MacGregor I, McLaughlin L, Drummond O, Prowse C, Ferguson J
National Science Laboratory, Scottish National Blood Transfusion Service, Edinburgh, Midlothian, UK.
Acta Haematol. 1995;94 Suppl 1:18-23; discussion 24. doi: 10.1159/000204039.
The thrombogenicity of prothrombin complex concentrates (PCCs) has been known as a risk factor since their first clinical use about 30 years ago. The development of in vivo models to define the thrombogenic components in PCCs was instrumental in providing a logical basis for selecting in vitro assays to screen for the distribution of such components during the manufacture of PCCs, and to minimize their appearance in the final product. Even so, these thrombogenic components are not completely removed, as shown in our canine nonstasis model of thrombogenicity: PCCs were still found to elicit a thrombogenic response, shown by increased fibrinopeptide A, fibrin(ogen) degradation products, activated partial thromboplastin time, and decreased fibrinogen and platelet counts when clinically relevant doses were used. The new generation of high-purity factor IX (HP-FIX) concentrates differs from PCCs because these products contain only negligible amounts of clotting factors other 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 than PCC doses that did elicit a response. Likewise, HP-FIX products were much less thrombogenic than PCCs when tested in small-animal stasis and nonstasis thrombogenicity models. Small-animal models are also useful 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 data will be shown to be minimal if ongoing clinical studies continue to demonstrate the low thrombogenic potential of HP-FIX concentrates in humans.
自大约30年前凝血酶原复合物浓缩剂（PCCs）首次临床应用以来，其血栓形成性就一直被视为一个风险因素。体内模型的开发用于确定PCCs中的血栓形成成分，这有助于为选择体外检测方法提供逻辑依据，以筛查PCCs生产过程中此类成分的分布情况，并尽量减少其在最终产品中的出现。即便如此，这些血栓形成成分并未被完全去除，正如我们犬类非血流停滞血栓形成模型所显示的那样：当使用临床相关剂量时，仍发现PCCs会引发血栓形成反应，表现为纤维蛋白肽A增加、纤维蛋白（原）降解产物增加、活化部分凝血活酶时间延长，以及纤维蛋白原和血小板计数减少。新一代高纯度凝血因子IX（HP-FIX）浓缩剂与PCCs不同，因为这些产品除凝血因子IX外，其他凝血因子的含量可忽略不计，活化凝血因子的含量较低，而且在我们检测的产品中，不含具有凝血活性的磷脂。当我们在犬类非血流停滞模型中输注多种HP-FIX产品时，在剂量远高于能引发反应的PCC剂量时，未观察到血栓形成反应。同样，在小动物血流停滞和非血流停滞血栓形成模型中进行测试时，HP-FIX产品的血栓形成性比PCCs低得多。小动物模型也有助于评估凝血因子IXa作为浓缩剂潜在血栓形成污染物的作用，并确保最终产品中的含量降至最低。如果正在进行的临床研究继续证明HP-FIX浓缩剂在人体内的血栓形成潜力较低，那么与推断体内模型数据相关的局限性将被证明是极小的。
