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'