Factor IX concentrate therapy and thrombosis: relation to changes in plasma antithrombin III

Commercial factor IX (fIX) concentrate therapy has been associated with thrombogenic complications, the cause of which is uncertain. We have previously reported that infusion of these fIX concentrates led to a decrease in antithrombin III (ATIII) functional activity, but not antigen, from pre-infusion levels. The patient plasmas also showed a cathodal shift in ATIII antigen by crossed immunoelectrophoresis (CIEP). We chose to characterize these ATIII changes more extensively in additional patients, by functional assays, radial immunodiffusion (RID), and CIEP. The effects of commercial fIX concentrate therapy on plasma ATIII levels appear to be dose-related, with most pronounced effects at 100 U/Kg; the effects are also cumulative, with a persistence of ATIII changes 24 hours after infusion in patients on daily therapy. We also studied pre- and post-infusion ATIII levels in patients who received 100 U/Kg of a more purified fIX concentrate (American Red Cross), which contains little or no activated clotting factors and has been shown to be non-thrombogenic in animal models. These patients showed no change post-infusion in ATIII levels by clotting, amidolytic, or RID assays, nor any significant change by CIEP. These data suggest that the ATIII changes that occur predictably after commercial fIX concentrate therapy are caused by a contaminating protein or proteins other than fIX and that the ATIII changes observed are related to the thrombotic complications of these commercial concentrates.