Discussion
TGA on patient’s PRP[17] can evaluate patient coagulation status at different times of emicizumab treatment. TGA was performed every week, during treatment initiation phase, prior to administration of emicizumab weekly loading doses, ETP and Peak increased over time during the first month. ETP and Peak vary at basal, in our two cases it appears that there is a slight variability of TG at baseline from 6 to 25%. Correction with emicizumab seemed to depend on basal level of TG for each patient. During stabilisation phase, ETP and Peak levels seemed to vary depending on delay between emicizumab injection and sample collection, suggesting that ETP and Peak levels during stabilisation phase are not constant. TG induced by emicizumab might be correlated with its pharmacokinetics (bioavailability after absorption, distribution and elimination). It has been described that emicizumab mean absorption half-life is 1.6 +/- 1 day and elimination half-life is 28 days[18], suggested that increase of TG might be fast after emicizumab injection and decrease over a week. It could be interesting to correlate blood levels of emicizumab[19] and TG, as an additional factor to explain TG variability.
TG under emicizumab stay below normal. BPA was added for surgery[20]. In vitro spiking was only performed with Novoseven® [21]. For case n°1, according to our spiking results, 120 µg/kg of Novoseven® should have been used the day of surgery (ETP and Peak were closer to normal). TG capacity on the day of surgery was 79% of normal without BPA and 90% after BPA. Minimum level of TG to achieve an effective haemostasis is unknown. Another case report suggests that low TG capacity at 69% of normal on surgery’day and low TG capacity at 25% of normal few days after surgery might be sufficient for efficient haemostasis[22]. Low doses of BPA were sufficient here for safe surgery[23].
For case n°2, on surgery’day TG capacity was 100% of normal without BPA and 108% after BPA. It suggested that BPA dose should be selected and adjusted according to basal TG values at T0 when BPA is necessary. BPA doses were lower compared to other studies[21],[24].
Use of BPA for patients under emicizumab depend on surgery type. In HAVEN 1-4 studies, 214 minor surgeries were performed, minor surgeries were mostly dental (n=63) and central venous access device procedures (n=34). All patients with haemophilia A with inhibitors had rFVIIa prophylaxy for surgeries[25].
In conclusion, TGA in patients with severe haemophilia A under emicizumab could evaluate patient coagulation state, even if TG is not perfectly stable over time. Interferences between emicizumab and rFVIIa are not all known and TG interpretation is difficult when performed together. Ex vivo TG results on patients PRP with emicizumab and Novoseven® might be useful to manage treatment during surgeries. In vitro spiking might be performed with the same delay after emicizumab than the day of surgery to better reflect the in vivo.
For future, we could dose emicizumab in blood to interpret TG. It could be interesting to determine minimal ETP and Peak necessary for safe surgery.