Moons A H M, Bijsterveld N R, Koch K T, Meijers J C M, Tijssen J G P, van der Poll T, Büller H R, Peters R J G
Neth Heart J. 2004 Feb;12(2):48-54.
Exposure of tissue factor (TF) to the circulation during coronary stent implantation initiates coagulation activation and may contribute to the risk of thrombotic complications. In this study, we investigated whether inhibition of TF-factor VIIa by recombinant Nematode Anti-coagulant Protein c2 (rNAPc2) is able to suppress haemostatic and inflammatory activity in patients undergoing elective intracoronary stenting.
In a randomised, double-blind design, 102 patients received either placebo or rNAPc2 (biological half-life >50 hours) at doses of 3.5, 5.0, 7.5 and 10.0 μg/kg as a single subcutaneous administration two to six hours before angioplasty. All patients also received aspirin, clopidogrel and unfractionated heparin (activated clotting time >250 seconds during angioplasty). Serial blood samples were collected before and after the intervention.
At 30 hours after stenting, all rNAPc2 treatment groups but not the placebo group demonstrated a reduction from baseline of prothrombin fragment F1+2 and D-dimer plasma levels (to 23 and 12% below baseline values at the highest dose, respectively), which were significantly lower in three rNAPc2 groups compared with placebo (p≤0.03). TF plasma levels were initially reduced in all rNAPc2 groups and returned to baseline values 18 hours after stent implantation. These three markers all increased to above baseline values in the placebo group. Levels of P-selectin, antithrombin III and interleukin-8 were not or only slightly affected by the intervention or by rNAPc2, whereas a significant 2.8 to 4.1 fold increase of C-reactive protein plasma levels was found in all patient groups after the procedure.
In contrast to the inflammatory response, coagulation activation after elective coronary stent implantation, which is observed in spite of the use of multiple antithrombotic drugs, can be attenuated by inhibition of the TF-factor VIIa complex using rNAPc2. Inhibition of the TF-mediated pathway of coagulation may be an important target to prevent thrombotic complications after coronary stenting.
在冠状动脉支架植入过程中，组织因子（TF）暴露于循环系统会引发凝血激活，并可能增加血栓形成并发症的风险。在本研究中，我们调查了重组线虫抗凝血蛋白c2（rNAPc2）抑制TF-因子VIIa是否能够抑制择期冠状动脉内支架植入患者的止血和炎症活性。
采用随机、双盲设计，102例患者在血管成形术前2至6小时接受皮下注射安慰剂或rNAPc2（生物半衰期>50小时），剂量分别为3.5、5.0、7.5和10.0μg/kg。所有患者还接受阿司匹林、氯吡格雷和普通肝素（血管成形术期间活化凝血时间>250秒）。在干预前后采集系列血样。
支架植入后30小时，所有rNAPc2治疗组而非安慰剂组的凝血酶原片段F1+2和D-二聚体血浆水平较基线降低（最高剂量时分别降至基线值以下23%和12%），三个rNAPc2组与安慰剂组相比显著降低（p≤0.03）。所有rNAPc2组的TF血浆水平最初降低，支架植入后18小时恢复至基线值。安慰剂组这三个标志物均升高至基线值以上。P-选择素、抗凝血酶III和白细胞介素-8水平未受干预或rNAPc2影响或仅轻微受影响，而术后所有患者组的C反应蛋白血浆水平显著升高2.8至4.1倍。
尽管使用了多种抗血栓药物，但择期冠状动脉支架植入后的凝血激活与炎症反应不同，可通过rNAPc2抑制TF-因子VIIa复合物来减弱。抑制TF介导的凝血途径可能是预防冠状动脉支架植入后血栓形成并发症的重要靶点。
