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THROMBOPHILIA ANDCORONARY ARTERY DISEASE
Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009
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Proteina C: Meccanismo anticoagulante
Vi VIIIi FIIa PS APC TM PC EPCR Endothelial cell
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GENETIC POLIMORPHYSM
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FACTOR 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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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
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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 Study NEJM, 1995; 332: 1995 374 vs 704 7.0 / Cushman et al. Cardiovascular Health Study Thromb Haemost, 1998; 79: 1998 147 vs 482 N.A. Juul et al. Copenaghen City Health Study Blood, 2002; 100: 3-10 2002 962 vs 7907
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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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HYPERHOMOCYSTEINEMIA
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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 Iatrogenic causes of elevated homocysteine include methotrexate therapy, theophylline, L-dopa and the co-administration of niacin and bile acid sequestrants. Increased risks of atherosclerotic disease based on micromolar increases in homocysteine were derived from a metanalysis of 27 studies (JAMA 1995;274: )
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Homocysteine Metabolism and Vascular Dysfunction
Homocysteine (HC) is formed by demethylation of methionine via S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHC). HC is eliminated in the methionine cycle by remethylation through the action of methionine synthase (MS), a vitamin B12-dependent enzyme. In this reaction, methyltetrahydrofolate (CH3THF) serves as the methyl donor, and is formed from methylene tetrahydrofolate (CH2THF) through the action of methyltetrahydrofolate reductase (MTHFR). CH2THF is formed from tetrahydrofolate (THF), a folate derivative. Alternatively, HC can participate in transsulfuration in which it condenses with with serine through the action of the vitamin B6-dependent enzyme, cystathionine--synthase (CBS). Cystathionine then splits into cysteine and -ketobutyrate. HC can modify vascular cell function by forming a direct disulfide protein derivative, as in the case of the fibrinolytic receptor, annexin II; by inducing a prothrombotic phenotype through largely unknown mechanisms; or by undergoing auto-oxidation, generating superoxide radicals (redox stress), leading to depletion of nitric oxide (NO) and expression of acute stress-related genes. Redox stress may also activate the proinflammatory transcription factor NF-B, which may induce expression of of TNF-, RAGE/EN-RAGE, VCAM-1, tissue factor, and MMP-9. TNF- may also induce activation and nuclear translocation of NF-B. Thus, there are two pathways shown which reduce homocysteinelevels which are modified by folate, pyridoxine (B6) and B12. Hajjar KA, J Clin Invest 107:663, 2001
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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 ai polimorfismi di 4 fattori dell’emostasi (fattore V G1691A, fattore VII G10976A, protrombina G20210A, e inibitore dell’attivazione del plasminogeno G/5G)
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ANTICOAGULANTI VS ANTI AGGREGANTI
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20% % % RATE RATIO vs ASA P NNT
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PRIMARY OUTCOME ADVERSE EVENTS
MAJOR Non Fatal Bleeding % yr p<0.001 NNT
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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. INR monitoring AGE
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Recommendations 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 Moderate intensity oral VKA (target INR 2.5) with ASA (< 100 mg/d) OVER ASA Alone ( 2 B)
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? POTRANNO I NUOVI ANTICOAGULANTI
OFFRIRE NUOVE PROSPETTIVE NEL TRATTAMENTO DEI PAZIENTI CON TROMBOFILIA E CARDIOPATIA ISCHEMICA ?
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WARFARIN ….. O
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Dabigatran ?
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RELY
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RELY
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STUDIO TROMBOFILIA A CHI ?
Pazienti con Trombosi Coronarica in età giovanile Pazienti con Trombosi Coronarica senza malattia aterosclerotica Embolia Paradossa
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STUDIO TROMBOFILIA QUALI ESAMI ? Proteina C, Proteina S, AT
APC Resistance, Mutazione Protrombina LAC, Anti Clp, Anti 2 GPI, Anti Protrombina Omocisteinemia ( Lp(a) PAI I Ag )
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STUDIO TROMBOFILIA QUALI ASPETTATIVE ? CON QUALI RICADUTE ?
Identificazione di pazienti a particolarmente alto rischio tromboembolico CON QUALI RICADUTE ? Possibile utilizzo di trattamento combinato anti aggregante + anticoagulante ***
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