Haemophilia

Introduction

• Haemophilia is a hereditary bleeding disorder caused by deficiency of specific coagulation factors.

• It results in prolonged or spontaneous bleeding due to defective blood clot formation.

• The disorder primarily affects the intrinsic pathway of the coagulation cascade.

• Haemophilia is most commonly inherited as an X-linked recessive condition.

• Males are predominantly affected, while females usually act as carriers.

• The two major forms are Haemophilia A (Factor VIII deficiency) and Haemophilia B (Factor IX deficiency).

• Bleeding typically occurs into joints, muscles, and soft tissues, rather than superficial skin.

• Hemarthrosis (joint bleeding) is the hallmark clinical feature.

• Laboratory findings characteristically show prolonged aPTT with normal PT and platelet count.

• With advances in factor replacement therapy and gene therapy, haemophilia is now a manageable chronic disorder.

Types of Haemophilia

Haemophilia is classified based on the specific coagulation factor deficiency. The major types are described below:

1. Haemophilia A

• Also called Classic Haemophilia

• Caused by Factor VIII deficiency

• Accounts for 80–85% of cases

• Inheritance: X-linked recessive

• Common features:

  • Severe hemarthrosis

  • Muscle hematomas

  • Prolonged bleeding after surgery

• Laboratory findings:

  • ↑ aPTT

  • Normal PT and bleeding time

2. Haemophilia B

• Also known as Christmas Disease

• Caused by Factor IX deficiency

• Accounts for 15–20% of cases

• Inheritance: X-linked recessive

• Clinical presentation is indistinguishable from Haemophilia A

• Diagnosed by Factor IX assay

3. Haemophilia C

• Caused by Factor XI deficiency

• Very rare

• Inheritance: Autosomal recessive

• Affects both males and females

• Usually presents with:

  • Mild bleeding

  • Post-operative bleeding

• Less common hemarthrosis

4. Acquired Haemophilia

• Caused by autoantibodies against clotting factors (commonly Factor VIII)

• Seen in:

  • Elderly individuals

  • Postpartum women

  • Autoimmune disorders

• Not inherited

• Presents with:

  • Sudden severe bleeding

  • No family history

Table

Genetic Basis

Haemophilia is primarily a genetic disorder of blood coagulation caused by mutations affecting genes responsible for clotting factor synthesis.

1. Mode of Inheritance

• Haemophilia A and B follow an X-linked recessive inheritance

• Predominantly affects males

• Females are usually asymptomatic carriers

2. Gene Involvement

• These genes encode Factor VIII and Factor IX, respectively

• Mutations lead to partial or complete absence of functional clotting factors

3. Types of Genetic Mutations

• Point mutations

• Insertions or deletions

• Inversions (common in severe Haemophilia A)

• Nonsense mutations leading to truncated proteins

Severity of haemophilia correlates with the type and extent of mutation.

4. Carrier State in Females

• Females have two X chromosomes

• One normal gene compensates for the defective one

• Some carriers may show:

  • Mild bleeding

  • Reduced factor levels (due to lyonization / X-chromosome inactivation)

5. Inheritance Pattern

• Carrier mother × normal father →

  • 50% sons affected

  • 50% daughters carriers

• Affected father × normal mother →

  • All daughters carriers

  • Sons unaffected

6. De Novo Mutations

• ~30% of cases occur due to new (sporadic) mutations

• No previous family history

• Important in genetic counseling

7. Genetic Basis of Haemophilia C

• Caused by Factor XI gene mutations

• Autosomal recessive inheritance

• Affects both males and females

• More common in certain ethnic populations

8. Clinical Significance

• Helps in:

  • Prenatal diagnosis

  • Carrier detection

  • Genetic counseling

  • Personalized therapy and prognosis

Pathophysiology

Haemophilia is a coagulation disorder resulting from a defect in the intrinsic pathway of the coagulation cascade, leading to impaired fibrin clot formation and persistent bleeding.

1. Normal Coagulation 

• Hemostasis occurs in three stages:

  1. Vascular constriction

  2. Platelet plug formation

  3. Coagulation cascade → fibrin clot

• The intrinsic pathway involves Factors VIII, IX, XI, and XII

• Factor VIII acts as a cofactor for Factor IXa in activating Factor X

2. Primary Defect in Haemophilia

• Reduced or absent factor activity leads to:

  • Poor conversion of prothrombin → thrombin

  • Reduced fibrinogen → fibrin

  • Weak, unstable clot formation

3. Effect on Hemostasis

• Platelet plug forms normally

• Fibrin stabilization is defective

• Clot breaks down easily → recurrent bleeding

4. Site-Specific Bleeding

• Joints (hemarthrosis):

  • Repeated bleeding → synovial inflammation

  • Cartilage destruction → haemophilic arthropathy

• Muscles:

  • Hematoma formation

  • Compartment syndrome in severe cases

• Soft tissues & CNS:

  • Life-threatening hemorrhage

5. Severity Correlation

• Severity depends on residual clotting factor level

• <1% activity → spontaneous bleeding

• 1–5% → bleeding after minor trauma

• 5% → bleeding after surgery/major trauma

6. Development of Inhibitors

• Some patients develop alloantibodies against infused clotting factors

• Neutralize therapeutic factor VIII or IX

• Causes treatment resistance and severe bleeding

7. Acquired Haemophilia 

• Autoantibodies against Factor VIII

• Sudden onset bleeding

• No family history

Clinical Features

1. General Bleeding Manifestations

• Prolonged bleeding after:

  • Minor cuts

  • Tooth extraction

  • Surgery or trauma

• Excessive bleeding after injections or vaccinations

• Delayed bleeding (bleeding may restart hours after injury)

2. Hemarthrosis 

• Most commonly affected joints:

  • Knee

  • Ankle

  • Elbow

• Clinical signs:

  • Pain and swelling

  • Warmth and restricted movement

• Recurrent episodes lead to:

  • Synovial inflammation

  • Cartilage destruction

  • Haemophilic arthropathy

3. Muscle Bleeding

• Deep muscle hematomas (thigh, calf, iliopsoas)

• Painful swelling and stiffness

• Can cause:

  • Nerve compression

  • Compartment syndrome

  • Functional disability

4. Skin and Mucosal Bleeding

• Easy bruising (ecchymosis)

• Subcutaneous hematomas

• Gum bleeding

• Epistaxis (nosebleeds)

5. Internal and Life-Threatening Bleeding

• Intracranial hemorrhage (most serious complication)

• Gastrointestinal bleeding

• Retroperitoneal hemorrhage

• Hematuria (blood in urine)

6. Bleeding in Children

• Excessive bleeding after circumcision

• Large bruises during crawling or walking

• Joint swelling in toddlers

• Delayed diagnosis in mild cases

7. Severity-Based Clinical Presentation