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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