Johns Hopkins University, Baltimore, MD, USA.
J Thromb Thrombolysis. 2012 Jan;33(1):22-7. doi: 10.1007/s11239-011-0654-x.
Randomized trials suggest superior and safe stroke prevention in patients with atrial fibrillation after anticoagulation with dabigatran (D) at a 150 mg BID as described in the RE-LY prospective randomized open-label trial when compared to warfarin. Thrombin generation (TG) is a cornerstone of coagulation cascade, and represents a critical biomarker of atherothrombosis. We, therefore, sought to define the effect of D in escalating concentrations on the time course of TG using the Calibrated Automated Thrombogram(®) (CAT) technology in patients after ischemic stroke. Serial plasma samples were obtained from 20 patients with ischemic stroke documented by neuroimaging, who were treated with aspirin for at least 30 days. The impact of 0.1, 0.23, 0.46, 0.69 mM D in platelet-poor plasma (PPP) on TG indices was assessed using fluorogenic substrate CAT device. The following integrated CAT parameters: TGmax, start time (t-start) peak time (t-peak), and mean time (t-mean) were calculated for each D dose and compared with those of the vehicle. Preincubation of PPP with D resulted in dose-dependent significant inhibition of most TG indices. The TGmax was gradually reduced from 447 ± 21 nM at baseline and reach significance for 0.46 mM D (355 ± 44 nM, P = 0.03); and decreased further at 0.69 mM D to 302 ± 27 nM (P = 0.01). The t-peak has been achieved 2-3 times later than after vehicle already at 0.23 nM D. The t-start was delayed 3-4 fold starting from 0.23 mM concentration of D (P < 0.001 for all), but not different from D 0.1 mM (1.5 vs. 1.6; P = 0.34). The t-mean was not significantly affected by D. D in vitro impacts indices of TG predominantly by dose dependent inhibition of endogenous TG, and delayed thrombin production. This preliminary evidence, while intriguing, requires confirmation in post-stroke patients receiving orally dosed D in order to determine whether these findings are clinically relevant.
随机试验表明，与华法林相比，在 RELY 前瞻性随机开放标签试验中描述的每天两次 150 毫克剂量的达比加群（D）抗凝治疗后，心房颤动患者的卒中预防效果更好且更安全。凝血酶生成（TG）是凝血级联反应的基石，也是动脉血栓形成的关键生物标志物。因此，我们试图使用校准自动化血栓图（CAT）技术在缺血性卒中后的患者中，确定递增浓度的 D 对 TG 时间过程的影响。从 20 名经神经影像学证实的缺血性卒中患者中连续获得血浆样本，这些患者接受了至少 30 天的阿司匹林治疗。使用荧光底物 CAT 设备评估血小板缺乏血浆（PPP）中 0.1、0.23、0.46、0.69mM D 对 TG 指数的影响。为每个 D 剂量计算并与载体相比，计算以下综合 CAT 参数：TGmax、起始时间（t-start）、峰值时间（t-peak）和平均时间（t-mean）。PPP 与 D 预孵育导致大多数 TG 指数呈剂量依赖性显著抑制。TGmax 逐渐从基线时的 447±21nM 降低，在 0.46mM D 时达到显著水平（355±44nM，P=0.03）；在 0.69mM D 时进一步降低至 302±27nM（P=0.01）。与载体相比，在 0.23nM D 时，t-peak 已经达到 2-3 倍晚。t-start 从 0.23mM D 浓度开始延迟 3-4 倍（P<0.001），但与 0.1mM D 无差异（1.5 对 1.6；P=0.34）。t-mean 不受 D 的影响。D 在体外主要通过抑制内源性 TG 来影响 TG 指数，从而延迟凝血酶的产生。虽然这一初步证据很有趣，但需要在接受口服剂量 D 的卒中后患者中进行确认，以确定这些发现是否具有临床意义。
