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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
BMSSES
PESEES
ZESBES
unknown D
ES0
10
20
30
40
%n=245
%
early
ST
late S
T0
20
40
60
80
100%
early
ST
late S
T0
20
40
60
80
100
%
Results: Timing of ST depending on stent type
DES, n=166 BMS, n=79
SES
PES
EES
ZES
0
20
40
60
80
100early STlate ST
%
# 14
Results: Platelets and coagulation – key players in ST
Platelets, nuclei Fibrinogen, nuclei
RBCCD41
FGN0
20
40
60
80
100C
over
age
(% o
f tot
alth
rom
bus
area
)
RBCCD41
FGN0
20
40
60
80
100
Cov
erag
e (%
of t
otal
thro
mbu
s ar
ea)
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 S
T0
2500
5000
7500
10000
leuk
ocyt
es /
mm
2
DESBMS
Spont. MI
0
2000
4000
6000
8000
10000
leuk
ocyt
es /
mm
2
p=0.44
p<0.001
DESBMS
Spont. MI
0
2500
5000
7500
neut
roph
ils /
mm
2
early
ST
late S
T0
2500
5000
7500
neut
roph
ils /
mm
2
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 vWF
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;
early
ST
late S
T0
20
40
60
80
100
NET
s / m
m2
DESBMS
Spont. MI
0
50
100
150
200
NE
Ts /
mm
2
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 S
T0
250
500
750
1000
eosi
noph
ils /
mm
2 p=0.63
Luna
Results: Evidence of eosinophils in very late ST – impact of stent type
20'
SESPES
EESZES
0
200
400
600
eosi
noph
ils /
mm
2 p=0.14
DESBMS
0
200
400
600
eosi
noph
ils /
mm
2 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'