¿Pruebas de función plaquetaria-genotipado en la práctica clínica diaria? Antonio Tello Montoliu, MD, PhD University of Florida College of Medicine-Jacksonville Cursos de la Casa del Corazón 2012 Nuevos antiagregantes en SCA. Como gestionar el cambio
46
Embed
¿Pruebas de función plaquetaria/genotipado en la práctica ...secardiologia.es/images/e-learning/cdc/3-funcion-plaquetaria... · ¿Pruebas de función plaquetaria-genotipado en
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
¿Pruebas de función plaquetaria-genotipado
en la práctica clínica diaria?
Antonio Tello Montoliu, MD, PhD
University of Florida College of Medicine-Jacksonville
Cursos de la Casa del Corazón 2012 Nuevos antiagregantes en SCA. Como gestionar el cambio
Conflictos de interés
• No declara.
Respuesta a fármacos antiplaquetarios Variabilidad individual en la respuesta a la terapia
antiagregante
% Platelet Aggregation (LTA-ADP 20mmol/L)
97.5
92.5
87.5
82.5
77.5
72.5
67.5
62.5
57.5
52.5
47.5
42.5
37.5
32.5
27.5
22.5
17.5
12.5
7.5
2.5
20
15
10
5
0
Nu
mb
er
of
Pati
en
ts
Riesgo de sangrado Riesgo isquémico
Adapado de Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43.
No-respondedor Hypo-reponsiveness
Extra-respondedor Hyper-reponsiveness
Antiplatelet drugs response variability
Genetic Factors
-Aspirin:
-Polymorphisms GP IIa subunit
(PlA ); COX-1 (C50T); CYP
(2C9); UDP (UGT1A6);
FXIII(Val34Leu)
-Clopidogrel:
- Polymorphism CYP (2C19);
GPIa, P2Y12; GPIIIa
Cellular Factors
-Accelerated platelet turnover.
-Upregulation of platelet signaling
pathways.
-Dysregulation of Ca+2 metabolism.
ncrease oxidative stress.
Clinical Factors
-Poor compliance.
-Drug interactions:
-Aspirin vs NSAID
-Clopidogrel vs PPI, statins,
CCB, coumadin.
-Clinical characteristics:
-ACS
-DM/insulin resistance
-Elevated BMI.
Tomado de: “Pharmacodynamics and Pharmacogenetics- guided antithrombotic therapy” Tello-Montoliu & Angiolillo.
Test Basis Able to monitor Advantages Disadvantages
Turbidometric aggregometry
Platelet aggregation Aspirin P2Y12 inhibitors
Historical gold standard
Large sample volume Complex sample preparation Time-consuming
Impedance aggregometry
Platelet aggregation Aspirin P2Y12 inhibitors
Whole-blood assay
Large sample volume Complex sample preparation Time-consuming
VASP phosphorylation state (flow cytometry)
P2Y12 activation-dependent signaling
P2Y12 inhibitors
Whole-blood assay Very small sample volume Most specific for assessing P2Y12 blockers effect Can be shipped to core lab
Complex sample preparation Requires flow cytometer and experienced technician
ISAR-REACT-4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) Platelet Substudy
Sibbing D, . et al. J Am Coll Cardiol 2012;in press
Respuesta a clopidogrel modificada por polimorfismo
Intestinal absorption
Platelet inhibition
MDR-1
Platelet membrane receptors P2Y12 , GP IIb/IIIa, GP Ia
Clopidogrel
(oral ingestion of pro-drug)
Ge
ne
tic
ta
rge
ts
N
S
O
Cl
O CH3 C
HOOC
* HS
N
O
Cl
OCH3
CYP enzyme system Two sequential steps:
One step: CYP3A4, CYP3A5, CYP2C9, CYP1A2
Both steps: CYP2B6, CYP2C19
Tomado de Marín F, et al. JACC 2009:54;1041.
Fisiología plaquetaria
Angiolillo et al. EHJ, 2010
Holmes MV, et al. JAMA. 2011 28;306(24):2704-14
Respuesta a aspirina
Gurbel PA et al. Circulation 2007:115;3156
Respuesta a fármacos antiplaquetarios Definiciones
• Hiper / Hipo: Definiciones basadas en test de laboratorio
Antes
Treatment
Después Tratamiento
Cambio absoluto: 68%-32%= 36%
Cambio Relativo: (68%-32%)/68% * 100 = 53%
On-treatment platelet reactivity: 32%
Tomado de: “Pharmacodynamics and Pharmacogenetics- guided antithrombotic therapy” Tello-Montoliu & Angiolillo. En “Handbook of Personalized Medicine: Advances in Nanotechnology, Drug Delivery and Therapy” Pan Stanford Publishing ( 2012)
Respuesta a fármacos antiplaquetarios Definiciones