PAI-1 and TAFI in advanced carotid plaque

What is it about?

Essentials • Fibrinolysis inhibitors are localized in advanced atheroma by immunohistology of endarterectomies. • Neovascular endothelium/neocapillaries show thrombin-activatable fibrinolysis inhibitor (TAFI). • Macrophage areas show free plasminogen activator inhibitor (PAI-1), notably in the vulnerable part • Free PAI-1 and TAFI stabilize active plaque area by inhibition of fibrinolysis and inflammation Summary Background: Fibrinolysis plays an important role in destabilization of atherosclerotic plaques and is tightly regulated by specific inhibitors. Objective: The fibrinolysis inhibitors PAI-1 and TAFI were quantified and described in the morphological context of advanced carotid plaques (AHA VI-VIII) to elucidate their role in plaque stability. Methods: Immunohistochemistry in serial sections along the longitudinal axis of endarterectomies from patients with symptomatic carotid stenosis (n=19) were studied using an antibody specific for free PAI-1 (I205), an antibody with high affinity for TAFI/TAFIa (CP17) and established antibodies for SMC (a-actin), endothelial cells (Von Willebrandt Factor, VWF), macrophages (CD68) and platelets (CD42). Results: PAI-1 and TAFI show a specific distribution in these advanced plaques with a maximum corresponding to the internal carotid artery (ICA). Free PAI-1 was mainly detected in macrophages and in intravascular thrombi, TAFI in endothelial cells (EC), but also macrophages. The one-way ANOVA analysis with Bonferroni’s correction showed a significant increase of macrophages and EC, TAFI and PAI-1 in areas with high neovascularization in endarterectomy sections corresponding to ICA. High Spearman factors for TAFI, PAI-1 and VWF indicate neovascularization as the main source for plasma proteins, transported by platelets into the atheroma (PAI-1) or expressed by EC (TAFI). CD68 is highly associated to VWF, PAI-1 and especially TAFI, underlining the role of macrophages in fibrinolytic activity and inflammation. Conclusion: The abundance of free PAI-1 and TAFI in the plaque may inhibit plasmin generation and thereby counteract plaque destabilization by fibrinolysis, cell migration and inflammation.

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