How is haemophilia B diagnosed?

First-line laboratory tests

Test

APTT(1) (activated cephalin time)

Mixing test (2)

PT (prothrombin time)

TT (thrombin time)

BT (bleeding time)

Results

increased

corrected

normal

normal

normal

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

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

Specialised tests

  • The clotting activity of factor IX 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 VIII, XI and XII).
  • Levels of Von Willebrand factor (ristocetin cofactor/antigen activity) are normal.

Differential diagnosis

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

Anti-factor IX antibodies

Acquired haemophilia B is associated with the presence in non-haemophiliac subjects of antibodies directed against factor IX. 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 IX 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 IX, against which they are immunised due to the development of antibodies directed against factor IX.

Vitamin K deficiency

Since the synthesis of factor IX is dependent upon vitamin K, levels of factor IX are low in the event of vitamin K deficiency or treatment with vitamin K antagonists.
In this event, the levels of other vitamin K-dependent coagulation factors (II, VII, X) are also low, as are proteins S and C.

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