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

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Page 1: THROMBOPHILIA ANDCORONARY ARTERY DISEASE Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009

THROMBOPHILIA ANDCORONARY ARTERY DISEASE

Giovanni Barillari

ANCO FVG Palmanova 17 ottobre 2009

Page 2: THROMBOPHILIA ANDCORONARY ARTERY DISEASE Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009
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Proteina C: Meccanismo anticoagulanteProteina C: Meccanismo anticoagulante

TM EPCR

Endothelial cell

FIIa

Vi

VIIIi

PC APC PS

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GENETIC POLIMORPHYSMGENETIC POLIMORPHYSM

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FACTOR V LEIDENFACTOR V LEIDEN

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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

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• 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

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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. /

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Prevalence of FVL mutation : patients with ischemic arterial events vs control subjects.

Kim and Becker, Am Heart J, 2003

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PROTHROMBIN G20210A Mutation

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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

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Prevalence of G20210 mutation : patients with ischemic arterial events vs control subjects.

Kim and Becker, Am Heart J, 2003

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HYPERHOMOCYSTEINEMIAHYPERHOMOCYSTEINEMIA

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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

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QuickTime™ and aGIF decompressor

are needed to see this picture.

Hajjar KA, J Clin Invest 107:663, 2001

Homocysteine Metabolism and Vascular Dysfunction

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Prevalence of MTHFR CC TT mutation : patients with ischemic arterial events vs control subjects.

Kim and Becker, Am Heart J, 2003

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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)

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ANTICOAGULANTIANTICOAGULANTI

VSVS

ANTIANTI

AGGREGANTIAGGREGANTI

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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

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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

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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

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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)

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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

??

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WARFARIN ….. OWARFARIN ….. O

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Dabigatran ?Dabigatran ?

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RELYRELY

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RELYRELY

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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

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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 )

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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 ***