Il rischio tromboembolico nelle patologie arteriose evenose della donna

Plinio FabianiPortoferraio

Tromboembolismo: di che cosa stiamo

parlando?

• Nel sistema venoso– Trombosi venosa profonda

• con o senza embolia polmonare

• Nel sistema arterioso– Embolia cerebrale– Embolia periferica

Plinio Fabiani

Precisiamo: Sesso o Genere?

definizione OMS

• Sesso: classificazione di maschio o femmina in relazione alle funzioni riproduttive, si basa sulle caratteristiche biologiche che definiscono uomo o donna

• Genere : comprende comportamenti, attività e attributi che una società considera specifici per l’uomo e per la donna, e il modo di vedersi come maschio o femmina anche in relazione al proprio ruolo sociale

Rudolf Virchow 1821-1902

• Rallentamento del flusso

• Lesione endoteliale

• Alterazioni della coagulazione

Tromboembolismo venoso (TEV)entità del problema

• Nord America e Europa incidenza annua– TVP 160/100.000– EP sintomatica non fatale 20/100.000– EP fatale (autopsia) 50/100.000– S. Postflebitica con ulcere (prev.) 75/100.000

- Probabilità ALTA- Probabilità ALTA 3 3

- Probabilità MODERATA 1-2- Probabilità MODERATA 1-2

- Probabilità BASSA- Probabilità BASSA 0 0

B-MODE

v. femorale superficiale dx

a. Femorale superficiale a. Femorale superficiale

TROMBOSI VENOSA PROFONDA

SEGNI INDIRETTI

B-MODE:

• INCOMPRIMIBILITÀ

•

Basale Compressione

Vena Vena femorale femorale comune comune

Age-specific incidence rates of venous thromboembolism in siblings.

Zöller B et al. Circulation. 2011;124:1012-1020

Copyright © American Heart Association, Inc. All rights reserved.

Contraccettivi OraliGravidanza e post-partum

Contraccettivi OraliGravidanza e post-partum

Sex Difference in Risk of Second but Not of FirstVenous Thrombosis

Paradox Explained

Rachel E.J. Circulation. 2014;129:51-56

When female reproductive risk factors are taken into account, the risk of a first venous thrombosis is twice as high in men as in women.

OR

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*aggiustato per IMC e fumo

8

6

4

2

0

OR=1

0.0 0.5 1.0

USADanimarc

aInghilterra

FranciaCina

Differenze di genere per le malattie autoimmuni

Prevalenza relativa fra i sessi del Lupus Eritematoso Sistemico

Femmine Maschi

S.T. Ngo et al. / Frontiers in Neuroendocrinology 35 (2014) 347–369

Fattori associati alla trombofilia con meccanismo noto

Perdita di funzione Aumento di funzione

Antitrombina III Fattore V di Leiden

Proteina C Protrombina G20210A

Proteina S Aumento fattore VIII

ASSOCIAZIONE FRA DIFETTI TROMBOFILICIE CONTRACCETTIVI ORALI

0

5

10

15

20

25

30

35

CO

FV LEIDEN

--

--

+

--

--

+

+

+

Ris

chio

R

ela

t ivo

(Vandenbroucke et al, Lancet 1996)

Screening for Factor V Leiden Mutation

• Not cost effective• Adverse

psychological and insurance effects

8000 Screened

400 FVL

1 DVT

More than 500,000 women would need to be screened to prevent 1 death from PE

THROMBOPHILIAAND VENOUS THROMBOEMBOLISMInternational Consensus Statement

Guidelines According to Scientific Evidence

• TEV non provocato (spontaneo)• TEV età<50 fattore predisponente transitorio• TEV in corso di CO, terapia estrogenica sostitutiva , gravidanza• TEV ricorrente• Tromboflebile superficiale ricorrente in assenza di cancro e vene varicose• TV in sede insolita (arti superiori, mesenteriche, seni cerebrali)• Necrosi cutanea indotta da warfarin• Parerenti asintomatici di trombofilici sintomatici• 2 aborti consecutivi o 3 non consecutivi o una morte fetale• Grave pre-eclampsia• TEV in bambini

Int Angiol 2005;24:1-26

Martinelli, I. et al. Nat. Rev. Cardiol. 11, 140–156 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.211

Martinelli, I. et al. Nat. Rev. Cardiol. 11, 140–156 (2014); published online 14 January 2014; doi:10.1038/nrcardio.2013.211

USA 1960: la FDA approva la commercializzazione di Enovid® con

indicazione contraccettiva.EUROPA 1961 Anovlar®

F.M. Primiero, 2012F.M. Primiero, 2012150 mcg di mestranolo 9,85 mg di noretinodrel

norethindrone acetate 4 mg + ethinyl estradiol 50 µg

Generazioni di contraccettivi orali combinati

I generazione II generazione III generazione IV generazione

Norethisteroneo Norethindrone(e.g. Loestrin®)

Levonorgestrel(e.g. Microgynon®)

Desogestrel(Mercilon®, Marvelon®)

Drospirenone (Yasmin®)

Rischio di trombosi in rapporto al Progestinico

(30-40 μg di Etinil Estradiolo)Progestinico Rapporto fra tassi di

incidenza rispetto a levonorgestrel

Levonorgestrel (II g) 1,00

Noretisterone (I g) 0,98

Norgestimate 1,19

Drospirenone (IV g) 1,64

Desogestrel (III g) 1,82

Gestodene (III g) 1,86

Ciproterone acetato 1,88

BMJ 2009;339:b2890

Likelihood of developing a blood clot (number of women with a blood clot

per 10,000 women-years).

http://www.fda.gov/Drugs/DrugSafety/ucm299305

This guideline focuses on the risk factors unique to women, such as •reproductive factors, and those that are more common in women, including •migraine with aura, •obesity, •metabolic syndrome, and •atrial fibrillation. http://stroke.ahajournals.org/content/early/2014/02/06/01.str.0000442009.06663.48

Fem

ale

-male

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o

Stroke 2014 Bushnell et al Guidelines for Prevention of Stroke in Women

61%

Prevalence of Risk Factors Women are older at stroke onset1-7

and more likely to have: Atrial fibrillation4,5,8,9

Hypertension2,3,5,9

Dementia2

Congestive heart failure3

1. Appelros et al. Stroke 2009, 40:1082-10902. Eriksson M et al. Stroke. 2009;40:909-9143. Niewada M et al. Neuroepi. 2005;24:123–128.4. Silva GS et al. Cerebrov Dis 2010;30:470–475

1. Petrea RE et al. Stroke 2009;40;1032-10372. Kapral MK et al. Stroke 2005;36;809-8143. Gargano JW et al. Stroke 2008;39;24-294. Reid JM et al. Stroke 2008;39;1090-10955. Di Carlo A et al. Stroke 2003;34;1114-1119

Effects of Stroke Risk Factors: Sex Related

Women with DM have greater stroke risk compared to men with DM1

MetS: doubles stroke risk in women but not in men2

Migraines: 2-fold increased risk of stroke in women Even higher in women >45 years and those on OCP3

Atrial fibrillation Women with AF have a two-fold greater risk of stroke than

men with AF4

1. Almdal et al. Arch Int Med. 2004;164:1422–26.2. Boden-Albala et al. Stroke. 2008;39:30–35.3. Etminan M et al. BMJ 2005;330;63.4. Wang TJ et al. JAMA 2003;290;1049-1056

Gender differences in the risk of stroke and peripheral embolism in AF: the ATRIA study

RR = 1.6 (1.3-1.9)

RR = 1.6 (1.0-2.3)

RR = 1.8 (1.4-2.3)

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Rat

e (%

)

Fang MC, et al. Circulation 2005;112:1687-91

Date of download: 11/5/2014

Copyright © The American College of Cardiology. All rights reserved.

From: Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation

J Am Coll Cardiol. 2001;37(3):691-704. doi:10.1016/S0735-1097(00)01178-5

Transesophageal echocardiographic image of a mobile and protruding thrombus (arrow) located in the left atrial appendage of a patient with AF scheduled to undergo DC cardioversion. Cardioversion was postponed in this patient. AF = atrial fibrillation; DC = direct current.

Figure Legend:

Outcomes at 6 months• 676 consecutive admissions to teaching hospital• Female sex: independent predictor of poor outcome at 6

mo: 1.57, 95% CI 1.03–2.36, p=0.04

Silva GS et al. Cerebrovasc Dis 2010;30:470–475

Perché l’ictus cardioembolico ha una prognosi severa?

• Più grave all’inizio• Assenza di circoli di compenso e lesioni

multiple • Alto rischio di recidiva • Alto rischio di trasformazione emorragica

CHADS2 -> CHA2DS2VAScCHA2DS2-VASc Risk

Score

CHF or LVEF < 40%

1

Hypertension 1

Age > 75 2

Diabetes 1

Stroke/TIA/ Thromboembolism

2

Vascular Disease

1

Age 65 - 74 1

Female 1

CHADS2 Risk Score

CHF 1

Hypertension 1

Age > 75 1

Diabetes 1

Stroke or TIA 2

From ESC AF Guidelines

http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-afib-FT.pdf

• Oral anticoagulation in women aged ≤65 years with AF alone (no other risk factors; women with CHADS2=0 or CHA2DS2-VASc=1) is not recommended (Class III; Level of Evidence B). Antiplatelet therapy is a reasonable therapeutic option for selected low-risk women (Class IIa; Level of Evidence B).

• New oral anticoagulants are a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent AF and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance 15 mL/min), lower weight (<50 kg), or advanced liver disease (impaired baseline clotting function) (Class I; Level of Evidence A).

Gravidanza e ictus

• 34 ictus per 100.000 parti – (III trim e post partum)

• vs 21 ictus per 100.000

• Stasi,• Edema• Ipercoagulabilità

– Resistenza alla PC– Bassi livelli di Proteina S– Aumento del fibrinogeno

Pregnancy Complications and the Long-term Risk of Stroke

• An expanding body of research has shown that complications of pregnancy – preeclampsia, – gestational diabetes, – pregnancy-induced hypertension

• are associated with higher risk for future CVD and stroke beyond the childbearing years than among women without these disorders

Novel Anticoagulants

• Dabigatran• Rivoroxaban• Apixaban• Edoxaban

New Anticoagulants