Patients with severe congenital hemophilia A (CHA) have a 25-40% lifetime risk of alloantibody (inhibitor) development to FVIII. Patients with acquired hemophilia A (AHA) spontaneously develop neutralizing autoantibodies to factor VIII. In both cases, patients require pro-hemostatic therapy with bypassing agents: recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC) and more recently recombinant porcine factor VIII (rpFVIII).
Anti-human FVIII (hFVIII) inhibitors typically bind to the A2 and C2 domains of the FVIII molecule. RpFVIII is an effective pro-hemostatic treatment for AHA and CHA given the immunologic difference in the A2 and C2 domains of the rpFVIII while maintaining sufficient hFVIII homology to act as an effective cofactor to human FIX in the intrinsic tenase.
However, some anti-hFVIII antibodies cross-react with rpFVIII and may interfere with its hemostatic function. Cross-reacting antibodies were reported in 35% of subjects in a phase II/III trial prior to initiation of rpFVIII. Moreover, de novo rpFVIII inhibitors may develop during or after the treatment with rpFVIII and may affect its hemostatic function.
Here we describe the largest case series to date on baseline cross-reactivity of rpFVIII inhibitors and post-treatment de novo inhibitor development in patients with CHA and AHA to address the paucity of published literature in this area.
First, we describe the frequency of baseline cross-reacting rpFVIII inhibitors in patients with AHA and CHA (with inhibitors) at our institution. Second, we describe the effect of baseline rpFVIII antibodies on FVIII recovery after treatment with rpFVIII. We also describe the frequency and timing of de novo rpFVIII inhibitor development after exposure to rpFVIII.
Institutional research ethics board approval was obtained.
Electronic charts of patients admitted to our institution with AHA or CHA who underwent testing for rpFVIII inhibitors were reviewed retrospectively.
RpFVIII inhibitor assay is performed in the special coagulation laboratory using the Nijmegen modified Bethesda assay. The patient sample is initially heat-treated at 57
Twenty-seven patients (7 CHA, 20 AHA) underwent testing for porcine inhibitors since assay availability in 2016. 61% (5/7 CHA, 11/20 AHA) of patients had a detectable rpFVIII inhibitor prior to exposure to rpFVIII; median titer 1.6 BU/ml (range 0.6-192).
Eight patients with AHA with baseline cross-reacting inhibitors received rpFVIII. Of those, three achieved an initial FVIII recovery beyond 100% (132%, 148% and 177%) after approximately 100U/kg of rpFVIII and all three had very low anti-rpFVIII Bethesda titers (0.70, 0.85 and 0.9 BU/ml). Five patients did not achieve a FVIII recovery above 50% (46%, 46%, 40%, 36% and 0%) despite approximately 100U/kg of rpFVIII.
Most patients who received rpFVIII were tested weekly for the duration of their treatment or hospital stay. Upon discharge, patients who were seen in clinic for follow up were tested for anti-hFVIII and anti-rpFVIII.
Two AHA patients without a baseline inhibitor who received rpFVIII treatment developed a de novo inhibitor after 20 days (1 BU/ml) and 133 days (12 BU/ml), respectively. One AHA patient had a rise in baseline anti-rpFVIII titer after exposure to rpFVIII.
In conclusion, we found that 61% of patients with AHA and CHA tested for rpFVIII inhibitors had a detectable baseline cross-reacting inhibitor which is higher than previously described. Of those patients with a baseline inhibitor treated with rpFVIII, only 37.5% of patients had an appropriate rise in FVIII. Finally, 13% of patients without baseline inhibitors developed a de novo inhibitor after exposure to rpFVIII, an incidence comparable to previously published findings.
Pavenski:Bioverativ: Research Funding; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria; Ablynx: Honoraria, Research Funding. Teitel:BioMarin: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Sholzberg:Takeda: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding.
Recombinant porcine factor VIII is used to treated patients with congenital hemophilia A with allo inhibitors
Asterisk with author names denotes non-ASH members.