Department of Biochemistry, University of Vermont, Burlington Vermont, United States of America.
PLoS One. 2012;7(1):e29178. doi: 10.1371/journal.pone.0029178. Epub 2012 Jan 11.
Factor (f)Xa is a critical enzyme in blood coagulation that is responsible for the initiation and propagation of thrombin generation. Previously we have shown that analysis of computationally generated thrombin profiles is a tool to investigate hemostasis in various populations. In this study, we evaluate the potential of computationally derived time courses of fXa generation as another approach for investigating thrombotic risk. Utilizing the case (n = 473) and control (n = 426) population from the Leiden Thrombophilia Study and each individual's plasma protein factor composition for fII, fV, fVII, fVIII, fIX, fX, antithrombin and tissue factor pathway inhibitor, tissue factor-initiated total active fXa generation was assessed using a mathematical model. FXa generation was evaluated by the area under the curve (AUC), the maximum rate (MaxR) and level (MaxL) and the time to reach these, TMaxR and TMaxL, respectively. FXa generation was analyzed in the entire populations and in defined subgroups (by sex, age, body mass index, oral contraceptive use). The maximum rates and levels of fXa generation occur over a 10- to 12- fold range in both cases and controls. This variation is larger than that observed with thrombin (3-6 fold) in the same population. The greatest risk association was obtained using either MaxR or MaxL of fXa generation; with an ∼2.2 fold increased risk for individuals exceeding the 90(th) percentile. This risk was similar to that of thrombin generation(MaxR OR 2.6). Grouping defined by oral contraceptive (OC) use in the control population showed the biggest differences in fXa generation; a >60% increase in the MaxR upon OC use. FXa generation can distinguish between a subset of individuals characterized by overlapping thrombin generation profiles. Analysis of fXa generation is a phenotypic characteristic which may prove to be a more sensitive discriminator than thrombin generation among all individuals.
因子 (f)Xa 是血液凝固中的关键酶，负责启动和促进凝血酶生成。此前，我们已经证明，计算生成的凝血酶谱分析是一种用于研究各种人群止血功能的工具。在这项研究中，我们评估了计算得出的 fXa 生成时间过程作为另一种研究血栓形成风险的方法的潜力。利用莱顿血栓形成研究中的病例 (n=473) 和对照 (n=426) 人群以及每个个体的血浆蛋白因子 fII、fV、fVII、fVIII、fIX、fX、抗凝血酶和组织因子途径抑制剂的组成，使用数学模型评估组织因子启动的总活性 fXa 生成。通过曲线下面积 (AUC)、最大速率 (MaxR) 和最大水平 (MaxL) 以及达到这些水平的时间 (TMaxR 和 TMaxL) 评估 FXa 生成。FXa 生成在整个人群和定义的亚组（按性别、年龄、体重指数、口服避孕药使用情况）中进行分析。在病例和对照中，fXa 生成的最大速率和水平在 10-12 倍范围内变化。这种变化比同一人群中凝血酶 (3-6 倍) 观察到的变化更大。使用 fXa 生成的最大速率或最大水平获得最大的风险关联；超过第 90 百分位的个体的风险增加约 2.2 倍。这种风险与凝血酶生成 (MaxR OR 2.6) 相似。在对照人群中按口服避孕药 (OC) 使用情况分组显示 fXa 生成的差异最大；OC 使用时最大速率增加超过 60%。FXa 生成可以区分具有重叠凝血酶生成谱的个体子集。fXa 生成分析是一种表型特征，在所有个体中，它可能比凝血酶生成更敏感地鉴别。
