Background: Secondary microthrombosis is a major pathophysiologic mechanism leading to brain damage following transient mechanical vascular occlusion (TMVO), the most widely used experimental stroke model. Whether secondary microthrombosis also occurs in non-TMVO stroke models represents an important issue for clinical translation of antimicrothrombosis therapeutic strategies.
Objectives: To assess the occurrence and the pathogenic role of secondary microthrombosis in two thrombin-induced stroke models in mice and non-human primates (Macaca mulatta).
Methods: Stroke was induced in mice and non-human primates by intra-arterial administration of recombinant thrombin. This method induces the formation of a fibrin-rich thrombus, which is spontaneously dissolved in the following hours by the endogenous fibrinolytic system. Perfusion-weighted imaging and fluorescent-lectin microangiography were performed after recanalization to detect secondary microthrombosis. Moreover, to investigate its pathogenic role, thrombin-induced stroke was induced in bradykinin receptor B1 (B1R) knockout mice, which are protected from the thromboinflammation responsible for secondary microthrombosis in TMVO models.
Results: Reperfusion was stable and complete in all mice and non-human primates tested, revealing no secondary decrease in cerebral blood flow. No evidence of secondary microthrombosis was found in the two models. Accordingly, deficiency in B1R did not protect the mice from brain damage after thrombin-induced stroke.
Conclusions: Our data demonstrate that secondary microthrombosis does not occur after thrombin-induced stroke. In view of this, the pathophysiologic roles of hematologic players promoting or protecting against secondary microthrombosis (such as factor XII, von Willebrand factor, and T cells) deserve to be re-evaluated in non-TMVO stroke models.
Keywords: bradykinin; coagulation; inflammation; ischemia; stroke; thrombosis.
© 2013 International Society on Thrombosis and Haemostasis.