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THROMBOPHILIA ANDCORONARY ARTERY DISEASE. Giovanni Barillari ANCO FVG Palmanova 17 ottobre 2009. VIIIi. Vi. PS. APC. PC. Proteina C: Meccanismo anticoagulante. FIIa. TM. EPCR. Endothelial cell. GENETIC POLIMORPHYSM. FACTOR V LEIDEN. Factor V Leiden.

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THROMBOPHILIA ANDCORONARY ARTERY DISEASE

Giovanni Barillari

ANCO FVG Palmanova 17 ottobre 2009

slide3

VIIIi

Vi

PS

APC

PC

Proteina C: Meccanismo anticoagulante

FIIa

TM

EPCR

Endothelial cell

factor 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
slide14

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
slide16

Prevalence of FVL mutation : patients with ischemic arterial events vscontrol 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
slide22

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

Kim and Becker, Am Heart J, 2003

hyperhomocystinemia
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
slide38

Homocysteine Metabolism and Vascular Dysfunction

Hajjar KA, J Clin Invest 107:663, 2001

slide41

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

Kim and Becker, Am Heart J, 2003

slide42

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)

anticoagulanti
ANTICOAGULANTI

VS

ANTI

AGGREGANTI

slide48

20% 16.7% 15%

RATE RATIO vs ASA0.81 0.71

P0.03 0.001

NNT 100 67

slide49

PRIMARY OUTCOME ADVERSE EVENTS

MAJOR Non Fatal Bleeding 0.17 % yr 0.68 0.57 p<0.001

NNT 250 200

slide50

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

slide51

Recommendations

  • 2.11For 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)
slide52

POTRANNO I

NUOVI ANTICOAGULANTI

OFFRIRE NUOVE PROSPETTIVE NEL TRATTAMENTO

DEI PAZIENTI CON TROMBOFILIA E

CARDIOPATIA ISCHEMICA

?

slide57

STUDIO TROMBOFILIA

  • A CHI ?
  • Pazienti con Trombosi Coronarica in età giovanile
  • Pazienti con Trombosi Coronarica senza malattia aterosclerotica
  • Embolia Paradossa
slide58

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 )
slide59

STUDIO TROMBOFILIA

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