How is Haemophilia A Diagnosed?

⁽¹⁾ APTT is increased in isolated cases; the degree of lengthening depends on the severity of factor VIII deficiency and on the sensitivity of the reagent to factor VIII deficiency.

⁽²⁾ Lengthening of APTT may be corrected by mixing the patient's plasma in equal parts with a pool of normal plasma.

• The clotting activity of factor VIII is determined to establish the diagnosis and ascertain the severity of the disease. The assay may be performed on serial dilutions of the patient's plasma to exclude any interference from circulating lupus anticoagulant antibodies.
• Activity levels are normal for other factors of which a deficiency can cause isolated lengthening of APTT (factors IX, XI and XII).
• Levels of Von Willebrand factor (ristocetin cofactor/antigen activity) are normal.

Differential diagnosis involves ruling out other causes for lengthening of APTT associated with decreased activity of factor VIII:

Anti-factor VIII Antibodies

• Acquired haemophilia A is associated with the presence in non-haemophiliac subjects of antibodies directed against factor VIII. This is a rare disease that can occur in particular in women during or at the end of pregnancy, in patients with autoimmune disease, and in elderly subjects.
  The most common clinical sign is the presence of marked haematomas. Since the disease may be life-threatening, appropriate therapy must be given quickly.
  Diagnosis involves screening for a specific inhibitor directed against factor VIII using the Bethesda method or the Nijmegen method. These inhibitors are also seen more frequently (10 to 15% of patients) in haemophiliac subjects receiving replacement therapy containing factor VIII, against which they are immunized due to the development of antibodies directed against factor VIII.

Type 2N (Normandy) Von Willebrand Disease

• This is characterized by the presence of variants of Von Willebrand factor having a low affinity for binding to factor VIII. Levels of factor VIII are low and levels of von Willebrand factor are normal, while the level of activity of factor VIII depends on the type of VWF mutations present. Differential diagnosis with regard to haemophilia A involves determining the affinity of the patient's Von Willebrand factor for factor VIII.

Others Pathologies

• There are other forms of Von Willebrand disease in which levels of factor VIII are correlated with Von Willebrand factor
• Combined factor VIII/factor V deficiency is a rare anomaly with an estimated prevalence of one per million; this prevalence is nevertheless far higher than the theoretical combined prevalence of factor VIII deficiency and factor V deficiency.
  This abnormality is due to mutations on the genes [normally ERGIC (also known as LMAN1), and less frequently MCFD2] coding for the transport proteins involved in the intracellular transportation of factors VIII and V, and generally results in a moderate reduction in factors VIII and V (5 to 20%).

Laboratory diagnosis is based on simultaneous lengthening of APTT and Prothrombin times, after which factor V deficiency may be demonstrated. It is recommended that activity levels of factor VIII should be determined at least once in all patients with constitutional factor V deficiency in order to ensure this anomaly is not overlooked.