Hemophilia

Haemophilia is an X-linked recessive bleeding disorder of males, caused by a deficiency of factor VIII (haemophilia A) or factor IX (haemophilia B). Haemophilia A occurs in 1 in 5,000 male births and haemophilia B in 1 in 30,000.

Inheritance. Males, with their single X chromosome, are affected; females are carriers and usually asymptomatic. 30% of cases are new mutations, with no family history.

Severity. The residual factor activity sets the bleeding pattern (see Classification). Most orthopaedic pathology occurs in severe haemophilia, where haemarthroses are recurrent and spontaneous.

The clotting defect. Factor IX activates factor X, and factor VIII, an intrinsic-pathway cofactor, accelerates that activation. A deficiency of either impairs thrombin generation and leaves an unstable clot.

From bleed to arthropathy. Haemophilic arthropathy develops through a recognisable sequence:

1. Haemarthrosis - bleeding into the joint space
2. Iron deposition - haemoglobin breakdown releases iron (haemosiderin)
3. Synovitis - iron-induced chronic synovial inflammation
4. Enzyme release - synovial enzymes degrade cartilage
5. Cartilage destruction - progressive chondrolysis
6. Secondary changes - subchondral cysts, osteopenia, osteophytes
7. End-stage arthropathy - joint destruction, contractures, disability

The vicious cycle. Haemarthrosis induces synovitis, which causes synovial proliferation and neovascularisation. The synovium is highly vascular and its fragile new vessels bleed more easily, so bleed leads to synovitis leads to more bleeds, and the joint is progressively destroyed.

Why hinge joints. The knee, ankle and elbow are affected more than ball-and-socket joints. They have a large synovial surface area, carry high mechanical loading and are poorly protected by the surrounding muscle.

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Acute haemarthrosis. The joint becomes acutely painful, warm and swollen, often without trauma, and is held in a position of comfort, usually flexion, with limited movement. There may be a prodromal tingling sensation, an "aura". The patient may recall minor trauma or may have been undertreated with a missed prophylaxis dose, and the frequency of bleeds is important for prognosis. On examination:

• Tense effusion, increased warmth and tenderness
• Guarding and muscle spasm
• Other sites of bleeding, which must be checked for

Chronic arthropathy. The cumulative damage of repeated haemarthroses presents as chronic pain, stiffness and limited movement, with muscle wasting and angular deformity. Walking, stairs and daily activities become difficult, walking aids may be needed, and the disability is progressive. On examination:

• Chronic effusion and crepitus
• Fixed flexion contracture, especially at the knee
• Quadriceps wasting
• Valgus or varus deformity
• Limb-length discrepancy

Target joints. A target joint bleeds repeatedly and develops more severe arthropathy than a non-target joint. The distribution:

• Knee - 45%, the most frequently affected
• Ankle - 30%
• Elbow - 20%
• Shoulder, hip and wrist - 5%

The relative rank of ankle and knee differs between cohorts and eras, shifting towards the ankle in populations on modern prophylaxis (see the elbow review in the Evidence Base). At the ankle, expect equinus contracture and tibiotalar destruction; subtalar involvement is common. The radiographic signs of the haemophilic knee are under Investigations.

Haemophilia causes muscle bleeds as well as joint bleeds, and the muscle bleeds are orthopaedic emergencies in their own right. Like the haemarthrosis, they are treated with factor first, imaging second.

Iliopsoas haematoma, the great mimic. A spontaneous bleed into the iliopsoas presents with groin, lower-abdominal or hip pain, the hip held flexed and externally rotated, and pain on extension, mimicking a septic hip, an acute abdomen or appendicitis. Expansion in the iliacus compartment can compress the femoral nerve, giving quadriceps weakness, a lost patellar reflex and anterior-thigh numbness. Diagnose with ultrasound or CT, and treat with urgent factor replacement, rest and graded mobilisation, not primarily surgery.

Compartment syndrome. A bleed into a closed fascial compartment (forearm, calf) can raise the pressure enough to cause an acute compartment syndrome, and the flexor-forearm bleed is the haemophilic route to a Volkmann ischaemic contracture. Treat with immediate factor correction. Fasciotomy is reserved for an established compartment syndrome, and only under full factor cover.

Coagulation. The APTT is prolonged (intrinsic pathway), while the PT/INR is normal (extrinsic pathway intact) and so is the bleeding time (platelet function intact). A reduced factor VIII assay identifies haemophilia A and a reduced factor IX assay haemophilia B. During treatment, monitor factor levels, and trough levels on prophylaxis.

Inhibitors. The inhibitor screen (Bethesda assay) detects antibodies to the factor and is the critical preoperative test. Inhibitors develop in 25-30% of severe haemophilia A, against 3-5% of severe haemophilia B, and significantly complicate treatment.

Preoperative work-up. Alongside the inhibitor screen, request:

• Factor level and recovery study
• Blood group and crossmatch
• Hepatitis B, C and HIV status (historical transfusion risk)
• Full blood count
• Liver function, as there may be hepatitis-related liver disease

Radiographs. Plain films show the established damage and are graded with the Pettersson score:

• Widened intercondylar notch at the knee - the classic sign
• Squaring of the inferior pole of the patella
• Epiphyseal overgrowth
• Periarticular osteoporosis
• Subchondral cysts
• Joint-space narrowing
• Secondary osteoarthritic change

MRI is the gold standard for early disease. It detects synovitis, and joint damage generally, before clinical or radiographic signs appear, which matters for early intervention. It assesses cartilage and shows haemosiderin deposits (low signal on all sequences), bone marrow oedema and cyst formation, scored with the Denver MRI scale.

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Ultrasound is the point-of-care test for acute haemarthrosis, showing the effusion and synovial hypertrophy, and is increasingly used for monitoring.

A swollen, painful joint in a young male is not always a haemophilic haemarthrosis. The bleeding history and the coagulation profile are the key discriminators.

Plan with haematology. Coordination with haematology is essential for every procedure: never proceed to surgery without haematology input and a confirmed factor cover plan. Check inhibitor status (Bethesda assay) beforehand, because it affects the treatment strategy.

Factor targets. The level and its duration depend on the size of the operation:

• Pre-operatively: raise the factor level to 100%
• Major surgery: maintain 50-80% for 10-14 days, tapering as healing progresses
• Minor surgery: maintain 30-50% for 3-7 days
• Bolus or continuous infusion

The arithmetic. For factor VIII, 1 IU/kg raises the plasma level by about 2%, so correcting a severe patient (baseline near 0%) to 100% takes roughly 50 IU/kg. Its half-life is about 8-12 hours, so it is redosed roughly every 8-12 hours, or given by continuous infusion. Factor IX distributes into the extravascular space, so 1 IU/kg raises the level by only about 1% and roughly 100 IU/kg is needed to reach 100%; its longer half-life, about 18-24 hours, allows less frequent dosing.

Where the arithmetic stops. These rules apply only to standard factor concentrates. They do not translate to emicizumab, which is not measured in factor units and interferes with one-stage factor VIII assays, or to a patient with inhibitors, who is treated with bypassing agents rather than factor arithmetic. Always confirm the plan with haematology and a recovery study.

Inhibitors. Management depends on the titre:

• Low titre (under 5 BU): high-dose factor may work
• High titre (over 5 BU): bypassing agents are required - FEIBA (Factor Eight Inhibitor Bypassing Activity) or recombinant factor VIIa (rFVIIa, NovoSeven)
• Immune tolerance induction for the long term

Of the disease. The orthopaedic complications are those of the arthropathy itself (see Clinical Presentation): progressive joint destruction, fixed flexion contractures, angular deformity, muscle wasting and weakness, and limb-length discrepancy.

Pseudotumour. Rare but serious: an encapsulated haematoma in soft tissue, muscle or bone that enlarges progressively if untreated and may erode bone. Treat with factor replacement, and surgery if it is large.

Of surgery. The surgical complications are:

• Intraoperative bleeding and postoperative haematoma
• Infection, at a higher rate than in the general population
• Wound-healing problems
• Stiffness, especially at the knee
• DVT/PE, which paradoxically still occurs (see Controversies)

Of treatment. Factor therapy brings its own:

• Inhibitor development (see Investigations)
• Transfusion-transmitted infection, now historical (HCV, HIV)
• Allergic reactions to factor concentrates
• Central venous catheter complications, if a port is present

With prophylaxis. Joint disease is markedly reduced, life expectancy is approaching normal and quality of life has improved dramatically.

Without it. Historically, severe arthropathy developed by adolescence, wheelchair dependence was common, and patients faced multiple joint replacements and significant disability.

Arthroplasty. 85-90% of patients are satisfied with pain relief, function improves significantly and survivorship is 85-90% at 10 years. The price is a higher complication and revision rate than in the general population: blood loss is increased, stiffness is more common and infection runs at 5-10% against 1-2%, although results are improving with modern protocols. The Ernstbrunner series in the Evidence Base (mean follow-up 18 years) reports 59% survival at 20 years for any revision, in a cohort operated on before modern prophylaxis.

Prognosis depends on:

• Severity of haemophilia - severe is worse
• Adherence to prophylaxis - critical
• Inhibitor status - inhibitors worsen prognosis
• Age at first bleed - earlier is worse
• Number of target joints

Global Epidemiology:

• Hemophilia A affects approximately 1 in 5,000 male births; Hemophilia B approximately 1 in 30,000 male births
• Hemophilia A accounts for roughly 80-85% of cases worldwide; Hemophilia B for 15-20%
• The World Federation of Hemophilia (WFH) Annual Global Survey identifies over 200,000 people with hemophilia, but case identification remains far below expected prevalence in low-income regions
• Around 30% of cases arise from de novo mutations with no family history

Side-by-Side Guidelines:

Optimal prophylaxis target. Traditional regimens aim for troughs above 1%, but breakthrough bleeds still occur at this level. Individualised, higher-trough or pharmacokinetic-guided dosing versus fixed regimens is debated, balanced against cost and venous access.

Emicizumab in non-inhibitor patients. Non-factor therapy dramatically lowers bleeding rates, but long-term joint-protection data, and its interaction with breakthrough bleeds requiring factor or bypassing agents, are still maturing.

Timing and choice of synovectomy. Radiosynovectomy, arthroscopic and open synovectomy all reduce bleeding, but comparative long-term superiority and the threshold for intervention are not firmly established. Radionuclide availability drives practice regionally.

Implant choice in arthroplasty. The balance between cemented and cementless fixation, and between constrained and less-constrained knee implants, is unresolved in young, often osteopenic haemophilic patients with deformity.

VTE prophylaxis after major surgery. Haemophilia is not fully protective against venous thromboembolism, especially with factor correction. Whether and how to give chemical thromboprophylaxis perioperatively is genuinely uncertain and is individualised with haematology.

Gene therapy durability. AAV-mediated factor gene transfer can achieve sustained factor expression, but durability, hepatotoxicity, immune responses and long-term joint outcomes remain under active study.