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.