia (FISH) provides a performance-based score for assessment of musculoskeletal function. 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.

Laboratory Studies

Platelets count, bleeding time (BT), PT, and APTT 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

  1. X-rays: Poor sensitivity in detecting early subtle synovial and cartilage changes distinctive of early hemophilic arthropathy.
  2. Ultrasound: Higher sensitivity in detecting hemarthrosis and synovial inflammation as well as intramuscular hematomas
  3. CT: It is better than conventional radiography in detecting subchondral cysts and erosions.
  4. MRI: It is the most sensitive imaging modality for evaluating hemorrhagic arthropathy.

Supplemental Assessment Tools

Hemophilia Activities List (HAL) assesses disability. It is a disease-specific, self-rated questionnaire based on the International Classification of Functioning, Disability, and Health (ICF) classification. World Federation of Hemophilia recommends the Hemophilia Joint Health Score, which picks up the early signs of joint damage. It monitors joint changes over time or assessing efficacy of treatment. 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.

Early Predictions of Outcomes

The severity of disease depends on the level of Factor VIII (hemophilia A) or Factor IX (hemophilia B) present on factor assay testing. If the mother is a known carrier, prenatal diagnosis can be done at 9 to 11 weeks by chorionic villus sampling (CVS) or by blood sampling at 18 or more weeks.

Environmental

Adaptations to the home, school, or work environment should 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.

Social Role and Support System

Psychological and social support should be available for patients and their families. Chronic pain may adversely affect family and other interpersonal relationships. Poorly managed acute pain in early childhood may lead to fear of medical treatment and promote inactivity, pain and potential social isolation at an important time in development.

Professional Issues

Not applicable

3. REHABILITATION MANAGEMENT & TREATMENTS SECTION

Available or Current Treatment Guidelines

The most important initial management is prevention of hemarthroses and subsequent arthropathy through intravenous clotting factor replacement therapy. Ideally, replacement therapy should be initiated early, before or soon after the first joint bleed (before joint damage occurs).

At Different Disease Stages4

Acute phase: Goals are to avoid muscular atrophy, maintain an adequate degree of articular mobility, control the recurrence of hemarthroses, and recover joint function if possible. For lower limb bleeding, one day of bed rest followed by three to four days of weight bearing avoidance via crutches and elevation when sitting. For the knee, a compressive bandage or a long-leg posterior plaster splint is needed. Patient may continue to ice over a 24 to 48 hour period supplemented with analgesia. Aspirin containing products and NSAIDs must be avoided.

Subacute phase: Treat with hematological substitutive therapy and 2-3 weeks of immobilization with a semi-flexible splint. Following each transfusion, patient should finish an exercise program focusing on active joint mobility. Flexion contracture of few days’ duration should be treated with oxford’s inverted dynamic splints, extension-desubluxation hinged casts, dynamica splints and traction followed by a polypropylene orthosis. A flexion contracture with a duration ranging from weeks to months may require surgery.

Chronic phase: Radioactive synoviorthesis is the “gold standard” during this stage once hematologic treatment fails. Up to three synoviortheses are recommended, with a three-month interval between them. If these fail, a surgical synovectomy would be indicated.

Coordination of Care5

  1. A multidisciplinary team that addresses the wide-ranging needs of people with hemophilia/hemophilic arthropathy should coordinate care. This team includes:
  2. Medical director (a pediatric and/ or adult hematologist)
  3. Nurse coordinator who acts as the first contact for patients with an acute problem. The coordinator also educates patients and their families.
  4. A musculoskeletal expert (physiatrist, orthopedist, rheumatologist, physiotherapist, occupational therapist) who can address prevention as well as treatment
  5. Lab specialist
  6. Psychosocial expert (preferably a social worker, or a psychologist) familiar with available community resources

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. 5

Measurement of Treatment Outcome

One tool developed specifically to evaluate the functional wellbeing of hemophilia patients is the Hemophilia Joint Health Score, 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

Translation into Practice

Physicians should encourage physical activity to promote physical fitness and normal neuromuscular development, with attention paid to muscle strengthening, coordination, general fitness, physical functioning, healthy body weight, and self-esteem. Weight-bearing activities that promote development and maintenance of good bone density should be encouraged.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Preventative strategies such as prophylaxis and procedures such as synovectomy have provided good results but are expensive and their timing in individual patients is not well defined. There is a need to explore newer serological markers that can help monitor joint disease initiation and progression. These serological markers then can dictate the timings of interventions such as prophylaxis and synovectomy.1

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Secondary prophylaxis- transfusion with recombinant factor after onset of hemophilic arthropathy in an attempt to reduce or halt progression is controversial. It is unclear whether the benefits justify the costs of the therapy.

REFERENCES

  1. Acharya S. Hemophilic joint disease- current perspective and potential future strategies. Transfusion and Apheresis Science 38 (2008) 49-55
  2. Acharya S. Exploration of the pathogenesis of haemophilic joint arthropathy: understanding implications for optimal clinical management. British Journal of Hematology, 156, 13-23.
  3. Lobet S, Hermans C, Lambert C. Optimal management of hemophilic arthropathy and hematomas. Journal of Blood Medicine 2014:5 207-218
  4. Rodriguez-Merchan E.C. Articular bleeding (hemarthrosis) in hemophilia. An Orthopedist’s point of view. Treatment of Hemophila. April 2008. No 23
  5. Srivastava A, Brewer A, Mauser-Bunschoten E et al. Guidelines for the management of Hemophilia. World Federation of Hemophilia.
  6. Simpson M L, Valentino L. Management of joint bleeding in hemophilia. Expert Rev. Hematol. 5(4), 459-468 (2012)
  7. Steven MM, Yogarajah S, Madhok R, Forbes CD, Sturrock RD. Haemophilic arthritis. Q J Med. 1986;58(226):181.
  8. Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group J Intern Med. 1994;236(4):391.
  9. Lan HH, Eustace SJ, Dorfman D. Hemophilic arthropathy. Radiol Clin North Am. 1996;34(2):446.
  10. Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg. 2004 Jul;12(4):234-45.
  11. Jansen NW, Roosendaal G, Lafeber FP. Understanding haemophilic arthropathy: an exploration of current open issues. Br J Haematol. 2008;143(5):632.
  12. Steven MM, Yogarajah S, Madhok R, Forbes CD, Sturrock RD. Haemophilic arthritis. Q J Med. 1986;58(226):181.
  13. Madhok R, Bennett D, Sturrock RD, Forbes CD. Mechanisms of joint damage in an experimental model of hemophilic arthritis. Arthritis Rheum. 1988;31(9):1148.
  14. Gurcay E, Eksioglu E et al. A prospective series of musculoskeletal system rehabilitation of arthropathic joints in young male hemophilic patients. Rheumatol Int (2008) 28:541-545

Author Disclosure

Jaspreet Singh, MD
Nothing to Disclose

Navdeep Singh Jassal, MD
Nothing to Disclose

Ritika Oberoi-Jassal, MD
Nothing to Disclose

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