Ischaemic stroke: a thrombo-inflammatory disease?

Abstract

Ischaemic stroke is a leading cause of death and disability worldwide. The complex cellular interactions leading from thromboembolic vessel occlusion to infarct development within the brain parenchyma in acute stroke are poorly understood, which translates into only one approved effective treatment, thrombolysis. Importantly, however, patients can develop progressive stroke despite reperfusion of previously occluded major intracranial arteries, a process referred to as 'reperfusion injury' which can be reproduced in the mouse model of transient middle cerebral artery occlusion (tMCAO). Although pathological platelet and coagulant activity have long been recognized to be involved in the initiation of ischaemic stroke, their contribution to infarct maturation remained elusive. Experimental evidence now suggests that early platelet adhesion/activation mechanisms involving the von Willebrand factor (vWF) receptor glycoprotein (GP) Ib, its ligand vWF, and the collagen receptor GPVI are critical pathogenic factors in infarct development following tMCAO, whereas platelet aggregation through GPIIb/IIIa is not. Further experimental work indicates that these pathways in conjunction with coagulation factor XII (FXII)-driven processes orchestrate a 'thrombo-inflammatory' cascade in acute stroke that results in infarct growth. This review summarizes these recent developments and briefly discusses their potential clinical impact.

Figure 1. Simplified model of thrombus formation

At sites of vascular injury the ECM becomes exposed to the flowing blood, allowing platelet adhesion and aggregation as well as coagulation. GPIb initiates haemostasis and thrombosis by recruiting platelets to the injured vessel wall, but it may also be involved in immune cell recruitment under inflammatory conditions. GPVI is the central activating platelet collagen receptor required for thrombus formation on the ECM but may also promote inflammation by triggering the release of PolyP. PolyP activate FXII leading to coagulation (via thrombin) and inflammation (via bradykinin). In parallel, thrombin generation is triggered by exposed tissue factor (TF, extrinsic pathway) also leading to coagulation and further platelet activation. Cellular activation and inside-out upregulation of GPIIb/IIIa (integrin αIIbβ3) affinity is essential for firm platelet adhesion and aggregation, the latter through binding of fibrinogen (Fg). EC, endothelial cell.

Figure 2. Blocking of early platelet adhesion and activation protects mice from acute ischaemic stroke

Upper panel, representative 2,3,5-triphenyltetrazoliumchloride (TTC)-stained coronal brain sections on day 1 after tMCAO. Ischaemic infarctions (white areas) appear smaller in anti-GPIbα-treated mice, vWF^−/− mice and anti-GPVI-treated mice compared with wild-type controls and this was confirmed by infarct volumetry (lower panel). In contrast, blocking of the final common pathway of platelet aggregation using anti-GPIIb/IIIa F′(ab)₂ could not reduce stroke size indicating that mechanisms beyond platelet-derived thrombus formation are operative during infarct evolution. *P < 0.05; **P < 0.01 compared with wild-type mice (n = 8–10/group); one-way ANOVA, Bonferroni's multiple comparisons post test. (Adapted from Kleinschnitz et al. 2007, .)

Figure 3. FXII plays a central role in stroke progression in mice

Infarct volumes as measured from TTC-stained coronal brain sections (A) and neurological Bederson score (B) on day 1 after tMCAO. Genetic ablation (FXII^−/− mice) or pharmacological blockade (rHA-Infestin-4) of FXII immediately before stroke markedly protects mice from acute ischaemic brain damage (white areas) as does disruption of the bradykinin receptor B1 (B1R^−/−). B1R belongs to the proinflammatory kallikrein–kinin system that is also activated by FXII. *P < 0.05; **P < 0.01; ***P < 0.0001 compared with wild-type mice (n = 8–10/group): one-way ANOVA, Bonferroni's multiple comparisons post test (A); Kruskal–Wallis test, Dunn's multiple comparison post test (B). Horizontal lines indicate median. (Adapted from Kleinschnitz et al. 2006; Austinat et al. 2009; Hagedorn et al. 2010.)