Incampo Francesca, Carrieri Cosimo, Galasso Rita, Marino Renato, Ettorre Cosimo P, Semeraro Nicola, Colucci Mario
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Thrombosis and Haemophilia Center, Policlinico, Bari, Italy.
Thromb Res. 2014 Apr;133(4):634-9. doi: 10.1016/j.thromres.2013.12.035. Epub 2014 Jan 4.
Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance.
Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively.
In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis.
Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings.
维生素K拮抗剂（VKA）治疗通过抑制凝血酶介导的凝血酶激活纤溶抑制物（TAFI）的活化来降低纤维蛋白溶解抵抗。由于在抗凝治疗起始阶段低分子量肝素（LMWH）与VKA联合使用，我们评估了双重抗凝对纤维蛋白溶解抵抗的影响。
研究了两组患者：1）服用华法林稳定的患者；2）开始口服抗凝治疗的患者，在双重抗凝期间及依诺肝素撤药后进行评估。仅比较国际标准化比值（INR）在2至3之间的样本。分别通过血栓弹力图（TEG）和比浊法在血液和血浆中评估凝块对组织型纤溶酶原激活剂（t-PA）诱导的纤维蛋白溶解的抵抗。
在接受双重抗凝的患者中，血液纤维蛋白溶解时间（TEG）显著短于仅服用华法林的患者，且与LMWH水平显著相关。促纤溶作用部分归因于凝血酶依赖性TAFI活化的降低：1）双重抗凝显著降低了凝血酶和TAFIa的生成；2）在华法林处理的血液中添加依诺肝素可降低TAFI介导的纤维蛋白溶解抑制作用。接受双重抗凝的患者还表现出凝块强度降低，这是一种已知可降低纤维蛋白溶解抵抗的现象。在血浆中未观察到LMWH联合使用的促纤溶作用，可能是因为TAFIa的生成低于抑制纤维蛋白溶解所需的阈值。
VKA治疗的患者联合使用LMWH通过依赖TAFI和不依赖TAFI的机制降低血凝块的纤维蛋白溶解抵抗。有必要进一步研究以评估这些发现的临床意义。
