THE INTERFACE BETWEEN THROMBOSIS AND INFLAMMATION THE MULTIVALENT ROLE OF TISSUE FACTOR (TF)

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1 Φλεγμονώδης επαγωγή του Ιστικού Παράγοντα και ρύθμιση θρομβωτικών και μη-θρομβωτικών εκδηλώσεων THE INTERFACE BETWEEN THROMBOSIS AND INFLAMMATION THE MULTIVALENT ROLE OF TISSUE FACTOR (TF)

2 TF/FVIIa complex is the prima ballerina in the in vivo coagulation. Rappaport and Rao, Cytokines and molecules TF agonists and inducers correlation and link with human clinical disorders Inflammation - Immune response ΤF MF (Multivalent Factor)

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4 Αυτό το σύμπλεγμα είναι ικανό να ενεργοποιήσει τον FX και τον FIX.

5 ΜΟΝΤΕΛΟ ΤΡΙΠΛΟΥ ΣΥΜΠΛΟΚΟΥ TF/VIIa/Xa

6 Το απλοποιημένο μοντέλο ενεργοποίησης του μηχανισμού της πήξης

7 TF expression -Brain, heart, lung, kidney, placenta, cancer cells, smooth (vascular) muscle cells (hemostatic envelop) -TF is not expressed in healthy endothelial cells? -TF is expressed in stimulated monocytes (peripheral blood, CD14) -Τhe role of neutrophils? Blood- borne TF The pattern of TF expression in cells is complex and is influenced by differentiation as well as various agonists. TF is subject to postranslational modifications

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9 as-htf: ENA SPLICE VARIANT TOY TF (Bogdanov et al; April 2003, Nat Med) Σχηματική απόδοση των splice variants του TF Κόκκινο: εναρκτήρια ακολουθία, Πράσινο: εξωκυττάρια περιοχή, Μπλε: διαμεμβρανική περιοχή, Κίτρινο: ενδοκυττάρια περιοχή, Πορτοκαλί: Ίδια ακολουθία as-htf, Λευκό: Μη μεταφραζόμενες περιοχές.

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11 Ο ιστικός παράγοντας ως κομβικό σημείο στην παθογένεση μη θρομβωτικών καταστάσεων

12 Η ενεργοποίηση των υποδοχέων PAR (protease activated receptors) από τις πρωτεάσες του μηχανισμού της πήξης

13 Το εξωγενές σύστημα της πήξης σε θρομβωτικές και μη διαταραχές

14 INFLAMMATION IMMUNOSTIMULATION CHEMOTAXIS NEUTROPHIL C5a COMPLEMENT ACTIVATION J. Immunol, 2006 Oct 177 K. Ritis, et al TF INDUCTION NEUTROPHIL

15 P. Redecha, R. Tilley, M. Tencati, J. E. Salmon, D. Kirchhofer, N. Mackman, and G. Girardi Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury Blood, October 1, 2007; 110(7):

16 Neutrophil activation by the tissue factor/ Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome Patricia Redecha, Claus-Werner Franzke, Wolfram Ruf, Nigel Mackman, and Guillermina Girardi J. Clin. Invest. 118(10): (2008). doi: /jci36089.

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18 J. Kourtzelis et al Transplantation 2010;90: )

19 Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis A. Zernecke et al

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21 GPVI mediated platelet adhesion and aggregation onto plaque collagen occurred within 1 min. The formation of thrombin and fibrin was driven entirely by plaque TF. Reininger A at al. J Am Coll Cardiol 2010;55:

22 Atherosclerosis / Inflammation / TF / endothelial dysfunction / VSMCs and myofibroblasts migration and proliferation / lumen narrowing ACS /Blood borne TF???

23 S(V)MCs, Fibroblasts, Myofibroblasts DERIVED TF Produce TF after inflammatory induction Inducers (PDGF, angiotensin II, THROMBIN????) Thrombin 1. Induces migration and 2. Induces TF expression.via ET 1 signaling (2011)

24 Circ J 2010; 74: 3 12)

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26 TF mediates intimal hyperplasia and luminal narrowing TF mediates arterial changes by mechanisms not dependent on thrombosis TF/Thrombin driven (PARs) fibrotic process /tissue remod. Over expression of CTGF. Vicious circle= inflammation /TF Thrombin and proteases, PARs = ETA, CTGF /ET 1 TF (antipars, bosentan, dabigatran)

27 Kambas, Chrysanthopoulou Mitroulis, Skendros 2011, J Immun, in press

28 EFFECT OF CARDIOVASCULAR RISK FACTORS ON TF EXPRESSION Hypertension, NFkB activation, angiotensin II Dysipidemia, oxidized LDL, beneficial effect of statins on TF expression Diabetes, glucose levels=tf levels, ROS, NFkB activation, DM II and IL1 b Leptin (Napoleone et al 2007 J. Thromb. Hemost., Rafail et al Thromb. Res 2008)

29 PROSPECTIVES I Blood - borne TF or circulating TF -Membrane microparticles -astf (procoagulant activity, cell signaling or both?) -Cellurar origin of astf -Circulating TF has both coagulation dependent and independent activity? -Circulating TF signaling is only indirect (PAR1, 2)??? -Are there representative clinical models related with circulating TF? (eg. ACS, cancer, APS, ARDS)

30 PROSPECTIVES II

31 Miró Poetess Κ. Καμπάς Α. Χρυσανθοπούλου Γ. Μητρούλης Π. Σκένδρος Ε. Αποστολίδου Μ. Σπελέτας, Σ. Γιαγλής Γ. Κολιός, Σ. Βραδέλης Σ. Κωνσταντινίδης, Κ. Schaefer Μ. Δούμαs, Μarc Iglartz Γ. Πνευματικός Κ. Ρίτης J. D. Labris, Σ. Ραφαήλ, Γ. Κουρτζέλης