Results of histopathological thrombus evaluation in patients - - PowerPoint PPT Presentation

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

Nakazawa, J. Cardiol. 2011

Stent thrombosis – mechanisms and triggers differ with time after PCI

time

Procedure Delayed Healing

Fibrin deposition uncovered stent struts neoatherosclerosis

Abnormal Vascular Response

underexpansion

Platelets' Inflamma,on' Coagula,on'

Cellular'mechanisms'?'

Stent thrombosis – moderated and implemented by a fatal triad ?

Therapeu1c'target'?'

XII XIIa Contact pathway activation Extrinsic pathway activation Platelet recruitment and activation Fibrin

Engelmann & Massberg, Nat. Rev. Immunol. 2013; Schulz et al., J Thromb Haemost. 2013; Massberg et al., Nat. Med. 2010;

Plt TF inactive TF active

Stent thrombosis – relevance of inflammatory cells ?

PRESTIGE – Register (PREvention of Stent Thrombosis by an Interdisciplinary Global European effort)

Germany

• R.Byrne, M.Joner, A.Kastrati,

DHZ, Munich

• S.Massberg, C.Schulz, LMU

Munich

• F.-J. Neumann, D. Trenk, C.

Valina, HZF. Bad Krozingen

Netherlands

• J. ten Berg, T. Godschalk, D. Jhagroe, St.

Antonius Hospital, Nieuwegein

Italy

• G. Guagliumi, Azienda Ospedaliera Papa

Giovanni XXIII, Bergamo

France

• L. Feldman, P. Steg, INSERM, Paris

Poland

• D. Dudek, R. Wojdyla, Jagiellonian

University Medical College, Krakow

Spain

• F. Alfonso, Hospital Universitario de la

Princesa, Madrid

Belgium

• T. Adriaenssens, W. Desmet, P. Sinnaeve,

Katholieke Universiteit Leuven

Lithuania

• G. Kerch, Rigas Tehniska Universitate

UK

• A. Gershlick, A. Goodall, N. Malik,

University of Leicester

Project Funding

PRESTIGE – a multi-disciplinary European approach

PRESTIGE Stent thrombosis cohort

Suspicion of stent thrombosis Angiographic confirmation of stent thrombosis Blood sampling Thrombus aspiration (when indicated) IVUS and/or OCT of the target vessel (if possible/when available) PCI Angiography + IVUS and/or OCT post-emergent PCI Fix aspirated thrombus for analysis ST n=253

• Spont. MI n = 104

Histological sub study

Standard histological stainings Immunofluorescence stainings

Baseline characteristics

Early (<30d) n=79 Late (>30d) n=174 p-Value 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) n=79 Late (>30d) n=174 p-value 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) n=79 Late (>30d) n=174 p-value 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

BMS SES PES EES ZES BES unknown DES

10 20 30 40

%

n=245

%

e a r l y S T l a t e S T 20 40 60 80 100

%

e a r l y S T l a t e S T 20 40 60 80 100

%

Results: Timing of ST depending on stent type

DES, n=166 BMS, n=79

SES PES EES ZES 20 40 60 80 100 early ST late ST

%

# 14

Results: Platelets and coagulation – key players in ST

Platelets, nuclei Fibrinogen, nuclei

RBC CD41 FGN

20 40 60 80 100 Coverage (% of total thrombus area)

RBC CD41 FGN

thrombus area)

34 7

# 15

Results: Recruitment of leukocytes

HE

Neutrophil elastase, nuclei

HE

Neutrophil elastase, nuclei

# 16

Results: Recruitment of leukocytes – impact of timing & stent type

early ST late ST 2500 5000 7500 10000 leukocytes / mm2 D E S B M S S p

• n

t . M I 2000 4000 6000 8000 10000 leukocytes / mm2

p=0.44 p<0.001

DES BMS

• Spont. MI

2500 5000 7500 neutrophils / mm2 early ST late ST 2500 5000 7500 neutrophils / mm2

p=0.81 p=0.007

Total leukocyte numbers Total neutrophil numbers

Arterial thrombosis – an inflammatory process called “Immunothrombosis” '

„netting“ neutrophil

XII XIIa Contact pathway activation TFact TFPI degradation Extrinsic pathway activation Inactivation of plasma anticoagulants Platelet recruitment and activation H2 H3 v W F Plt act.Plt Fibrin

Relevance for human ST ??

Engelmann & Massberg, Nat. Rev. Immunol. 2013; Schulz et al., J Thromb Haemost. 2013; Massberg et al., Nat. Med. 2010;

e a r l y S T l a t e S T 20 40 60 80 100 NETs / mm2 DES BMS

• Spont. MI

50 100 150 200 NETs / mm2

Results: NET formation in human ST

18' NET

p=0.75 p=0.13

Neutrophil elastase, nuclei Neutrophil elastase, nuclei

Results: Evidence of eosinophils in ST – impact of timing

19'

early ST late ST

250 500 750 1000

eosinophils / mm2 p=0.63

Luna

Results: Evidence of eosinophils in very late ST – impact of stent type

20'

SES PES EES ZES

200 400 600

eosinophils / mm2

p=0.14

DES BMS 200 400 600 eosinophils / mm2

p=0.61

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!

Simultaneous publication: Eur Heart J doi:10.1093/eurheartj/ehv419

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'