10.4081/btvb.2022.42
Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period, 112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%) carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of antithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.
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Paolo Simioni
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Bleeding, Thrombosis and Vascular Biology
Women's health
Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study
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Original Articles
2022-11-03
2022-06-02
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Bleed Thromb Vascul Biol
Paolo Simioni
2022/11/03
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Lussana F, Dentali F, Abbate R, et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009;124:e19-25.
Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study
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1
                                                                                                           ORIGINAL ARTICLE

Combined oral contraceptives and the risk of venous thromboembolism
carriers of antithrombin, protein C or S deficiency:
Sub-analysis of a prospective cohort study
Daniela Tormene,1 Elena Campello,1 Chiara Simion,1 Anna Poretto,1 Paolo Prandoni,2 Paolo Simioni1
1
  Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padua Medical School, Padua, Italy; 2Arianna
Foundation on Anticoagulation, Bologna, Italy



ABSTRACT
     Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these
defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this
association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment
with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect
of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period,
112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from




                                                                                              ly
these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period




                                                                                       on
of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%)
carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of
0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of an-




                                                                                 e
tithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events
that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families
                                                                            us
has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.
                                                                            al
                                                                             INTRODUCTION
                                                         ci

  Correspondence: Daniela Tormene, Department of Medicine,
  Thrombotic and Hemorrhagic Diseases Unit, University of Padua                  Since the 1960s, inherited coagulation disorders have
                                                       er


  Medical School, Via Giustiniani 2, 35128 Padua, Italy.
  Tel.: +39.049.8218287                                                      been identified which predispose to a greater risk of de-
                                                      m



  E-mail: daniela.tormene@unipd.it                                           veloping thrombotic events. This predisposition was sum-
                                                                             marized in the term thrombophilia. Women carrying these
                                          om




  Key words: Major thrombophilia, Combined oral contraceptives,              thrombophilic conditions are expected to develop throm-
  Venous thromboembolism, Prospective cohort study, Women's
  health.                                                                    botic events at a younger age than males, especially dur-
                                                                             ing pregnancy and estroprogestinic treatment.
                                    -c




  Contributions: The authors contributed equally.                                It has been shown that the use of combined oral con-
                           on




                                                                             traceptives (COCs), containing a combination of ethinyl-
  Conflict of interest: The authors declare no potential conflict of in-
  terest.                                                                    estradiol and progestagen, increases the risk of developing
                                                                             thrombotic events in women using them compared with
                     N




  Funding: None.                                                             non-users.1-3 Although the amount of estrogens contained
                                                                             in these preparations has substantially decreased in recent
  Received for publication: 2 June 2022.
  Revision received: 28 August 2022.                                         years, the thrombotic risk associated with the use of COCs
  Accepted for publication: 10 October 2022.                                 has not diminished accordingly, mainly due to the current
                                                                             use of progestin components (such as gestodene, deso-
  Publisher’s note: All claims expressed in this article are solely those    gestrel or drospirenone) that are far more thrombogenic
  of the authors and do not necessarily represent those of their affili-
  ated organizations, or those of the publisher, the editors and the re-
                                                                             than those (such as levonorgestrel) used in the past, or to
  viewers. Any product that may be evaluated in this article or claim        the use of alternative routes of administration (transder-
  that may be made by its manufacturer is not guaranteed or endorsed         mal or via vaginal ring).
  by the publisher.                                                              Women who are carriers of major thrombophilic de-
                                                                             fects, such as the deficiency of antithrombin (AT), protein
  ©
   Copyright: the Author(s), 2022
  Licensee PAGEPress, Italy                                                  C (PC) or protein S (PS) have been repeatedly shown to
  Bleeding, Thrombosis and Vascular Biology 2022; 1:42                       exhibit a higher thrombotic risk than non-carriers during
  doi:10.4081/btvb.2022.42                                                   the administration of hormonal drugs.4 However, although
                                                                             their use is generally discouraged, in clinical practice it is
  This work is licensed under a Creative Commons Attribution-
  NonCommercial 4.0 International License (CC BY-NC 4.0).                    not infrequent to see young women who still use them.
                                                                                 In the framework of a prospective cohort study

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:42
40                                                       D. Tormene et al.




launched in 1998 for assessing and quantifying the asso-             mography pulmonary angiography or ventilation/perfu-
ciation of inherited deficiency of natural anticoagulants            sion lung scanning. Cerebral or splanchnic vein throm-
with the risk of spontaneous and risk related venous                 boses were diagnosed by a cerebral/abdominal
thromboembolism (VTE),5 we had the opportunity to fol-               angio-computed tomography scan or magnetic resonance.
low-up over time a considerable number of women in fer-
tile age who were family members of probands with a                  Laboratory assays
defect of AT, PC or PS. We report here our experience on
                                                                         Laboratory tests for AT, PC and PS were performed
the risk associated with the use of the COCs in women
                                                                     according to methods previously described.6 The follow-
with and without thrombophilia.
                                                                     ing reference values were considered: for AT antigen con-
                                                                     centration, 70% to 120%; AT activity, 70% to 120%; PC
                                                                     antigen concentration, 65% to 130%; PC chromogenic or
MATERIALS AND METHODS
                                                                     coagulometric activities, 65% to 130%; total PS antigen
Study subjects                                                       concentration, 60% to 120%; and free PS antigen concen-
    All patients presenting to the Thrombosis Unit of the            tration, 60% to 108%; protein S activity, 65 to 130%.
University-Hospital of Padua with a documented episode               DNA analyses for FVL and prothrombin variant G20210A




                                                                                             ly
of VTE between April 1998 and October 2015 were                      and plasma homocysteine assay were performed using
                                                                     previously described methods.6,7 The criteria used for the




                                                                                      on
screened for deficiencies of AT, PC, and PS. The presence
of a deficiency was confirmed by testing the patients on two         classification of the different types of AT, PC and PS de-
separate occasions. When possible, gene sequencing was               fects were those previously reported.6 Subjects who pre-
                                                                     sented with the same defect in two consecutive laboratory



                                                                                e
also performed to identify the lesions responsible for the
                                                                     determinations performed at an interval of at least one
defects. Patients with a confirmed deficiency of AT, PC, or
PS acted as probands. All women aged 15 to 50 years who
were family members of index patients were retrieved and
                                                                             us
                                                                     month were potentially carriers of an inherited defect. To
                                                                     confirm the inheritance, the same defect had to be present
                                                                   al
asked to participate in the study, provided they did not have        in at least one first-degree family member. Where possi-
active cancer, antiphospholipid antibody syndrome or pre-            ble, sequencing of AT, PC and PS genes was performed
                                                       ci

vious VTE. A detailed medical history was obtained prior             to identify the lesions responsible for the defects and con-
                                                     er


to the laboratory assessment of the deficiency status. Close         firm the hereditary pattern (40% of patients). In women
attention was paid to the presence of cardiovascular risk fac-       under estrogen treatment or during pregnancy, blood sam-
                                                    m




tors such as hyperlipidemia, diabetes and smoking habit.             ples were collected at least three months after withdrawal
                                                                     of hormonal treatment or delivery, respectively. In this
                                           om




    All consenting women were followed up until October
2017. Approval for this study was obtained from the local            study we included only quantitative defects. Type I de-
Ethical Committee at Padua University.                               fects (concomitant reduction of antigen and activity to
                                     -c




                                                                     about 50%) were considered for AT and PC deficiency
Study objective and design                                           and type I (concomitant reduction of total and free PS
                              on




                                                                     antigen and PS activity to about 40-50%) and type III de-
    The study objective was to assess the incidence of               fects (normal total PS antigen reduced free PS antigen and
VTE complications in women in fertile age who were
                         N




                                                                     PS activity to about 40-50%) for PS deficiency.
family members of probands with inherited deficiency of
antithrombin, protein C or S defects while on combined               Statistical analysis
estrogen-progestin therapy. To this purpose, women meet-
ing the eligibility criteria were labelled as being or not               The incidence of thromboembolic events occurring
carriers of these abnormalities and were followed up                 during the periods of hormonal therapy and its 95% CI
prospectively over time. The use of oral contraceptives              was calculated in carriers and non-carriers of throm-
was discouraged but not prohibited.                                  bophilia. The relative risk (RR) for the development of
    A follow-up was performed every 6 months, either by              COC-related VTE was calculated by dividing the inci-
a visit to the study Center or by telephone contact. On              dence rate of VTE in carriers by that found in non-carri-
each occasion, they were enquired about the use of hor-              ers. Observation time was defined as the months of use
monal therapy (type of drug, duration of its administra-             of COCs from the beginning of use until the development
tion). In case of clinical signs or symptoms of                      of the first VTE or until the discontinuation of treatment.
thromboembolic events, they were instructed to undergo               Kaplan-Meier survival analysis was conducted to com-
proper objective tests to confirm or rule out the clinical           pare VTE free survival for COCs users with and without
suspicion. Diagnosis of deep vein thrombosis of the lower            thrombophilia. A log rank test was conducted to determine
or upper limbs was made by compression ultrasound, and               if there were differences in the VTE free survival distri-
that of pulmonary embolism was made by computed to-                  butions between groups.

                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:42
    Combined oral contraceptives and the risk of venous thromboembolism in carriers of antithrombin, protein C or S deficiency 41




                                                                    cluded in the study used preparations with desogestrel and
RESULTS                                                             gestodene (14/19 in the carrier group and 13/17 in the
Subjects and use of estrogen-progestin drugs                        non-carrier group).
                                                                        The doses of ethinylestradiol present in the COCs used
    Out of approximately 2000 patients who were tested              by the women included in the study ranged from 20 to 30
in the study period, 88 unrelated probands with an ob-              µg; these dosages were equally distributed within each
jectively documented VTE and a deficiency of AT, PC                 observation group.
or PS were identified. Of the 205 eligible women of                     Table 1 also shows for each participant in the study,
child-bearing age who belonged to these families, 197               the data relating to the age at which estrogen-progestogen
gave their informed consent for participation in the                therapy was started, the months of use of the therapy and
study and were enquired for the presence of the                     the months of exposure at the onset of the first VTE. The
same defects. Of them, 112 (57%) were carriers of an                use of estrogen-progestogen therapy was continuous, and
inherited defect, whereas the remaining 85 were not                 no women in the study discontinued and resumed therapy
(Figure 1).                                                         during the study period.
    During the study period, 19 of the 112 (17%) carriers
of inherited thrombophilia used estrogen-progestin
                                                                    Incidence of combined oral contraceptives related VTE




                                                                                     ly
preparations for an overall period of 276 months, com-
pared with 17 of the 85 (20%) non-carriers for an overall               VTE events developed in 12 of the 19 (63.2 %) carri-




                                                                              on
period of 992 months. The mean age at the start of use              ers, leading to a monthly event rate of 4.3% (95% CI: 2.2
of estrogen-progestogen therapy was 31 years in the car-            to 7.6), and in 2 of the 17 (11.8%) non-carriers, leading
rier group and 39 years in the non-carrier group, respec-           to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a RR



                                                                        e
tively. All women included in the study had normal BMI,             of 21 (95% CI, 4.7 to 92) (Table 2).
did not have cardiovascular risk factors.
    Preparations containing cyproterone acetate, deso-
                                                                 us     Carrier women developed the thrombotic event after
                                                                    an average of six months of combined oral contraceptive
                                                           al
gestrel, gestodene, drospirenone and etonogestrel were              use versus nine months in the non-carrier group.
used in the two groups (Table 1). Most of the women in-                 In both groups the thrombotic events occurred without
                                              ci
                                            er
                                           m
                                  om
                             -c
                     on
                 N




Figure 1. 88 unrelated patients with VTE and AT, PC or PS served as probands. 197 women (family members) of child-bearing age
were enrolled. 112 out of 197 (57%) were carriers of an inherited defect and 85 were non-carriers.


                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:42
42                                                            D. Tormene et al.




other risk conditions for thrombosis such as surgery, plas-                    In Table 3, the incidence of COCs-related VTE is
tercast/trauma or prolonged immobilization.                                 shown for each type of defect. The RR for VTE during
    Of the 12 thrombotic events that occurred in carriers of                COCs use in carriers as compared to non-carriers was 6.6
inherited thrombophilia, 9 were isolated deep vein throm-                   (95% CI, 1.0 to 47) for AT, 24.4 (95% CI, 4.8 to 124) for
bosis (DVT) of the lower limbs, and 3 were DVT associ-                      PC and 64 (95% CI, 13 to 318) for PS defects.
ated with pulmonary embolism (PE); the 2 events that                           Figure 2 shows the VTE-free survival in carriers vs
occurred in non-carriers were isolated DVT (Table 1).                       non-carriers of defects (Panel A) as well the VTE-free sur-


Table 1. Characteristics of women’s relatives with and without AT, PC, PS deficiency. Exposure to COCs. VTE events.
Age at when        COCs type         Exposure months      Exposure months         Type of VTE           Deficiency          Concomitant
starting to       used at onset                              at first VTE                                                  thrombophilic
receive COCs         of VTE                                                                                                    defects
20                  Gestodene                 6                                                            AT                   None




                                                                                                       ly
30                 Desogestrel              120                                                            AT                   None
21                  Gestodene                14                   14                  DVT                  AT                   None




                                                                                               on
20                 Vaginal Ring               4                                                            AT                   None
40                  Gestodene                 1                    1                  DVT                  AT                   None




                                                                                         e
25                Drospirenone               72                                                            NO                   None
48
42
47
                    Gestodene
                    Gestodene
                    Gestodene
                                              4
                                              4
                                              3
                                                                   4
                                                                   4
                                                                   3
                                                                                  us  DVT
                                                                                      DVT
                                                                                    DVT + PE
                                                                                                           PC
                                                                                                           PC
                                                                                                           PC
                                                                                                                                None
                                                                                                                                None
                                                                                                                                None
                                                                            al
30                 Desogestrel                8                    8                DVT + PE               PC                   None
                                                           ci

40                 Vaginal Ring               6                    6                  DVT                  PC                   None
20                 Desogestrel               12                                                            PC                   None
                                                         er


38                  Gestodene                24                                                            PC                   None
                                                        m



35                  Gestodene                36                                                            PC                   None
28                  Gestodene                36                                                            NO                   None
                                              om




44                  Gestodene                48                                                            NO                   None
36                  Gestodene                 8                                                            NO                   None
                                        -c




31                  Gestodene                48                                                            NO                   None
34                  Gestodene                12                   12                  DVT                  NO                   FVL
                                  on




18                 Ciproterone               12                                                            NO                   None
38                 Desogestrel               12                                                            NO                   None
                           N




30                Drospirenone                2                    2                  DVT                   PS                  None
24                  Gestodene                 1                    1                  DVT                   PS              G20210A PV
17                Drospirenone                1                    1                DVT + PE                PS                  None
20                  Gestodene                 4                    4                  DVT                   PS                  None
21                 Ciproterone               14                   14                  DVT                   PS              G20210A PV
43                  Gestodene                12                   12                                        PS                  None
18                 Desogestrel              180                                                            NO                   None
24                 Desogestrel               72                                                            NO                   None
22                 Vaginal Ring               6                    6                  DVT                  NO                   None
25                 Ciproterone               48                                                            NO               G20210A PV
22                  Gestodene                36                                                            NO                   None
26                  Gestodene                12                                                            NO                   None
18                  Gestodene               180                                                            NO                   FVL
20                 Desogestrel               30                                                            NO                   None
40                 Desogestrel              180                                                            NO                   None
AT, antithrombin; PC, protein C; PS, protein S; COCs, combined oral contraceptives; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE,
pulmonary embolism; FVL, Factor V Leiden.


                                         Bleeding, Thrombosis and Vascular Biology 2022; 1:42
    Combined oral contraceptives and the risk of venous thromboembolism in carriers of antithrombin, protein C or S deficiency 43




vival according to the different type of defect (Panel B).
The VTE-free survival distribution was statistically sig-                  DISCUSSION
nificant different (p=0.001 and p<0.001 respectively).                         Despite the low incidence of venous thrombosis
    Figure 3 illustrates the incidence of thrombotic events                among women of reproductive age, the use of oral con-
and the RR related to the type of progestins used in com-                  traceptives and major inherited thrombophilic defects
bined oral contraceptive pills.                                            (i.e., deficiency of antithrombin, protein C or protein S)



Table 2. Total cohort of women who have used COCs treatment and the risk of VTE.
                                                               Carriers                                                    Non-carriers
N women                                                          19°                                                            17*
Months of COCs treatment                                         272                                                            992
Number of VTE                                                    12°                                                            2**
Proportion of pts with VTE                            63.2% (95% CI, 33 to 110)                                      11.8% (95% CI, 1.4 to 42.5)




                                                                                                ly
Incidence of VTE (%) per p/months of COCs             4.3% (95% CI, 2.2 to 7.6)                                      0.2% (95% CI, 0.02 to 0.7)




                                                                                        on
                                                                                    RR 21 (95% CI, 4.7 to 92)
COCs, combined oral contraceptives; VTE, venous thromboembolism. °2 with G20210A prothrombin variant; * *2 with Factor V Leiden, 1 with G20210A
prothrombin variant; **1 with Factor V Leiden.




                                                                                  e
                                                                          us
Table 3. Women who have used COCs treatment and the risk of VTE according to type of defect.
                                                         AT               PC                                    PS       Non-carriers (N-C)
                                                                 al
Number of women                                           5                8                                    6°               17*
                                                   ci

Months of COCs treatment                                 148              97                                    34               992
                                                 er


Number of VTE                                             2                5                                    5°               2**
Incidence of VTE per % p/months of COCs                                                 RR (95% CI)
                                                m



 AT 1.4 (95% CI 0.16 to 4.8)                                                      AT 6.6 (95% CI, 1.0 to 47)
 PC 5.2 (95% CI 1.7 to 12)                                                     PC 24.4 (95% CI, 4.8 to 124)
                                      om




 PS 15 (95% CI 5 to 34)                                                           PS 64 (95% CI, 13 to 318)
 N-C 0.2 (95% CI, 0.03 to 0.7)
                                 -c




AT, antithrombin; PC, protein C; PS, protein S; COCs, combined oral contraceptives; VTE, venous thromboembolism. °2 with G20210A prothrombin
variant; *2 with Factor V Leiden, 1 with G20210A prothrombin variant; **1 with Factor V Leiden.
                          on
                   N




Figure 2. VTE-free survival in users of combined oral contraceptives with and without thrombophilia. A) VTE-free survival in patients
with and without hereditary thrombophilia. B) VTE-free survival according to hereditary thrombophilia types.


                                         Bleeding, Thrombosis and Vascular Biology 2022; 1:42
44                                                        D. Tormene et al.




interact synergistically to increase the thromboembolic               a similar retrospective family cohort study, where VTE
risk. Although the use of contraceptive hormonal therapy              events were reported to occur almost ten times more fre-
is generally discouraged in carriers of these abnormalities,          quently in deficient than in non-deficient females during
in clinical practice it is not infrequent to see women who            the use of COCs;8 and with those of old prospective stud-
use them. As we had the opportunity to follow-up over                 ies, in which fertile women with defects of natural coag-
time a considerable number of women who were family                   ulation inhibitors were found to exhibit a more than a
members of probands with a deficiency in the natural an-              hundred-fold risk of VTE than control healthy women
ticoagulants, we could estimate and quantify the risk of              during use of estrogen-progestogen therapy.9,10
COCs-related VTE through the comparison between car-                      The strength of our study lies in its prospective design,
riers and non-carriers of these defects.                              in the recruitment of a broad number of women in fertile
     The rate of VTE events that was recorded during a fol-           age who were family members of symptomatic carriers
low-up of 276 and 992 months of COCs use in carriers                  of deficiencies of natural anticoagulants, in the adoption
and non-carriers, respectively, was considerably higher in            of predefined criteria for the endpoint adjudication, and
the 19 carriers of these abnormalities, (4.3% patient-                in a reasonably long follow-up that was conducted with
months) than in the 12 non-carriers (0.2% patient-                    an identical approach both in carriers and in non-carriers.
months), leading to a RR for VTE of more than 20. The                 Selection bias was prevented by including index patients




                                                                                                ly
risk was similarly higher among users of pills containing             on the basis of the occurrence of previous VTE and ex-




                                                                                         on
desogestrel and gestodene (RR=26.6) and among users of                cluding family members with a previous episode of VTE.
pills containing drospirenone or cyproterone acetate                  Confounding bias was prevented by screening all re-
(RR=20). All women developed the thrombotic event                     cruited subjects for other thrombophilic abnormalities




                                                                                   e
within approximately one year of COCs use, with an av-                (such as factor V Leiden, G20210 prothrombin mutation
erage of six months in the carrier group and nine months
in the non-carrier group, suggesting that the thrombotic
risk is to be expected earlier in the former than in the lat-
                                                                              us
                                                                      and hyperhomocysteinemia) potentially accounting for
                                                                      the thrombotic risk. Among the study limitations there are
                                                                      the small sample size correlated to the rarity of the throm-
                                                                     al
ter. Indeed, the use of estrogen-progestogen preparations             bophilic defects considered and the relatively low number
is expected to further reduce the levels of coagulation in-           of subjects that used contraceptive pills. As regards the
                                                        ci

hibitors already genetically reduced.                                 first point, also in a previously similar prospective multi-
                                                      er


     The results of this prospective study are in line with           center study (the EPCOT study)14 the number of women
those of our previous retrospective family cohort study,              included, with AT/PC/PS defect, and users of estrogen-
                                                     m




which showed an annual incidence of COCs-related VTE                  progestin therapy was slightly higher (34); the results of
events of 4.3% and 0.7% in carriers and non-carriers, re-             this study also highlighted a greater thrombotic risk in car-
                                           om




spectively.6 These findings are consistent with those from            riers compared with non-carriers using estrogen-progestin
                                      -c
                              on
                         N




Figure 3. The incidence of thrombotic events and the RR related to the type of progestins used in combined oral contraceptive pills.


                                       Bleeding, Thrombosis and Vascular Biology 2022; 1:42
    Combined oral contraceptives and the risk of venous thromboembolism in carriers of antithrombin, protein C or S deficiency 45




therapy (1/34 versus 0/135). As regards the second point             4. van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Mei-
is not surprising, as they had been discouraged from using              jer K. Combined oral contraceptives, thrombophilia and the
them: in spite of this, the absolute number of events that              risk of venous thromboembolism: a systematic review and
were recorded in the follow-up of users of contraceptive                meta-analysis. J Thromb Haemost 2016;14:1393-403.
                                                                     5. Tormene D, Guerra L, Gavasso S, et al The incidence of
pills was high enough to produce a valid estimation of the
                                                                        VTE in asymptomatic carriers of a deficiency of at PC OR
thromboembolic risk, as confirmed by the relative narrow
                                                                        PS: a prospective cohort study. XXV Congress of the Inter-
confidence interval around the identified RR.                           national Society on Thrombosis and Haemostasis and 61st
    It should also be noted that the women enrolled in the              Annual SSC Meeting. 20-25 June 2015. Toronto, Canada.
study used, in most cases, preparations containing third-            6. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous
generation progestogens, cyproterone acetate and deso-                  thromboembolism in families with inherited thrombophilia.
gestrel, which cause a recognized greater thrombotic risk               Thromb Haemost 1999;81:198-202.
than second-generation preparations.11                               7. Simioni P, Tormene D, Manfrin D, et al. Prothrombin anti-
    The low number of women that used the vaginal ring                  gen levels in symptomatic and asymptomatic carriers of the
and the fact that none of the women enrolled in the study               20210A prothrombin variant. Br J Haematol
used pills containing levonorgestrel or dienogest pre-                  1998;103:1045-50.
cludes firm conclusions about these contraceptive modal-             8. van Vlijmen EF, Brouwer JL, Veeger NJ, et al. Oral contra-




                                                                                      ly
                                                                        ceptives and the absolute risk of venous thromboembolism
ities. However, also these estroprogestin preparations are
                                                                        in women with single or multiple thrombophilic defects: re-




                                                                              on
likely to increase the risk of VTE in women with major                  sults from a retrospective family cohort study. Arch Intern
thrombophilia as previously shown.4,11-13                               Med 2007;167:282-9.
                                                                     9. Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic car-




                                                                         e
                                                                        diovascular death and nonfatal venous thromboembolism in
CONCLUSIONS
    In conclusion, our study results strongly suggest that
                                                                  us    women using oral contraceptives with differing progestagen
                                                                        components. Lancet 1995;346:1589-93.
                                                                    10. Kemmeren JM, Algra A, Grobbee DE. Third generation oral
the thrombotic risk conferred by estro-progestin drugs in
                                                             al
                                                                        contraceptives and risk of venous thrombosis: meta-analysis.
women in fertile age that are identified as carriers of AT,             BMJ 2001;323:131-4.
                                                ci

PC or PS defects is high enough to discourage their use.            11. van Vlijmen EF, Veeger NJ, Middeldorp S, et al. The impact
    An additional obvious implication of our results is the
                                              er


                                                                        of a male or female thrombotic family history on contracep-
need for searching for inherited deficiencies of AT, PC or              tive counseling: a cohort study. J Thromb Haemost
                                             m



PS in all the family members of carriers of these abnor-                2016;14:1741-8.
malities in order to increase protection against throm-             12. Hugon-Rodin J, Horellou MH, Conard J, et al. Type of Com-
                                   om




boembolic events triggered by several risk factors,                     bined Contraceptives, Factor V Leiden Mutation and Risk
including contraceptive pills.15                                        of Venous Thromboembolism. Thromb Haemost
                                                                        2018;118:922-8.
                              -c




                                                                    13. Dinger J. COCs containing dienogest and 30 µg
                                                                        ethinylestradiol may carry a higher VTE_risk compared to
                      on




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