Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Thromb Res. 2010 May;125(5):432-7. doi: 10.1016/j.thromres.2009.11.018. Epub 2009 Dec 11.
Warfarin is routinely used in the prevention and treatment of prothrombotic events. During initiation of warfarin therapy levels of factor (F) VII and protein C decrease rapidly but prothrombin, FIX and FX decline much slower. Therefore, propagation of thrombin generation (TG) remains unaffected much longer, increasing the risk of inadequate anticoagulation. Recently, a novel agent, anti-IXa aptamer, RB006, has been developed. Therefore, we have evaluated the in vitro effects of this agent in warfarin plasma.
The investigation consisted of two parts. First, a computer simulated time course of TG with warfarin alone and in combination with FIXa inhibition was evaluated and, second, normal volunteer, protein C deficient, FVII deficient and commercial warfarin plasmas (INR 2.1 and 3.1) were spiked with increasing concentrations of aptamer (0-24 microg/ml) and its anticoagulant effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT) and TG with tissue factor and Actin as activators. Direct effects of aptamer on protein C were also evaluated.
Simulation of coagulation during warfarin induction showed that TG can be significantly delayed and decreased by inhibiting FIXa (i.e., with anti-FIXa aptamer). The anti-FIXa aptamer inhibited TG in all tested plasmas, but was most efficacious in warfarin and FVII deficient plasma. The aptamer itself did not inhibit protein C and had no effect on PT, but concentration-dependently increased aPTT.
The anti-FIXa aptamer potentiates the inhibitory effects of warfarin on TG, and may fill the need as an adjuvant agent during initiation of warfarin therapy.
华法林通常用于预防和治疗血栓前事件。在华法林治疗开始时，因子（F）VII 和蛋白 C 水平迅速下降，但凝血酶原、FIX 和 FX 下降速度要慢得多。因此，凝血酶生成（TG）的传播在更长时间内仍然不受影响，增加了抗凝不足的风险。最近，一种新型药物，抗 IXa 适体，RB006，已经被开发出来。因此，我们评估了这种药物在华法林血浆中的体外作用。
该研究包括两部分。首先，评估了单独使用华法林和联合使用 FIXa 抑制对华法林诱导的 TG 时间过程的计算机模拟，其次，在正常志愿者、蛋白 C 缺乏、FVII 缺乏和商业华法林血浆（INR 2.1 和 3.1）中加入递增浓度的适体（0-24 微克/毫升），并使用凝血酶原时间（PT）、活化部分凝血活酶时间（aPTT）和组织因子和 Actin 作为激活剂评估其抗凝效果。还评估了适体对蛋白 C 的直接作用。
华法林诱导过程中凝血的模拟表明，通过抑制 FIXa（即使用抗-FIXa 适体），TG 可以显著延迟和减少。抗-FIXa 适体抑制了所有测试血浆中的 TG，但在华法林和 FVII 缺乏的血浆中效果最为显著。适体本身不抑制蛋白 C，对 PT 没有影响，但浓度依赖性地增加 aPTT。
抗-FIXa 适体增强了华法林对 TG 的抑制作用，可能作为华法林治疗起始时的辅助药物填补了这一需求。
