• Save
Conti Laura. Emicrania e Trombofilia. ASMaD 2011
Upcoming SlideShare
Loading in...5
×
 

Conti Laura. Emicrania e Trombofilia. ASMaD 2011

on

  • 1,814 views

 

Statistics

Views

Total Views
1,814
Views on SlideShare
1,806
Embed Views
8

Actions

Likes
0
Downloads
0
Comments
0

3 Embeds 8

http://www.santeugenioroma.it 5
http://translate.googleusercontent.com 2
http://www.mefeedia.com 1

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • * 16/07/96 * ## Patients, particularly adults, rarely have just one risk factor. As we go along, see how many risk factors you can identify for this patient.
  • * 16/07/96 * ##
  • * 16/07/96 * ##
  • * 16/07/96 * ##
  • * 16/07/96 * ##
  • * 16/07/96 * ##

Conti Laura. Emicrania e Trombofilia. ASMaD 2011 Conti Laura. Emicrania e Trombofilia. ASMaD 2011 Presentation Transcript

  • Dr.ssa Laura Conti UOSD Patologia Clinica IRE Istituto Nazionale Tumori Regina Elena Roma Emicrania e Trombofilia
  • Definizione di Trombofilia ereditaria
    • Tendenza geneticamente determinata all’evento tromboembolico con una o più delle seguenti caratteristiche:
      • Tromboembolismo in giovane età
      • Tendenza alla recidiva
      • Inusuale localizzazione della trombosi
      • Storia familiare positiva
    • ( Lane et al, Thromb Haemost 1996)
  • Cause principali di trombofilia Disfibrinogenemia Variante 20210 Iperprotrombinemia Sindrome Nefrosica Iperomocisteinemia PNH Fattore V Leiden Sindromi Mieloproliferative Difetti di Proteina S Neoplasia e CVC Difetti di Proteina C APLA (LAC,ACA) Difetti di AT DIFETTI ACQUISITI DIFETTI EREDITARI
  • Prevalenza delle alterazioni trombofiliche Prevalenza % Rischio relativo Carenza di AT 1 5-50 Carenza di PC 3 7-10 Carenza di PS 1-2 6-10 Fattore V G1691A 15-20 7-10 Fattore II G20210A 6 2-3 Iperomocisteinemia 10 2 Aumento FVIII 25 4 LAC 5 9
  • La cascata coagulativa
  • Meccanismo Anticoagulante della Proteina C Corrente ematica VIIIa inattivo Superficie fosfolipidica Trombomodulina Va inattivo PC APC T T PC VIIIa V IXa PS VIII APC V Xa PS Va APC
  •  
  • Protrombina Anomala
    • SOSTITUZIONE DELLA GUANINA IN ADENINA NEL NUCLEOTIDE 20210 DEL GENE DELLA PROTROMBINA.
    • AUMENTATA CONCENTRAZIONE PLASMATICA DELLA PROTROMBINA >30%
    • AUMENTATO RISCHIO DI TROMBOSI VENOSE: IL 18 % DEI PAZIENTI GIOVANI CON TROMBOSI VENOSE E’ PORTATORE DI TALE ANOMALIA.
    • TALE DIFETTO E’ PRESENTE NELL’ 1.2-2.3 % DELLA POPOLAZIONE NORMALE.
  • Un Nuovo Fattore di Rischio Modificabile: l’Iperomocisteinemia “ L’Iperomocisteinemia è un fattore di rischio indipendente per malattia cardiovascolare?
  • Homocysteine and Endothelial Effects
    • The mechanism by which homocysteine exerts its cardiovascular disease effects are now being elucidated. Many authorities have studied this link. The working hypothesis is that elevated homocysteine levels:
    • 1. promote oxidant injury to the vascular endothelium
    • 2. impairs endothelium-dependent relaxation
    • 3. alters the coagulant properties of blood
    • References:
    • Ozdemir R, Barutcu I, et.al. Vascular Endothelial Function and Plasma Homocysteine Levels in Behcet’s Disease, Am J Cardiol 2004;94:522-525.
    • Austin RC, Lentz SR, Werstuck GH. Role of HyperHCYemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004 Jul;11 Supple 1:S56-64.
  • Homocysteine and Endothelial Effect s
    • Other theories include:
    • a) Elevated homocysteine levels release extracellular superoxide dismutase from the endothelial wall, causing a higher likelihood of atherosclerotic changes to the blood vessels
    • b) Moderate HyperHCYemia may develop secondary to cellular immune activation, usually in response to a chronic disease condition
    • c) Hyperhomocysteinemia decreases bioavailability of nitric oxide, thus decreasing endothelial vasodilator function.
    • References:
    • Nihei S, Tasaki H, et.al. HyperHCYemia is associated with human coronary atherosclerosis through the reduction of the ratio of endothelium-bound to basal extracellular superoxide dismutase. Circ J. 2004 Sep;68(9):822-8
    • Schroecksnadel K, Frick B, Winkler C, et.al. HyperHCYemia and immune activation. Clin Chem Lab Med. 2003;41:1438-1443.
  • Epidemiology
    • Prevalence of hyperhomocysteinemia is not insignificant:
    • 1. general population: 5 - 10%
    • 2. elderly population: 30 - 40%
    • 3. pts with vascular disease: 20 - 40%.
    • References:
    • Annu Rev Med 1998;49:31-62. HCY and cardiovascular disease. Refsum H, Ueland PM, et.al.
    • JAMA 1993;270:2693-8. Vitamin status and intake as primary determinants of HCYemia in an elderly population. Selhub J, Jacques PF, et.al.
    • Jacques PF, Bostom AG, Wilson PW, et.al. Determinants of plasma total HCY concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-621.
  • I Livelli Plasmatici di Omocisteina Totale. Distribuzione dei Valori di Omocisteina nella Popolazione “ Agreement among four homocysteine assay and results in patients with coronary atherosclerosis and controls” Yu, HH et al., Clinical Chemistry 2000 Range normale (a digiuno) 5-15  mol/l Desiderabile (?) <10  mol/l Iperomocisteinemia Moderata 16-30  mol/l Intermedia 31-100  mol/l Severa >100  mol/l
  • Homocysteine Metabolism THE LANCET Neurology Vol 2 July 2003, 425 – 428. B12 dependent methionine synthetase B6 dependent carbon exchange inhibition activated B6 dependent cystationine-beta-synthase Betaine in the liver Remethylation pathway Folic Acid dependent Urine Excess
  • Cause di Iperomocisteinemia
    •  Difetti genetici del metabolismo
    • dell’omocisteina (polimorfismo)
    • C  S (cystationine  -syntase)
    • polimorfismo G919A,T833C
    • MTHFR (methylene tetrahydrofolate
    • reductase) polimorfismo C677T,
    • A1298C, G1793A
    • Metionina sintetasi reduttasi
    • polimorfismo A66G
    •  Carenze nutrizionali (acquisite):
    • Folato
    • Vitamina B 12 e B 6
    • Metionina
    •  Patologie
    • Insufficienza renale cronica
    • Malattia renale terminale
    • Ipotiroidismo
    • Anemia perniciosa
    • Neoplasie (LLA, ovaio, mammella, pancreas)
    • Diabete tipo 2
    • Diabete tipo 1 e nefropatia
    • LES
    • Disordini iperproliferativi
    • Psoriasi grave
    • Malattie infiammatorie intestino
    • Trapianto di cuore o di altri
    • organi
    1
  • Ipotetici Effetti dell’Omocisteina sulla Funzione Endoteliale “ Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia” Weiss, N. et al., Vascular Medicine 2002 Vascular endothelial cells Omocisteina Alterata funzione vasodilatarice Stato protrombotico Reclutamento e adesione leucocitaria Attivazione e aggregazione piastrinica Dimetilarginina asimmetrica Chemochine Molecole di adesione Tissue factor Factor Va Thrombomodulina Attivazione Proteina C Legame antithrombina Legame Attivatore plasminogeno O 2 - Ossido nitrico Cellule endoteliali vascolari
  • Omocisteina e Malattie Cardiovascolari : Studi Caso-Controllo vs Studi Prospettici: Rischio Relativo di Coronaropatia (sx) o Malattie Cerebrovascolare (dx) Associato a Elevati Livelli di Omocisteina Plasmatica “ Blood levels of homocysteine and increased risks of cardiovascular disease. Causal or Casual?” Christen, WG et al., Arch Intern Med 2000 0.1 1.0 10.0 100.0 Relative risk (95% CI) 0.5 5.0 50.0 500.0 Relative risk (95% CI)
  • “ Homocysteine lowering with Folic Acid and B Vitamins in vascular disease” The Heart Outcomes Prevention Evaluaton (HOPE) 2 Investigators N Engl Med 2006 Livelli Plasmatici di Omocisteina Totale, Folato, Vitamina B6 e Vitamina B12 Percentuale di Pazienti con l’Endpoint Primario Composito di Morte per Cause Cardiovascolari, Infarto Miocardico, o Stroke HOPE-2 5522 soggetti di età > 55 anni che avevano una malattia vascolare o diabete trattati con una combinazione di acido folico 2.5mg, vitamina B 6 50mg e vitamina B 12 1mg o con placebo. Follow-up: 5 anni Baseline two five years years Baseline two years Baseline two years Baseline two years Total Homoysteine Folate Vitamna B6 Vitamina B12 Years Placebo 50 40 30 20 10 0 400 300 200 100 0 1000 800 600 400 200 0 25 20 15 10 5 0 Acido folico, B6, and B12 Placebo Folic acid B6, and B12 0 1 2 3 4 5 0.25 0.2 0.15 0.10 0.05 0.00 Proportion of Patients with Composite Primay Endpoint P=0.41
  • VISP STUDY
    • In the recently completed Vitamin Intervention for Stroke Prevention (VISP) study, Toole, et.al. investigated the homocysteine-lowering effects of B vitamins in over 40,000 men with established history of cerebrovascular accidents.
    • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
  • VISP STUDY
    • Even though a mean reduction of HCY in the high-dose vitamin supplementation group of 2 micromol/l greater than in the low-dose group was achieved, no significant effect on the above end points occurred.
    • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
  • VISP STUDY
    • Even though a mean reduction of HCY in the high-dose vitamin supplementation group of 2 micromol/l greater than in the low-dose group was achieved, no significant effect on the above end points occurred.
    • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.
  • Emicrania e trombofilia
    • Interrelationships among MTHFR C677T polymorphism, migraine and cardiovascular disease :
    • Women’s Health Study (WHS) : (25.000 white US women).
    • Women carryng the TT genotype had significantly higher serum homocysteine levels compared with carrier of the CC and CT genotypes.
    • Women carryng the TT genotype were less likely to have any history of migraine (age–adjusted OR = 0.89).
    • During a mean of 11.9 years of follow-up, 625 major CVD events were observed (275 ischemic strokes, 268 Myocardial infarction).
    • Women with any history of migraine had increased risk for maior CVD (adjusted HR 1.29 ), this risk was only apparent in women with active migraine with aura (multivariate adjusted HR 2.06 ).
    • The TT genotype in women with active migraine with aura increased risk for ischemic stroke (multivariate adjusted HR 4.19 ; p = 0.01)that was not seen for MI.
  • Markus Schürks, et al. Neurology 2008;71;505
  • Interrelationships between MTHFR 677TT genotype, migraine with aura, and ischemic stroke as well as other gene variants and environmental factors
  •  
  • Emicrania e trombofilia
    • Rubino et al. performed a meta-analysis of all published studies investigating the MTHFR gene and migraine.(Cephalagia 2009)
    • Conflicting data concerning the association between migraine and C677T polymorphism of the MTHFR gene, heterogeneity among study was high, ethnicity was a significant source of that.
    • Positive association between the TT genotype and only in migraine with aura compared with the CC genotype (Fixed effects OR 1.30, 95% confidence interval (CI) 1.06, 1.58; Random effects OR 1.66, 95% CI 1.06, 2.59). In the same subgroup a significant difference was observed in the comparision between TT and CT+CC genotypes (FE OR 1.32, 95% CI 1.10, 1.59; RE OR 1.63, 95% CI 1.10, 2.43).
  • E Rubino, and al. Cephalalgia 2009 29: 818
  • Emicrania e trombofilia
    • MTHFR genotypes associated with migraine clinical variables
    • Liu et al analysed the clinical profile, migraine symptoms, and treatments of 267 migraineurs previously genotyped for the MTHFR C677T variant.
    • The MTHFR group consisted of 27% males and 73% females; 94% of individual with the MTHFR TT genotype, suffered from MA as compared to 61% and 55% of individuals carrying the CC and CT genotypes respectively.
    • Of the 50 variables tested and after Bonferroni correction for multiple testing, migraine diagnosis, unilateral head pain, physical activity discomforts and stress as a migraine trigger were all factors that were significantly associated with MTHFR genotype.
  • Liu et al. BMC Research Notes 2010, 3:213
    • The inner lining of our bloods vessels is the Endothelium
    • It plays a central role in regulating the vasomotor tone
    • Local homeostasis and control of the coagulation process
    • Endothelial cells have ‘ Sensors ’ and release ‘ Mediators ’
    • ‘ Mediators ’ are the functional molecules on the cell surface
    The Vascular Endothelium
  • Changes in endothelium antithrombotic properties .
    • In cultured endothelial cells homocysteine
      • decreases thrombomodulin-dependent protein C activation.
      • enhances platelet adhesion
      • decreases intercellular adhesion molecule
    • Homocysteine impairs the processing and secretion of von Willebrand factor
    • In cultured endothelial cells homocysteine promotes thrombosis by
      • a) enhancing factor V activation;
      • b) affecting tissue plasminogen activator binding to the endothelium;
      • c) inhibiting heparan sulfate anticoagulant activity;
      • d) inducing synthesis of procoagulant tissue Factor.
  • Emicrania e trombofilia
    • Epidemiological studies suggest that migraine is associated with disorders of the cerebral, coronary, retinal and peripheral vasculature .
    • The vasculopathy of migraine is thought to reflect endothelial dysfunction, a disorder of endothelial activation (proinflammatory and procoagulant) and impaired vascular reactivity, which is a risk factor for vascular events.
    • Endothelial activation markers and polymorphism of gene associated with endothelial disfunction have been identified.
    • Angiotensin I-converting enzyme (ACE) deletion/deletion (DD) polymorphism has associated with endothelial dysfunction, possibly through effects on nitric oxide pathways.
    • Endothelial nitric oxide synthase (eNOS)gene Glu298Asp polimorphism has been demonstated to decrease NOS activity.
    • (eNOS)gene Glu298Asp genotypes in combination with the MTHFR 677 TT or ACE DD genotype increase the risk of ischaemic stroke.
  • Model of relationship of migraine and endothelial dysfunction
  • Regulatory Functions of the Endothelium Normal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis Platelet Disaggregation NO, PGI2 Adhesion Molecules CAMs, P,E Selectins Antiproliferation NO, PGI2, TGF-  , Hep Growth Factors ET-1, A-II, PDGF, ILGF, ILs Lipolysis Inflammation ROS, NF-  B PAI-1, TF- α , Tx-A2 tPA, Protein C, TF-I, vWF LPL Vogel R
  • Am J Cardiol 2004; 94: 1012-1016 Patent Foramen Ovale and Trombofilia
  • (from Giardini A et al, Am J Cardiol 2004; 94: 1014)
  • (from Giardini A et al, Am J Cardiol 2004; 94: 1015)
  • META-ANALYSIS (Pezzini et al., Thromb Haemost 2009;101:813-817)
    • Conflicting results are available on the association of Thrombophilia with patent foramen ovale.
    • They analysed data from six eligible studies.
    • The Prothrombin G20210 mutation was significantly associated with PFO-related stroke in comparison with both control subjects (OR 3.85, 95% , CI 2.22-6.66 ) and non PFO-associated stroke patients (OR 2.31; 95% CI 1,20-4.43).
    • Rischio di stroke e di recidiva ischemica verosimilmente aumentato nei pz con PFO e trombofilia
    • In tutti i pazienti con primo episodio di ischemia cerebrale ad età
    • <55 anni è opportuno eseguire uno screening per trombofilia
    • Necessità di ulteriori evidenze scientifiche con studi prospettici e popolazioni più ampie e accuratamente selezionate
    Patent Foramen Ovale and Trombofilia
  • Emicrania e trombofilia
    • Herak et al analyzed data for a total of 150 children with stroke (79),
    • TIA (36), or migraine (35) and 112 control subjects
    • Factor V G1691A has an important role in susceptibility to arterial ischemic stroke, both in perinatal/neonatal period and in childhood as well as transient ischemic stroke.
    • .
    • Human platelet alloantigen polymorphism HPA-2b may increase the risk of transient ischemic attacks and migraine, but this should be confirmed in larger studies. The presence of the human alloantigene -2b was associated with a 2.23 fold increase risk for mifgraine.
  • Anomalie congenite riscontrate in età pediatrica
    • In neonati , la trombosi della vena cava inferiore e l’infarto corticale dell’arteria cerebrale media sono stati osservati in soggetti con fattore V Leiden, in presenza o meno di altri fattori di rischio.
    • In bambini (0.1 - 18 aa.) con trombosi arteriose o venose, in varie sedi, è stata riscontrata la presenza del fattore V Leiden e di difetti degli inibitori AT, PC, PS (31.7 - 46 %).
  • Situazioni nelle quali è indicato eseguire uno screening per trombofilia
  • Linee guida per l’esecuzione di uno screening per trombofilia
  • DOMANDE?
    • GRAZIE!