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THROMBOPHILIA ANDCORONARY ARTERY DISEASE Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009.

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Presentation on theme: "THROMBOPHILIA ANDCORONARY ARTERY DISEASE Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009."— Presentation transcript:

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

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3 Proteina C: Meccanismo anticoagulante TM EPCR Endothelial cell FIIa Vi VIIIi PC APC PS

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9 GENETIC POLIMORPHYSM

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11 FACTOR V LEIDEN

12 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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14 Most common % 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

15 Factor V Leiden and Arterial thromboembolism (ATE) General population AuthorsYearPatients vs controls RR (VTE)RR (ATE) Ridker et al. Physicians Health Study NEJM, 1995; 332: vs / Cushman et al. Cardiovascular Health Study Thromb Haemost, 1998; 79: vs 482N.A./ Juul et al. Copenaghen City Health Study Blood, 2002; 100: vs 7907N.A./

16 Prevalence of FVL mutation : patients with ischemic arterial events vs control subjects. Kim and Becker, Am Heart J, 2003

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19 PROTHROMBIN G20210A Mutation

20 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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22 Prevalence of G20210 mutation : patients with ischemic arterial events vs control subjects. Kim and Becker, Am Heart J, 2003

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35 HYPERHOMOCYSTEINEMIA

36 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 B 6 ), or cobalamin (vitamin B 12 ) deficiencies –Renal failure Serum levels of homocysteine may be lowered by supplementation with folate, vitamin B 6, and vitamin B 12

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38 Hajjar KA, J Clin Invest 107:663, 2001 Homocysteine Metabolism and Vascular Dysfunction

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41 Prevalence of MTHFR CC TT mutation : patients with ischemic arterial events vs control subjects. Kim and Becker, Am Heart J, 2003

42 Meta-analisi di studi sulle coronaropatie rispetto ai polimorfismi di 4 fattori dellemostasi (fattore V G1691A, fattore VII G10976A, protrombina G20210A, e inibitore dellattivazione del plasminogeno G/5G)

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46 ANTICOAGULANTI VS ANTIAGGREGANTI

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48 20% 16.7% 15% RATE RATIO vs ASA RATE RATIO vs ASA P P NNT NNT

49 PRIMARY OUTCOME ADVERSE EVENTS MAJOR Non Fatal Bleeding 0.17 % yr p<0.001 NNT

50 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) demonstrating the benefits of long term anticoagulation…….. However major non fatal bleeding was 3 to 4 fold more frequent among warfarin only and combinantion group, thogh percentages per year relatively low However major non fatal bleeding was 3 to 4 fold more frequent among warfarin only and combinantion group, thogh percentages per year relatively low. INR monitoring AGE

51 Recommendations 2.11 For most patients after MI, in health-care settings in which Meticolous INR monitoring and high skill VKA Dose Titration are expected and widely accessible we suggest : Long term high intensity oral VKA (target INR 3.5) without ASA or Long 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 Alone( 2 B) OVER ASA Alone( 2 B)

52 POTRANNO I NUOVI ANTICOAGULANTI OFFRIRE NUOVE PROSPETTIVE NEL TRATTAMENTO DEI PAZIENTI CON TROMBOFILIA E CARDIOPATIA ISCHEMICA ?

53 WARFARIN ….. O

54 Dabigatran ? Dabigatran ?

55 RELY

56 RELY

57 STUDIO TROMBOFILIA A CHI ? Pazienti con Trombosi Coronarica in età giovanile Pazienti con Trombosi Coronarica in età giovanile Pazienti con Trombosi Coronarica senza malattia aterosclerotica Pazienti con Trombosi Coronarica senza malattia aterosclerotica Embolia Paradossa Embolia Paradossa

58 STUDIO TROMBOFILIA QUALI ESAMI ? Proteina C, Proteina S, AT Proteina C, Proteina S, AT APC Resistance, Mutazione Protrombina APC Resistance, Mutazione Protrombina LAC, Anti Clp, Anti 2 GPI, Anti Protrombina LAC, Anti Clp, Anti 2 GPI, Anti Protrombina Omocisteinemia Omocisteinemia ( Lp(a) PAI I Ag ) ( Lp(a) PAI I Ag )

59 STUDIO TROMBOFILIA QUALI ASPETTATIVE ? Identificazione di pazienti a particolarmente alto rischio tromboembolico Identificazione di pazienti a particolarmente alto rischio tromboembolico CON QUALI RICADUTE ?CON QUALI RICADUTE ? Possibile utilizzo di trattamento combinato anti aggregante + anticoagulante *** Possibile utilizzo di trattamento combinato anti aggregante + anticoagulante ***


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