Summary

Haemophilia is a group of X-Linked Recessive disorders characterized by a deficiency in specific clotting factors within the intrinsic coagulation pathway. It is the archetype of "Deep Tissue Bleeding", manifesting with haemarthroses (bleeding into joints) and muscle haematomas, distinguishing it from platelet disorders which cause superficial mucosal bleeding. Historical Context: Known as the "Royal Disease", as Queen Victoria was a carrier, passing it to the royal families of Europe (Russia, Spain, Germany). Modern Era: Treatment has evolved from plasma transfusions (high risk) to Recombinant Factors and now Bispecific Antibodies (Emicizumab) and Gene Therapy.

Classification

Key Facts

• Inheritance: X-Linked Recessive (Males affected, Females carriers).
• Hallmark: Hemarthrosis (Joint Bleeding).
• Key Test: Prolonged APTT, Normal PT.
• Treatment: Factor Replacement (Prophylaxis).

The Coagulation Cascade

Coagulation consists of two pathways (Intrinsic and Extrinsic) meeting at the Common Pathway to generate a "Thrombin Burst".

• The Activation: Tissue Factor (Extrinsic) initiates a small amount of Thrombin.
• The Amplification: Thrombin activates Factor VIII and Factor IX.
• The Propagation: The Activated Factor VIII/IX complex (The Tenase Complex) is required to activate Factor X massively.

The Defect: In Haemophilia, the "Amplification" step fails.

1. Primary Hemostasis (Platelets): Works fine. The patient stops bleeding initially ("Platelet Plug").
2. Secondary Hemostasis (Fibrin): Fails. The fibrin mesh is weak or nonexistent.
3. Clinical Result: Delayed re-bleeding. The plug washes away, and deep bleeding continues unchecked.

Image: Coagulation Cascade

Severity Definition

Severity correlates strictly with Factor Levels:

• Severe (<1%): Frequent spontaneous bleeds (1-2 per week). Joint damage inevitable without prophylaxis.
• Moderate (1-5%): Bleeding after minor trauma. Spontaneous bleeds rare.
• Mild (5-40%): Bleeding only after significant surgery or major trauma. Often undiagnosed until adulthood.

1. Musculoskeletal Bleeding (80%)

• Hemarthrosis: The hallmark.
  • Acute: Aura of warmth/tingling -> Severe Pain -> Swelling/Heat/Loss of movement.
  • Joints: Knee (Most common), Elbow, Ankle (The "Hinge" joints). Shoulders/Hips rare.
  • Chronic: "Target Joint" (Recurrent bleeds in same joint) -> Iron deposition -> Synovial Hypertrophy -> Cartilage destruction (Haemophilic Arthropathy).
• Muscle Haematomas:
  • Iliopsoas Bleed: Dangerous. Presents as groin pain and hip flexion deformity. Can compress Femoral Nerve.
  • Compartment Syndrome: Forearm (Volkmann's) or Calf.

2. Mucosal Bleeding

• Epistaxis (hard to stop).
• Gum bleeding (tooth brushing).
• Heavy menstrual bleeding (in symptomatic female carriers).

3. Life-Threatening Bleeds

• Intracranial Haemorrhage (ICH): Leading cause of death. Any head bump requires immediate treatment.
• Neck/Throat Bleeds: Airway obstruction.
• GI Bleed: Melena/Hematemesis.

Image: Hemarthrosis Cycle

4. Haemophilia B Severity Chart

1. The Clotting Screen

The classic triad results are diagnostic:

• APTT: Prolonged (Intrinsic Pathway failure).
• PT (INR): Normal (Extrinsic Pathway intact).
• Platelet Count: Normal.
• Bleeding Time: Normal (Primary hemostasis intact).

2. Factor Assays (Confirming the Diagnosis)

• Factor VIII Level: Low in Haemophilia A.
• Factor IX Level: Low in Haemophilia B.
• Bethesda Assay: Measures "Inhibitors" (Antibodies against the factor). Critical for treatment failure.

12. Clinical Case Studies

Case 1: The Toddler's Knee

Presentation: A 14-month-old boy (just started walking) presents with a swollen, hot right knee. He is crying and refuses to weight bear. There is no history of major trauma, just a "stumble". Family History: Mother has "heavy periods". Grandfather died young of a bleed. Investigation:

• APTT: 90s (Prolonged).
• Factor VIII: <1%. Diagnosis: Severe Haemophilia A (New diagnosis). Management:
• Admit.
• Recombinant Factor VIII immediately.
• Genetics referral.
• Start Prophylaxis.

Case 2: The "Head Bump"

Presentation: A 25-year-old male with known Severe Haemophilia B comes to A&E. He bumped his head on a cupboard door. He feels fine. GCS 15. Action:

• Junior Doctor Error: "Wait for CT scan".
• Correct Action: STAT Factor IX (100 IU/kg).
• Reason: Intracranial bleeds can expand rapidly even with minor trauma. Treatment must precede imaging. Outcome: CT showed small subdural. Because factor was given early, it did not expand. He survived intact.

3. Differential Diagnosis

Image: Acute Management Algorithm

The "Golden Rule"

TREAT FIRST. DO NOT WAIT FOR SCANS. DO NOT WAIT FOR ADMISSION. If a patient suspects a bleed, believe them. The "Aura" (tingling) precedes clinical signs.

1. Acute Bleed Management

• Goal: Raise Factor levels to 100% (Life threatening) or 50% (Joints).
• Haemophilia A:
  • Recombinant Factor VIII: Dose (IU) = Weight (kg) x 50.
• Haemophilia B:
  • Recombinant Factor IX: Dose (IU) = Weight (kg) x 100.
  • (Note: Factor 9 diffuses into extravascular space, so you need double the dose).

2. Adjuncts

• Tranexamic Acid: 1g IV/PO. Stabilizes the clot. (Avoid in Haematuria - causes clots in ureters).
• Desmopressin (DDAVP):
  • Indication: Mild Haemophilia A only.
  • Mechanism: Releases endogenous stored Factor VIII from Weibel-Palade bodies.
  • Limit: Tachyphylaxis (stops working after 3 days). Fluid restriction needed (causes hyponatraemia).

3. Supportive Care (R.I.C.E.)

For joint bleeds:

• Rest (Immobilize joint for 24-48h).
• Ice ( Vasoconstriction).
• Compression.
• Elevation.
• Analgesia: Paracetamol + Codeine. NEVER Aspirin/NSAIDs (Anti-platelet affect worsens bleeding). NEVER IM Injections (Causes haematoma).

The Prophylaxis Paradigm

Historically, we treated "On Demand" (when a bleed happened). Now, we use Primary Prophylaxis (Regular injections to prevent bleeds).

• Goal: Convert "Severe" phenotype to "Moderate" (>1% trough levels).
• Standard: Factor VIII IV injections 3x/week. Factor IX 2x/week.

The Game Changer: Emicizumab (Hemlibra)

• What is it?: A Bispecific Monoclonal Antibody.
• Mechanism: One arm binds Factor IXa, the other binds Factor X. It physically pulls them together, mimicking the action of Factor VIII.
• Administration: Subcutaneous injection (No IV access needed!).
• Frequency: Once every 2-4 weeks.
• Impact: Transforms life quality. Nearly zero bleeds. Valid for Haemophilia A (even with inhibitors).

The Rules

• Gene: F8 or F9 gene on the X chromosome.
• Males (XY): Have only one X. If it is mutated, they have the disease.
• Females (XX): Have two X's. The healthy X compensates. They are "Carriers".

Scenarios Table

Important: 30% of cases are De Novo mutations. (No family history).

• Gene Therapy: Uses Adeno-Associated Virus (AAV) vector to deliver a functional F8/F9 gene to the liver.
  • Roctavian (Valoctocogene roxaparvovec) for Haemophilia A.
  • Hemgenix (Etranacogene dezaparvovec) for Haemophilia B.
  • Goal: The "One Shot Cure".

1. History Checklist

• Bleeding Hx: Joints? Muscles? After dental work?
• Family Hx: "Grandfather on mother's side?"
• Treatment: "Are you on Prophylaxis or On-Demand?" "Do you have Inhibitors?"

2. Physical Signs

• Gait: Antalgic gait (due to knee/ankle arthropathy).
• Joints: Look for fixed flexion deformities, swelling, scars from replacements.
• Venous Access: Look for an Implantable Port (Port-a-Cath) or scarring in antecubital fossae.

3. Viva Questions

• Q: What is the target factor level for major surgery?
  • A: 100% (1.0 IU/ml).
• Q: How do you treat a head injury in a haemophiliac?
  • A: Give Factor FIRST. Then CT. Then admit.
• Q: What is the mechanism of Emicizumab?
  • A: Bispecific antibody bridging Factor IXa and X.

1. Srivastava A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020.
2. Manco-Johnson MJ, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia A. N Engl J Med. 2007.