Introduction

• X-linked recessive bleeding disorder
• Rarer acquired form exists with an autoimmune aetiology

Haemophilia A

• Due to decreased or absent factor VIII
• Incidence of 1:5000 men

Haemophilia B (Christmas disease)

• Due to decreased or absent factor IX
• Incidence of 1:30,000 men

X-linked forms may be inherited or arise from a spontaneous mutation

• A lack of functional factor VIII (or IX) leads to a disruption in the normal intrinsic coagulation cascade.
• Causes excessive haemorrhage in response to trauma and occasionally spontaneously.
• The hallmark is haemorrhage into joints. This can be painful and leads to long-term inflammation and a haemophiliac arthropathy.
• The knee, ankle and elbow account for approximately 80% of the involved joints.
• Bleeding leads to synovial inflammation which predisposes that joint to further bleeds.
• Repeated haemarthroses lead to progressive synovial hypertrophy, haemosiderin deposition, fibrosis, and damage to cartilage, with subchondral bone-cyst formation. This results in permanent deformities, malalignment, loss of mobility and arthritis.
• With recurrent haemarthroses, iron deposits elucidate synovial hypertrophy characterised by villous sinuses, neovascularisation and infiltration of lymphocytes.

Figure 1. The coagulation cascade

• Severity of disease same as other affected family members.
• Haemarthroses begin at age 12–18 months.
• Usually affects knee, hips, elbows, shoulders or ankles.
• Results in severe pain, warmth, boggy swelling and tenderness, loss of movement, joint usually flexed and may have a mild fever.
• May lead to compartment syndrome occasionally but fasciotomy is unwise unless clotting factors given.
• Joint degeneration usually begins before age of 15 years due to cartilage degeneration.
• Muscle haemorrhage (intramuscular bleeds) most common in psoas, thigh, calf, forearm, may cause permanent contracture (Volkmann’s).
• Iliacus syndrome may lead to flexion contracture of hip and a tender mass in iliac fossa (recovery may take several weeks to months).
• Muscle wasting and fixed deformities feature.

• Synovial lining heavily laden with haemosiderin.
• Repeated haemarthrosis can lead to chronic synovitis and hypertrophy, accumulation of haemosiderin, release of lysosomal enzymes (cathepsin D), release of plasmin, fibrosis of synovium and cartilage destruction.
• Synovial changes occur as the synovium is easily damaged and predisposes to further bleeds.
• Also there is subchondral haemorrhage with loss of cartilage support and hyperaemic stimulation of epiphysial growth.
• Enzymatic processes and intracellular iron deposits induce an inflammatory response which leads to continued breakdown of articular cartilage.
• Chondrocytes also exhibit iron deposition, which may lead to necros

• Direct irritant effect of blood on cartilage causes synovial reaction and inflammation.
• Bleeds may be spontaneous from sub-synovial vascular tissue, or traumatic.

• Approximately 30% of patients with severe haemophilia A develop alloantibody inhibitors that can bind factor VIII.
• These inhibitors are typically immunoglobulin G (IgG) that neutralises the coagulant effects of replacement therapy.

• Any history of haemorrhage disproportionate to trauma or familial bleeding disorders.
• Joint pain, warmth, stiffness, inability to walk.
• Central nervous system, gastrointestinal, genitourinary symptoms secondary to bleeding.

• Signs of haemorrhage:

1. Tachycardia
2. Hypotension
3. Tachypnea

• Joint tenderness, warmth, restricted range of movement:

1. Often the knees

• Intramuscular haematomas:

1. In the iliacus muscle the femoral nerve can be compressed and L4 paraesthesia may be the presenting sign.

• Compartment syndrome.
• Leg length discrepancy due to epiphyseal overgrowth.
• Fractures due to generalised osteopenia.

Haemophilic pseudotumours:

• Due to slow expansion of repeated haemorrhages in bone or soft tissue
• Develop slowly
• Can restrict movement, erode and invade bone or cause neurovascular compression
• With a mortality rate of approximately 20%, surgical removal should only be performed in specialised haemophiliac treatment centres.

• Mild: 5–25% of factor present
• Moderate: 1–5%
• Severe: <1%

This classification directly reflects the severity of clinical symptoms. The bleeding diathesis of the mild form may only present during surgeries, dental extractions and injuries, whereas spontaneous joint and muscle bleeds are largely confined to patients with severe haemophilia.

• 1% of severe spontaneous bleeds often crippling.
• 1–5% of severe bleeds after minor injury occasional spontaneous bleeding.
• 5–25% of severe bleeding after surgery.
• 25–50% of bleeding after major surgery.
• 50–100% of normal bleeding in major surgery.

Labs:

• Full blood count (check Hb levels)
• Activated partial thromboplastin time (APPT) prolonged
• Prothrombin time (PT) normal
• Plasma factor VIII or IX inhibitor assay

Screening:

• Bethesda assay
• Blood factor VIII or IX inhibitors are positive
• Measures the amount of factor VIII or IX antibody in the blood

• Epiphyseal overgrowth
• Generalised osteopenia
• Irregularity of the joint space
• Joint effusion
• Specific findings:

1. Squaring of patella and femoral condyles (Jordan's sign)
2. Ballooning of distal femur
3. Widening of intercondylar notch
4. The patella may appear long and thin

Figure 2. Radiographs of haemophiliac arthropathy of the knee

1. Soft tissue swelling.
2. Osteoporosis, epiphysial overgrowth but joint integrity maintained.
3. Disorganisation joint, subchondral cysts, squaring of patella (Jordan’s sign), inter-condylar widening, enlarged femoral condyles that appear to fall off the patella.
4. Narrowing joint space and cartilage destruction.
5. Marked narrowing joint and fibrous capsular contracture leading to decreased range of movement.

Magnetic resonance imaging, computed tomography and ultrasound scans may all be useful.

• Physiotherapy
• Analgesia
• Multimodal input via haemophilia centre

• The relevant factor can be replaced.
• The factor levels can be increased relative to the risk of potential bleeding.
• Acute haematomas – 30% factor level.
• Acute haemarthrosis – 50%.
• Surgery – 100% for first week.
• In patients with inhibitors, factor VIII inhibitor bypassing activity (FEIBA) or recombinant factor VIIa may be used.
• Replacement of the deficient factor is the mainstay of treatment for bleeding episodes, according to the type and severity of bleeds and until complete resolution of bleeding or surgical wound healing.

• Recent data on the use of prophylactic clotting factor replacement has been shown to slow the natural course of haemophiliac arthropathy.
• Primary prophylaxis is defined as the infusion of concentrates started after the first joint bleed or before age 2 years, and is now the first line of treatment in children with severe haemophilia.
• Secondary prophylaxis aims to delay the progression of joint damage and occurs after age 2 years or after two or more joint bleeds.
• In a recent prospective, randomised study, continuous prophylactic clotting factor replacement of 25 to 40 units/kg of factor VIII three times weekly or factor IX two to three times weekly in patients with haemophilia A and B, respectively, was shown to slow the natural course of haemophiliac arthropathy.

• Synovectomy: radioactive or surgical.
• Contracture release.
• Fasciotomy if compartment syndrome and clotting cascade has been normalised.
• Joint replacement for end-stage arthropathy.
• Total knee arthroplasty (TKA) has been proved to restore function and relief of pain but can be technically challenging due to arthrofibrosis, joint surface erosions and bony synovial cysts. Current recommendations are for a posterior-stabilised cemented design.