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

3. Proteina C: Meccanismo anticoagulanteVi
VIIIi
FIIa PS
APC TM PC
EPCR
Endothelial cell

9. GENETIC POLIMORPHYSM

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

14. 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

15. 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

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

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

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

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 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: )

38. 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

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 dell’emostasi (fattore V G1691A, fattore VII G10976A, protrombina G20210A, e inibitore dell’attivazione del plasminogeno G/5G)

46. ANTICOAGULANTI VS
ANTI
AGGREGANTI

48. 20% % %
RATE RATIO vs ASA P
NNT

49. PRIMARY OUTCOME ADVERSE EVENTS
MAJOR Non Fatal Bleeding % 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.
INR monitoring
AGE

51. 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)

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

53. WARFARIN ….. O

54. Dabigatran ?

55. RELY

56. RELY

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

58. 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 )

59. 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 ***