La prevenzione della gravidanza con estro

La prevenzione della
gravidanza con estroprogestinici e rischio
Tromboembolico
Paolo Simioni, MD, PhD
Dipartimento di Medicina
Università di Padova
Women and venous thromboembolism
Naess et al, JTH 2007
Pill and venous thromboembolism
The first observation that the combined oral contraceptive
pill might be associated with a thromboembolic problem
was a case report in 1961 of a pulmonary embolus in a
woman who had been using the first commercially available
product, Enovid, for endometriosis
R elevance of horm one use for VTE
risk in the general population
JTH 2013; 11 (Suppl 1): 180-191
The Cochrane Library 2014, Issue 3, network meta-analysis based on 26 studies
Adjusted RR of VTE
for users versus
non-users of a
progestin-only
contraceptive, all
subgroups
combined
injectable
formulation only
•Women who used OC with ethinylestradiol at a dose of 30-40 μg had a risk of arterial
thrombosis that was 1.3 to 2.3 times as high as the risk among nonusers.
•Women who used pills with ethinylestradiol at a dose of 20 μg had a risk that was 0.9-1.7
times as high, with only small differences according to progestin type.
•Among 10,000 women who use desogestrel with ethinylestradiol at a dose of 20 μg for 1
year, 2 will have arterial thrombosis and 6.8 women taking the same product will have
venous thrombosis.
The Danish cohort study is the largest study to date that examines the risk of MI and stroke
in OC users.
The number of “extra” arterial thrombotic events attributable to hormonal contraceptives is
1 to 2 per 10,000 women/year and the probability of an event for an individual woman is
small.
The study suggests that a lower estrogen dose may be better for preventing MI and possibly
stroke but there is no significant difference according to progestin type for risk of stroke or
MI.
Hypertension was associated with increased risk of stroke but not MI and surprisingly
smoking was not associated with increased risk of stroke or MI with OC use.
The progestin-only products including LNG-releasing IUD and subcutaneous implants did
not significantly increase the risk of stroke or MI and they should be considered in older
women and women with risk factors for arterial thrombosis.
M echanism s of horm onal therapy
related throm bosis
CLOTTING CASCADE AND SYSTEMS OF
PHYSIOLOGICAL INHIBITION IN HUMANS
Extrinsic pathway
Contact phase
XII
TFPI
XIIa
XI
PS
Xa
XIa
sEPCR
IX
(IIa)
VIIIa
X
PC
PCa
PS
TF-VIIa
IXa
Ca2+ PL
EPCR
Endothelial cells
ATIII
Xa
Va
II
IIa
TM
TF-VII
Fibrinogen
Ca2+ PL
HCII
IIa
Unstable
fibrin
Ca2+
XIIIa
Stable
fibrin
15
CLOTTING CASCADE AND SYSTEMS OF
PHYSIOLOGICAL INHIBITION
Contact phase
XII
Estrinsic pathway
TFPI
XIIa
PS
XI
Xa
TF-BEARING
CELLS
XIa
sEPCR
IX
TF-VIIa
IXa
TF-VII
PLATELETS
(IIa)
VIIIa
X
PC
PCa
PS
Ca2+ PL
Va
II
EPCR
IIa
TM
ATIII
Xa
Fibrinogen
ENDOTHELIAL
CELLS HCII
Ca2+ PL
IIa
Unstable
fibrin
Ca2+
ENDOTHELIAL
CELLS
XIIIa
Stable
fibrin
EFFECTS OF ORAL CONTRACEPTIVES
Prothrombotic
Antithrombotic
Procoagulant
Anticoagulant
FII, FVII, FVIII, FIX, FX, FXI
Fibrinogen
Protein C
Anticoagulant
Profibrinolytic
Protein S
Antithrombin
Plasminogen
α 1 -antitrypsin
Haemostatic Balance and Oral contraceptives
Procoagulant
Clotting factors
Protein S
APC resistance
Anticoagulant
Protein C
Fibrinolysis
Clin Appl Thromb Hemost 2011; 17: 323
APC Sensitivity Ratio in Normal
and Factor VLeiden Plasma
7
6
5
4
3
2
1
controls heterozygote homozygote
Factor VLeiden
Acquired APC Resistance and Oral Contraceptives
6
nAPC-sr
5
4
3
2
1
0
<
p<0.0001
no OC
><
p<0.0001
OC 2nd
><
OC 3rd
n.s.
>
no OC
Heterozygote
FV Leiden
• Protein S and TFPI are more
likely candidates to explain
hormone-induced APC
resistance.
• 3 rd generation OC cause a
more pronounced decrease in
the protein S levels as
compared to 2 nd generation
OC.
• Progestins do not induce adverse changes in haemostasis-
factors.
• No negative effects on the haemostatic system have been
observed with either oral or parenteral application, in cyclic or
continuous regimens.
• Oral contraception containing only progestagen is associated
with no or only a marginally increased risk of VTE.
• Oral and transdermal contraception with similar hormones
had similar adverse effects on vascular risk markers.
•This suggests that this transdermal contraceptive has at least
a similar thrombosis risk as its oral counterpart.
Obstet Gynecol 2008
Obstet Gynecol 2008
• Oral and Transdermal
contraception with similar
hormones had similar
adverse effects on vascular
risk markers.
Obstet Gynecol 2008
•This suggests that this
transdermal contraceptive
has at least a similar
thrombosis risk as its oral
counterpart.
Drospirenone OC
Cyproterone OC
Vaginal ring
2 nd OC
Levonrogestrel only- OC
Desogestrel only- OC
Levonorgestrel- IUD
3 nd OC
Transdermal patch
• Sex hormone binding globulin
(SHBG) is a glycoprotein that
specifically binds estrogens
and testosterone.
• The plasma levels increase
dose-dependently upon
estrogen intake, but decrease
after intake of progestagen.
• Linear relationship between
SHBG levels during use of
combined OC and the risk of
VTE.
• SHBG can function as a
surrogate marker for VTE
among users of combined OC
Horm one use in w om en at increased
risk of VTE
Main causes of thrombophilia
INHERITED DISORDERS
ACQUIRED DISORDERS
AT III DEFECTS
APLA (LAC, ACA)
PROTEIN C DEFECTS
CANCER
PROTEIN S DEFECTS
MYELOPROLIFERATIVE SDR
FV LEIDEN MUTATION
PNH
PROTHROMBIN 20210A
NEPHROTIC SYNDROME
DYSFIBRINOGENEMIA
ELEVATED FACTOR VIII
ELEVATED FACTOR IX
(FIX PADUA)
ELEVATED FACTOR XI
MILD HYPERHOMOCYSTEINEMIA
Clinical manifestations of
thrombophilia
• Family history of venous thromboembolism involving males and females
• Spontaneous or risk period related venous thromboembolism at a young
age (<45 years)
• Recurrent venous thromboembolism
• Thrombosis in unusual site (cerebral sinuses, mesenterial, portal)
• Recurrent foetal loss, Preeclampsia, HELLP syndrome, IUGR
• Vitamin K antagonist-induced skin necrosis
• Neonatal purpura fulminans
• Heparin resistance
• Deficiencies of antithrombin,
protein C and protein S, the
homozygous forms of factor V Leiden
and prothrombin G20210A are strong
thrombophilias.
• Heterozygous FV Leiden and
prothrombin G20210A and high levels
of fVIII mild thrombophilias.
Lijfering WM, Blood 2009
•The absolute risk of a first DVT are
1.52%-1.90% per year for strong TF
and 0.34%-0.49% per year for those
mild.
Wu O. et al, Health Technol Assess 2006
Wu O. et al, Health Technol Assess 2006
Wu O. et al, Health Technol Assess 2006
•According to the criteria of the World Health Organization, combined OC are
contra-indicated in women with any thrombophilia, as well as among those
with a prior history of VTE, regardless of the VTE presentation (proximal or
distal deep vein thrombosis, or pulmonary embolism), and those receiving
chronic anticoagulant treatment for VTE.
• The Royal College of Obstetricians and Gynaecologists advises that the use
of combined OC poses an unacceptable health risk for women with a known
thrombogenic mutation.
These recommendations make no distinction between the different VTE risk
of thrombophilic defects.
• The absolute risk of VTE in asymptomatic carriers of strong thrombophilia
is 4.3% (95% CI: 1.4-9.7) per year of oral contraceptive use.
• The absolute risk in asymptomatic carriers of mild thrombophilia is 0.5%
per year of oral contraceptive use.
Hematology Am Soc Hematol Educ Program 2011
• 56 women need to be tested for strong thrombophilia and approximately
28 thrombophilic women need to refrain from OC use to prevent one venous
thrombosis event.
• The lower risk in the FV Leiden and prothrombin mutation leads to a large
number of women who need to avoid the use of OC to prevent one VTE (333
women). To do so, it is necessary to test a high number of women (about
666).
Hematology Am Soc Hematol Educ Program 2011
This was a case–control study in Sweden carried out between 2003 and 2009,
which included 948 patients with VTE and 902 individuals in a control group, all
aged 18–54 years.
OR for use of COC 5.3 (95% 4.0–7.0).
OR for use of COC with the factor V Leiden mutation 20.6 (95% 8.9–58).
OR for use of progestogen-only contraception and FVL 5.4 (95% CI 2.5–13).
OR for use of very low dose progestogen-only contraception (IUD) and FVL 3.2
(95% 1.2–10.4) in line with that of carriers without hormonal contraception (OR
2.6, 95% 1.8–3.7).
Only six women in the case group and 10 women in the control group were
carriers of the prothrombin mutation and users of progestogen-only
contraception, reduced but imprecise OR 0.73 (95% 0.22–2.23).
– No or only slightly increased risk: Levonorgestrel IUS, progestogen-only pill, estrogenfree oral contraceptives
– Moderately increased risk: COCs with < 50 μg EE containing norethisterone,
norethisterone acetate, levonorgestrel, norgestimate, chlormadinone acetate,
dienogest; COC with estradiol valerate and dienogest; vaginal combined
estrogen/progestogen ring, depot injectables
– Highly increased risk : COC with < 50 μg EE containing desogestrel, gestodene,
cyproterone acetate or drospirenone; combined estrogen/progestogen contraceptive
patch
General screening for thrombophilia prior to the prescription of oral
contraceptives (OC) is not recommended.
Laboratory testing for thrombophilia should be limited to women with a
positive family and/or personal history of VTE or vascular occlusion.
Additional individual risk factors must be considered.
Consider contraception with low risk profile.
A MULTIFACTORIAL MODEL FOR
THROMBOSIS IN YOUNG PATIENTS WITH
THROMBOPHILIA ON HORMONAL THERAPY
Risk of
thrombosis
Supra-Additive effect
Thrombosis threshold
Age
Obesity, etc
FV Leiden
OCT
Age
HRT
PROTHROMBIN ‘‘Padua 2 ‘’
(Italy)
SYMPTOMS
PT (%)
INR
PTT (SEC)
FII ATTIVITA’
(%)
PROBAND
F, 27yrs
- PE during OCT
- (previous VTE in
childhood)
63,1
1,31
53,5
55,6
Sister, affected
no
84,8
1,11
28,1
68,2
Mother, affected
no
85,2
1,11
30,2
78,7
Father, normal
no
107,5
0,96
25,2
117,4
Simioni 2013, personal data
Thrombophilia and OCT use: personal suggestions
- No in severe thrombophilia
- No if positive personal or family history of
VTE (in the presence of thrombophilia)
- Consider risk/benefit ratio in less
severe thrombophilia (asymptomatic)
- Consider preference of the patient in less
severe thrombophilia (asymptomatic)
- Use of low risk preparations (progestogen only; levonorgestrel
IUD)
- Careful information of signs and symptoms of
VTE
- Immediate diagnosis with objective tests in the
presence of clinical suspect of VTE
Grazie per l’attenzione!
Staff di laboratorio:
Claudia M. Radu
Cristiana Bulato
Sabrina Gavasso
Patrizia Zerbinati
Mariangela Fadin
Graziella Saggiorato
Francesca Sartorello
Staff clinico:
Paolo Simioni
Luca Spiezia
Daniela Tormene
Fabio Dalla Valle
Elena Campello
Sara Maggiolo
The Anatomical Theatre
University of Padua