Results of histopathological thrombus evaluation in patients presenting with stent thrombosis across Europe: a report of the PRESTIGE Consortium Dr. med. Julia Riegger Medizinische Klinik u. Poliklinik I Ludwig-Maximilians-Universität, Munich, Germany for the PRESTIGE-Consortium
Conflicts of interest: none
Stent thrombosis – mechanisms and triggers differ with time after PCI Delayed Healing Fibrin deposition uncovered stent struts Procedure Abnormal Vascular Response underexpansion neoatherosclerosis time Nakazawa, J. Cardiol. 2011
Stent thrombosis – moderated and implemented by a fatal triad ? Cellular'mechanisms'?' Coagula,on' Therapeu1c'target'?' Platelets' Inflamma,on'
Stent thrombosis – relevance of inflammatory cells ? Fibrin Extrinsic Contact pathway pathway activation activation XIIa XII TF active Platelet recruitment Plt and activation TF inactive Engelmann & Massberg, Nat. Rev. Immunol. 2013; Schulz et al., J Thromb Haemost. 2013; Massberg et al., Nat. Med. 2010;
PRESTIGE – Register ( PRE vention of S tent T hrombosis by an I nterdisciplinary G lobal E uropean effort) Germany Spain • R.Byrne, M.Joner, A.Kastrati, UK DHZ, Munich • F. Alfonso, Hospital Universitario de la • S.Massberg, C.Schulz, LMU • A. Gershlick, A. Goodall, N. Malik, Princesa, Madrid Munich University of Leicester • F.-J. Neumann, D. Trenk, C. Valina, HZF. Bad Krozingen Netherlands Poland • J. ten Berg, T. Godschalk, D. Jhagroe, St. • D. Dudek, R. Wojdyla, Jagiellonian Antonius Hospital, Nieuwegein University Medical College, Krakow Italy Belgium • G. Guagliumi, Azienda Ospedaliera Papa • T. Adriaenssens, W. Desmet, P. Sinnaeve, Giovanni XXIII, Bergamo Katholieke Universiteit Leuven France Lithuania • L. Feldman, P. Steg, INSERM, Paris • G. Kerch, Rigas Tehniska Universitate
Project Funding
PRESTIGE – a multi-disciplinary European approach PRESTIGE Stent thrombosis cohort Histological sub study Suspicion of stent thrombosis Standard histological stainings Angiographic confirmation of stent thrombosis Blood sampling Fix aspirated ST n=253 thrombus for Thrombus aspiration (when indicated) Spont. MI n = 104 analysis IVUS and/or OCT of the target vessel (if possible/when available) Immunofluorescence stainings PCI Angiography + IVUS and/or OCT post-emergent PCI
Baseline characteristics Early (<30d) Late (>30d) p-Value n=79 n=174 Age 66 [57,74] 62 [54,72] 0.94 Sex Male 68.4% 82.2% 0.014 Coronary artery disease 1-vessel 48.0% 59.1% 0.24 2-vessel 33.3% 28.0% 3-vessel 18.7% 12.9% Multivessel disease 52.0% 40.9% 0.11 History of coronary bypass 6.4% 9.2% 0.46 Ejection fraction < 30% 2.7% 2.4% >0.99
Baseline characteristics Early (<30d) Late (>30d) p-value n=79 n=174 Risk factors Diabetes 38.5% 20.2% 0.002 Hypertension 55.3% 41.3% 0.043 Ex-/smoker 65.4% 72.3% 0.22 Hypercholesterolaemia 83.5% 90.2% 0.13 Clinical presentation Unstable angina pectoris 3.8% 3.5% 0.629 Non-ST-elevation MI 11.5% 16.2% ST-elevation MI 84.6% 80.3%
Baseline characteristics Early (<30d) Late (>30d) p-value n=79 n=174 Antiplatelet Therapy Aspirin 87.3% 80.7% 0.20 ADP-receptor antagonist 82.3% 25.0% <0.001 Clopidogrel 66.2% 60.5% Prasugrel 10.8% 25.6% Ticagrelor 23.1% 14% Dual antiplatelet therapy 75.9% 20.9% <0.001 Coexisting conditions Renal failure (GFR<30ml/min) 7.8% 5.8% 0.580 Dialysis 1.3% 1.1% >0.99 Stroke 7.7% 5.2% 0.57 Autoimmune disease 1.4% 2.9% 0.67 Active malignancy 3.9% 3.0% 0.71
Results: Frequency of stent types 40 n=245 30 % 20 % 10 0 BMS SES PES EES ZES unknown DES BES
Results: Timing of ST depending on stent type early ST 100 late ST 100 100 BMS, n=79 DES, n=166 80 80 80 60 60 60 % % % 40 40 40 20 20 20 0 0 0 T T T T S S S S SES PES EES ZES y e y e t l t l r r a a a a l l e e
Results: Platelets and coagulation – key players in ST Platelets, nuclei Fibrinogen, nuclei 100 Coverage (% of total thrombus area) thrombus area) 80 60 40 20 34 7 0 CD41 CD41 FGN FGN RBC RBC # 14
Results: Recruitment of leukocytes HE Neutrophil elastase, nuclei HE Neutrophil elastase, nuclei # 15
Results: Recruitment of leukocytes – impact of timing & stent type Total leukocyte numbers Total neutrophil numbers 10000 7500 p=0.44 p=0.81 neutrophils / mm 2 leukocytes / mm 2 7500 5000 5000 2500 2500 0 0 early ST late ST early ST late ST p<0.001 p=0.007 7500 10000 neutrophils / mm 2 leukocytes / mm 2 8000 5000 6000 4000 2500 2000 0 0 S S I DES BMS Spont. MI M E M D . B t n o p S # 16
Arterial thrombosis – an inflammatory process ' called “Immunothrombosis” Relevance for human ST ?? Fibrin Extrinsic Contact pathway Inactivation of Platelet recruitment pathway activation plasma and activation activation anticoagulants TFPI XII XIIa „netting“ act.Plt degradation TFact neutrophil Plt H2 H3 v W F Engelmann & Massberg, Nat. Rev. Immunol. 2013; Schulz et al., J Thromb Haemost. 2013; Massberg et al., Nat. Med. 2010;
Results: NET formation in human ST NET Neutrophil elastase, nuclei Neutrophil elastase, nuclei 100 200 p=0.75 p=0.13 80 150 NETs / mm 2 NETs / mm 2 60 100 40 50 20 0 0 T T DES BMS Spont. MI S S y e l t r a a l e 18'
Results: Evidence of eosinophils in ST – impact of timing 1000 p=0.63 eosinophils / mm 2 750 500 Luna 250 0 early ST late ST 19'
Results: Evidence of eosinophils in very late ST – impact of stent type 600 600 p=0.61 p=0.14 eosinophils / mm 2 eosinophils / mm 2 400 400 200 200 0 0 DES BMS SES PES EES ZES 20'
Conclusions - PRESTIGE: largest ST registry - Inflammation is a hallmark in ST with higher numbers of leukocytes in ST compared to spontaneous MI - NETs, central effectors of immunothrombosis, were detected in 23% of human ST - Eosinophils were observed with higher numbers in very late ST in SES and EES - Pharmacological targeting of immunothrombosis may represent a realistic target for novel therapies
Thank you to all investigators! Tom'Adriaenssens' Peter'Sinnaeve' Elena'Guerra' Amir'Rosenthal' Giulio'Guagliumi' Dariusz'Dudek' Anthony'Gershlick' Emanuele'Barbato' Ota'Hlinomaz' Michael'Joner' Alexander'Rzany' Kenichi'Komukai' Łukasz'Rzeszutko' Alison'H.'Goodall' Ann'Belmans' Helene'Abergel' Adnan'Kastra,' Chris,an'Schulz' Vasile'Sirbu' Roman'Wojdyla' Simon'Hetherington' Ian'Buysschaert' Laurent'Feldman' Elisabeth'Kennerknecht' Kris,n'Steigerwald' Garry'Kerch' Wojciech'Zasada' Jonathan'Hill' Mickaël'Chausson' Mar,ne'JandrotXPerrus' Ildiko'Konrad' Tomohisa'Tada' Giovanni'Amoroso' Fernando'Alfonso' Damian'Kelly' Dries'De'Cock' Didier'Letourneur' Tobias'Koppara' Anna'Titova' Jurriën'ten'Berg' Javier'Cuesta' Nikesh'Malik' Jo'Dens' Pierre'Mangin' Steffen'Massberg' Dietmar'Trenk' Willem'J.M.'Dewilde' Miguel'Medina' Keith'Oldroyd' Walter'Desmet' Véronique'Olivier' FranzXJosef'Neumann' Chris,an'Valina' Thea'C.'Godschalk' Colin'Berry' Helen'Routledge' Sandrine'Gau,er' Caroline'Roques' Vasilis'Ntziachristos' Andreas'Vogelsang' Antonius'Heestermans' James'Co_on' Joanne'Shannon' Nick'Hiltrop' Robert'A.'Byrne' Sheryl'Opinaldo' Erion'Xhepa' Darshni'A.'Jhagroe' Nick'Curzen' Venkatesan'Suresh' Katleen'Vandenberghe' Sue'Chandraratne' Vanessa'Philippi' Chiara'Bernelli' Joanne'J.'Wykrzykowska' Margaret'McEntegart' Azfar'Zahman' Paul'Vermeersch' Ma_hias'Gratz' Julia'Riegger' Micol'Coccato' Mark'H.M.'Winkens' Robert'Gerber' Simultaneous publication: Eur Heart J doi:10.1093/eurheartj/ehv419
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