Cross‐reacting inhibitors against recombinant porcine factor VIII in acquired hemophilia A: Data from the GTH‐AH 01/2010 Study

Abstract

Background: Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA).Inhibitors in AHA can sometimes cross-react with rpFVIII.Objectives: To assess the frequency, strength, and determinants of cross-reactivity.Patients/methods: Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA).Results: Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (<1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of >100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of <3.8 BU/mL predicted absent cross-reactivity with 90% likelihood. Conclusion:Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of >100 BU/mL.

International recommendations on the diagnosis and treatment of acquired hemophilia A

“…Cross-reacting anti-rpFVIII inhibitors were found in 44% of patients in a recent study. 49 A retrospective study used a lower starting dose of 100 U/kg in six of seven patients given rpFVIII as second-line therapy, with five of these six patients achieving FVIII:C >100% after infusion (one patient had unmeasurable FVIII:C). 50 Overall, treatment was effective in five of the seven patients.…”

Continuous infusion of recombinant porcine factor VIII for neurosurgical management of intracranial haemorrhage in a patient with severe haemophilia A with factor VIII inhibitor

“…In vitro cross-reactivity of the FVIII inhibitor to porcine FVIII has been well described for patients with congenital and acquired HA, [7][8][9][10] with higher levels of titre inhibitors having a higher degree of cross-reactivity; however, the clinical impact of this cross-reactivity has not been well studied. The de novo development or anamnestic rise in porcine inhibitor titre generally occurs after 8 exposure days.…”

The Art of Detecting Antibodies against Factor VIII

“…Antibodies against human FVIII usually react much less with rpFVIII. However, 44% of patients with acquired hemophilia show at least some degree of cross-reactivity, 19 and some patients will develop de novo cross-reactivity during treatment. 20 NBA:POR is a modified NBA using rpFVIII laboratory standard (provided by the manufacturer of susoctocog alfa) instead of SHP as a FVIII source.…”

“…20 NBA:POR is a modified NBA using rpFVIII laboratory standard (provided by the manufacturer of susoctocog alfa) instead of SHP as a FVIII source. 19 The rpFVIII substrate is usually supplied in high concentrations (e.g., 11 U/mL) and should be diluted in FVIII deficient plasma. FVIII:CBA is the preferred test for RA determination because chromogenic assays can underestimate the activity of rpFVIII.…”