The recent development of a humanized, bi-specific, and monoclonal antibody mimicking
the function of activated factor VIII was a revolution in the management of patients
suffering from severe hemophilia A with inhibitors.[1] The phase III randomized studies have shown a more efficient prophylaxis of this
subcutaneous administered drug in these patients compared with recombinant FVIIa (rFVIIa)
and activated prothrombin complex concentrates (aPCC).[2]
[3] Nonetheless, there are “real life” matters that need to be explored in this new
era of managing hemophilia patients, such as surgery management under emicizumab,
especially in children.[4]
[5]
[6] Here, we report the first case, to our knowledge, of major orthopedic surgery managed
with factor VIII infusions in a child with inhibitor receiving emicizumab.
Our patient is a 9-year-old boy with severe hemophilia A. He presented an inhibitor
after the 10th exposed day with a factor VIII (FVIII) concentrate (historic peak:
412 BU/mL). Thereafter, he presented an important intracranial hemorrhage (subdural
and intraparenchymal hematomas). The first treatment with rFVIIa (Novoseven, 90 µg/kg/2
h) and tranexamic acid was inefficient. It was therefore switched with aPCC (FEIBA
80 IU/kg/8 h) that was rapidly effective. He also presented some knees and left hip
hemarthrosis responsible for arthropathies. Several attempts of immune tolerance induction
through Port-a-Cath failed whatever the FVIII concentrate used, recombinant FVIII
or plasma-derived FVIII. Because of an insufficient efficacy of rFVIIa for totally
stopping some bleeding events, a prophylaxis with aPCC was performed with daily infusion
of 80 IU/kg. Given the cumbersome nature of this treatment, emicizumab (Hemlibra)
was introduced instead of aPCC in December 2018. Emicizumab was started with 3 mg/kg/week
for 4 weeks and then adapted to 1.5 mg/kg/week. The boy had no more bleeding including
clinically evident hemarthrosis. However, the left hip arthropathy worsened with aggravation
of limping and pain leading to the use of a wheelchair. Hip X-ray showed an osteonecrosis
of the left femoral head requiring a femoral varization osteotomy that was planned
in June 2020. Because the inhibitor titer was low at 2 BU/mL, rFVIII-Fc (Elocta) was
administered to normalize the coagulation during the surgery. A rFVIII-Fc bolus with
6,000 IU (150 IU/kg) was initially administered, followed by a continuous infusion
12 IU/kg/h ([Fig. 1A]). The emicizumab treatment was continued (1.5 mg/kg/week).
Fig. 1 (A) Evolution of FVIII:C and haemoglobin levels. (B) Evolution of thrombin generation assays. Reference values were established in 32
healthy patients.
This complex surgery performed on rFVIII-Fc required a close monitoring with frequent
FVIII:C measures to adjust rFVIII-Fc administrations. All FVIII:C levels were measured
with a chromogenic method (STA-R Max3 analyzer ; TriniCHROM FVIII:C reagent – Stago)
by using bovine coagulation factors X and IXa that do not interfere with emicizumab.[7]
[8]
[9] In same plasma samples, thrombin generation assays (TGA) were performed by using
low concentration of tissue factor (1 pM) as suggested for the TGA in hemophilia A
patients.[10] TGA were performed before the surgery without rFVIII-Fc and throughout rFVIII-Fc
infusions ([Fig. 1B]).
The FVIII:C level measured 30 minutes after bolus was high at 242% and maintained
above 200% during the first 24 hours, following postsurgery without change of the
rFVIII-Fc infusion rate ([Fig. 1A]). The orthopedic surgery included a proximal femoral derotation osteotomy and then
fixed by osteosynthesis material ([Fig. 2]). No bleeding (or other complication) occurred during and after surgery with low
per-operatory blood loss (200 mL). His immediate postsurgery hemoglobin level was
11.8 g/dL. After the first postsurgery day, the FVIII:C levels progressively decreased
until 100% at H28. At the 78th hour, a 50 IU/kg rFVIII-Fc bolus was performed for
drains ablation. After a new peak, the FVIII:C level further decreased despite maintaining
the continuous infusion at the dose of 10 IU/kg/h because of the inhibitor resurgence
at H162 with a titer of 1.8 BU/mL which rose to 33 BU/mL at H200. TGA's parameters
evolved within normal ranges during first postsurgical 24 hours and then progressively
decreased together with FVIII:C levels ([Fig. 1B]). The 6th postsurgery day, rFVIII-Fc was replaced with rFVIIa boluses at 90 µg/kg
that were stopped after 1 day. During his stay, the patient did not bleed and therefore
did not require any red blood cell concentrate transfusion; the lowest hemoglobin
he presented was 7.9 g/dL and was only corrected with a single iron sucrose injection
(Venofer). Furthermore, no markers of coagulation activation were detected during
rFVIII-Fc and rFVIIa treatments. Always receiving a prophylaxis with emicizumab alone,
the patient was able to walk within 2 months after surgery and presented no bleeding.
Fig. 2 The arrow on the left shows the severe arthropathy of the left hip with a coxa plana
and an alteration of cartilageneous and osseous structures. The arrow on the right
shows the osteosynthesis material inserted after the varisation osteotomy of the femoral
neck.
To date, most of the surgery reports performed with emicizumab in cases with inhibitor,
concerned adults. rFVIIa was most used to prevent bleeding during and after surgical
procedures. In pediatrics, only minor procedures were described.[4]
[5]
[6]
[11]
[12]
[13] Our case is so, to our knowledge, the first description of a major orthopaedic surgery
managed with FVIII concentrates in a child with severe hemophilia A with inhibitor
while receiving a prophylaxis with emicizumab. The choice we made of using rFVIII-Fc
for bleeding prevention during and after the surgery was foremost driven by the presence
of a low titer inhibitor. Furthermore, we prohibited aPCC because of its thrombotic
risk in association with emicizumab.[14] Finally, rFVIIa was ruled out because it was often only partially effective for
this patient. We show here that, as for some adults reported to date, major surgeries
can be safely managed with FVIII concentrates in children with severe hemophilia A
with inhibitor while receiving emicizumab. This dual treatment could also be applicable
without an inhibitor at the doses usually administered.[15] In our patient, the FVIII:C chromogenic assay appeared to be a reliable tool for
peri-surgical monitoring in children despite concomitant treatment with emicizumab
as it was proposed.[8]
[9] TGA with low TF concentration performed in parallel to FVIII:C measures could be
helpful.[9] However, our results did not show a perfect correlation between TGA's parameters
and normalized FVIII levels. The TGA with these conditions is so not enough reliable
for the monitoring of emicizumab treatments and need further adjustments. Finally,
it was rapidly observed that maintaining the prophylaxis with emicizumab reduces the
duration of post-surgical treatment in major orthopaedic surgeries.[13] Indeed, for our patient, as already reported for adults receiving emicizumab, FVIII
or rFVIIa injections were only necessary until the 7th day postsurgery. Thereafter,
prevention with emicizumab alone was sufficient to protect against late bleeding during
rehabilitation.
