Acquired haemophilia A

Close collaboration between clinicians, laboratory staff and a haemophilia centre experienced in the management of inhibitors is necessary to diagnose and monitor patients with acquired haemophilia A (AHA). Initial investigation in any patient with unexplained bleeding symptoms should include a full blood count to assess platelet number and a coagulation screen, including activated partial thromboplastin time (aPTT) and prothrombin time (PT).^1-3

Any acute or recent bleeding symptoms in a patient with no previous history of a bleeding disorder and an unexplained, isolated prolonged aPTT and a normal PT are suggestive of AHA and should prompt further investigation to achieve a differential diagnosis. Irrespective of the presence or absence of bleeding symptoms, an isolated prolonged aPTT outside the normal range should be investigated further. If a patient exhibits bleeding symptoms suggestive of AHA, further investigation is prudent even if the aPTT appears to be normal.

Algorithm for the laboratory diagnosis of suspected acquired haemophilia A.^1,3

Mixing tests

Mixing tests can be used to distinguish between factor deficiencies and the presence of an inhibitor. A prolonged aPTT after 1–2 h using a mixture of normal and patient plasma is indicative of autoantibodies, however factor activity assays (FVIII, IX, XI, XII) should be performed in parallel.^1-3

Factor activity assays

An isolated low FVIII activity level is suggestive of AHA. A decreased level of all intrinsic pathway coagulation factors may represent an artefact caused by depletion of FVIII in the substrate plasma by the inhibitor or the presence of a lupus anticoagulant due to phospholipid inhibition in the assay, therefore specific lupus anticoagulant tests should also be performed.

Inhibitor titre quantification (Bethesda) assay

The Nijmegen-modified Bethesda assay can be used to quantify the titre of alloantibodies, which exhibit type 1 kinetics, however use of the Bethesda assay to quantify the complex, non-linear type 2 kinetics associated with autoantibodies may inaccurately represent the potency.^4,5 Autoantibody titre and residual FVIII activity levels correlate poorly with clinical severity and bleeding risk, therefore treatment decisions should not be solely based on these laboratory values.^1,2,6

Lupus anticoagulant tests

Lupus anticoagulant may also be associated with a prolonged aPTT, a positive Bethesda assay and low intrinsic factor levels, therefore specific tests may need to be undertaken to distinguish between lupus anticoagulant and acquired FVIII inhibitors.⁵ Autoantibodies to FVIII and lupus anticoagulant may be present in the same patient sample, therefore a FVIII-antibody-specific enzyme-linked immunosorbent assay (ELISA) or an aPTT reagent insensitive to lupus anticoagulant may be useful to distinguish between the two.²

1. Collins P, Baudo F, Huth-Kuhne A, et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes 2010;3:161.

2. Huth-Kuhne A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009;94:566-75.

3. Franchini M, Castaman G, Coppola A, et al. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management. Blood Transfus 2015;13:498-513.

4. Kasper CK, Aledort L, Aronson D, et al. Proceedings: A more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 1975;34:612.

5. Verbruggen B, van Heerde WL, Laros-van Gorkom BA. Improvements in factor VIII inhibitor detection: From Bethesda to Nijmegen. Semin Thromb Hemost 2009;35:752-9.

6. Baudo F, Collins P, Huth-Kühne A, et al. Management of bleeding in acquired hemophilia A: Results from the European Acquired Haemophilia (EACH2) registry. Blood 2012;120:39-46.