La preparazione alla PCI nelle SCA

Razionale all’impiego degli antiaggreganti e degli anticoagulanti

Firenze, 23 gennaio 2010

Maddalena Lettino Fondazione IRCCS Policlinico S. Matteo, Pavia

Hemostasis is the process that maintains the integrity of a closed, high-pressure circulatory system after vascular damage

An impermeable platelet and fibrin plug is formed at the site of injury (to prevent blood loss)

Platelets and coagulation must be localized, avoiding clot propagation in the vessel lumen

The clot is later dissolved by protease reaction, fibrinolysis, which also prevents the vessel from being occluded by the clot

La lesione della parete vascolare mette il sangue a contatto con le cellule subendoteliali.

Il FXa si lega al FVa sulla superficie della cellula.

Il complesso TF/ FVIIa attiva FIX e FX.

Il fattore tissutale (TF) viene esposto e si lega al FVIIa o FVII che viene di conseguenza convertito in FVIIa.

1. Fase di Inizio

Toschi V et al, Circulation 1997

Il complesso FXa/FVa converte piccole quantità di protrombina in trombina.

La trombina così generata attiva FVIII, FV, FXI e le piastrine a livello locale.Il FXIa converte il FIX in FIXa.

2. Fase di Amplificazione

Le piastrine attivatelegano FVa, FVIIIae FIXa.

Gli anticoagulanti

L’eparina non frazionata (UFH)

Le eparine a b.p.m.(LMWH)

Gli inibitori del Xa (fondaparinux)

Gli antitrombinici diretti (bivalirudina)

• MW > 5.4 kDa• >17 monosaccharide units• Anti-FXa and anti-thrombin activity• p = pentasaccharide

Figure 1. Differences between the mechanism of AT-mediated inhibition of FXa and that of thrombin by heparins. Inactivation of FXa only requires binding of a short heparin residue containing a short pentasaccharide chain to AT, whereas for thrombin inhibition both binding to AT and to thrombin is necessary, which is only possible with molecules of a MW > 5.4 kDa and consisting or more than 17 monosaccharide units.

AT Xa

p

AT Xa

p

AT IIa

p

AT

p

MSIIa

• MW 1.7-5.4 kDa• 5-17 monosaccharide units

• Only anti-FXa activity • p = pentasaccharide

MS

MS MS MS

MS MS MS

Factor Xa: At the core of the coagulation cascade1

Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2

Intrinsic pathway Extrinsic pathway

1. Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2. Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.

Intrinsic pathway

1

50

Xa X

II

FibrinFibrinogen

Clot

Xa

Va

PL

Ca2+

IIa

VIIIa

Ca2+

PL

IXa

ThrombinThrombin

Active siteActive site

ValVal

ArgArg

Fibrinogen Fibrinogen binding sitebinding site

C Mattson, AstraZeneca

ValVal

ArgArg

FibrinFibrin

FibrinopeptidesFibrinopeptides

ThrombinThrombin

C Mattson, AstraZeneca

ThrombinThrombin

DTIDTI

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArgValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

ValVal

ArgArg

C Mattson, AstraZeneca

Platelets and Coronary Thrombosis

Davies MJ. Am J Cardiol. 2001 Aug 16;88(4A):2F-9F

Coronary plaque Erosion/rupture Thrombotic occlusion

Il complesso FVIIIa/FIXa attiva il FX sulla superficie delle piastrine attivate.

Il FXa in associazione alFVa converte quantità maggiori di protrombinain trombina generando un “burst” di trombina.

3. Fase di Propagazione

Il “burst” di trombina induce la formazione di un coagulo stabiledi fibrina.

Adhesion

The Role of Platelets in Atherothrombosis

Aggregation1

Activation2

3

clopidogrel

Thrombogenesis

Platelet Aggregation

GPIIb/IIIa

Fibrinogen

GPIIb/IIIa InhibitorsBinding

Steric hindranceNonspecific

Binds with 3 chainon GPIIb/IIIa, v33

Competitive blockadeHighly specific for GPIIb/IIIaMimic amino acid sequences

AbciximabSmall molecule

Artist’s conception.Artist’s conception.

Recettori piastrinici

CONTROL CONTROL

TFPI TFPI

LIPID RICH PLAQUE

Badimon JJ, Lettino M, Toschi V et al, Circulation 1999

Platelet TF & Thrombus Growth

Nemerson Y, 2000

3.6 months

P-selectin

ADP

Unstimulated

Tissue Factor

ADP

Unstimulated

47 KDa

HUVECTNF

RestingRestingPlateletsPlatelets

TF

Camera et al ATVB 2003

1000 bp

700 bp

500 bp

200 bp

100 bp

TF

CD 45Pla

tele

tsN

egat

ive C

trl

TF pla

smid

Leuko

cyte

s

Mar

ker

Platelets contain TF mRNA

Camera M et al, 2002

Hemostasis is the process that maintains the integrity of a closed, high-pressure circulatory system after vascular damage

An impermeable platelet and fibrin plug is formed at the site of injury (to prevent blood loss)

Platelets and coagulation must be localized, avoiding clot propagation in the vessel lumen

The clot is later dissolved by protease reaction, fibrinolysis, which also prevents the vessel from being occluded by the clot

Aggregati di piastrine attivate e leucociti possono migrare distalmente all’occlusione coronarica e compromettere il microcircolo, limitando il beneficio della riperfusione. In sede di lisi/frantumazione del trombo lo stimolo alla retrombosi e’ elevatissimo

La microembolizzazione periferica e la riocclusione

Inibitori del recettore GPIIbIIIa

AnticoagulantiAntiaggreganti piastrinici

Clopidogrel Improved Coronary Perfusion1

*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (odds ratio: 0.64 [0.530.76]; p <0.001)

Placebo(n=1,739)

Clopidogrel(n=1,752)

21.7

15.0

5

10

15

20

25Pr

imar

y en

dpoi

nt*

(%)

36% reduction*p <0.001

1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

Formazione e propagazione del trombo

Microembolizzazione periferica

Riocclusione