致密且危险：组织型纤溶酶原激活物抵抗的纤维蛋白溶解失活表型是由于异常的纤维蛋白聚合。
Dense and dangerous: The tissue plasminogen activator-resistant fibrinolysis shutdown phenotype is due to abnormal fibrin polymerization.
机构信息
From the Department of Surgery (N.D., Z.T.O., A.M.S., K.F.), University of Vermont, Burlington, Vermont; Ernest E Moore Shock Trauma Center at Denver Health (J.R.C., H.M., E.E.M.), University of Colorado Denver, Denver, Colorado; Department of Pharmacology (G.H., M.T.N.), University of Vermont, Burlington; and Department of Biochemistry (S.B.), University of Vermont, Colchester, Vermont.
出版信息
J Trauma Acute Care Surg. 2020 Feb;88(2):258-265. doi: 10.1097/TA.0000000000002554.
BACKGROUND
Both hyperfibrinolysis and fibrinolysis shutdown can occur after severe trauma. The subgroup of trauma patients with fibrinolysis shutdown resistant to tissue plasminogen activator (t-PA)-mediated fibrinolysis have increased mortality. Fibrin polymerization and structure may influence fibrinolysis subgroups in trauma, but fibrin architecture has not been characterized in acutely injured subjects. We hypothesized that fibrin polymerization measured in situ will correlate with fibrinolysis subgroups.
METHODS
Blood samples were collected from trauma patients and noninjured controls. We selected samples across a range of fibrinolysis phenotypes (shutdown, physiologic, hyperfibrinolysis) and t-PA sensitivities (sensitive, physiologic, resistant) determined by thrombelastography. Plasma clots were created in situ with fluorescent fibrinogen and imaged using confocal microscopy for analysis of clot architecture in three dimensions. For each clot, we quantified the fiber resolvability, a metric of fiber distinctness or clarity, by mapping the variance of fluorescence intensity relative to background fluorescence. We also determined clot porosity by measuring the size and distribution of the gaps between fibrin fibers in three-dimensional space. We compared these measures across fibrinolysis subgroups.
RESULTS
Fiber resolvability was significantly lower in all trauma subgroups compared with controls (n = 35 and 5, respectively; p < 0.05). We observed markedly different patterns of fibrin architecture among trauma patients stratified by fibrinolysis subgroup. Subjects with t-PA-resistant fibrinolysis shutdown exhibited abnormal, densely packed fibrin clots nearly devoid of pores. Individuals with t-PA-hypersensitive fibrinolysis shutdown had highly irregular clots with pores as large as 2500 μm to 20,000 μm, versus 78 μm to 1250 μm in noninjured controls.
CONCLUSION
Fiber resolvability was significantly lower in trauma patients than controls, and subgroups of fibrinolysis differ in the porosity of the fibrin clot structure. The dense fibrin network in the t-PA-resistant group may prevent access to plasmin, suggesting a mechanism for thrombotic morbidity after injury.
背景
严重创伤后可发生过度纤溶和纤溶失活。对组织型纤溶酶原激活剂（t-PA）介导的纤溶作用有抵抗的纤溶失活创伤患者亚组的死亡率增加。纤维蛋白聚合和结构可能会影响创伤中的纤溶亚组，但尚未对急性损伤患者的纤维蛋白结构进行特征描述。我们假设原位测量的纤维蛋白聚合与纤溶亚组相关。
方法
从创伤患者和非损伤对照中采集血液样本。我们选择了一系列纤溶表型（失活、生理性、过度纤溶）和 t-PA 敏感性（敏感、生理性、抵抗）的样本，这些样本通过血栓弹性描记法确定。用荧光纤维蛋白原位形成血浆凝块，并使用共焦显微镜对其进行三维成像，以分析凝块结构。对于每个凝块，我们通过映射荧光强度相对于背景荧光的方差来量化纤维分辨率，这是纤维清晰度或清晰度的度量。我们还通过测量三维空间中纤维之间的间隙的大小和分布来确定凝块孔隙率。我们比较了这些指标在不同纤溶亚组之间的差异。
结果
与对照组相比（分别为 n = 35 和 5），所有创伤亚组的纤维分辨率均显著降低（p < 0.05）。我们观察到，根据纤溶亚组分层的创伤患者的纤维蛋白结构具有明显不同的模式。t-PA 抵抗性纤溶失活的患者表现出异常的、紧密堆积的纤维蛋白凝块，几乎没有孔隙。t-PA 超敏性纤溶失活的个体的凝块极不规则，其孔隙的大小可达 2500 μm 至 20,000 μm，而非损伤对照中仅为 78 μm 至 1250 μm。
结论
与对照组相比，创伤患者的纤维分辨率明显降低，纤溶亚组在纤维蛋白凝块结构的孔隙率上存在差异。t-PA 抵抗组中致密的纤维网络可能阻止纤溶酶的进入，这表明损伤后血栓发病率增加的一种机制。
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