Autoantibodies affecting the activity or accelerating the clearance of clotting factors (acquired inhibitors) can develop in patients with autoimmune or malignant disorders, but also in subjects without apparent underlying conditions. Such inhibitors are most frequently directed against factor VIII (FVIII) or von Willebrand factor (VWF), giving rise to acquired haemophilia A (AHA) or acquired von Willebrand’s syndrome (AVWS), respectively1,2. Rarely autoantibody inhibitors can impair the activity of other clotting factors. Indeed, there are descriptions of acquired inhibitors of fibrinogen (FI), factors II (FII), V (FV), VII (FVII), IX (FIX), X (FX), XI (FXI), XII (FXII) and XIII (FXIII), either in children or in adults, with or without associated disorders3. Similarly to alloantibodies that occur following replacement therapy in patients with congenital bleeding disorders, acquired inhibitors are type IgG4 polyclonal immunoglobulins (rarely IgM or IgA) targeting several functional epitopes of the clotting factors4–6. Their kinetics of inactivation are usually complex (second order or exponential) with rapid initial inactivation, followed by a slower phase or a period of equilibrium in which the factor activity can still be measured7. More rarely, these immunoglobulins show first order kinetics, i.e. linear, since the amount of factor inactivated is directly proportional to the concentration of the antibody or to the duration of the incubation. Patients can have a sudden onset of bleeding and, not infrequently, firstly are admitted to hospital wards where clinicians are not experts in the management of coagulation disorders. Rarely, patients do not have bleeding symptoms initially and the diagnosis may be delayed. The severity of the initial bleeding does not predict the severity of subsequent haemorrhagic manifestations8. As a consequence, patients with acquired inhibitors to one of the key haemostatic factors are at a high risk of unpredictable severe, sometimes fatal, bleeding, particularly if a definitive diagnosis has still not been made. On rare occasions acquired inhibitors can develop during the puerperium9–12 or in patients on anticoagulant or anti-platelet treatment13–16. In such cases, it is possible that the bleeding is attributed to obstetric or pharmacological reasons. These features do, therefore, make it difficult to recognise the disease and reach the correct diagnosis. Ideally patients with a deficiency of any clotting factor should be managed in specialised centres for the treatment of haemophilia and inherited bleeding disorders. Indeed, this is recommended by the World Federation of Hemophilia (WFH), numerous experts and national and international guidelines17–22. In Italy, patients with acquired inhibitors are mainly managed in Haemophilia Centres (52 centres distributed throughout the country), whose activities are coordinated by the Italian Association of Haemophilia Centres (AICE, Associazione Italiana Centri Emofilia). This association promotes an uniform approach to the treatment of patients with congenital bleeding disorders and acquired bleeding syndromes due to autoantibodies. In the 10 years since the publication of the preceding AICE guidelines on the diagnosis and treatment of patients with haemophilia and inhibitors21, a considerable amount of new information has been published which can be useful for guiding therapeutic choices in patients with AHA, even if no data from prospective, controlled clinical trials are available yet. In contrast, the rarity of inhibitors against other clotting factors strongly influences the possibility of establishing homogeneous treatment practices, based on clearcut evidence. The treatment strategies for patients with such inhibitors are, therefore, largely derived from those adopted for patients with AHA. For this reason it is even more important that the therapeutic approach to these very rare haemostatic disorders is as homogeneous as possible, shared among clinicians, and based on available published information, although limited. AICE, therefore, considered it appropriate to revise the previous recommendations on the management of AHA and the general principles of the diagnosis and treatment of inhibitors against other clotting factors. To this end, a specifically convened working group conducted a review of the literature with the primary objective of determining the quality of the evidence available. PubMed was searched using the following keywords: inhibitor, autoantibodies, acquired, h(a)emophilia, von Willebrand disease, factor VIII, IX, II, V, VII, X, XI, XII, XIII, von Willebrand factor, bleeding, management, treatment, factor concentrate, desmopressin, rFVIIa, APCC, immunosuppression, steroid, cyclophosphamide, cyclosporin, immunoglobulins, rituximab, immunoadsorption, immune tolerance induction. The GRADE system was used to define the levels of evidence and the strength of the recommendations derived from the evidence available23. The treatment principles and recommendations were collected in a provisional version of this document and submitted to the consideration of AICE members and, finally, approved during the AICE General Assembly on November 3rd, 2014.
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Jul 1, 2016
M Shima + 2
Open Access
