Plasma exchange and immunosuppressive therapy in a case of mild haemophilia A with inhibitors and a life-threatening lower limb haemorrhage.

The development of inhibitors in severe haemophilia A is a well-known serious complication of exposure to factor VIII (FVIII) concentrates. It occurs in up to 30% of patients and makes bleeding episodes refractory to standard treatment. In mild haemophilia A treatment with FVIII concentrates is indicated after trauma and for surgery; this treatment, too, may be complicated by the occurrence of inhibitors, with the frequency of this complication being reported to be between 3% and 13%1–3. In such patients it represents a major challenge and changes the phenotype from mild to severe, so that the patients are at risk of spontaneous bleeding. Unlike in severe haemophilia A, only few risk factors have been recognised, such a positive family history of inhibitors, age at first exposure, age at peak treatment, some missense mutations in the factor VIII gene and intensive FVIII replacement treatment, often in the setting of surgery and continuous infusion delivery3–6. According to the main guidelines7–9, bleeding episodes in patients with haemophilia and inhibitors should be treated with bypassing agents prior to immune tolerance induction (ITI). The success of ITI is higher when its initiation is delayed until the inhibitor titre has fallen below 10 BU/mL. For patients with mild haemophilia A and inhibitors, a trial of bypassing therapy on demand should precede consideration of ITI. The choice of therapy depends on the inhibitor titre: large doses of FVIII can be sufficient to control major haemorrhage if the antibody titre is less than 5 BU/mL, while if it is higher FVIII overtreatment is unlikely to be effective without the removal of antibodies. In this case, recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrates (FEIBA) are recommended in the acute phase of bleeding; when one of these fails, the other product may be used. If both the bypassing agents cannot ensure control of bleeding, an alternative approach could be the use of concomitant antibody removal and high-dose FVIII, as historically proposed three decades ago by Nillson and colleagues10–11 and still considered effective12–14. A similar approach has also been used in the setting of acquired haemophilia A15,16. High-titre antibodies can be removed temporarily by extracorporeal adsorption of the antibody to protein A-sepharose or to polyclonal sheep antibodies in columns17–19. Therapeutic plasma exchange (TPE) still has a role in the treatment of coagulation factor inhibitors, as reported in international guidelines 13. ITI has been used in few patients with mild haemophilia A and the success rate in such patients seems lower than that in patients with severe haemophilia A3,14. The success of this approach is defined as the elimination of the inhibitors, the normalization of the half-life of infused FVIII and the absence of an anamnestic response. The eradication of inhibitors may be achieved with immune modulation using drugs such as steroids and cyclophosphamide10,11. We present the case of a patient with mild haemophilia A with high titre inhibitors and life-threatening bleeding unresponsive to bypassing agents. The critical situation required the use of both removal of the antibodies by TPE, overtreatment with plasma-derived FVIII concentrates and stabilisation of the clinical response with immunosuppressive therapy and early start of ITI.