thrombophilia andcoronary artery disease giovanni barillari anco fvg palmanova 17 ottobre 2009
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THROMBOPHILIA ANDCORONARY ARTERY DISEASE
Giovanni Barillari
ANCO FVG Palmanova 17 ottobre 2009
Proteina C: Meccanismo anticoagulanteProteina C: Meccanismo anticoagulante
TM EPCR
Endothelial cell
FIIa
Vi
VIIIi
PC APC PS
GENETIC POLIMORPHYSMGENETIC POLIMORPHYSM
FACTOR V LEIDENFACTOR V LEIDEN
Factor V Leiden
• Factor V is activated to Va, which acts as a cofactor in the conversion of prothrombin to thrombin
• Normally, Factor Va is degraded by APC and limits prothrombin conversion to thrombin
• Arginine is replaced by Glutamine (Arg506Gln) on the factor V gene, resulting in a protein called factor V Leiden
• Factor V Leiden is less susceptible to inactivation by APC and is now considered “resistant to APC”– This results in a prothrombotic state
• Most common - 40-50% of inherited thrombophilias Found in 5% of the Caucasian population
• Found in 10-20% of patients with first episode of idiopathic DVT
• Found in 50% of patients with recurrent DVT
• 90-95% of those with factor V Leiden are heterozygous Homozygotes have a more severe course
• Acquired forms of APC resistance found in pregnancy, use of OCPs, elevated Factor VIII or those with antiphospholipid antibodies
Factor V Leiden
Factor V Leiden and Arterial thromboembolism (ATE)
“ General population”
Authors Year Patients vs controls
RR (VTE) RR (ATE)
Ridker et al.Physicians Health StudyNEJM, 1995; 332:912-917
1995 374 vs 704 7.0 /
Cushman et al.Cardiovascular Health StudyThromb Haemost, 1998; 79:912-915
1998 147 vs 482 N.A. /
Juul et al.Copenaghen City Health StudyBlood, 2002; 100: 3-10
2002 962 vs 7907 N.A. /
Prevalence of FVL mutation : patients with ischemic arterial events vs control subjects.
Kim and Becker, Am Heart J, 2003
PROTHROMBIN G20210A Mutation
Prothrombin G20210A Mutation
• A Vitamin K-dependant protein synthesized in the liver
• Due to substitution of adenine for guanine
• Results in 30% higher prothrombin levels– This promotes generation of thrombin and impairs
inactivation of Factor Va by APC
• Found in 2% of the Caucasian population
• Seen in 6-10% of patients presenting with first episode of unprovoked DVT
Prevalence of G20210 mutation : patients with ischemic arterial events vs control subjects.
Kim and Becker, Am Heart J, 2003
HYPERHOMOCYSTEINEMIAHYPERHOMOCYSTEINEMIA
Hyperhomocystinemia• Independent risk factor for atherosclerotic and thromboembolic
disease• A 5 µM increase in serum level confers a 80% increased risk to
women and a 60% increased risk to men for atherosclerotic vascular disease
• In patients with coronary artery disease, serum homocysteine levels increase with the number of stenosed coronary vessels
• Hyperhomocystinemia may reflect: – Genetic defects– Folate (most common), pyridoxine (vitamin B6), or cobalamin (vitamin
B12) deficiencies– Renal failure
• Serum levels of homocysteine may be lowered by supplementation with folate, vitamin B6, and vitamin B12
QuickTime™ and aGIF decompressor
are needed to see this picture.
Hajjar KA, J Clin Invest 107:663, 2001
Homocysteine Metabolism and Vascular Dysfunction
Prevalence of MTHFR CC TT mutation : patients with ischemic arterial events vs control subjects.
Kim and Becker, Am Heart J, 2003
Meta-analisi di studi sulle coronaropatie rispetto Meta-analisi di studi sulle coronaropatie rispetto ai polimorfismi di 4 fattori dell’emostasi (fattore V ai polimorfismi di 4 fattori dell’emostasi (fattore V
G1691A, fattore VII G10976A, protrombina G1691A, fattore VII G10976A, protrombina G20210A, e inibitore dell’attivazioneG20210A, e inibitore dell’attivazione
del plasminogeno -1 -675 4G/5G)del plasminogeno -1 -675 4G/5G)
ANTICOAGULANTIANTICOAGULANTI
VSVS
ANTIANTI
AGGREGANTIAGGREGANTI
20% 16.7% 15%20% 16.7% 15%
RATE RATIO vs ASARATE RATIO vs ASA 0.81 0.710.81 0.71
PP 0.03 0.0010.03 0.001
NNTNNT 100 100 67 67
PRIMARY OUTCOMEPRIMARY OUTCOME ADVERSE EVENTS ADVERSE EVENTS
MAJOR Non Fatal BleedingMAJOR Non Fatal Bleeding 0.17 % yr 0.68 0.57 0.17 % yr 0.68 0.57 p<0.001p<0.001
NNTNNT 250 200 250 200
The cumulative hazard curves for the primary end point showed a significant The cumulative hazard curves for the primary end point showed a significant divergence between warfarin groups and the ASA Only group at 4 years (p 0.003) divergence between warfarin groups and the ASA Only group at 4 years (p 0.003) demonstrating the benefits of long term anticoagulation……..demonstrating the benefits of long term anticoagulation……..
However major non fatal bleeding was 3 to 4 fold more frequent among warfarin However major non fatal bleeding was 3 to 4 fold more frequent among warfarin only and combinantion group, thogh percentages per year relatively lowonly and combinantion group, thogh percentages per year relatively low.
INR INR monitoringmonitoring
AGEAGE
RecommendationsRecommendations
2.112.11 For most patients after MI, in health-care settings in whichFor most patients after MI, in health-care settings in which
Meticolous INR monitoring and high skill VKA Dose Titration are Meticolous INR monitoring and high skill VKA Dose Titration are expected and widely accessible we suggest :expected and widely accessible we suggest :
• Long term high intensity oral VKA (target INR 3.5) without ASA orLong term high intensity oral VKA (target INR 3.5) without ASA or
• Moderate intensity oral VKA (target INR 2.5) with ASA (< 100 mg/d)Moderate intensity oral VKA (target INR 2.5) with ASA (< 100 mg/d)
OVER ASA AloneOVER ASA Alone ( 2 B)( 2 B)
POTRANNO I POTRANNO I
NUOVI ANTICOAGULANTINUOVI ANTICOAGULANTI
OFFRIRE NUOVE PROSPETTIVE NEL OFFRIRE NUOVE PROSPETTIVE NEL TRATTAMENTOTRATTAMENTO
DEI PAZIENTI CON DEI PAZIENTI CON TROMBOFILIA ETROMBOFILIA E
CARDIOPATIA ISCHEMICACARDIOPATIA ISCHEMICA
??
WARFARIN ….. OWARFARIN ….. O
Dabigatran ?Dabigatran ?
RELYRELY
RELYRELY
STUDIO TROMBOFILIASTUDIO TROMBOFILIA
A CHI ?A CHI ?
• Pazienti con Trombosi Coronarica in età Pazienti con Trombosi Coronarica in età giovanilegiovanile
• Pazienti con Trombosi Coronarica senza Pazienti con Trombosi Coronarica senza malattia ateroscleroticamalattia aterosclerotica
• Embolia ParadossaEmbolia Paradossa
STUDIO TROMBOFILIASTUDIO TROMBOFILIA
QUALI ESAMI ?QUALI ESAMI ?
• Proteina C, Proteina S, ATProteina C, Proteina S, AT
• APC Resistance, Mutazione Protrombina APC Resistance, Mutazione Protrombina
• LAC, Anti Clp, Anti LAC, Anti Clp, Anti 2 GPI, Anti Protrombina2 GPI, Anti Protrombina
• Omocisteinemia Omocisteinemia
• ( Lp(a) PAI I Ag )( Lp(a) PAI I Ag )
STUDIO TROMBOFILIASTUDIO TROMBOFILIA
QUALI ASPETTATIVE ?QUALI ASPETTATIVE ?
• Identificazione di pazienti a particolarmente Identificazione di pazienti a particolarmente alto rischio tromboembolicoalto rischio tromboembolico
•CON QUALI RICADUTE ?CON QUALI RICADUTE ?
• Possibile utilizzo di trattamento combinato anti Possibile utilizzo di trattamento combinato anti aggregante + anticoagulante ***aggregante + anticoagulante ***