Inhibition of thrombin attenuates stenosis after arterial injury in minipigs
Inhibition of thrombin attenuates stenosis after arterial injury in minipigs
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DOI：
10.1016/s0735-1097(96)00362-2
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发表时间：
1996-12-01
影响因子：
24
通讯作者：
Eisenberg, PR
中科院分区：
文献类型：
--
作者：
Abendschein, DR;Recchia, D;Eisenberg, PR
目标。我们试图确定Xa因子对凝血酶或凝血酶原激活的短暂而深刻的抑制是否会限制动脉损伤后新生内膜的形成和狭窄。凝血酶已被认为是新血管内膜形成的中介物，但辅助应用抗凝剂并不能有效减少冠状动脉成形术患者的再狭窄。我们从重复球囊充气前15min开始静脉注射重组水飞蓟素(2 mg/kg体重，然后每小时2 mg/kg，n=9)，肝素(100U/kg/h，n=6)或重组扁虱抗凝肽(rTAP，1-mg/kg，然后每小时3 mg/kg，n=5)，Xa因子的特异性抑制剂，从重复球囊充气前15分钟开始，直到重复球囊充气后3h，足以破坏动脉内弹力层的小型猪。在注射抗凝剂结束时，部分凝血活酶时间比基线水平增加了六到七倍。球囊损伤后4周，组织学测量显示，重组水飞蓟素组、rTAP组和肝素组猪的管腔狭窄率分别为29+/-16%、52+/-19%和76+/-18%(P<；0.02，与肝素组相比)。在r-水飞蓟素治疗的动物中，狭窄显著减少，这表明凝血酶在球囊诱导的动脉损伤后新生内膜形成中起主要作用。对于球囊血管成形术后的再狭窄，相对较短的时间间隔内对凝血酶MAP的直接抑制尤其有效。(C)1996年，由美国心脏病学会
Objectives. We sought to determine whether brief, profound inhibition of thrombin or prothrombin activation by factor Xa limits neointimal formation and stenosis after arterial injury.Background. Thrombin has been implicated as a mediator of neointimal formation, but adjunctive administration of anticoagulant agents has not proven effective to decrease restenosis in patients undergoing coronary angioplasty.Methods. We infused recombinant desulfatohirudin (r-hirudin, bolus of 2 mg/kg body weight followed by 2 mg/kg per h, n = 9), heparin (100 U/kg per h, n = 6) or recombinant tick anticoagulant peptide (rTAP, 1-mg/kg bolus followed by 3 mg/kg per h, n = 5), a specific inhibitor of factor Xa, intravenously, beginning 15 min before and for up to 3 h after repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina in a carotid artery of minipigs with hypercholesterolemia induced by feeding them an atherogenic diet.Results. Partial thromboplastin time was increased six- to sevenfold over baseline levels at the end of the infusions of the anticoagulant agents. Lumen stenosis measured histologically 4 weeks after balloon-induced carotid injury was 29 +/- 16% (mean +/- SEM) in r-hirudin-treated, 52 +/- 19% in rTAP-treated and 76 +/- 18% in heparin-treated pigs (p < 0.02 for r-hirudin vs. heparin treatment).Conclusions. The marked reduction of stenosis in r-hirudin-treated animals indicates that thrombin plays a major role in neointimal formation after balloon-induced arterial injury. A relatively brief interval of profound, direct inhibition of thrombin map be particularly effective to attenuate restenosis after balloon angioplasty. (C) 1996 by the American College of Cardiology