La preparazione alla PCI nelle SCA Razionale all’impiego degli antiaggreganti e degli anticoagulanti Firenze, 23 gennaio

1. 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

2. 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

5. 1. Fase di Inizio La lesione della parete vascolare mette il sangue a contatto con le cellule subendoteliali. Il fattore tissutale (TF) viene esposto e si lega al FVIIa o FVII che viene di conseguenza convertito in FVIIa. Il complesso TF/ FVIIa attiva FIX e FX. Il FXa si lega al FVa sulla superficie della cellula.

6. Toschi V et al, Circulation 1997

7. 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 attivate legano FVa, FVIIIa e FIXa.

9. Gli anticoagulanti L’eparina non frazionata (UFH) Le eparine a b.p.m.(LMWH) Gli inibitori del Xa (fondaparinux) Gli antitrombinici diretti (bivalirudina)

10. AT Xa AT Xa p p IIa IIa AT AT MS p p MS MS MS MS MS MS MS • MW 1.7-5.4 kDa • 5-17 monosaccharide units • Only anti-FXa activity • p = pentasaccharide • 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.

11. IXa VIIIa Ca2+ PL Xa Va Ca2+ PL Factor Xa: At the core of the coagulation cascade1 Intrinsic pathway Intrinsic pathway Extrinsic pathway 1 Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin2 X Xa 50 II IIa Fibrin Fibrinogen Clot 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.

12. Fibrinogen binding site Arg Val Active site Thrombin C Mattson, AstraZeneca

13. Arg Val Fibrin Thrombin Fibrinopeptides C Mattson, AstraZeneca

14. Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Val Val Val Val Val Val Val Val Val Val Val Val Val DTI Thrombin C Mattson, AstraZeneca

15. Platelets and Coronary Thrombosis Coronary plaque Erosion/rupture Thrombotic occlusion Davies MJ. Am J Cardiol. 2001 Aug 16;88(4A):2F-9F

16. 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. Il “burst” di trombina induce la formazione di un coagulo stabiledi fibrina. 3. Fase di Propagazione

18. The Role of Platelets in Atherothrombosis Adhesion Aggregation 1 3 Activation 2

20. clopidogrel

21. Thrombogenesis Platelet Aggregation GPIIb/IIIa Fibrinogen

23. GPIIb/IIIa Inhibitors Binding Small molecule Abciximab Artist’s conception. Competitive blockadeHighly specific for GPIIb/IIIaMimic amino acid sequences Steric hindrance Nonspecific Binds with 3 chain on GPIIb/IIIa, v3

24. Recettori piastrinici

26. CONTROL CONTROL TFPI TFPI LIPID RICH PLAQUE Badimon JJ, Lettino M, Toschi V et al, Circulation 1999

27. Platelet TF & Thrombus Growth 3.6 months Nemerson Y, 2000

28. TF 47 KDa Resting Platelets HUVEC TNFa Unstimulated Unstimulated ADP ADP Tissue Factor P-selectin Camera et al ATVB 2003

29. Platelets contain TF mRNA Leukocytes Platelets TF plasmid Negative Ctrl Marker 1000 bp 700 bp 500 bp TF 200 bp CD 45 100 bp Camera M et al, 2002

30. 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

32. La microembolizzazione periferica e la riocclusione Inibitori del recettore GPIIbIIIa Anticoagulanti Antiaggreganti piastrinici 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

33. Clopidogrel Improved Coronary Perfusion1 25 36% reduction* p <0.001 21.7 20 15.0 15 Primary endpoint* (%) 10 5 Placebo (n=1,739) Clopidogrel (n=1,752) *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 [0.530.76]; p <0.001) 1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

34. Formazione e propagazione del trombo Microembolizzazione periferica Riocclusione