Department of Neurology, University Heidelberg, INF 400, 69120 Heidelberg, Germany.
Stroke. 2011 Dec;42(12):3594-9. doi: 10.1161/STROKEAHA.111.624650. Epub 2011 Oct 13.
Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.
In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later.
DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent.
The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
达比加群酯（DE）最近已被批准用于预防心房颤动引起的中风。然而，在发生脑出血（ICH）的情况下，缺乏有效的拮抗剂是一个主要关注点。本研究的目的是建立一种与达比加群相关的ICH 小鼠模型，并测试不同止血因子在预防血肿增大方面的疗效。
在接受 DE（4.5 或 9.0mg/kg）的 C57BL/6 小鼠中，反复进行体内和体外凝血检测以及达比加群血浆水平检测。在通过纹状体胶原酶注射诱导 ICH 后 30 分钟，小鼠接受生理盐水、凝血酶原复合物浓缩物（PCC；100U/kg）、鼠新鲜冷冻血浆（200μL）或重组人凝血因子 VIIa（8.0mg/kg）的静脉内注射。24 小时后，在脑冷冻切片上定量 ICH 体积。
DE 显著延长了尾静脉出血时间和依沙凝块时间长达 4 小时，与达比加群的血浆水平相对应。在连续 T2*MRI 上观察到颅内血肿扩大主要发生在最初的 3 小时内。高剂量的 DE 抗凝会显著增加血肿体积。PCC 并在一定程度上，新鲜冷冻血浆可预防由 DE 引起的血肿过度扩大，而重组人凝血因子 VIIa 则无效。PCC 可预防血肿生长并逆转尾静脉出血时间，这与剂量有关。
该研究提供了强有力的证据表明，PCC 并在一定程度上，新鲜冷冻血浆可预防与达比加群相关的 ICH 小鼠模型中血肿的过度扩大。这种策略的疗效和安全性必须在临床研究中进一步评估。
