Haemophilia -

Definition

Inherited disorder of intrinsic clotting

Classification

Haemophilia A
- Classic form
- Deficiency of Factor VIII
- Most common cause of severe disease (1:10,000)
- X-linked recessive
  - Only males
  - Females carriers
  - (1/2 sons are affected, all daughters are carriers, rare homozygous females)
- 30% new mutations
- Severity depends on the level of clotting factor
  - > 50% – normal
  - 25-50% – seldom a problem
  - 5-25% – severe bleed with surgery (Mild)
  - 1-5% – severe bleed with minor injury (Moderate)
  - < 1% – spontaneous bleed (Severe)
- 50% are moderate to severe
- 5% have antibodies to Factor VIII
  - Very difficult to treat
  - Infused factor rapidly destroyed
  - Contraindication to surgery
- Most have near normal life expectancy
Haemophilia B
- Christmas Disease
- Deficiency of Factor IX
- Less common (1:50,000)
- Also X-linked recessive
- Similar spectrum of activity
- Identical to Haemophilia A clinically
- Treat in same way with Factor IX cryoprecipitate
Von Willebrands disease
- VWB factor (VIII-R) functions
  - Carrier for factor VIII (VIII-C)
  - Facilitates adhesion of platelets to subendothelial collagen
- Reduced or dysfunctional VWB factor due to
  - Abnormal endothelial VWF production
  - Increased endothelial cell VWF proteolysis
- Leads to diminished platelet adherence at sites of vascular injury
  - Bleeding times prolonged
  - While platelet counts are normal
- VIII-C is also ↓
  - In absence of VIII-R » VIII-C is not transported effectively from liver
  - Unbound VIII-C rapidly catabolised
- Autosomal Dominant
- Treat with Cryoprecipitate or DDAVP

Epidemiology

Combined incidence of ~ 1/10,000
Manifestations of factor VIII & IX deficiency indistinguishable

Clinical Features

Presentation
- Male with positive family history
  - May present after circumcision
  - First bruising at 3/12
  - Severe bruising at walking age
  - May have spontaneous haemarthroses
    - Knee > Elbow > Ankle
  - Milder forms may present after dental extraction or operative procedure
- Bleeding
- Bruises
- Muscle haematomas
- Haemarthroses
  - May occur some time after the injury as defect in clot formation (1st stage) rather than haemostasis (2nd stage)
  - May be no trauma
- HIV
  - 70% of haemophiliacs who received untreated pooled Factor VIII are HIV positive
  - 90% of severe haemophiliacs HIV positive

Investigations

APTT ↑
PT ↑
Bleeding time normal
Platelet count normal
Low Factor VIII coagulant (VIII-C) activity diagnostic

Treatment

Blood Products
Initially used FFP
- Volume too great
- High levels of factor VIII not achieved
Then cryoprecipitate
- Higher levels Factor VIII
- Exact amount unknown
- Store at very low temperature
Now use heat-treated Factor VIII concentrates
Factor VIII concentrates
- Preparation
  - Initially pooled & untreated Factor VIII
    - High HIV & Hepatitis risk
- Now treated
  - Detergent & Heat
- Activity lower
- Available in dried concentrated form
- Recombinant Factor VIII being developed
- Administration
  - 1U/ kg ↑ the Factor VIII by 2%
  - Half life of 6-12 hours
  - Aim to achieve level of
    - 15% in mild bleed
    - 30% in severe bleed
  - Repeat in 8 hours
  - Administration at home possible
  - Beginning to be used prophylactically

Haemophilic Arthropathy

Haemarthrosis = synovial hypertrophy = more prone to injury
Bleeding » synovitis » bleeding
Recurrent Intraarticular Bleed causes
- Chronic synovitis
- Progressive articular destruction
All severe haemophiliacs have arthropathy by adolescence

Pathology

Joint
- Synovial tissue trapped & nipped in joint
- Haemorrhage into joint leading to
  - Synovitis
  - Synovial fibrosis
  - Haemosiderin accumulation in synovial cells
    - Makes synovium more susceptible to further injury
    - Synoviocytes rupture when iron storage excessive
- Intrarticular clots producing fibrous tissue
  - Adhesions across joint that tear & bleed
- Synovial cavity divided into small loculated spaces
- Vascular pannus covers the articular surface & destroys it
- Cartilage progressively destroyed by
  - Synovial cell death releasing
    - Lysosomal enzymes
    - Iron which interferes with cartilage metabolism (GAG & procollagenase)
  - Vascular pannus
  - Prolonged immobilization
- Subchondral bone exposed
- Subchondral cysts may appear
- Osteoporosis due to disuse
- Increased blood flow to joint results in epiphyseal overgrowth
Think Haemophilia if see
- Destroyed joint
- Epiphyseal overgrowth
- Lytic bony lesion
Muscle
- Recurrent bleeds lead to fibrosis & contracture
- May result in deformity
- May be complicated by
  - Compressive nerve palsy
  - Compartment syndrome
Cysts
- Massive bleed into muscle (usually thigh)
- Haematoma encapsulated prior to resorption
- Enlarges by osmosis & more bleeds (thus grows rather than resorbed)
- Filled with old degenerative blood products
- May erode through skin or viscus
- Can become abscess
Pseudotumour
- Involves bone
- May occur by
  - Subperiosteal bleed
  - Intraosseous bleed
  - Bleed into muscle with loose periosteal attachment
- Subperiosteal form see periosteal stripping & new bone formation
- Intraosseous form see ill-defined lesion with extensive osteolysis & some new bone formation
- Confuse with
  - Sarcoma
  - GCT
  - ABC
- May destroy bone & lead to pathological fracture

Clinical

Joint
- Acute Haemarthrosis
  - Knee > Elbow > Ankle
  - Hip & Shoulder rarely
  - Joint is red, swollen & hot
  - Acutely painful
  - Held in flexion
- Subacute Haemarthrosis
  - After > 2 bleeds
  - Synovium thickened & boggy
  - Moderate restriction of ROM
  - Pain not prominent
- Chronic Haemarthrosis
  - After 6/12
  - Bleeds less frequent & more difficult to detect
  - Joint shows
    - Significant limitation of movement
    - Fibrous contracture
    - Muscle wasting
Muscle
- Most commonly affects affects
  - Iliopsoas
  - Thigh
  - Calf
  - Forearm
- Painful swelling
- Resisted ROM in associated joint
- Iliopsoas bleed can lead to femoral n compression
- Recurrent calf bleeds can lead to equinus contracture of foot
- Forearm bleed can lead to Volkmann’s
Pseudocysts
- Rare
- Involve mainly ilium & the femur

Radiological Classification

Stage	Description
1	Acute haemarthrosis Soft tissue swelling
2	Subacute haemarthrosis Epiphyseal osteoporosis Epiphyseal overgrowth
3	No significant narrowing of joint Squaring of patella Enlarged femoral condyles Widened intercondylar notch in knee Widened trochlear notch at elbow
4	Marked narrowing of joint space
5	Joint destruction Mimics RA / TB

Arnold & Hilgartner (1977) Classification of Haemophiliac Arthropathy

Prevention

Padded crib
Supervision & discourage high risk activities
Activity modification
Prophylaxis (very expensive – not practised in Australia)
- From 1-2yo until late teenage years
- After first joint bleed
- Maintain factor levels > 1%
- 3 weekly factor VIII/ 2 weekly factor IX

Treatment

Acute Haemarthrosis
- Usually treat at home
- Immediate IV dose of Factor VIII
  - To attain levels > 30% (30-50% for 24 hrs)
  - Usually single dose sufficient (30-50U VIII/kg/dose)
  - Pain quickly resolves
- Adequate analgesia (not NSAIDS)
- For first 24 hours
  - Immobilise
  - Firm compression
- Once bleeding stops
  - Ice packs
  - Mobilise
- Place of aspiration/ wash out controversial
  - Reduces pain & swelling
  - Removes toxic products of degradation
  - May need diagnostic aspiration to rule out infection
  - No evidence that decreases risk of arthropathy
Subacute Haemarthropathy
- Further treatment indicated if
  - Failure to respond to above regimen
- 2 bleeds in short period of time
- Initially
  - Prednisone for 5/7
  - 2-3 doses of Factor VIII for level > 30%
- If still not responding then 6-8 week course of
  - Factor VIII replacement prophylactically
    - Level > 20%
    - 3x/ week
  - Active PT
    - Quads & ROM
Chronic Haemarthropathy
- Nonoperative
  - 6 months of
    - Small doses of prednisone
    - Prophylactic Factor VIII replacement
    - Active PT
    - ± Inpatient traction to correct FFD
- Operative
  - Synovectomy
    - When non-op treatment fails
    - Not beyond Stage 3
    - Open or arthroscopic
    - Reduces number of bleeds
    - Doesn’t stop cartilage degeneration
  - Corrective Surgery
    - Stages 4 & 5
    - Presence of antibodies to Factor VIII (5% of Haemophilia A) is contraindication to elective surgery
    - Avoid pins that penetrate the skin
    - Screen for HIV & Hepatitis B pre op
    - Check Factor VIII levels intraop
    - Meticulous haemostasis
    - Increase Factor VIII levels for MUA & ROS
    - Tendon lengthening
      - Equinus ankle
      - Knee FFD
      - Volkmann’s forearm contractures
    - Osteotomy
- Most common deformity is FFD & Valgus knee
- Can be corrected with supracondylar osteotomy
- Arthrodesis
  - Not often performed due to multiple joint involvement
  - Useful for AJ & ST joint
- TJR
  - Hip & Knee
  - Tourniquet
  - Strict universal precautions
  - Meticulous haemostasis, layered closure
  - suction drain
  - Avoid excessive diathermy – wounds slough
  - Can do multiple joints/ procedures at the one sitting to achieve functional limb
  - Compared with non-haemophiliacs
    - incidence of periop complications
      - Bleed & Infection
    - failure rate
      - 50% at 10 years
  - Maintain Factor VIII levels at
    - 100-120% for 2 days
    - 80-100% for 2 weeks
    - 30-50% for 6 weeks
Muscle Bleed
- Immobilise for longer to prevent further bleed
- Initially splint in position of comfort
- Then when bleed ceased serial splint to functional position
- May require splintage for nerve palsy as well
Life-threatening spinal or cerebral bleed
- Minimum of 100% factor VIII 6 weeks