Management of bleeding in acquired haemophilia A with recombinant activated factor VII: does one size fit all? A report of four cases.

Abstract

Acquired haemophilia A (AHA) is a rare but clinically relevant bleeding disorder due to autoantibodies (inhibitors) against coagulation factor VIII (FVIII)1–3. AHA is usually triggered by infections, malignancies, autoimmune diseases, or pregnancy. Some cases associated with drug intake have also been described, but about half of cases remain unexplained and are classified as “idiopathic”. According to a 2-year prospective surveillance study from the UK, the incidence is approximately 1.5 cases per million persons per year1; the condition is most frequent in the elderly and the reported median age of affected individuals is above 70 years1,4,5. This acquired bleeding disorder should be suspected in subjects without a personal or family history of bleeding who have unexplained haemorrhages, prolonged activated partial thromboplastin time (APTT) and a normal prothrombin time. A mixing test which does not correct the APTT, in the absence of lupus anticoagulant and heparin administration, together with low FVIII levels and circulating FVIII inhibitor, confirm the diagnosis3. In the majority of cases bleeding is spontaneous and can range from mild to life-threatening1,3–5. Bleeding sites in patients with AHA differ from those associated with congenital haemophilia, traumatic muscle bleeds and haemarthroses being uncommon. Indeed, most events are spontaneous subcutaneous, deep muscle and retroperitoneal bleeds, although mucosal (gastrointestinal, lung, urogenital) and intracranial bleeds also occur. Bleeding is the main cause of death in the early phase of AHA and its severity does not correlate strictly with FVIII levels or inhibitor titre. The management of AHA is directed at controlling the bleeding, eradicating inhibitors in order to prevent subsequent haemorrhagic complications, and treating any underlying associated disease2,3. Early treatment of bleeds is recommended. Available haemostatic agents do not have predictable efficacy; therefore, clinical review by physicians experienced in the management of inhibitors, supported by appropriate imaging and laboratory studies, is important6–8. Among the different approaches to control haemorrhages in AHA patients, the use of desmopressin and antifibrinolytics is mostly anecdotal and reserved only for minor bleeding. In selected cases FVIII concentrates, either recombinant or plasma-derived, could be appropriate9. According to international recommendations, bypassing agents, i.e. recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), are considered the first-line approach for the treatment of bleeding episodes6,7. The dosages and regimens of rFVIIa (Novoseven®) that have been reportedly used in AHA are widely heterogeneous3,10–13, but current recommendations suggest bolus administrations of 90 μg/kg every 2–3 hours, until haemostasis is achieved6–7, similar to the treatment in patients with congenital haemophilia and inhibitors. The largest available collection of treatment records, the European Acquired Haemophilia (EACH2) registry, showed consistent concordance among physicians (rFVIIa dosage range 84.7–102.9 μg/kg every 2–6 hours)13. Unfortunately, due to the rarity of AHA, no methodologically rigorous study has been conducted to determine the most effective and safest dosage in this setting. Bypassing agents are generally well tolerated in AHA patients, although severe thrombotic complications may occur, such as myocardial infarction, disseminated intravascular coagulation, arterial and venous thrombosis, pulmonary embolism and stroke11,13. Although a causal relationship between bypassing agents and such thrombotic complications cannot be established in most cases, caution is required, in particular taking into account that the elderly age and frequent comorbidities of patients treated with these agents increase the risk of thromboembolism3,9,14. Here we describe four patients with AHA whose bleeds were treated with lower dosages and/or longer intervals of bolus administrations of rFVIIa than those recommended. These regimens were chosen because of the high risk of thrombotic complications, given the patients’ risk profile, concomitant with the need to treat severe, even life-threatening, haemorrhagic events.