Sequential Combined Bypassing Therapy (SCBT) Is Safe and Effective in the Treatment of Unresponsive Bleeding in Adults and Children with Haemophilia and Inhibitors.
Authors: Gringeri Alessandro , Fischer Kathelijn , Karafoulidou Anastasia , Klamroth Robert , Lopez Maria Fernanda , Mancuso Maria Elisa 
Published: October 2019

Abstract
Abstract 1294
Poster Board I-316

Background
Unfortunately, whatever is initially used, 10-20% bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled by bypassing agents. Sequential combined by-passing therapy (SCBT), the sequential alternate administration of recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) was reported to have a synergistic effect on thrombin generation and to be successful in 5 children with haemophilia and inhibitors with bleeds unresponsive to replacement and by-passing therapy with a single agent (Schneiderman et al, Haemophilia 2007;13:244-8). No information was available on safety and efficacy of SCBT in adult patients or for post-surgical bleeding. We report a survey promoted by the European Haemophilia Treatment Standardisation Board (EHTSB) on 11 SCBT courses in children and adults.

Methods
A web-based database was prepared in order to collect retrospective data on SCBT courses in a standardised and anonymous manner from patients' files. SCBT was defined as the administration of rFVIIa and APCC within 12 hours from each other.

Results
Eleven patients with high titre inhibitors underwent SCBT: 9 with haemophilia A and 2 with haemophilia B. Four were children aged 9-14 years (mean age: 10 years), and 7 were adults aged 24-45 years (mean age: 34 years). Two of the 4 children were suffering from knee joint bleeds refractory to high doses of rFVIIa (up to 270 μg/Kg/2 hours) and to high doses of APCC (up to 80 U/Kg /8 hours); another child had a calf bleed refractory to rFVIIa (270 mcg/kg /6 hours). The remaining child had a post-surgical bleed after an arthroscopic synovectomy treated for 3 days with rFVIIa 125 mcg/Kg every 2 hours. Five adults had undergone major surgery (removal of knee prosthesis, knee arthrodesis, total knee joint replacement, laparoscopic cholecystectomy and laparotomy for kidney rupture), initially treated with rFVIIa from 90 up to 270 mcg/Kg every 2 hours, and followed by significant bleed. One of these patients was switched to APCC 80 U/Kg every8 hours without success. An adult had a lower limb compartmental syndrome unresponsive to rFVIIa 180 mcg/Kg every 3 hours for 5 times and to FEIBA 75 U/Kg every 8 hours. Another adult had a post-traumatic muscle and joint bleed in the upper limb getting worse after 4 administrations of 200 mcg/Kg every 4 hours. SCT was administered in children and adults alternating one APCC dose to one to 3 rFVIIa doses: the intervals between an APCC dose and an rFVIIa dose ranged from 3 to 6 hours. APCC dosing ranged from 20 to 80 U/Kg every 8 to 12 hours. rFVIIa dosing ranged from 80 to 270 μg/Kg every 3 to 12 hours. Major bleeding control was achieved in 12-24 hours of SCBT in all patients. SCBT was discontinued after 1 to 15 days and patients underwent prophylaxis with FEIBA or rFVIIa for 2 to 28 days. No clinical adverse event was observed, but a rise of D-dimer levels occurred in 3 of 5 tested patients, without consumption of platelet and/or fibrinogen.

Conclusions
This survey reports 11 SCBT courses in 7 adults and 4 children to treat unresponsive bleeds after 6 major surgical procedures, 3 joint bleeds and 2 muscle bleeds. SCBT was efficacious without clinical adverse events; nevertheless it remains a salvage treatment for its potential risks. These data represent a sound background in order to plan a prospective clinical trial that is needed to confirm these findings and provide more solid evidence.

Disclosures
No relevant conflicts of interest to declare.