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THROMBOPHILIA ANDCORONARY ARTERY DISEASE

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

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

  3. GENETIC POLIMORPHYSM

  4. FACTOR V LEIDEN

  5. 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

  6. Factor V Leiden • 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

  7. Factor V Leiden and Arterial thromboembolism (ATE) “ General population”

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

  9. PROTHROMBIN G20210A Mutation

  10. 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

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

  12. HYPERHOMOCYSTEINEMIA

  13. 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

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

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

  16. Meta-analisi di studi sulle coronaropatie rispetto ai polimorfismi di 4 fattori dell’emostasi (fattore V G1691A, fattore VII G10976A, protrombina G20210A, e inibitore dell’attivazionedel plasminogeno -1 -675 4G/5G)

  17. ANTICOAGULANTI VS ANTI AGGREGANTI

  18. 20% 16.7% 15% RATE RATIO vs ASA0.81 0.71 P0.03 0.001 NNT 100 67

  19. PRIMARY OUTCOME ADVERSE EVENTS MAJOR Non Fatal Bleeding 0.17 % yr 0.68 0.57 p<0.001 NNT 250 200

  20. 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. AGE INR monitoring