Recombinant porcine factor VIII (rpFVIII) demonstrated a dose-dependent correction of thrombin generation and clot formation in blood samples from patients with congenital hemophilia A and FVIII inhibitors, according to a study in Research and Practice in Thrombosis and Haemostasis.
Porcine FVIII has been used in patients with hemophilia A and human FVIII inhibitors and was shown to be similar enough to achieve hemostatic functions of the human protein. Comparatively, porcine FVIII derived from pig plasma carries a risk of allergic reactions and thrombocytopenia.
rpFVIII is a recombinant B-domain deleted, 1,448-amino acid heterodimer with a molecular mass of 170 kDa, composed of 90-kDa heavy chain and 80-kDa light chain. rpFVIII is approved for the treatment of acquired hemophilia A but not for congenital hemophilia A.
In this study, Claude Negrier, MD, PhD, of Hôpital Louis Pradel and Université Claude Bernard Lyon 1 in France, and colleagues evaluated in vitro thrombin generation and clot formation responses to rpFVIII in blood from 20 patients with congenital hemophilia A. The study was conducted at three clinical sites in three countries.
Included patients were ages 11 to 70 years, and FVIII activity was <0.01 IU/mL. Two patients provided a second sample at a later visit, leaving the researchers with 22 blood samples. There was variation in human FVIII and porcine FVIII inhibitor titers across the samples. The mean FVIII inhibitor titer was 14 BU/mL for human FVIII inhibitors and 12 BU/mL for porcine FVIII inhibitors.
Twenty samples were analyzed using calibrated automated thrombography (CAT) to assess thrombin generation. Thrombin generation was restored with rpFVIII in 65% of samples. In the majority of these samples, restoration was achieved with the lowest rpFVIII concentration (2.7 U/mL).
CAT analysis data showed correction of thrombin generation was rpFVIII-dose-dependent and porcine FVIII-inhibitor-titer dependent. Correction of thrombin generation with rpFVIII occurred in all patients with
- low human FVIII inhibitors and low porcine FVIII inhibitor titers and
- all samples with high human FVIII inhibitors and low porcine FVIII inhibitor titers.
According to the researchers, these observations were supported by statistical testing that showed an inverse correlation between porcine FVIII inhibitor titer and thrombin generation response to rpFVIII and measured by endogenous thrombin potential and peak height (2.7-10.8 U/mL rpFVIII Spearman correlation coefficient: -0.594 to -0.773; p<0.01).
“This effect and the low thrombotic risk profile associated with rpFVIII could be important considerations when evaluating treatment options for the management of individual patients with inhibitors to FVIII, in particular those for whom the use of bypassing agents is unsuitable or ineffective,” the researchers wrote.
In contrast, in samples with high porcine FVIII titers, no restoration of thrombin generation occurred with rpFVIII.
The analyses also showed that clot structures in low anti-porcine inhibitor titer plasmas were similar to those in non-inhibitor plasma.
Dr. Negrier and colleagues discussed several limitations of the study, including the in vitro setting and small number of subject samples.
“Although it was shown that rpFVIII corrected thrombin generation parameters when added to human hemophilic plasma containing FVIII inhibitors, these are surrogate markers that may not directly reflect clinical hemostatic efficacy,” the researchers acknowledged.
Finally, the study was not able to capture consecutive patients as originally planned, which may bias the results with participants motivated to participate in research.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Negrier C, Oldenburg J, Kenet G, et al. Recombinant porcine factor VIII corrects thrombin generation in vitro in plasma from patients with congenital hemophilia A and inhibitors [published online ahead of print, 2022 June 19]. Res Pract Thromb Haemost. doi: 10.1002/rth2.12731.
