Comprendre le pourquoi du traitement antithrombotique dans...

Laboratoire Hématologie et CREATIF

& Consultation hémostase, thromboses, anti-thrombotiques

Laboratoire Thrombose et Athérosclérose * IVS

hôpital Lariboisière

[email protected]

01 42 81 12 13 (24/24 7/7)

Fax : 01 49 95 63 97

01 49 95 80 78

Centre de Référence et

d’Education

des AntiThrombotiques

d’Ile de France L. Drouet

Comprendre le pourquoi du

traitement antithrombotique

dans le SCA

Université Paris VII

UMRS937

C. Bal*, L. Drouet*

J-G Dillinger**, P. Henry**

E. Houdart *** ,D. Calvet ****, JL Mas****

*Consultation hémostase thromboses antithrombotiques

Laboratoire Hématologie & IVS

**service de cardiologie

***service de neuroradiologie Hôpital Lariboisière

****service de neurologie Hôpital Sainte Anne

http://www.ap-hop-paris.fr/default.htm

http://www.univ-paris-diderot.fr/index.php

http://www.univ-paris-diderot.fr/index.php


traitement antithrombotique dans le

SCA

l’histoire naturelle du SCA

100 s-1

2600 s-1

650 s-1

Dépendant du flux sanguin

Dépendant du flux

sanguin

à cause des GR

MECHANICAL INJURY TO THE PIG CAROTID

THROMBUS EVOLUTION UNTIL PASSIVATION

1.6

1.4

1.2

1

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60 HOURS

volts

Enchainement de phases d’agrégation et de désagrégation

Embolisations distales qui détruisent

le lit capillaire d’aval du thrombus initial

platelets, coagulation but also leucocytes Microemboli plug microcirculation; activated monocytes and neutrophils implicated in inflammatory response

Limbruno et al, Circulation. 2003; 08:171 Leucocytes involvement

Microparticles

Cellule

Tumorale

développement

secondaire

d’un thrombus de

coagulation

Fuchs et al NET Impact on Deep Vein Thrombosis Arterioscler Thromb Vasc Biol 2012

Ishihara M et al. Eur Heart J. 2006; 97:1558-1563.

Usefulness of combined white blood cell count and plasma glucose for

predicting in-hospital outcomes after acute myocardial infarction

0

1

2

3

4

5

6

7

8

9

LOW MEDIUM HIGH

Anova, p<0.001

<8.3 8.3-11 >11 G/L

WBC count

Anova, p<0.001

<133 133-182 >182 mg/dl

PG

0

1

2

3

4

5

6

7

8

9

10

LOW MEDIUM HIGH

L’angioplastie primaire est la méthode de reperfusion la plus efficace dans le traitement des IDM

Thrombus burden

Importance du thrombus dans les SCA

• Coronary arteriography is not sensitive in detecting thrombus seen with angioscopy—

angiography misses 4 out of 5 thrombi in troponin positive patients

White CJ et al. In: Textbook of Interventional Cardiology. 2003:873-891.

Okamatsu et al, Circulation 2004; 109:465-470.

Tn - Tn - Tn + Tn +

9%

18%

86%

34%

Angiogram Angioscope

% T

hro

mb

us

P=0.0001

P=0.41

Only 1 of 5 thrombi

detected on angio

T=red, globular mass of thrombus (clot); UA=unstable angina; W=guidewire within the lumen.

• Many ACS patients already have significant clot burden

Platelets +++

Crystal like structure = Cholesterol

Johanne Silvain

Red Cells

Johanne Silvain

Fibrin Mesh +++

Johanne Silvain

stable angor

instable

<

<

<

<

<

IdM sans onde Q

STEMI AI/Non STEMI Athérothrombose

PCI /

Angioplastie

stenting

angor IdM avec onde Q

Angioplastie+stenting un modèle de thrombose

artérielle / plaquettaire quasi expérimental

Thrombose de stent =

thrombose plaquettaire



SCA

• Le pourquoi du traitement antiplaquettaire

• Le pourquoi du traitement anticoagulant

– Le pourquoi de l’héparine

– Le pourquoi de l’inhibition de la thrombine



SCA


– Quel antiplaquettaire choisir

– Quand débuter le traitement


– Arguments pour choisir une héparine

– Arguments pour choisir l’inhibition directe de la

thrombine



SCA


– Quel antiplaquettaire choisir

• Le meilleur rapport efficacité antiplaquettaire /risque

hémorragique

– Quand débuter le traitement

• Pour que l’on ait l’efficacité au moment où l’on en a besoin

CURE Efficacy CREDO Efficacy

CURE Safety* CREDO Safety**

Yusuf S, et al. N Engl J Med 2001;345:494-502 Steinhubl SR, et al. JAMA 2002;288:2411-2420

Primary Endpoint: Faster Onset of Action and

Higher Level of Platelet Inhibition

Maximum Inhibition of Platelet Aggregation (ADP 5µmol/L)

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5 6 24

Time (h)

(%)

In

hib

itio

n

300 mg LD600 mg LD900 mg LD

p< 0.05 vs. 300 mg LD

Maximum Inhibition of Platelet Aggregation (ADP 20 µmol/L)

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6 24

Time (h)

(%)

Inh

ibit

ion

300 mg LD

600 mg LD

900 mg LD

Higher Levels of Inhibition of Platelet Aggregation Suggesting a

Dose-Effect Relationship

p< 0.05 vs. 300 mg LD

Healthy Volunteer

Crossover Study

-20

0

20

40

60

80

100

IPA

at

24 h

ou

rs (

%)

Response to

Prasugrel 60 mg Response to

Clopidogrel 300 mg

Clopidogrel Responder

Clopidogrel Non-responder

Inte

rpati

en

t

Vari

ab

ilit

y

Inte

rpatie

nt

Varia

bility

From Brandt JT AHJ 153: 66e9,2007

N=66

MPA by Treatment Sequence and Period M

ax

ima

l P

late

let A

gg

reg

ati

on

(%

)

(20

µM

AD

P)

Pre-LD Post-LD Visit 3 Visit 4

Clopidogrel

150 mg

Prasugrel

10 mg

*

* p = 0.003 vs. clopidogrel 900 mg

(n = 32)

Prasugrel Clopidogrel

n = 19

Clopidogrel Prasugrel

n = 18

0

10

20

30

40

50

60

70

80

90

Clopidogrel

900 mg

Pre-LD Clopidogrel

150 mg

Prasugrel

10 mg

p = 0.016 p = 0.001

(Day 15) (Day 29)

Inhibition of ADP-Induced Platelet Aggregation by Ticagrelor vs. Clopidogrel

Ticagrelor (100 mg bid)

Time, hours

0

20

40

60

80

100

8 12 8 12

Inhibition %

24

Day 1 Day 14

4 2 4 2

Husted SE, Eur Heart J, 2006;27:1038-47 DISPERSE STUDY . Stable CHD patients

No loading dose

Inhibition %

Time, hours

Clopidogrel (75 mg od) Day 1 Day 14

0

20

40

60

80

100

8 12 8 12 24 4 2 4 2

Ticagrelor

63 patients avec

VASP<15 sur 122

patients soit 51.6 %

0

10

20

30

40

50

60

70

80

VA

SP

0

10

20

30

40

50

60

70

80

VA

SP

0

20

40

60

80

100

VA

SP

Prasugrel

Clopidogrel

50 patients avec

VASP<15 sur 947

patients soit 5.2%

73 patients avec

VASP<15 sur 285

patients soit 25.6%

Red blood cell

ENT-1

Adenosine

ADP Ticagrelor

AC

A2A P2Y12

Gs Gi cAMP

Platelet

Platelet activation/aggregation

Nylander S et al JTH2013, 11: 1867-76

A2a

tica

gre

lor

ENT-1 Adenosine

The VerifyNow PRUTest also uses PGE1 to increase intraplatelet cAMP

and reduce the contribution of the P2Y1 receptor on activation. This makes

the test more specific for the effects of ADP on the P2Y12 receptor.

Mr R… 64 ans Motif d’appel:

Douleur thoracique

Facteurs de risque:

Tabagisme actif (35 PA) Dyslipidémie traitée par régime seul HTA sous monotégrapie (IEC) Antécédents médicaux:

SAS, adénome de prostate et cataracte bilatérale

HDLM:

Survenue le 18 Février vers 1h du matin, douleur thoracique rétrosternale irradiant dans les deux épaules.

Consulte son pharmacien vers 14h30 devant la persistance de la symptomatologie et appel du SAMU

Arrivée à 14h43, PA 102/63mmHg, FC=96min, Sat 94% AA

Traitement initial

HNF 5000 UI

Prasugrel 60mg

Aspégic 500mg IV

Bivalirudin en salle de KT

Exploration agrégation plaquettaire: Aspirine

ASA H2

ASA H24

1111111111111111111

11111111111111111

111111111111111111

Coagulation – inflammation marqueurs

Exploration agrégation plaquettaire

Défaut

Absorption

High

Turnover

Absorption OK

High

Turnover

Exploration agrégation plaquettaire: Prasugrel

Prasugrel Exploration plaquettaire: index VASP

Parodi G et al Rapid study JACC 13

En analyse multivariée la première cause de retard

à l’apparition de l’effet antiplaquettaire est

la prescription de morphine

0 0,5 1 1,5 2 2,5 3 3,5 4

Events / Size, Clopidogrel OR [CI 95%] Relative Weight [%] Pretreatment No Pretreat

0/205 4/171 24/930 24/1063 31/1345 2/96 0/515 85/4325

3·03 [0·12-74·80] 0·26 [0·03-2·32] 0·53 [0·27-1·05] 0·75 [0·41-1·40] 1·06 [0·64-1·75] 0·18 [0·01-3·85] 3·02 [0·12-74·25] 0·80 [0·57-1·11]

1·0% 2·2% 23·2% 28·3% 43·1% 1·2% 1·0% 100%

49/1515 14/832 63/2347

0·92 [0·65-1·30] 1·34 [0·77-2·34] 1·04 [0·74-1·46]

68·2% 31·8% 100%

19/990 110/1076 6/166 18/574 18/2679 12/332 183/5817

0·73 [0·36-1·49] 0·39 [0·31-0·50] 1·56 [0·57-4·25] 1·24 [0·64-2·41] 0·60 [0·24-1·52] 0·46 [0·25-0·86] 0·68 [0·42-1·09]

16·2% 24·0% 11·9% 17·0% 12·9% 17·8% 100%

1/204 1/164 13/933 18/1053 32/1313 0/103 1/513 66/4283

105/3511 114/5087 219/8598

OR=0·80 CI 95% [0·57-1·11] P=0·17

13/923 209/4879 12/217 18/467 6/1481 76/4477 334/12444

OR=1·04 CI 95% [0·74-1·46] P=0·83

OR=0·68 CI 95% [0·42-1·09] P=0·11

Randomized CT

Observational from RCT

Observational

ARMYDA5 Preload CIPAMI CLARITY PCI CREDO PCI CURE Davlouros et al. PRAGUE 8 All

ACUITY PCI REPLACE 2 All

Amin et al. Dorler et al. Fefer et al. Feldman et al. Szuk et al. Chan et al. All

Pre-treatment better No Pre-treatment better

Death

N=8,608

N=10,945

N=18,261

Bellemain-Appaix A et al. JAMA 2012;308:2507-2516

Pharmacodynamic Sub-Study

Data presented as median ± SEM. * p<0.05 relative to the No pre-treatment group. LD = loading dose.

Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg; No Pre-treatment=Placebo/Prasugrel 60 mg

Hours (post LD2)

P2Y

12 R

eacti

on

Un

its

0

50

100

150

200

250

300

350

Pre-treatment (30/30)

No Pre-treatment (0/60)

Pre LD1(baseline)

Pre LD2 0.5 2 3 41 24

Approximate

time of PCI

*

*

30 mg

LD1

Placebo

LD1

60 mg

LD2

30 mg

LD2

*P<0.05

1° Efficacy Endpoint

(PCI Patients)

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

5

10

15

20

Pre-treatment14.1

CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout

PCI Cohort

No Pre-treatment13.8

HR, 1.03(95% 0.84, 1.26)P=0.77

HR, 1.01(95% 0.82, 1.24)P=0.93

Pre-treatment13.1

No Pre-treatment13.1

1372

1389

1191

1206

1187

1202

1183

1194

1179

1189

1177

1186

1177

1172

No. at Risk, Efficacy

End Point:

No pre-treatment

Pre-treatment

All TIMI Major Bleeding

(PCI Patients)

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

1

2

3

4

5

Pre-treatment1.7

No Pre-treatment0.7

HR, 2.65 (95% 1.23, 5.70) P=0.010All TIMI Major Bleeding

PCI Cohort

HR, 2.69(95% 1.13, 6.40)P=0.02

Pre-treatment1.4

No Pre-treatment0.5

1372

1389

1356

1364

1302

13141280

1293

1272

1282

1268

1280

1249

1269

No. at Risk, All TIMI

Major Bleeding:

No pre-treatment

Pre-treatment



SCA







SCA





The endothelial glycocalyx

A negatively charged, organized mesh of membranous glycoproteins,

proteoglycans, GAGs and plasma proteins

Major components: Hyaluronic acid and heparan sulfate proteoglycans

Electron microscopy image of the endothelial glycocalyx in a coronary capillary

Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511

Endothelial glycocalyx Physiological functions

Glycocalyx

Endothelium

Subendothelial space

Endothelium NO-synthesis,

superoxide dysmutation

Permeability

sieving barrier

Coagulation

Inhibition of platelet adhesion Coagulation regulatory factors

Inflammation Prevention of

Leukocyte adhesion

Nieuwdorp M et al. Curr Opin Lipidol 2005,16:507-511

Under physiological conditions

Roles: Barrier, storing compartment, coagulation/inflammation pathways, shear stress

transducer

vasomotricity Blood flow regulation

STACKENOX - Results

H4 H6 H10

Effect on anti-Xa (median IU/mL)

Day 3 => Effect of 70/kg i.v. UFH bolus according to the timing of administration after SC

enoxaparin in healthy subjects chronically treated with enoxaparin

Drouet L et al Am Heart J. 2009 Aug;158(2):177-84.

Time from last enoxaparin injection (hours)

GAGs - Beyond anticoagulation

GAG Physiological activities

and therapeutic potential

Alter Glomerular architecture and

tubular reabsorption

Alter binding of growth factors, Cytokines and chemokines

Inhibition of Heparanase

activity

Alter leukocyte rolling

Modulation of gene expression of pathogenic factors

(TGF, VEGF) Interaction with endothelial

glycocalyx

Modulation of Binding to receptor

for AGEs

Modulation of complement

activity

Coating of Artificial surfaces

Quand l’angioplastie-stenting est réalisée sans

héparine = augmentation des événements

thrombotiques sur matériel et péri-procéduraux

les données cliniques : • Avec le fondaparinux (Oasis 5 et 6) amendement

• Avec la bivalirudine (Horizon et EuroMax)

• Avec l’otamixaban (TAO)

Mais pas avec l’enoxaparine (Essence, Atoll)

OASIS 5 NEJM 2006

Besoin d’un minimum d’héparine au moment de la procédure

• In Atoll, the rate of guidewire or catheter thrombosis

was extremely low and similar (1 and 1) in the arm

receiving 0.5mg/KG iv bolus enoxaparin or UFH

• In TAO, the rate of guidewire or catheter thrombosis

was lower with otamixaban. But the patients

received an additional use of HNF for

anticoagulation of the material at the time of PCI

Montalescot G et al Lancet 2011; 378 : 693–703, Steg G, et JAMA. 2013;310(11):1145-1155

Quand l’angioplastie-stenting est réalisée sans

héparine = augmentation des événements

thrombotiques sur matériel et péri-procéduraux

les hypothèses physiopath :

• Effet de surface des glycanes



SCA





INJURED VESSEL

Platelets

Activated Platelets

Collagen

ADP

TXA2

Fibrinogen Fibrin

THROMBIN

Tissue Factor

THROMBIN

Tissue Factor

Tissue Factor

fibrinolysis

Cinétique des marqueurs plasmatiques

Av AP AP H 2 H 6 H 1 2 H 2 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

Av AP AP H 2 H 6 H 1 2 H 2 4

0

2

4

6

8

Fibrinogène (g/l)

Av AP AP H 2 H 6 H 1 2 H 2 4

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

D-Dimères (ng/ml)

Av AP AP H 2 H 6 H 1 2 H 2 4

0

1 0

2 0

3 0

4 0

MF (µg/ml)

TAT (µg/l)

Cinétique des TAT selon le blush myocardique

Av AP AP H 2 H 6 H 1 2 H 2 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

Av AP AP H 2 H 6 H 1 2 H 2 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

Av AP AP H 2 H 6 H 1 2 H 2 4

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

TAT (µg/l) TAT (µg/l)

TAT (µg/l)

B L U S H M Y O C A R D IQ U E

B lu s h 0 /1 B lu s h 2 B lu s h 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

TAT (µg/l)

Blush 0/1 Blush 2

Blush 3

Burst de thrombine et paramètres de dommages myocardiques

TAT (µg/l) TAT (µg/l)

Cinétique des microparticules

Av AP AP H 2 H 6 H 1 2 H 2 4

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

1 4 0 0

MPE CD144/µl

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

T1

T2

T3

Thrombin is inhibited by antithrombin. In vivo thrombin generation results is inactive proteinase/inhibitor complexes (TAT complex). The ex-vivo measrument of these complexes is an indicator of thrombin generation.

Mean ± SD plasma levels of TAT assessed by ELISA at baseline, after 30 min of bivalirudin infusion, and 2 h

POST-termination of the infusion

Carey Kimmelstiel et al Circ Cardiovasc Interv. 2011

Syste

mic

TA

T

(ug

/l)

HORIZONS-AMI

● Three-year all cause mortality

p-value = 0.03

3-yr HR [95%CI]

0.75 [0.58, 0.97]

5.9%

7.7%

All-

Cause M

ort

alit

y (%

)

0

1

2

3

4

5

6

9

10

0 12 15 18 21 24 27 30 33 36

Months

3 6 9

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa inhibitor (n=1802)

7

8

Stone GW et al. Lancet 2011;377:2193-204

UFH + GPI vs. Time: 30-Day Event Rate

Bivalirudin vs. Time: 30-Day Event Rate

Neutrophils

Monocytes

ActivatedPlatelets

Endothelial Cells

ActivatedPlatelets

Resting Platelets

Monocyte

ADP +

TXA2

Resting Platelets

II Tenase Complex

Thrombin

THROMBIN

Prothrombin

Prothrombinase Complex

TF

Activated Platelets

Fibrin

PAR-1

PAR-4

PAR-1

PAR-4

TAFI

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