TY - JOUR
T1 - Effects of dabigatran in vitro on thrombin biomarkers by calibrated automated thrombography in patients after ischemic stroke
AU - Serebruany, Victor
AU - Sani, Yanti
AU - Lynch, Donald
AU - Schevchuck, Alex
AU - Svetlov, Stan
AU - Fong, Alan
AU - Thevathasan, Lionel
AU - Hanley, Dan
N1 - Funding Information:
The research work on this project was supported by the Discovery ARC grant no. DP0664423. Authors thank Prof. Jean Pierre Crouzeix and Dr Danny Ralph, our partner investigators, for their valuable contribution to the project. We are also grateful to Prof. Peter Dixon and Dr Glyn Wittwer from Centre of Policy Studies, Monash University for many fruitful discussions.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - Dabigatran
KW - In vitro
KW - Thrombin
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U2 - 10.1007/s11239-011-0654-x
DO - 10.1007/s11239-011-0654-x
M3 - Article
C2 - 22065286
AN - SCOPUS:84858864730
SN - 0929-5305
VL - 33
SP - 22
EP - 27
JO - Journal of Thrombosis and Thrombolysis
JF - Journal of Thrombosis and Thrombolysis
IS - 1
ER -