THROMBOPHILIA ANDCORONARY ARTERY DISEASE

Giovanni Barillari

ANCO FVG Palmanova 17 ottobre 2009

Proteina C: Meccanismo anticoagulanteProteina C: Meccanismo anticoagulante

TM EPCR

Endothelial cell

FIIa

Vi

VIIIi

PC APC PS

GENETIC POLIMORPHYSMGENETIC POLIMORPHYSM

FACTOR V LEIDENFACTOR 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

• 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

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. /

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

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

Kim and Becker, Am Heart J, 2003

HYPERHOMOCYSTEINEMIAHYPERHOMOCYSTEINEMIA

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

QuickTime™ and aGIF decompressor

are needed to see this picture.

Hajjar KA, J Clin Invest 107:663, 2001

Homocysteine Metabolism and Vascular Dysfunction

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

Kim and Becker, Am Heart J, 2003

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)

ANTICOAGULANTIANTICOAGULANTI

VSVS

ANTIANTI

AGGREGANTIAGGREGANTI

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

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

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

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)

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

??

WARFARIN ….. OWARFARIN ….. O

Dabigatran ?Dabigatran ?

RELYRELY

RELYRELY

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

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 )

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 ***