Introduction to Haemophilia: Types, Genetics, and Clinical Features

Outcomes of Haemophilia Session

On completion of this session you should be able to: Describe the different types of haemophilia Differentiate haemophilia A and B Explain the genetic and molecular basis of Haemophilia A and B

Disorders of Coagulation

Bleeding disorders can be either inherited or acquired Inherited disorders are less common than acquired disorders

Inherited Bleeding Disorders

• Inherited bleeding disorders include:

X-Linked Disorders

Haemophilia A - FVIII Locus Xq28 Haemophilia B - FIX locus Xq27

Autosomal Disorders

Haemophilia C - FXI locus 4q35 von Willebrand disease - vWF locus 12p13

Haemostatic Role of FVIII/IX

Bleeding occurs due to a failure of secondary haemostasis Primary haemostasis occurs normally Stabilisation of the platelet plug is defective Inadequate amounts of fibrin are generated Diagnosed through a normal PT an abnormal APTT abnormal factor assay

Key Complexes in Haemostasis

Intrinsic Pathway

Tenase FVIIIa FIXa FX

Extrinsic Pathway

FVIIa TF FX 1 Xa Xa Xa Va Prothrombinase Thrombin

Clinical Features of Haemophilia

• Joint/soft tissue bleeds + excessive bruising Recurrent, painful haemarthroses + muscle haematomas
• Synovitis
• Suffocation Dental complications Spontaneous haematuria +/- GI bleed Spontaneous intracerebral haemorrhage Pathological fractures of bones Large elbow joint bleed Arthrocentesis

FVIII and FIX Mutations

FACTOR VIII Mutations

The same mutation occurs in all members of a family

• 50% patients - frame shift mutations Plus 5% large/small deletions and insertions Remaining are point mutations: mis-sense non-sense Flip-tip mutation

FACTOR IX Mutations

Significantly smaller and less complex than FVIII gene

• More than 2800 mutations are recorded
• Point mutations predominate, with almost 70% of these being missense
• short additions/deletions, gross gene deletions and complex rearrangements uncommon

Treatment for Haemophilia

Treatment is beyond the scope of this lecture series, although you should be aware that plasma derived and recombinant factors can be used to manage haemophilia. Prophylaxis should be started in patients to prevent bleeding, and in particular to avoid the first joint bleed. However, intervention does largely depend on the initial plasma level of FVIII/FIX.

• On demand interventions can also be used when necessary. In Haemophilia A there is the risk of inhibitors forming, particularly in those with complex mutations. Managing these cases can be clinically challenging.