Sequential combined bypassing therapy : a rescue option in refractory bleeds – the Italian experience

Background: Replacement therapy is ineffective in patients with high titre inhibitor and bypassing agents are required to induce clot formation. Unfortunately, whatever by-passing agent is initially used, some bleed (10-20%) cannot be controlled. A synergistic effect of sequential administration of two agents has been recently reported in patients who failed to respond to a single agent. Methods: Sequentially combined bypassing therapy (SCT) was used in 2 children (8 and 14 year-old) and 2 adults (40 and 45 year-old) with haemophilia A and high-responding inhibitors, unresponsive to the single treatment with APCC and rFVIIa. Results: The children were suffering from joint bleeds refractory to high doses of NovoSeven (up to 270 lg Kg-1every 2 h) and to high doses of FEIBA (up to 80 U Kg-1every 8 h). The adults had undergone major orthopaedic surgery (removal of knee prosthesis, knee arthrodesis), initially treated with NovoSeven up to 270 lg Kg-1every 2 h, with only an initial control (first 12-24 h), followed by significant bleed. One of these patients was switched to FEIBA 80 U Kg-1every 8 h without success. SCT was administered alternating one FEIBA dose (range 60-80 U Kg-18-12 h-1) to one NovoSeven dose (range 90-270 lg Kg-18-12 h-1). Complete bleeding control was achieved in 24-48 h. SCT was discontinued and patients underwent prophylaxis with FEIBA. No clinical adverse event was observed, but a rise of D-dimer levels occurred. Conclusions: SCT can represent a valid rescue treatment of refractory bleeds. An international survey on combined by-passing therapy has recently started (www.intersectsurvey.org)