在稀释诱导的凝血功能障碍中对凝血酶生成进行治疗性纠正：基于健康受试者数据集的计算分析。

Therapeutic correction of thrombin generation in dilution-induced coagulopathy: computational analysis based on a data set of healthy subjects.

机构信息

DoD Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, USA.

出版信息

J Trauma Acute Care Surg. 2012 Aug;73(2 Suppl 1):S95-S102. doi: 10.1097/TA.0b013e3182609bca.

DOI:10.1097/TA.0b013e3182609bca

PMID:22847103

Abstract

BACKGROUND

Prothrombin complex concentrates (PCCs), which contain different coagulation proteins, are attractive alternatives to the standard methods to treat dilution-induced (and, generally, traumatic) coagulopathy. We investigated the ability of a novel PCC composition to restore normal thrombin generation in diluted blood. The performance of the proposed PCC composition (coagulation factors [F] II, IX, and X and the anticoagulant antithrombin), designated PCC-AT, was compared with that of FVIIa and PCC-FVII, which is the PCC composition containing FII, FVII, FIX, and FX (main components of most PCCs).

METHODS

We used a thoroughly validated computational model to simulate thrombin generation in normal and diluted blood for 472 healthy subjects in the control group of the Leiden Thrombophilia Study. For every simulated thrombin curve, we calculated and analyzed five standard thrombin generation parameters.

RESULTS

The three therapeutic agents (FVIIa, PCC-FVII, and PCC-AT) caused statistically significant changes in each of the five thrombin generation parameters in diluted blood. Factor VIIa tended to primarily impact clotting time, thrombin peak time, and maximum slope of the thrombin curve, whereas in the case of PCC-FVII, thrombin peak height and the area under the thrombin curve were affected particularly strongly. As a result, these two therapeutics tended to push those respective parameters outside their normal ranges. PCC-AT significantly outperformed both FVIIa and PCC-FVII in its ability to normalize individual thrombin generation parameters in diluted blood. Furthermore, PCC-AT could simultaneously restore all five thrombin generation parameters to their normal levels in every subject in the study group.

CONCLUSIONS

Our computational results suggest that PCC-AT may demonstrate a superior ability to restore normal thrombin generation compared with FVIIa and PCC-FVII.

摘要

背景

含有不同凝血蛋白的凝血酶原复合物浓缩物（PCC）是治疗稀释诱导（通常是创伤性）凝血功能障碍的标准方法的替代品。我们研究了一种新型 PCC 成分在稀释血液中恢复正常凝血酶生成的能力。所提出的 PCC 成分（凝血因子[F] II、IX 和 X 以及抗凝剂抗凝血酶）的性能与 FVIIa 和 PCC-FVII 进行了比较，后者是含有 FII、FVII、FIX 和 FX（大多数 PCC 的主要成分）的 PCC 成分。

方法

我们使用经过充分验证的计算模型模拟了莱顿血栓形成研究对照组 472 名健康受试者的正常和稀释血液中的凝血酶生成。对于每个模拟的凝血酶曲线，我们计算和分析了五个标准的凝血酶生成参数。

结果

三种治疗剂（FVIIa、PCC-FVII 和 PCC-AT）在稀释血液中均引起了五个凝血酶生成参数中的每一个参数的统计学显著变化。因子 VIIa 倾向于主要影响凝血时间、凝血酶峰值时间和凝血酶曲线的最大斜率，而在 PCC-FVII 的情况下，凝血酶峰值高度和凝血酶曲线下面积受到的影响特别强烈。因此，这两种治疗剂倾向于将这些参数推向其正常值范围之外。PCC-AT 在将稀释血液中各个凝血酶生成参数正常化方面的能力明显优于 FVIIa 和 PCC-FVII。此外，PCC-AT 可以同时将所有五个凝血酶生成参数恢复到研究组中每个受试者的正常水平。