Some
hemophilia A patients who have developed inhibitors are poorly responsive to activated
prothrombin complex concentrates (aPCC) after daily dosage, but the mechanism(s) underlying this remain unknown. We examined two representative cases. In case 1, we found that changing to
recombinant factor VIIa (
rFVIIa)
therapy was more effective, and the response to aPCC was restored within ~2 weeks.
Tissue factor (TF)-triggered
thrombin generation demonstrated a prolonged lag-time and decreased peak
thrombin, and this impairment was focused on TF pathway inhibitor (
TFPI). Plasma-free
TFPI was elevated post-infusion of aPCC, while this was unaffected by
rFVIIa.
TFPI returned to normal range within 2-3 weeks. Plasmas obtained from patients with poor or good response to aPCC (aPCC-poor or aPCC-good), and good response to
rFVIIa (FVIIa-good) demonstrated that free
TFPI levels are increased in both aPCC groups, but not in FVIIa-good.
TFPI levels pre- and post-infusion in aPCC-poor were significantly higher than those in aPCC-good. Addition of anti-
TFPI antibody to the reaction samples demonstrated a greater increase of peak
thrombin in aPCC-poor compared to aPCC-good, showing the higher
TFPI activity in aPCC-poor. Free
TFPI contained in aPCC corresponded to the increasing levels in plasma. In conclusion,
TFPI in aPCC attenuated
thrombin generation, and the reduced effectiveness of
therapy in these circumstances appeared to be related to
TFPI activity.