Haemophilia A & B

Learning outcome

1. Describe the pathophysiology, inheritance, clinical and laboratory features of Haemophilia A and B

Haemophilia A

Pathophysiology

Haemophilia A is a condition caused by reduced FVIII activity due to defective synthesis of the FVIII molecule. Its prevalence is estimated at 1 in 5,000 males. No significant geographical variation in its prevalence is reported.

The condition is inherited as an X-linked recessive disorder. Heterozygous females (X^HX^h) serve as carriers and are asymptomatic, as the normal allele in the unaffected chromosome produces enough FVIII to maintain haemostasis. Affected hemizygous males (X^hY) do not produce sufficient FVIII to maintain haemostasis and are at risk of bleeding. Family history is however absent in about 30% of cases, likely due to a recent spontaneous mutation.

Clinical features

Haemophilia A can be classified into mild, moderate and severe forms based on the level of FVIII remaining in them. Males with severe haemophilia A characteristically present with bleeding into the joints (haemathroses). Other common sites of bleeding include intramuscular and subcutaneous bleeds.

A tendency to bruise easily may be noted but superficial bleeds such as petechiae is not a common feature of Haemophilia A. The earliest manifestation in severe haemophilia may be bleeding from the umbilical stump or bleeding following circumcision.

Wound bleeding is usually delayed for several hours. This is reflective of the action of FVIII in the secondary haemostatic process, where it is necessary for generating FXa that partakes in the ‘thrombin burst’ and maintaining deposition of fibrin.

Deep haematomas may cause serious consequences from the compression of vital structures such as the airway, artery or peripheral nerves. Intracranial haemorrhage, though uncommon, can be a cause for death.

In sub-optimally managed patients, repeated bleeding into the joints, especially the knee and ankles, result in chronic athropathy and deformities.

Laboratory features

An isolated APTT prolongation with normal PT and TT is noted. The APTT is corrected on performing a mixing test. In the mixing test, equal volumes of patient plasma and normal plasma is added and the APTT repeated on the 1:1 normal:patient plasma. A patient with coagulation factor deficiency as in Haemophilia A, will have the APTT corrected to normal values. This occurs because the normal plasma contains 100% FVIII and a patient with Haemophilia A will have 0-20% FVIII, depending on the severity. Even in severe Haemophilia A with 0% FVIII, the dilution of patient plasma with normal 100% plasma i.e. 1 in 2 dilution, will result in a final concentration of 50% FVIII. APTT usually begin to show a prolongation at FVIII levels below 30%, therefore at concentration of 50%, the APTT would be normal.

A non-corrected APTT with normal plasma, on the hand could mean that the function of FVIII is being inhibited by a substance that cannot be diluted easily. This can occur in the presence of lupus anticoagulants which interfere with assembly of FVIII on lipid surfaces or antibodies directed against FVIII that inhibit its function.

A FVIII assay will confirm the diagnosis. Boys with severe haemophilia A have FVIII levels <1%, while moderate and severe have levels of 2-5% and 5-20% FVIII respectively.

Treatment

Patients with severe Haemophilia A require FVIII replacement to treat bleeding episodes and prevent complications of recurrent bleeds, especially into large joints. FVIII is provided by intravenous administration of FVIII concentrates. Prophylactic FVIII administered 2-3 times weekly may be necessary for some patient with frequent bleeds.

In mild and moderate haemophilia A, DDAVP may be used to stimulate release of residual FVIII from endothelial cells. Tranexamic acid is also often used to prevent the fibrinolysis and breakdown of of formed clots.

One of the complications that may arise from administration of FVIII concentrates is the development of antibodies against FVIII, known as FVIII inhibitors. FVIII inhibitors severely limit the efficacy of administered FVIII, and other modalities of treatment such as FVIII bypassing agents (rFVIIa, FEIBA) or emicizumab.org/wiki/Emicizumab may need to be used at great cost.

Haemophilia B

Haemophilia B is caused by deficiency of FIX. Similar to haemophilia A, it is an X-linked recessive condition. The prevalence of Haemophilia B is however much lower as compared to Haemophilia A, with estimates of 1 in 25-30,000 males.

The clinical presentation of Haemophilia B is generally similar to haemophilia A, although it tends to be less severe. Haemathroses is typical in severe haemophilia B. The APTT is prolonged and corrected with normal plasma. FIX levels will be low.

Replacement of factor IX remains the mainstay of treatment for haemophilia B patients.