tselepis 2
DESCRIPTION
ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Αλέξανδρος Δ. Τσελέπης, MD, PhD Καθηγητής Βιοχηµείας - Κλινικής Χηµείας The Coagulation Cascade Η θροµβίνη µετατρέπει το Ινωδογόνο σε ινώδες και ενεργοποιεί τα αιµοπετάλια Θρόµβος PAR : protease activated receptor PARs -1, -2, -3, -4 Κυτταρικές δράσεις των υποδοχέων PAR Shah R, et al. Am Heart J 2009;157:253-62 Thrombin and vascular cells Δοµικά και λειτουργικά χαρακτηριστικά των PARs Shah R, et al. Am Heart J 2009;157:253-62TRANSCRIPT
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Αλέξανδρος Δ. Τσελέπης, MD, PhDΚαθηγητής Βιοχηµείας - Κλινικής Χηµείας
ΠΑΝΕΠΙΣΤΗΜΙΟ ΙΩΑΝΝΙΝΩΝΕΡΕΥΝΗΤΙΚΟ ΚΕΝΤΡΟΑΘΗΡΟΘΡΟΜΒΩΣΗΣ
Ανταγωνιστές των αιµοπεταλιακών υποδοχέων της θροµβίνης. Θα έχουν θέση
στη νεώτερη αντιαιµοπεταλιακή φαρµακολογία;
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The Coagulation Cascade
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Η θροµβίνη µετατρέπει το Ινωδογόνο σε ινώδες και ενεργοποιεί τα αιµοπετάλια
Θρόµβος
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PAR : protease activated receptor
PARs -1, -2, -3, -4
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Κυτταρικές δράσεις των υποδοχέων PAR
Shah R, et al. Am Heart J 2009;157:253-62
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Thrombin and vascular cells
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Δοµικά και λειτουργικά χαρακτηριστικά των PARs
Shah R, et al. Am Heart J 2009;157:253-62
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Αιµοπεταλιακοί υποδοχείς της θροµβίνης
PAR-1(υψηλής συγγένειας
υποδοχέας με
7 διαμεμβρανικές
περιοχές)
PAR4 (“χαμηλής
συγγένειας”
υποδοχέας)
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AA sequences of the PAR-1 and PAR-4 N-terminal exodomains
Jacques SL, et al. Biochem. J. 2003; 376:733–740
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Vu TK, Cell 1991;64:1057PAR-1
SFLLRN
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Rate limiting step in PAR1 activation is localization of thrombin to the receptor
Proteolytic cleavage is rapid
De Candia E, et al. J Biol Chem 2001;276:4692
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PAR1 = high affinity thrombin receptor(activated by 1 nM thrombin)
hirudin-likebinding site
tethered ligand
cleavage site
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Πρωτεολυτική
ενεργοποίηση του PAR1
Landis, R.C., et al. Ann Thorac Surg 2001;72:2169-75
Σχάση με τη δράση
της θρομβίνης
Ενεργο
ποίηση
G
= Προσδέτης (SFLLRN)
(Coughlin, S.R., et al. J Throm Hemost 2005;3:1800-14)
LDPR
LDPR
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Brass LF, et al. Chest 2003;124;18S-25S
Δοµικά και λειτουργικά χαρακτηριστικά του
PAR-1
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Τhe 8th helix of PAR-1 is important for signaling to G protein
Swift S, et al. JBC 2006; 281:4109–4116
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White HD, et al. Am Heart J 2011;161:450-61
Σηµατοδοτικές πορείες που ενεργοποιούνται από τους PAR-1 υποδοχείς
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#*
0
20
40
60
80
100
120
Baseline 5-days 30-days
Plat
elet
agg
rega
tion
(% m
axim
um)
ADP, 5µmol/L ADP, 10µmol/L
TRAP, 10µmol/L
**
#
#
Fig. 1
Kalatzi, et al. JTH 2011
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How to shut off a permanently activated receptor?
Internalize the receptor
GG
Ca2+ Internalisation anddesensitization
Ishii K, et al. J Biol Chem 1993;268:9780
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19
SPRI
3/14/2004 4spr8 1
LDPR SFLLRNP LDPRNRLLFS
Thrombin""
Signal
Antagonist
X
A PAR-1 antagonist should blocktethered ligand mechanism
PAR-1 Antagonist (TRA)SPRI
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PotencyThrombin is the most potent activator of
plateletsLess bleeding than current anticoagulants
and antiplateletsFibrin pathway unaffectedPlatelet activation by other agonists
unaffected
Therapeutic Profile Anticipated for a PAR-1 Antagonist
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Angiolillo DJ, et al. Eur Heart J 2009
Ανταγωνιστές του PAR-1
Vorapaxar Atopaxar
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Ανταγωνιστές του PAR-1
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Angiolillo DJ, et al. Eur Heart J 2009
PAR-1 antagonists
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Atopaxar
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LANCELOT-ACSStudy design
O’Donoghue ML, et al. Circulation. 2011;123:1843-1853
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LANCELOT-ACSIPA in response to TRAP
400-mg loading dose
O’Donoghue ML, et al. Circulation. 2011;123:1843-1853
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LANCELOT-ACSCURE and TIMI bleeding
O’Donoghue ML, et al. Circulation. 2011;123:1843-1853
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LANCELOT-ACSCURE and TIMI bleeding
O’Donoghue ML, et al. Circulation. 2011;123:1843-1853
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LANCELOT-ACSThe incidence of CVD, MI or stroke up to week 12
O’Donoghue ML, et al. Circulation. 2011;123:1843-1853
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LANCELOT-CADStudy design
Wiviott SD, et al. Circulation. 2011; 123:1854-1863
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LANCELOT-CADIPA in response to TRAP
Wiviott SD, et al. Circulation. 2011; 123:1854-1863
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LANCELOT-CADEfficacy events
Wiviott SD, et al. Circulation. 2011; 123:1854-1863
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LANCELOT-CADCURE and TIMI bleeding
Wiviott SD, et al. Circulation. 2011; 123:1854-1863
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Vorapaxarin patients undergoing non-urgent PCI
Becker RC, et al. Lancet 2009; 373: 919–28
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Vorapaxar TIMI bleeding
0
1.25
2.50
3.75
5.00
TIMI Major/Minor TIMI Major TIMI Minor
PlaceboAll40 mg
%
Becker RC, et al. Lancet 2009; 373: 919–28
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0
2.5
5.0
7.5
10.0
Death/MACE Death/MI MACE MI
40 mgAllPlacebo
%
Becker RC, et al. Lancet 2009; 373: 919–28
Vorapaxar No significant reductions in Death/MACE/MI
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Conclusions
• In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding
• In patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events
• Vorapaxar was not associated with an increase in TIMI major, minor, or non-TIMI bleeding
• While not statistically significant, Vorapaxar was associated with
– Death/MACE: ↓32% overall; ↓46% with 40 mg– MI: ↓41% overall; ↓52% with 40 mg
• Larger trials are required to fully establish the efficacy and safety of atopaxar
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Η δράση της θροµβίνης στα αιµοπετάλια
Brass LF, et al. Chest 2003;124;18S-25S
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Platelet effector signals
αγβ
Activation ofGPIIbIIIa
PI3K Akt
PLCβ Ca2+
PKC
αγβ
PAR4
PAR1
1 nM
20 nM
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Angiolillo DJ, et al. Eur Heart J 2009
Σηµατοδοτικές πορείες που ενεργοποιούνται από τους PAR-1