PDF(Pubmed)
Abstract：
Preclinical evaluation of drugs in animals helps researchers to select potentially informative clinical laboratory markers for human trials. To assess the utility of animal thrombin generation (TG) assay, we studied the sensitivity of animal plasmas to triggers of TG, human Tissue Factor (TF), and Activated Factor XI (FXIa). Pooled human, mouse, rat, guinea pig, rabbit, bovine, sheep, and goat plasmas were used in this study. TF- or FXIa-triggered TG and clotting were measured via fluorescence and optical density, respectively. Thrombin peak height (TPH) and time (TPT), clot time (CT), and fibrin clot density (FCD) were all analyzed. The trigger low and high sensitivity borders (LSB and HSB) for each assay parameter were defined as TF and FXIa concentrations, providing 20 and 80% of the maximal parameter value, unless the baseline (no trigger) value exceeded 20% of the maximal, in which case, LSB was derived from 120% of baseline value. Normal human samples demonstrated lower TPH HSB than most of the animal samples for both TF and FXIa. Animal samples, except mice, demonstrated lower TPT LSB for FXIa versus humans. Most rodent and rabbit samples produced baseline TG in the absence of TG triggers that were consistent with the pre-activation of blood coagulation. FCD was not sensitive to both TF and FXIa in either of the plasmas. Animal plasmas have widely variable sensitivities to human TF and FXIa, which suggests that optimization of trigger concentration is required prior to test use, and this complicates the extrapolation of animal model results to humans.
摘要：
在动物中对药物进行临床前评估有助于研究人员为人体试验选择潜在的信息性临床实验室标志物。为了评估动物凝血酶生成（TG）测定的实用性，我们研究了动物血浆对TG触发物的敏感性，人组织因子(TF),和活化因子XI(FXIa)。汇集的人类，鼠标,rat,豚鼠,兔子,牛,绵羊,和山羊血浆被用于这项研究。通过荧光和光密度测量TF或FXIa触发的TG和凝血，分别。凝血酶峰高（TPH）和时间（TPT），凝块时间(CT),和纤维蛋白凝块密度（FCD）均进行分析。每个测定参数的触发低和高灵敏度边界（LSB和HSB）定义为TF和FXIa浓度，提供最大参数值的20%和80%，除非基线（无触发）值超过最大值的20%，在这种情况下,LSB来源于基线值的120%。对于TF和FXIa,正常人样品显示出比大多数动物样品更低的TPHHSB。动物样本,除了老鼠,与人类相比，FXIa的TPTLSB较低。大多数啮齿动物和兔样品在不存在TG触发因素的情况下产生基线TG,这与血液凝固的预激活一致。FCD对任一血浆中的TF和FXIa均不敏感。动物血浆对人类TF和FXIa的敏感性差异很大，这表明在测试使用之前需要优化触发浓度，这使得将动物模型结果外推至人类的过程变得复杂。
