Haemophilia

• Haemophilia is a bleeding disorder resulting from deficiency or dysfunction of specific clotting factors.
• It is usually inherited in an X-linked recessive pattern, predominantly affecting males.
• Female carriers may have symptoms due to lyonisation and reduced clotting factor levels.

Types of Haemophilia

• Caused by factor VIII deficiency or dysfunction.
• Incidence: ~1 in 4,000–5,000 live male births.

• Caused by factor IX deficiency or dysfunction.
• Incidence: ~1 in 15,000–30,000 live male births.
  
  

• Caused by factor XI deficiency.
• Inherited in an autosomal recessive pattern.
• More common in Ashkenazi Jewish populations.
  
  

• Autoimmune-mediated; antibodies form against clotting factors (commonly factor VIII).
• Affects both sexes equally.
• Often associated with autoimmune disease, malignancy, postpartum state, or medications.
  
  
  

Severity Classification

• Severe: <1% clotting factor activity – spontaneous and frequent bleeding.
• Moderate: 1–5% activity – bleeding with minor trauma or surgery.
• Mild: >5% to <40% activity – bleeding typically only with major trauma or surgery.
  
  

• Caused by mutations in:
  • F8 gene for factor VIII (Haemophilia A).
  • F9 gene for factor IX (Haemophilia B).
• Located on the X chromosome (Xq).
• ~30% of cases result from de novo mutations.
• Female carriers have a 50% chance of transmitting the mutation to offspring:
  • Sons: 50% chance of being affected.
  • Daughters: 50% chance of being carriers.
    
    

Inheritance Pattern

• Haemophilia A and B are typically inherited in an X-linked recessive manner.
• Males are almost exclusively affected as they possess a single X chromosome; if it carries the mutation, they manifest the disease.
• Female carriers may experience bleeding symptoms if lyonisation (random inactivation of one X chromosome) leads to reduced clotting factor levels.
• Rare female cases with severe haemophilia occur due to:
  • Extreme lyonisation.
  • Homozygosity for the mutation (e.g. affected father and carrier mother).
  • Turner syndrome (monosomy X).
  • Somatic or germline mosaicism.
    
    

Genetic Basis and Mutation Types

• The F8 gene (factor VIII) and the F9 gene (factor IX) are both located on the long arm of the X chromosome (Xq).
• Approximately 30% of cases result from de novo (spontaneous) mutations, often in families with no prior history.
• Haemophilia A:
  • ~50% of severe cases are due to intrachromosomal inversions in introns 1 and 22 of the F8 gene.
  • Other mutations include deletions, insertions, point mutations (missense or nonsense), and abnormal splicing.
• Haemophilia B:
  • Most commonly caused by point mutations and deletions in the F9 gene.
• Mutation-specific databases are available to support clinical interpretation.
  
  

Sporadic and Mosaic Cases

• In some cases, the mutation arises during early embryogenesis (somatic mosaicism) or affects the parental germline, resulting in a child with haemophilia despite no family history.
• Genetic counselling is critical for assessing risk in such families.
  
  

Acquired Haemophilia

• A rare non-hereditary condition caused by the development of autoantibodies, typically targeting factor VIII.
• Not genetically transmitted; occurs sporadically.
• Most often seen in postpartum women, the elderly, and individuals with:
  • Autoimmune disorders (e.g. lupus, rheumatoid arthritis).
  • Inflammatory bowel disease.
  • Diabetes mellitus.
  • Viral infections (e.g. hepatitis).
  • Malignancies (e.g. lymphoproliferative disorders).
  • Monoclonal gammopathies.
  • Exposure to certain drugs (e.g. penicillin, phenytoin).
    
    
• Clinical presentation differs from congenital haemophilia, with predominant mucocutaneous and soft tissue bleeding.
  
  

Overview of Normal Coagulation

• Haemostasis involves a finely regulated coagulation cascade comprising two interlinked pathways:
  • Extrinsic (tissue factor) pathway: Activated by endothelial injury, exposing tissue factor (TF) which binds factor VIIa. This complex subsequently activates factors IX and X.
  • Intrinsic (contact activation) pathway: Triggered by exposure of blood to negatively charged surfaces, activating factor XII, which in turn activates prekallikrein to kallikrein and leads to activation of factor XI to XIa. Factor XIa then activates factor IX to IXa.
• Both pathways converge at the activation of factor X to Xa, initiating the common pathway, which culminates in thrombin generation.
• Thrombin (factor IIa) has multiple haemostatic roles:
  • Cleaves fibrinogen to form fibrin monomers.
  • Activates factor XIII to XIIIa for fibrin cross-linking.
  • Releases and activates factor VIII from von Willebrand factor (vWF).
  • Activates platelets to expose phospholipids necessary for clot formation.
• A critical step is the assembly of tenase (factors VIIIa + IXa) and prothrombinase (factors Va + Xa) complexes on phospholipid surfaces in the presence of calcium.
  
  

Role of Factors VIII and IX in the Intrinsic Pathway

• Factor VIII and factor IX are essential cofactors in the tenase complex.
• Factor IXa, in complex with VIIIa, phospholipids, and calcium, massively accelerates activation of factor X to Xa.
• This step is pivotal for the generation of thrombin in sufficient quantities for stable clot formation.
  
  

Pathophysiological Mechanism in Haemophilia

• In Haemophilia A (factor VIII deficiency) or Haemophilia B (factor IX deficiency):
  • The intrinsic pathway is functionally impaired.
  • Formation of the tenase complex is inefficient or absent.
  • This leads to inadequate activation of factor X, significantly reducing thrombin production.
  • Consequently, fibrin formation is delayed and insufficient, resulting in:
    • Formation of unstable clots that are easily disrupted.
    • Prolonged or spontaneous bleeding, especially into joints and muscles.
• The severity of bleeding correlates with the degree of thrombin generation impairment, which depends on the residual activity of factor VIII or IX.
  
  
  

Clinical Consequences

• Insufficient thrombin generation leads to delayed haemostasis even in response to minor vascular injury.
• Bleeding in haemophilia is often delayed rather than immediate, with slow oozing that can persist or recur if not treated.
• Because thrombin also plays roles in platelet activation and fibrin stabilisation, its deficiency affects both primary and secondary haemostasis.
  
  
  

Global Distribution and Prevalence

• Haemophilia occurs worldwide across all ethnic groups.
• Globally, it is estimated that over 1.2 million people are affected by haemophilia, predominantly males.
• Approximately 400,000 individuals are living with haemophilia A or B worldwide.
• Haemophilia A accounts for 80–85% of cases, making it more prevalent than haemophilia B.
  
  

Incidence Rates

• Haemophilia A:
  • Occurs in 1 in 4,000 to 1 in 5,000 live male births.
  • 50–66% of cases are severe (factor VIII activity <1%).
• Haemophilia B:
  • Occurs in 1 in 15,000 to 1 in 30,000 live male births.
  • 33–50% of cases are severe (factor IX activity <1%).
• Haemophilia C (factor XI deficiency):
  • Very rare, affecting 1 in 100,000 people.
  • Higher prevalence (~8%) among Ashkenazi Jews.
    
    

National Estimates

• United States:
  • Estimated incidence: 1 in 4,334 live male births.
  • ~33,000 males living with haemophilia (based on 2012–2018 surveillance).
• United Kingdom:
  • ~6,000 people living with haemophilia.
• India, Bangladesh, Indonesia, and China:
  • Account for 43% of the global haemophilia population, yet only 12% are diagnosed due to limited access to testing and care.
    
    

Sporadic Cases and Genetic Background

• While haemophilia is primarily inherited, sporadic cases are common due to de novo mutations.
  • ~55% of severe haemophilia A and 43% of severe haemophilia B cases occur without a family history.
  • In mild to moderate forms, ~30% of cases are sporadic.
• Some individuals with sporadic haemophilia may have undiagnosed carrier mothers, particularly in regions where carrier screening is limited.
  
  

Female Involvement

• Although classically a male disease due to X-linked recessive inheritance, females can be affected in rare circumstances:
  • Skewed lyonisation, compound heterozygosity, X-chromosome loss, or Turner syndrome.
• Mild haemophilia is reported in up to 25% of heterozygous female carriers.
  • These individuals are now increasingly recognised as having mild haemophilia rather than merely being "symptomatic carriers."
    
    

Acquired Haemophilia

• A rare, non-inherited autoimmune condition.
• Incidence in the UK is 1.48 per million per year.
• Affects 1 to 3 per million population globally.
• Equal sex distribution.
• Associated with various conditions such as autoimmune disease, malignancy, postpartum state, and certain medications.

Impact of Consanguinity

• In regions with high consanguinity rates (e.g. parts of the Middle East and North Africa), haemophilia prevalence may be higher.
• This may reflect both increased mutation transmission and improved detection due to familial clustering.
  
  
  

Lifespan and Diagnosis

• With modern treatment and prophylaxis, individuals with haemophilia can expect a normal life expectancy.
• However, underdiagnosis remains a challenge, especially in low- and middle-income countries due to limited access to diagnostic facilities and specialised care.
  
  

Risk Factors

• Two-thirds of patients with congenital haemophilia have a positive family history.
• Enquire about affected male relatives (e.g., uncles, cousins, grandfathers).
• Lack of family history does not exclude diagnosis—spontaneous mutations account for up to 55% of severe haemophilia A and 43% of haemophilia B cases.
  
  

• Males are predominantly affected due to X-linked recessive inheritance.
• In females, ask about a history of bleeding symptoms during menstruation, childbirth, or surgery, as ~25% of carriers may meet criteria for mild haemophilia.
  
  

• New unexplained bleeding in older adults warrants evaluation for acquired haemophilia.
• Ask about autoimmune conditions, malignancy, or postpartum status, all of which may precipitate inhibitor formation.
  
  

Bleeding History

• Recurrent joint swelling, pain, and reduced range of motion, especially in knees, elbows, and ankles.
• Bleeding typically affects one joint at a time but can involve multiple sites.
• In infants: irritability, refusal to use limb.
• In adults: warmth, stiffness, pain.
  
  

• Spontaneous or trauma-induced muscle haematomas, especially in the quadriceps, hamstrings, iliopsoas, biceps, and triceps.
• Iliopsoas bleeding may cause lower abdominal/back pain, flexed hip posture, and paraesthesia due to femoral nerve compression.
• Compartment syndrome may occur in deep muscle bleeds (e.g., forearm, calf).
  
  

• Recurrent nosebleeds, bleeding gums, oral bleeding post dental work.
• Easy bruising, often on lower limbs.
• In acquired haemophilia, mucocutaneous bleeding predominates, not joint bleeds.
  
  

• History of bleeding several hours to days post-procedure (e.g., dental extraction, circumcision, heel prick).
• Delayed wound healing or oozing.

• Especially in neonates and infants; may present with seizures, poor feeding, irritability, bulging fontanelle.
• In older children/adults: headache, vomiting, focal neurological deficits, or altered consciousness.

• Haematemesis, melaena, haematuria, suprapubic pain.
• Retroperitoneal bleeds may mimic acute abdomen.
  
  

• Excessively heavy or prolonged menstrual bleeding.
• Postpartum haemorrhage.
• Important to elicit if female relatives have had bleeding issues.
  
  

• Progressive mass following recurrent deep muscle bleeding, particularly in untreated patients.
• May present with pain, limited movement, or neurovascular compression.

• Musculocutaneous bleeds post intramuscular injections or unexplained bruising during early mobility.
  
  
  

Temporal Aspects and Triggers

• In severe haemophilia, spontaneous bleeding typically begins during infancy.
• Moderate disease often presents after trauma, around toddler age.
• Mild cases may remain undiagnosed until adulthood.
  
  

• Important in assessing bleeding phenotype severity.
• Ask specifically about past dental extractions, circumcisions, and major or minor injuries.
  
  

• History of inadequate response to usual factor replacement therapy.
• Increasing frequency or severity of bleeds.
  
  
  

Special Considerations in Females

• May be reduced due to lyonisation.
• Assess for history of abnormal bleeding during menstruation, childbirth, or surgical interventions.
• Inquire whether baseline factor levels were ever tested.
  
  

• History of prenatal counselling.
• Bleeding during previous pregnancies or postnatally.
  
  
  

History to Exclude Alternative or Coexisting Disorders

• NSAIDs, aspirin, anticoagulants, and herbal supplements (e.g., fish oil) may exacerbate bleeding.
• Ask about over-the-counter and prescription drug history.
  
  

• In acquired haemophilia, assess for autoimmune disease, diabetes, malignancy, hepatitis, or recent infections.

Musculoskeletal Signs

• Most common site of spontaneous bleeding in severe haemophilia.
• Swollen, warm, and painful joints, especially knees, ankles, and elbows.
• Reduced range of motion and guarding in the affected joint.
• May lack classic signs if examined shortly after onset.
• Chronic or recurrent haemarthroses result in:
  • Joint deformities.
  • Fixed flexion contractures.
  • Gait abnormalities (e.g., toe-walking or joint protection stances).
    
    

• Present as painful, swollen, and warm soft-tissue masses, typically in:
  • Quadriceps.
  • Hamstrings.
  • Iliopsoas.
  • Biceps or triceps.
• Iliopsoas bleeding:
  • Presents with lower abdominal, groin, or back pain.
  • Hip held in flexion with internal rotation.
  • Pain on extension but not on rotation.
  • Possible femoral nerve involvement: paraesthesia in the medial thigh, absent patellar reflex, quadriceps weakness.
  • Urgent factor replacement is critical.
    
    

• Results from bleeding into confined muscle compartments (e.g., calf, forearm).
• Signs include tense swelling, pain out of proportion, paraesthesia, pallor, and pulselessness.
• A musculoskeletal emergency requiring urgent surgical and haematological intervention.
  
  

• Large, chronic cystic masses resulting from recurrent muscle or bone bleeds.
• Can cause limb swelling, deformity, pressure effects on adjacent structures, or pathological fractures.
• Examination may reveal immobile, firm masses, often near bones.
  
  
  

 Mucocutaneous and Skin Findings

• Easy bruising, especially on the shins or arms.
• May be spontaneous or after minor trauma.
• Large or deep subcutaneous haematomas may occur in severe cases.

• Extensive cutaneous purpura, often without joint involvement.
• Seen in acquired haemophilia, typically in older adults.

• Persistent bleeding from venepuncture, intramuscular injections, heel pricks, or circumcision sites.
• Bleeding may be delayed by several hours or days.
  
  

Neurological Examination

• Especially in neonates and infants with severe haemophilia.
• Findings vary with age:
  • Neonates: bulging fontanelle, hypotonia, seizures, pallor, decreased feeding.
  • Children/Adults: headache, vomiting, irritability, seizures, altered consciousness, focal deficits.
• High suspicion required even in absence of trauma.
  
  

• Presents with back pain, radicular symptoms, limb weakness, and sensory disturbances.
• Examination may show lower limb weakness, altered reflexes, or urinary retention.
• Peripheral nerve compromise (e.g., femoral nerve with iliopsoas bleed, median or ulnar nerve with forearm bleeds).
  
  
  

Cardiopulmonary and Abdominal Findings

• Symptoms include chest pain, dyspnoea, and haemoptysis.
• May progress to respiratory distress due to airway compromise.
  
  

• Distended, tender abdomen with or without trauma.
• May mimic acute abdomen or retroperitoneal mass.
• Associated with guarding, rigidity, or signs of peritonism.
  
  

• Pallor, tachycardia, hypotension, and tachypnoea in the setting of acute blood loss.
• Suggests significant or internal haemorrhage.
  
  
  

Genitourinary Findings

• Often painless.
• May lead to palpable bladder distension, colic from clot obstruction, or flank tenderness.
  
  

• Bleeding signs such as:
  • Petechiae or ecchymosis, especially peri-menstrual or postpartum.
  • Prolonged bleeding at surgical sites (e.g., episiotomy).
  • Anaemia-related findings if menorrhagia is significant.
    
    

Initial Evaluation

• Diagnosis begins with clinical suspicion based on:
  • Personal or family history of bleeding.
  • Male sex.
  • Bleeding into joints and muscles.
  • Excessive bleeding after procedures (e.g. circumcision, venepuncture).
• Haemophilia A and B are clinically indistinguishable without laboratory testing.
  
  

• Carrier screening and prenatal testing (e.g. chorionic villous sampling or amniocentesis) for families with known haemophilia.
• Umbilical cord or neonatal blood testing in newborns with suspected haemophilia.
  • Note: Factor IX levels are physiologically low at birth, limiting its diagnostic value in neonates.
    
    
    

Baseline Laboratory Testing

• Typically prolonged in haemophilia A and B (intrinsic pathway defect).
• aPTT may be normal in mild cases; further testing is warranted if clinical suspicion remains.
  
  

• Generally normal in haemophilia.
• Helps differentiate from other bleeding disorders (e.g. combined factor deficiencies or platelet disorders).
  
  

• Performed if aPTT is prolonged.
• Correction of aPTT after mixing with normal plasma suggests factor deficiency.
• Failure to correct indicates inhibitor presence (e.g. acquired haemophilia).
  
  

• Definitive diagnosis of haemophilia A or B.
• Factor activity levels:
  • <1%: severe.
  • 1–5%: moderate.
  • 6–40%: mild.
    
    

• Evaluates for anaemia and excludes thrombocytopenia.
  
  

• Differentiates from von Willebrand disease, particularly in patients with mucocutaneous bleeding.
  
  
  

Inhibitor Screening

• Routine in patients with known haemophilia receiving factor replacement.
• Recommended:
  • After intensive factor exposure (>5 consecutive days).
  • In case of recurrent or unexpected bleeds, poor clinical response, or low factor recovery.
  • Before planned surgery.
    
    

• Quantifies inhibitory antibodies to factor VIII or IX.
• Results expressed in Bethesda Units (BU):
  • Low responder: <5 BU.
  • High responder: ≥5 BU.
    
    

• Reduces false positives and improves specificity.
  
  

Genetic and Molecular Testing

• Identifies specific mutations in the F8 or F9 gene.
• Important for:
  • Confirming diagnosis.
  • Predicting inhibitor risk.
  • Determining carrier status in relatives.
• Patients with large deletions in F9 are at higher risk for anaphylaxis or nephrotic syndrome with factor IX infusions.
  
  

Imaging and Advanced Diagnostics

• For suspected intracranial haemorrhage, especially in neonates or with neurological symptoms.
  
  

• For suspected iliopsoas bleeds, gastrointestinal haemorrhage, or retroperitoneal haematoma.
  
  

• Evaluates joint health in recurrent haemarthroses.
• Detects early haemophilic arthropathy and pseudotumours.
  
  

• Used for suspected upper or lower gastrointestinal bleeding.

• Evaluate chronic joint damage and structural changes.
  
  
  
  

Specialised Testing in Acquired Haemophilia

• Suspected in older adults or postpartum women with no personal/family bleeding history.
• Characterised by:
  • Isolated prolonged aPTT.
  • Low factor VIII activity.
  • Failure to correct with mixing study.
  • Presence of factor VIII inhibitors.
    
    

Antenatal and Reproductive Testing

• Fetal sex may be determined by maternal blood testing from 4–5 weeks, or ultrasound from 11–13 weeks.
  
  

• Performed on amniocentesis (from 15 weeks) or CVS (10–14 weeks).
• Direct mutation testing is possible if the familial mutation is known.
  
  

• Option for known carriers undergoing IVF.
  
  

Von Willebrand Disease (VWD)

• Autosomal inheritance (affects both sexes equally).
• Predominantly mucocutaneous bleeding: epistaxis, menorrhagia, easy bruising.
• Rarely causes deep tissue or joint bleeds.
  
  

• VWD can reduce factor VIII levels (particularly in type 2N and type 3), mimicking haemophilia A.
  
  

• VWF antigen, ristocetin cofactor activity, VWF multimer analysis.
• Factor VIII activity (especially in type 2N).
• Genetic testing for VWF mutations.
  
  
  

Platelet Disorders

• Mucocutaneous bleeding pattern: gum bleeding, epistaxis, petechiae.
• Normal coagulation studies but abnormal platelet aggregation or morphology.
  
  

• Common in uraemia, liver disease, or due to antiplatelet medications.
• May mimic bleeding diatheses.
  
  

• Platelet function tests (aggregation studies).
• Electron microscopy (for dense granule storage defects).
• Closure time or bleeding time (screening but nonspecific).
  
  
  

Other Coagulation Factor Deficiencies

• Ashkenazi Jewish population.
• Prolonged aPTT with provoked bleeding, not spontaneous.
• Normal levels of factor VIII and IX.
  
  

• Delayed bleeding after trauma or surgery.
• May cause umbilical stump bleeding, ICH in neonates, poor wound healing.
• Normal PT, aPTT, and platelet function.
• Diagnosed with factor XIII activity assay.
  
  

• Autosomal recessive.
• Prolonged PT and aPTT, unlike isolated haemophilia.
• Often seen in consanguineous families.
  
  

• May present with bleeding or paradoxically with thrombosis.
• Require specific coagulation factor assays.
  
  
  

Connective Tissue Disorders

• Mucosal bleeding, skin hyperextensibility, joint hypermobility.
• Bleeding is typically not musculoskeletal.
• Diagnosis: clinical exam, genetic testing, or biopsy.
  
  

• Presents with mucosal bleeding, gum disease, perifollicular haemorrhage.
• Risk factors: poor nutrition, critical illness, alcoholism.
  • Diagnosis: clinical features, low serum ascorbate.
    
    

Fabry Disease

• Pain in extremities, angiokeratomas, renal and cardiac involvement.
• Bleeding is mucosal, not musculoskeletal.
• Diagnosis: enzyme assay, genetic testing.
  
  
  

Disseminated Intravascular Coagulation (DIC)

• May present with widespread bleeding and thrombosis.
• Associated with severe infection, malignancy, or obstetric complications.
• Lab features: low platelets, prolonged PT/aPTT, elevated D-dimers, decreased fibrinogen.
  
  
  

Acquired Haemophilia

• Seen in elderly, postpartum women, or associated with autoimmune disease/malignancy.
• Presents with mucocutaneous and deep bleeding, often severe.
• Lab: prolonged aPTT that does not correct with mixing studies.
  
  

Child Abuse (Non-accidental Injury)

• Look for:
  • Inconsistent history.
  • Multiple injuries at different healing stages.
  • Patterns suggestive of inflicted trauma (e.g., belt marks, immersion burns).
• Labs: may show anaemia or normal clotting studies.
• Imaging: skeletal surveys, head CT or MRI to identify occult injuries.
  
  
  

Antiphospholipid Syndrome (APS)

• Prolonged aPTT on lab testing, but paradoxically associated with thrombosis, not bleeding.
  • Should be differentiated using mixing studies and anticardiolipin / lupus anticoagulant assays.
    
    

Principles of Comprehensive Care

• Haemophilia management is best delivered in multidisciplinary, specialised haemophilia centres.
• Core components include:
  • Prompt treatment of bleeding episodes to prevent joint damage.
  • Prophylaxis to prevent spontaneous bleeds.
  • Rehabilitation following joint or muscle bleeds.
  • Orthopaedic assessment for chronic joint issues.
  • Management of inhibitors, the most serious treatment complication.
  • Pain control, with avoidance of NSAIDs.
  • Dental care integrated with haemostatic planning.
  • Education on home therapy, bleed recognition, and emergency care.
  • Genetic counselling for family planning and prenatal decisions.
  • Psychosocial support and quality-of-life monitoring.
  • Exercise and physiotherapy, personalised to joint health and fitness levels.
    
    

Acute Bleeding Management (No Inhibitors)

• Treatment should begin within 2 hours of symptom onset, especially for joint bleeds.
• Bleeds may be preceded by an aura—tingling, tightness, or warmth in the joint.
• Factor replacement therapy is the mainstay:
  • Haemophilia A: Recombinant or plasma-derived factor VIII.
  • Haemophilia B: Recombinant or plasma-derived factor IX.
• Dosing is tailored to bleed site and severity, with trough levels monitored for serious bleeds.
• Adjunctive therapies:
  • Tranexamic acid or aminocaproic acid for mucosal bleeding.
  • Desmopressin (DDAVP) for mild haemophilia A, given subcutaneously or intranasally.
  • Analgesia: Paracetamol, opioids, or COX-2 inhibitors.
• Home infusion can be performed by trained patients, parents, or nurses for uncomplicated bleeds.
  
  
  

Acute Bleeding Management (With Inhibitors)

• Low-responder: <5 BU/mL.
• High-responder: ≥5 BU/mL.

• High-dose factor concentrate (VIII or IX) using the formula:
   Dose (IU/kg) = 2 × BU × % correction desired.
  
  

• Bypassing agents:
  • Recombinant activated factor VII (rFVIIa): 90–120 mcg/kg every 2–3 hours IV.
  • aPCC (FVIII inhibitor bypassing activity): Activated clotting complex.
• Caution:
  • Avoid aPCC with antifibrinolytics (risk of thrombosis).
  • Avoid aPCC within 6 months of starting emicizumab.
    
    

• for Haemophilia A only
• Subcutaneous weekly/biweekly/4-weekly dosing.
• Not used for acute bleeds.
• Requires bovine chromogenic assays for accurate monitoring.
  
  
  
  

Site-Specific Bleed Management

• Administer full factor dose urgently before diagnostic confirmation.
• Maintain factor levels at 80–100% (peak) and 40–50% (trough) for 10–14 days.
• Include subspecialist input, supportive care, and antifibrinolytics where indicated.
• Contraindications: Antifibrinolytics in haematuria and thoracic bleeds.
  
  
  

• Early factor replacement ± PRICE protocol.
• Physiotherapy initiated post-bleed resolution.
• Monitor for compartment syndrome.
  
  

• Avoid antifibrinolytics.
• Use hydration (1.5× maintenance) and factor replacement.
  
  

• Recurrent haemarthrosis → risk of chronic arthropathy.
• Radioactive synovectomy (e.g., yttrium-90) if frequent bleeding.
• Surgical synovectomy or joint replacement for refractory cases.
  
  

Mild Haemophilia and Mucosal Bleeding

• Use only in patients with documented responsiveness.
• Produces 2–4× rise in factor VIII levels.
• Avoid in children <2 years.
• Restrict fluids post-dose to avoid hyponatraemia.
• Intranasal doses: 150 mcg (<50 kg), 300 mcg (>50 kg).
• Intravenous route for inpatient use.
  
  

• Oral or nasal bleeds in moderate–severe haemophilia.
• Do not use in haematuria or with aPCC.
  
  
  

Prophylaxis

• Defined as continuous administration of haemostatic agents to prevent spontaneous bleeding.
• Indications:
  • Severe haemophilia (FVIII/IX <1%).
  • Moderate/mild haemophilia with severe bleeding phenotype.
• Types:
  • Primary: Before 2nd large joint bleed and joint damage.
  • Secondary: After 2+ joint bleeds but before arthropathy.
  • Tertiary: After joint disease onset.
    
    
    

• Haemophilia A:
  • Standard FVIII: 2–3×/week.
  • Extended half-life FVIII: Every 5–7 days.
• Haemophilia B:
  • Standard FIX: 2×/week.
  • Extended half-life FIX: Every 7–14 days.
    
    

• For Haemophilia A (with/without inhibitors).
• SC injection with constant plasma levels.
• Not suitable for acute bleeds or Haemophilia B.
  
  
  

Immune Tolerance Induction (ITI)

• Goal: Eradicate inhibitors through daily or intermittent high-dose factor exposure.
• Regimens:
  • High-dose: 200 IU/kg/day.
  • Low-dose: 50 IU/kg, 3×/week.
• Success rate: ~70% for haemophilia A.
• Lower success in haemophilia B, especially with allergic reactions or nephrotic syndrome risk.
• Rituximab: May aid inhibitor eradication in mild/moderate haemophilia A.
  
  
  

Bypassing Agent Prophylaxis

• For patients unable to undergo ITI or with unsuccessful ITI.
• Decreases bleeding frequency, but less improvement in quality of life than factor prophylaxis.
• Home use is encouraged with patient training on preparation and administration
  
  

Life Expectancy and Disease Outlook

• In developed countries, individuals with haemophilia A or B can expect a near-normal life expectancy, particularly when:
  • Early diagnosis is made.
  • Access to regular factor replacement therapy or non-factor prophylaxis (e.g., emicizumab) is available.
  • Comorbidities, such as hepatitis C or HIV, are adequately treated.
• Patients with mild or moderate disease who receive appropriate treatment typically experience minimal long-term complications.
  
  

Prognostic Factors

• Individuals with severe haemophilia (factor activity <1%) are at higher risk of spontaneous bleeding, particularly into joints and muscles, and thus have a greater burden of disease if untreated.
  
  

• Regular prophylaxis reduces the frequency of bleeding and prevents joint damage.
• Even low-dose prophylaxis (e.g., 5–10 IU/kg 2–3 times weekly) significantly lowers bleeding rates and improves functionality.
  
  

• The presence of inhibitory antibodies to factor VIII or IX complicates management and is associated with increased morbidity.
• Successful immune tolerance induction improves long-term outcomes in patients with inhibitors.
  
  

• Multidisciplinary care, including physiotherapy, orthopaedic support, psychosocial services, and patient education, is associated with improved quality of life and reduced long-term disability.
  
  

Functional and Quality of Life Outcomes

• Patients on regular prophylaxis have:
  • Reduced annualised bleeding rates.
  • Preservation of joint function, especially when prophylaxis is started early.
  • Improved participation in school, work, and physical activity.
• In patients without adequate prophylaxis, chronic joint arthropathy remains a major complication, leading to reduced mobility, pain, and reduced independence.
• Psychosocial health is significantly better in individuals receiving consistent, effective treatment and education.
  
  
  

Prognosis in Resource-Limited Settings

• In developing countries, the prognosis is poorer due to:
  • Delayed diagnosis.
  • Limited access to clotting factor concentrates and prophylactic therapy.
  • Higher incidence of preventable complications (e.g., intracranial haemorrhage, joint deformity).
  • Mortality is estimated to be nearly double that of the general population in some low-income settings.
  • Implementation of low-dose prophylaxis and increased availability of recombinant or extended half-life products could significantly improve outcomes.
    
    

Development of Inhibitors

• The most serious treatment-related complication in haemophilia is the development of inhibitory alloantibodies (IgG) against infused clotting factors VIII or IX.

• Haemophilia A: up to 30%.
• Haemophilia B: approximately 5%.
  
  

• Severe disease.
• Certain genetic mutations (e.g., large deletions, nonsense mutations).
• Early intensive factor exposure.
• Specific ethnic groups (e.g., African-Caribbean, Hispanic).

• Inhibitors typically develop early (before 50 exposure days), especially in severe haemophilia.
• May also appear later in mild/moderate disease (median age ~30 years).
  
  

• Suspect in patients with reduced response to factor infusions.
• Confirmed with the Nijmegen-modified Bethesda assay.
  
  

• Regular screening is advised:
  • Every 5 exposure days until 20 exposure days.
  • Every 10 exposure days between 21–50.
  • Twice annually until 150 exposure days.
  • Before surgery or after product switches.

• Low responders: titres persistently <5 BU/mL; often transient.
• High responders: titres ≥5 BU/mL; tend to persist and rise on re-exposure.
  
  

• High-dose factor concentrate may be effective in low responders.
• Bypassing agents (rFVIIa or aPCC) are required in high responders.
• Immune tolerance induction (ITI) is the main strategy to eliminate inhibitors:
  • Repeated daily factor infusions over months–years.
  • Up to 70% success in haemophilia A; ~30% in haemophilia B.
  • May involve immunosuppressives; monitor for infection risk.
• Emicizumab, a bispecific monoclonal antibody, mimics factor VIII function and is unaffected by inhibitors.
  
  

 Musculoskeletal Complications

• Results from recurrent joint bleeds, especially in knees, elbows, and ankles.
• 90% of untreated patients with severe disease develop joint degeneration by age 30.

• Chronic pain, decreased range of motion, joint deformities, and contractures.
• Muscle atrophy may also occur due to disuse and recurrent bleeds.

• Prophylactic factor replacement significantly reduces frequency and severity of joint damage.
• Early physiotherapy and targeted orthopaedic care improve outcomes.
  
  

Pseudotumours

• Pseudotumours arise from untreated or inadequately managed muscle bleeds.
  • Present as encapsulated masses, often adjacent to long bones or pelvis.
  • Can cause pressure effects, pathological fractures, or fistula formation.

• Clinical evaluation plus imaging (MRI preferred).

• Small lesions: conservative management + regular imaging.
• Large or expanding lesions: aspiration or surgical excision.
• Factor replacement is mandatory before and after intervention.
• In severe cases, amputation or urgent surgery may be required (e.g., abdominal pseudotumour).
  
  
  

Compartment Syndrome

• A musculoskeletal emergency caused by bleeding into deep, enclosed muscle compartments (e.g., forearm, calf).
• Signs:
  • Pain out of proportion, swelling, decreased movement, paraesthesia, pallor, weak pulses.
• Early intervention with aggressive factor replacement is essential to prevent permanent damage.
• Close monitoring for need for fasciotomy, in collaboration with orthopaedics.
  
  

Fractures

• More frequent in patients with haemophilic arthropathy due to osteoporosis or mechanical stress.
• Initial management includes:
  • Factor levels raised to ~50%.
  • Splinting, immobilisation, and early physiotherapy.
  • Surgical intervention may be needed depending on fracture type.
    
    
    

Allergic Reactions to Factor Products

• Primarily seen in haemophilia B.
• Anaphylaxis may be the first sign of inhibitor development.
• Such patients should be monitored closely for nephrotic syndrome during ITI.
• Avoid re-challenging without specialist supervision.
  
  

Blood-Borne Infections

• Past contamination of plasma-derived factor concentrates (1970s–80s) led to widespread HIV and hepatitis C transmission.
• Modern safety has improved due to:
  • Rigorous donor screening.
  • Viral inactivation (e.g., heat treatment, solvent-detergent processing).
  • Transition to recombinant products.
• Residual risks:
  • Emerging threats include non-enveloped viruses and prion diseases.
• Current management:
  • Antiretroviral therapy (HIV).
  • Pegylated interferon + ribavirin (HCV, where still indicated).
  • Routine viral monitoring and vaccination for hepatitis A/B.
    
    

General Haemorrhagic Risk

• Patients with severe disease not on prophylaxis are at high risk of spontaneous or life-threatening bleeding, particularly after trauma or surgery.
• Risk reduces significantly in patients on regular prophylaxis.
• Mild haemophilia carries lower risk, but bleeding can occur with surgical or dental procedures.
  
  

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