California Institute for Quantitative Biosciences at University of California, Berkeley, 2151 Berkeley Way, Berkeley, CA 94704-5230, USA.
Environmental Genomics and Systems Biology Division at E. O. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 955-512L, Berkeley, CA 94720, USA.
Sci Transl Med. 2017 Jan 4;9(371). doi: 10.1126/scitranslmed.aaf5045.
We present a methodology for personalizing the clinical treatment of severely injured patients with acute traumatic coagulopathy (ATC), an endogenous biological response of impaired coagulation that occurs early after trauma and shock and that is associated with increased bleeding, morbidity, and mortality. Despite biological characterization of ATC, it is not easily or rapidly diagnosed, not always captured by slow laboratory testing, and not accurately represented by coagulation models. This lack of knowledge, combined with the inherent time pressures of trauma treatment, forces surgeons to treat ATC patients according to empirical resuscitation protocols. These entail transfusing large volumes of poorly characterized, nontargeted blood products that are not tailored to an individual, the injury, or coagulation dynamics. Massive transfusion mortality remains at 40 to 70% in the best of trauma centers. As an alternative to blunt treatments, time-consuming tests, and mechanistic models, we used dynamical systems theory to create a simple, biologically meaningful, and highly accurate model that (i) quickly forecasts a driver of downstream coagulation, thrombin concentration after tissue factor stimulation, using rapidly measurable concentrations of blood protein factors and (ii) determines the amounts of additional coagulation factors needed to rectify the predicted thrombin dynamics and potentially remedy ATC. We successfully demonstrate in vitro thrombin control consistent with the model. Compared to another model, we decreased the mean errors in two key trauma patient parameters: peak thrombin concentration after tissue factor stimulation and the time until this peak occurs. Our methodology helps to advance individualized resuscitation of trauma-induced coagulation deficits.
我们提出了一种针对严重创伤合并急性创伤性凝血病（ATC）患者的临床治疗个体化方法。ATC 是创伤和休克后早期发生的一种内源性凝血功能障碍的生物学反应，与出血、发病率和死亡率增加有关。尽管对 ATC 的生物学特征已有描述，但它不易或快速诊断，也不能总是通过缓慢的实验室检测来捕捉，并且不能通过凝血模型准确地反映。这种知识的缺乏，再加上创伤治疗固有的时间压力，迫使外科医生根据经验性复苏方案来治疗 ATC 患者。这些方案需要输注大量特征不明确、非靶向的血液制品，而这些制品不能根据个体、损伤或凝血动力学进行调整。在最好的创伤中心，大量输血死亡率仍在 40%至 70%之间。作为替代盲目治疗、耗时测试和机械模型的方法，我们使用动力系统理论创建了一个简单、具有生物学意义且高度准确的模型，该模型（i）使用可快速测量的血液蛋白因子浓度，快速预测下游凝血的驱动因素，即组织因子刺激后的凝血酶浓度，（ii）确定需要额外添加多少凝血因子来纠正预测的凝血酶动力学，从而可能纠正 ATC。我们成功地在体外证明了与模型一致的凝血酶控制。与另一个模型相比，我们降低了两个关键创伤患者参数的平均误差：组织因子刺激后凝血酶的峰值浓度和达到该峰值的时间。我们的方法有助于推进创伤引起的凝血缺陷的个体化复苏。
