Abstract
BackgroundThrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice.Methodology/Principal Findings TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes were measured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p>0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO.ConclusionOur study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.
Highlights
The majority of ischemic strokes are caused by thromboembolic occlusion of brain arteries [1]
Our study shows that thrombin-activatable fibrinolysis inhibitor (TAFI) does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge
Thrombin is critically involved in thrombus stabilization via thrombin-dependent FXIIIa-driven cross-linking of the fibrin network and activation of thrombin-activatable fibrinolysis inhibitor (TAFI)
Summary
The majority of ischemic strokes are caused by thromboembolic occlusion of brain arteries [1]. Two distinct pathways of blood coagulation can initiate the formation of a fibrin thrombus, the extrinsic and the intrinsic pathway [5] Both are activated in a ‘‘waterfall-like’’ manner involving a series of trypsin-like serine proteases such as the tissue factor (TF)/FVIIa complex (extrinsic pathway) or FXII (intrinsic pathway) culminating in the generation of thrombin [6]. Available data on the role of TAFI in cerebral ischemia are limited but its function as an endogenous fibrinolysis inhibitor and the observation that TAFI-deficient (TAFI-/-) mice do not show abnormal bleeding [14,15] renders TAFI an attractive therapeutic target in different thromboembolic disorders including stroke. TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice
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