凝血因子 XIII：创伤中纤溶表型的未被认识的调节因子——与蛋白MENT及半胱氨酸组织蛋白酶降解纤溶酶原的潜在联系。
Coagulation factor XIII: An unrecognized regulator of fibrinolytic phenotypes in trauma-A potential link to protein MENT and cysteine cathepsin degradation of plasminogen.
作者信息
Moore Peter K, Moore Ernest E, Garner Raleigh, Hansen Kirk, Barrett Christopher D, Sauaia Angela, Chandler James, Janssen William J, Moore Hunter B
机构信息
From the Department of Medicine (P.K.M.), University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Surgery (E.E.M., A.S., J.C.), Denver Health Medical Center, Denver, Colorado; Department of Medicine (R.G., W.J.J.), National Jewish Health, Denver, Colorado; Department of Structural Biology and Biochemistry (K.H.), University of Colorado Anschutz Medical Center, Aurora, Colorado; Department of Surgery (C.D.B.), University of Nebraska Medical Center, Omaha, Nebraska; and Department of Surgery (H.B.M.), Advent Health, Denver, Colorado.
出版信息
J Trauma Acute Care Surg. 2025 Jul 25. doi: 10.1097/TA.0000000000004706.
BACKGROUND
Trauma-induced coagulopathy (TIC) has distinct fibrinolytic phenotypes based on viscoelastic testing. The underlying mechanisms behind differences in fibrinolytic responses to trauma are unclear. We hypothesized that plasma proteins crosslinked into fibrin clots by the transglutaminase activity of factor XIII (FXIII) may explain tissue-type plasminogen activator (tPA) responsiveness observed in fibrinolysis shutdown.
METHODS
Plasma samples from trauma patients were categorized into four fibrinolytic phenotypes (hyperfibrinolysis, hypofibrinolysis, fibrinolysis shutdown, and physiologic fibrinolysis) based on rapid thromboelastography and tPA-enhanced thromboelastography. Plasma underwent liquid chromatography-mass spectrometry proteomics for substrates of FXIII, evaluation for FXIII concentration/activity, and Western blotting to confirm proteomic findings. In vitro studies assessed cysteine cathepsin-mediated proteolysis of fibrinolytic and clot-related proteins.
RESULTS
Plasma proteomic analysis identified differences in levels of four proteins known to be crosslinked into fibrin in fibrinolysis shutdown patients, including increase in MENT, a cysteine cathepsin inhibitor. Patients with shutdown exhibited significantly higher plasma FXIII activity compared with other phenotypes. Western blotting confirmed that MENT was increased in shutdown and is crosslinked into fibrin clots. The targets of MENT, cysteine cathepsins, degraded coagulation and fibrinolytic proteins in vitro, including plasminogen, tPA, and fibrinogen. Cathepsin L exposure completely disrupted ex vivo fibrin clot formation and impaired fibrinolytic enzyme function, highlighting its potential multifaceted role in TIC pathophysiology.
CONCLUSION
Elevated FXIII activity and MENT incorporation into fibrin clots may regulate fibrinolysis shutdown in trauma patients with fibrinolysis shutdown by inhibiting cysteine cathepsin activity. These findings identify FXIII, MENT, and cysteine cathepsins as possible contributors to TIC that should be studied further.
LEVEL OF EVIDENCE
Basic Science; N/A.
背景
创伤性凝血病（TIC）基于粘弹性测试具有不同的纤维蛋白溶解表型。创伤后纤维蛋白溶解反应差异背后的潜在机制尚不清楚。我们假设，通过因子 XIII（FXIII）的转谷氨酰胺酶活性交联到纤维蛋白凝块中的血浆蛋白可能解释了纤维蛋白溶解停止时观察到的组织型纤溶酶原激活剂（tPA）反应性。
方法
根据快速血栓弹力图和tPA增强血栓弹力图，将创伤患者的血浆样本分为四种纤维蛋白溶解表型（高纤维蛋白溶解、低纤维蛋白溶解、纤维蛋白溶解停止和生理性纤维蛋白溶解）。血浆进行液相色谱-质谱蛋白质组学分析以检测FXIII的底物，评估FXIII浓度/活性，并进行蛋白质印迹以确认蛋白质组学结果。体外研究评估了半胱氨酸组织蛋白酶介导的纤维蛋白溶解和凝块相关蛋白的蛋白水解作用。
结果
血浆蛋白质组分析发现，在纤维蛋白溶解停止的患者中，已知交联到纤维蛋白中的四种蛋白质水平存在差异，包括半胱氨酸组织蛋白酶抑制剂MENT增加。与其他表型相比，纤维蛋白溶解停止的患者血浆FXIII活性显著更高。蛋白质印迹证实，MENT在纤维蛋白溶解停止时增加，并交联到纤维蛋白凝块中。MENT的靶标半胱氨酸组织蛋白酶在体外降解凝血和纤维蛋白溶解蛋白，包括纤溶酶原、tPA和纤维蛋白原。组织蛋白酶L暴露完全破坏了体外纤维蛋白凝块的形成，并损害了纤维蛋白溶解酶的功能，突出了其在TIC病理生理学中的潜在多方面作用。
结论
FXIII活性升高和MENT掺入纤维蛋白凝块可能通过抑制半胱氨酸组织蛋白酶活性来调节纤维蛋白溶解停止的创伤患者的纤维蛋白溶解。这些发现确定FXIII、MENT和半胱氨酸组织蛋白酶可能是TIC的促成因素，应进一步研究。
证据水平
基础科学；无。
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