Fibrinolysis inhibitors in plaque stability: a morphological association of PAI‐1 and TAFI in advanced carotid plaque

• Published in: Journal of thrombosis and haemostasis Vol. 15; no. 4; pp. 758 - 769
• Main Authors: Jönsson Rylander, A.‐C., Lindgren, A., Deinum, J., Bergström, G. M. L., Böttcher, G., Kalies, I., Wåhlander, K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.04.2017
• Subjects: Aged; Anticoagulants - pharmacology; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; ATHEROSCLEROTIC LESIONS; Carboxypeptidase B2 - metabolism; CARBOXYPEPTIDASE-U; Cardiac and Cardiovascular Systems; Carotid Arteries - pathology; Carotid Stenosis - pathology; Cell adhesion & migration; Cell and Molecular Biology; Cell- och molekylärbiologi; CORONARY-ARTERIES; Endarterectomy; ENDOTHELIAL FUNCTION; EXPRESSION; Female; Fibrinogen - pharmacology; Fibrinolysin - pharmacology; fibrinolysis; Fibrinolysis - drug effects; Humans; immuno histochemistry; Immunohistochemistry; IN-VITRO; Inflammation; ISCHEMIC-STROKE; Kardiologi; Macrophages - metabolism; Male; Middle Aged; Morphology; Myocytes, Smooth Muscle - metabolism; Pilot Projects; Plaque, Atherosclerotic - pathology; PLASMA-LEVELS; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 1 - metabolism; Platelet Glycoprotein GPIb-IX Complex - metabolism; thrombin; Thrombin - pharmacology; thrombin‐activatable fibrinolysis inhibitor; Thrombosis; TISSUE-PLASMINOGEN ACTIVATOR; von Willebrand Factor - metabolism; fibrinolysis; thrombin-activatable fibrinolysis inhibitor; Plasminogen Activator Inhibitor 1; immunohistochemistry; Endarterectomy
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.13641

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 plasminogen activator inhibitor type‐1 (PAI‐1) and thrombin‐activatable fibrinolysis inhibitor (TAFI) were quantified and described in the morphological context of advanced carotid plaques American Heart Association 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 smooth muscle cells (α‐actin), endothelial cells (von Willebrand 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, and TAFI in endothelial cells (ECs) but also macrophages. The one‐way ANOVA analysis with Bonferroni's correction showed a significant increase of macrophages and ECs, 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 of plasma proteins, transported by platelets into the atheroma (PAI‐1) or expressed by ECs (TAFI). CD68 was highly associated with 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.