1. Il rischio tromboembolico nelle
patologie arteriose e
venose della donna
Plinio Fabiani
Portoferraio

2. Tromboembolismo: di
che cosa stiamo
parlando?
• Nel sistema venoso
– Trombosi venosa profonda
• con o senza embolia polmonare
• Nel sistema arterioso
– Embolia cerebrale
– Embolia periferica

3. Plinio Fabiani

4. 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

6. Rudolf Virchow 1821-1902
• Rallentamento del
flusso
• Lesione endoteliale
• Alterazioni della
coagulazione

8. 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

9. - Probabilità ALTA- Probabilità ALTA 33
- Probabilità MODERATA 1-2- Probabilità MODERATA 1-2
- Probabilità BASSA- Probabilità BASSA 00

10. B-MODE
v. femorale superficiale dx
a. Femorale superficiale a. Femorale superficiale

11. TROMBOSI VENOSA PROFONDA
SEGNI INDIRETTI
B-MODE:
• INCOMPRIMIBILITÀ
•
Basale Compressione
VenaVena
femoralefemorale
comunecomune

12. 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 Orali
Gravidanza e post-partum
Contraccettivi Orali
Gravidanza e post-partum

13. Sex Difference in Risk of Second but Not of First
Venous 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.
ORaggiustato*conIC95%
*aggiustato per IMC e fumo
8
6
4
2
0
OR=1

16. 0.0 0.5 1.0
USA
Danimarca
Inghilterra
Francia
Cina
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

17. 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

21. ASSOCIAZIONE FRA DIFETTI TROMBOFILICI
E CONTRACCETTIVI ORALI
0
5
10
15
20
25
30
35
CO
FV LEIDEN
--
--
+
--
--
+
+
+
RischioRelativo
(Vandenbroucke et al, Lancet 1996)

22. 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

23. THROMBOPHILIA
AND VENOUS THROMBOEMBOLISM
International 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

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

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

26. USA 1960: la FDA approva la
commercializzazione di Enovid®
con
indicazione contraccettiva.
EUROPA 1961 Anovlar®
F.M. Primiero, 2012F.M. Primiero, 2012
150 mcg di mestranolo
9,85 mg di noretinodrel
norethindrone acetate 4 mg +
ethinyl estradiol 50 µg

28. Generazioni di contraccettivi orali
combinati
I generazione II generazione III generazione IV generazione
Norethisterone
o Norethindrone
(e.g. Loestrin®
)
Levonorgestrel
(e.g. Microgynon®
)
Desogestrel
(Mercilon®
, Marvelon®
)
Drospirenone
(Yasmin®
)

29. 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

30. 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

31. 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

32. Female-maleUSstrokemortalityratio
Stroke 2014 Bushnell et al Guidelines for Prevention of Stroke in Wome

33. 61%

35. 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, 40:1082-1090
2. Eriksson M et al. Stroke. 2009;40:909-914
3. 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;1032-1037
2. Kapral MK et al. Stroke 2005;36;809-814
3. Gargano JW et al. Stroke 2008;39;24-29
4. Reid JM et al. Stroke 2008;39;1090-1095
5. Di Carlo A et al. Stroke 2003;34;1114-1119

36. 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

37. 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)
AnnualThromboembolismRate(%)
Fang MC, et al. Circulation 2005;112:1687-91

38. 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:

41. 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

42. 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

43. CHADS2 -> CHA2DS2VASc
CHA2DS2-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

44. • 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).

45. 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

46. 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

47. Novel Anticoagulants
• Dabigatran
• Rivoroxaban
• Apixaban
• Edoxaban

48. New Anticoagulants