Pre-administration of a carboxypeptidase inhibitor enhances tPA-induced thrombolysis in mouse microthrombi: Evidence from intravital imaging analysis
Pre-administration of a carboxypeptidase inhibitor enhances tPA-induced thrombolysis in mouse microthrombi: Evidence from intravital imaging analysis
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DOI：
10.1016/j.thromres.2021.12.031
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发表时间：
2022-01-11
影响因子：
7.5
通讯作者：
Urano, Tetsumei
中科院分区：
文献类型：
--
作者：
Mathews, Nitty Skariah;Suzuki, Yuko;Urano, Tetsumei
简介：使用重组组织型纤溶酶原激活剂（rt-PA）的溶栓是急性血栓形成事件的首选药物治疗。然而，狭窄的治疗窗口和出血并发症限制了它的使用。我们描述了马铃薯块茎羧肽酶抑制剂（PTCI）的作用，活化凝血酶激活的纤维蛋白溶解抑制剂（TAFIa）的抑制剂，在体内Glu-纤溶酶原积累和微血栓动力学，并证明其对rt-PA介导的血栓溶解的影响。材料与方法：结合实时活体双光子激发荧光显微镜，我们在表达绿色荧光蛋白（GFP）的小鼠肠系膜小静脉中产生并成像激光诱导的微血栓。我们研究了微血栓动力学和血栓溶解模式在体内通过测量荧光强度的变化，标记Glu-纤溶酶原管理后的EACA，PTCI，和rt-PA。结果：PTCI通过抑制TAFIa而促进Glu-纤溶酶原在血栓中心的积聚，而EACA则抑制这一过程。外源性rt-PA有效地触发血栓内Glu-纤溶酶原激活，促进血栓溶解。与rt-PA单独给药相比，PTCI和rt-PA联合给药对溶栓无显著获益。然而，在rt-PA溶栓治疗前早期全身给予PTCI可加速凝块溶解，这可通过显著更快的达到峰值Glu-纤溶酶原荧光强度的时间和更短的达到接近完全凝块溶解的时间来证明（分别为P = 0.014和P = 0.003）。结论：在急性血栓形成事件早期给予PTCI可增强rt-PA介导的溶栓作用。需要进一步研究探索TAFI抑制剂作为溶栓或血栓预防辅助药物的潜力。
Introduction: Thrombolysis using recombinant tissue-type plasminogen activator (rt-PA) is the pharmacological treatment of choice in acute thrombotic events. However, a narrow therapeutic window and bleeding complications limit its use. We describe the role of carboxypeptidase inhibitor from potato tuber (PTCI), an inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), on Glu-plasminogen accumulation and micro thrombus dynamics in vivo and demonstrate its influence on rt-PA-mediated thrombolysis. Materials and methods: In conjunction with real-time intravital two-photon excitation fluorescence microscopy, we produced and imaged laser-induced microthrombi in the mesenteric venules of Green Fluorescent Protein (GFP)-expressing mice. We examined microthrombus dynamics and thrombolysis patterns in vivo by measuring the changes in the fluorescence intensity of labeled Glu-plasminogen following administration of epsilon aminocaproic acid (EACA), PTCI, and rt-PA. Results: PTCI enhanced Glu-plasminogen accumulation at the core of the thrombus by inhibiting TAFIa, while EACA inhibited this process. Exogenous rt-PA effectively triggered Glu-plasminogen activation within the thrombus and promoted thrombolysis. Administration of PTCI and rt-PA together showed no significant benefit on thrombolysis compared to rt-PA administration alone. However, early-phase systemic administration of PTCI before thrombolytic therapy by rt-PA expedited clot lysis as evidenced by significantly faster time to reach peak Glu-plasminogen fluorescence intensity and shorter time to achieve near-complete clot lysis (P = 0.014 and P = 0.003, respectively). Conclusions: PTCI potentiates rt-PA-mediated thrombolysis when administered early in acute thrombotic events. Further studies are warranted to explore the potential of TAFI inhibitors as adjunct agents in thrombolysis or thromboprophylaxis.