IN-VIVO MODELS OF THROMBOGENIC POTENTIAL - USEFULNESS AND LIMITATIONS

The thrombogenicity of prothrombin complex concentrates (PCCs) has bee n known as a risk factor since their first clinical use about 30 years ago. The development of in vivo models to define the thrombogenic com ponents in PCCs was instrumental in providing a logical basis for sele cting in vitro assays to screen for the distribution of such component s during the manufacture of PCCs, and to minimize their appearance in the final product. Even so, these thrombogenic components are not comp letely removed, as shown in our canine nonstasis model of thrombogenic ity: PCCs were still found to elicit a thrombogenic response, shown by increased fibrinopeptide A, fibrin(ogen) degradation products, activa ted partial thromboplastin time, and decreased fibrinogen and platelet counts when clinically relevant doses were used. The new generation o f high-purity factor IX (HP-FIX) concentrates differs from PCCs becaus e these products contain only negligible amounts of clotting factors o ther than factor IX, lower amounts of activated clotting factors, and, in products we have assayed, no coagulant-active phospholipids. When we infused a number of HP-FIX products in the canine nonstasis model, no thrombogenic response was observed at doses considerably greater th an PCC doses that did elicit a response. Likewise, HP-FIX products wer e much less thrombogenic than PCCs when tested in small-animal stasis and nonstasis thrombogenicity models. Small-animal models are also use ful for evaluating the role of factor IXa as a potential thrombogenic contaminant of concentrates and ensuring minimal amounts in the final product. The Limitations associated with extrapolating in vivo model d ata will be shown to be minimal if ongoing clinical studies continue t o demonstrate the low thrombogenic potential of HP-FIX concentrates in humans.