Sample Abstract

Predictors of response to combination therapy with recombinant factor VIIa and factor VIII in patients with hemophilia A and high titer inhibitors

Introduction and Objectives: Although the use of bypassing agents has significantly improved the treatment of hemophilia A patients who develop inhibitors, some patients, for unknown reasons, have a poor hemostatic response to bypass therapy. Improved treatment options for patients with inhibitors are needed. Studies from our laboratory and others have shown that even small amount of factor VIII (fVIII) activity can vastly improve the thrombin generation (TG) capability of recombinant factor VIIa (fVIIa) in patients with hemophilia A and inhibitors. Materials and Methods: Plasma from patients with congenital hemophilia A and high titer inhibitors was available from our IRB approved inhibitor bank. Each plasma sample was evaluated for response to 2 U/ml fVIII (~100 U/kg dosing) with and without 2.25 mcg/ml rfVIIa in a thrombin generation assay. Residual fVIII activity at 15 minutes after addition of 2 U/ml fVIII was measured using a one-stage coagulation assay. Results: 15 different patients with inhibitor titers ranging from 5.2-109 BU/ml were tested. In the 10 patients with inhibitor titers of 5.2-28 BU/ml only 1 patient with a titer of 20 BU/ml did not respond to fVIII supplementation. In the 5 patients with inhibitor titers >42 BU/ml, there was no increase in TG. A second specimen was available for 4 patients. All 3 patients who had increased TG in the presence of fVIII continued to have increased TG in the second specimen despite up to a 2-fold difference in inhibitor titer. A subset of 10 patients also had residual fVIII activity testing. In this group residual fVIII activity strongly correlated with peak TG (r2 = 0.86, p>0.001) and also correlated with ETP (r2 = 0.54, p=0.04). Conclusions: The majority of patients with hemophilia A and high titer inhibitors have improved TG with combined use of fVIII and rfVIIa over rfVIIa alone. Residual fVIII activity at 15 minutes was a predictor of both peak thrombin generation and ETP. An inhibitor titer above 42 BU/ml was associated with no response.