Safety and efficacy of sequential combined bypass therapy of bleeds unresponsive to a single bypassing agent

Background: Replacement therapy is ineffective in high-responders and bypassing agents are required. Unfortunately, whatever by-passing agent is initially used, some bleeds (10%–20%) cannot be controlled. A synergistic effect of sequential combination of bypass therapy (SCBT) has been recently reported. The European Haemophilia Treatment Standardization Board conducted a survey of patients who underwent SCBT in Europe. Methods: A web-based database was prepared in order to collect data on each courses of SCBT in a anonymous manner. SCBT was defined as administration of recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within a 12-h period. Results: SCBT was used in two children (8 & 14 year-old) and 4 adults (mean age:34,range:24–45) with haemophilia A (six patients) and B (one patient) and high-responding inhibitors, unresponsive to APCC or rFVIIa. The children had joint bleeds refractory to high doses of rFVIIa (up to 270 µg/Kg/2 h) and/or to high doses of APCC (up to 80 U/Kg/8 h). Three adults had undergone major surgery (knee prosthesis removal, knee arthrodesis, laparotomy for kidney rupture), initially treated with rFVIIa 120–270 µg/Kg/2 h, followed by significant bleed. One of these patients was switched to APCC 80 U/Kg/8 h without success. The fourth adult was suffering from lower limb compartmental syndrome and had no response after five times 180 µg/Kg/3 h and twice FEIBA 75 U/Kg. SCBT in children and adults included alternating one APCC dose (range 50–80 U/Kg) to one or two rFVIIa doses (range 90–270 µg/Kg) every 3–12 h. Complete bleeding control was achieved within 24 h in all patients. SCT was discontinued after 2–15 days and patients underwent prophylaxis with FEIBA or rFVIIa. No clinical adverse event was observed, but a rise of D-dimer levels occurred in three of six patients, without platelet and/or fibrinogen consumption. Conclusion: SCBT can represent a valid salvage treatment of unresponsive bleeds. A larger cohort or a prospective clinical trial are needed to confirm these findings