Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate
develop thromboembolic complications  and/or recurrent
in congenital factor XII deﬁciency—a study on 74 subjects from 14
Swiss families. Thromb Haemost 1991; 65: 117–21.
6 Dyerberg J, Stoﬀersen E. Recurrent thrombosis in a patient with factor
One other woman with FXII deﬁciency had a very low
XII deﬁciency. Acta Haematol 1980; 63: 278–82.
PAI-1 (plasminogen activator inhibitor) level and her OHP was
7 Koster T, Rosendaal FR, Brute E, Vandenbroucke JP. John Hag-
below the mean for the control group. This may indicate that
eman’s factor and deep-vein thrombosis: Leiden Thrombophilia
the OHP test could be a useful diagnostic tool for global
Study. Br J Haematol 1994; 87: 422–4.
assessments of overall thrombotic or hemorrhagic risk in
8 Zeerleder S, Schloesser M, Redondo M, Wuillemin WA, Engel W,
Furlan M, Lammle B. Re-evaluation of the incidence of thrombo-
individuals with combined genetic defects.
embolic complications in congenital factor XII deﬁciency—a study on
Although the number of subjects is relatively small, we
73 subjects from 14 Swiss families. Thromb Haemost 1999; 82: 1240–6.
believe that these results are promising and may indicate that
9 Braulke I, Pruggmayer M, Melloh P, Hinney B, Kostering H, Gunther
determination of OHP could be a method of choice for
E. Factor XII (Hageman) deﬁciency in women with habitual abortion:
recognizing prothrombotic conditions associated with FXII
new subpopulation of recurrent aborters? Fertil Steril 1993; 59: 98–101.
deﬁciency and for distinguishing individuals with similarly low
10 Ogasawara MS, Aoki K, Katano K, Ozaki Y, Suzumori K. Factor
FXII levels. It seems that this assay (rather than the simple
XII but not protein C, protein S, antithrombin III, or factor XIII is a
FXII concentration) could be used as a predictor of possible
predictor of recurrent miscarriage. Fertil Steril 2001; 75: 916–9.
11 Zeerleder SA, Asmis L, Redondo M, Sulzer I, Lammie B. A patient
with isolated prolongation of aPTT without hemorrhagic diathesisanamnesis: severe, hereditary factor XII deﬁciency. Ther Umsch 1999;
12 He S, Antovic A, Blomba¨ck M. A simple and rapid laboratory method
1 Tans J, Rosing J. Structural and functional characterisation of factor
for determination of haemostasis potential in plasma II. Modiﬁcations
XII. Semin Thromb Haemost 1987; 13: 1–14.
for use in routine laboratories and research work. Thromb Res 2001;
2 Wachtfogel YT, DeLa Cadena RA, Colman RW. Structural biology,
cellular intereactions and pathophysiology of the contact system.
13 Antovic JP, Antovic A. Does recombinant factor VIIa apart from
overall hemostasis regulate TAFI dependent ﬁbrinolysis—in vitro
3 Mannhalter C, Fischer M, Hopmeier P, Deutsch E. Factor XII activity
analysis using overall hemostasis potential (OHP) assay. Thromb
and antigen concentration in patients suﬀering from recurrent
thrombosis. Fibrinolysis 1987; 1: 259–63.
14 Levi M, Hack CE, de Boer JP, Brandjes DP, Buller HR, ten Cate JW.
4 Kluft C, Dooijewaard G, Emeis JJ. Role of the contact system in
Reduction of contact activation related ﬁbrinolytic activity in factor
ﬁbrinolysis. Semin Thromb Haemost 1987; 13: 50–68.
XII deﬁcient patients. Further evidence for the role of contact system
5 Lammle B, Wuillemin WA, Huber I, Krauskopf M, Zurcher C,
in ﬁbrinolysis in vivo. J Clin Invest 1991; 88: 1155–60.
Pﬂugshaupt R, Furlan M. Thromboembolism and bleeding tendency
Prothrombotic changes in users of combined oral contraceptivescontaining drospirenone and cyproterone acetate
H . A . A . M . V A N V L I E T , * T . A . W I N K E L , * I . N O O R T , * J . R O S I N G and F . R . R O S E N D A A L à*Leiden University Medical Center, Department of Gynecology and Reproductive Medicine, Leiden; Maastricht University, Cardiovascular
Research Institute Maastricht, Department of Biochemistry, Maastricht; and àLeiden University Medical Center, Department of Hematology and
Clinical Epidemiology, Leiden, the Netherlands
To cite this article: Van Vliet HAAM, Winkel TA, Noort I, Rosing J, Rosendaal FR. Prothrombotic changes in users of combined oral contraceptives
containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 2: 2060–2.
Oral contraceptives (OC) increase the risk of venous throm-bosis through changes in procoagulant, anticoagulant and
Correspondence: H.A.A.M. van Vliet, Leiden University Medical
ﬁbrinolytic parameters . Thrombin generation-based acti-
Center, Department of Gynecology and Reproductive Medicine, PO
vated protein C (APC) sensitivity is a global test for the net
Box 9600, 2300 RC Leiden, the Netherlands.
prothrombotic eﬀect and predicts the risk of venous thrombo-
Tel.: +31 71 5264065; fax: +31 71 5248181; e-mail: [email protected]
Recently, concern has been raised about the thrombotic risk
Received 1 July 2004, accepted 6 July 2004
of a new OC composed of 3 mg drospirenone (DRSP) and
Ó 2004 International Society on Thrombosis and Haemostasis
30 lg ethinylestradiol (YasminÒ, Schering AG, Berlin,
the group of switchers discontinued due to breast tender-
Germany) . Also, a recent study showed a four-fold
ness, increase in acne and hirsutism, pregnancy wish, a
increased risk of thrombosis for users of OC containing
previously unreported history of high blood pressure or
cyproterone acetate (CPA) compared with users of OC
surgery. One woman was lost to follow-up. The various
containing levonorgestrel (LNG) and an 18-fold increased risk
groups of OC users did not differ with respect to age and
It is desirable to predict the prothrombotic effect of new OC
Users of OC containing DRSP or CPA had higher nAPCsr
prior to the occurrence of many cases of thrombosis. Therefore,
than users of LNG-containing OC, respectively, 4.1 and 4.0 vs.
we compared the sensitivity to APC in users of drospirenone-
3.0 (Table 1). Similar results were found for users of desogestrel
containing OC with that in users of other OC, some of which
(DSG)- or gestodene (GTD)-containing OC. In the 39 women
are known to increase the risk of thrombosis (e.g. desogestrel-
who changed pills, the nAPCsr altered correspondingly, i.e. it
increased when switching from LNG-OC to DRSP-OC and
Healthy women using the same type of OC for at least four
decreased when switching from DRSP- or CPA-OC to LNG-
cycles were recruited by advertising in local newspapers, public
OC (Table 1). Exclusion of participants with the factor V
and university buildings, student houses and general practi-
Leiden mutation (n ¼ 14) or the prothrombin 20210 A
tioner waiting rooms. Exclusion criteria were age (< 18 years)
mutation (n ¼ 5) did not materially change the mean nAPCsr:
and contraindications for OC use as stated by the World
DRSP-OC (3.7), CPA-OC (4.0), DSG-OC (3.9), GTD-OC
Health Organization. Blood samples were drawn between days
(3.4) and remained all markedly higher than in users of LNG-
18 and 21 of the menstrual cycle. After the blood draw DRSP-
or CPA-containing OC users were requested to switch to a
In this study of prothrombotic effects among 156 healthy
second-generation OC: 150 lg LNG and 30 lg ethinylestradiol
users of various types of OC formulations, users of DRSP-
(Microgynon-30Ò, Schering AG) and second- or third-genera-
and CPA-containing OC were found more resistant to the
tion OC users were asked to switch to the DRSP-containing
anticoagulant action of APC than users of LNG-containing
OC. A second blood draw was performed between days
OC. In addition, we conﬁrmed previous results on prothrom-
18 and 21 of the fourth cycle after the change of OC type. The
botic effects of third-generation progestogen-containing OC
Medical Ethics Committee of the Leiden University Medical
(DSG, GTD) . The observations were not the result of
Center approved the study. All volunteers gave written
differences between women rather than between OC, as proved
by the results in women who switched OC. The prothrombotic
Normalized APC sensitivity ratios (nAPCsr) were deter-
effect of DRSP- and CPA-containing OC, as measured by
mined by quantifying the effect of APC on thrombin genera-
APC-sensitivity, was similar to the effect of OC containing the
tion (ETP-based APC-resistance test) as described previously
third-generation progestogens DSG and GTD, which have a
. The APC-resistance test was performed in duplicate and
two-fold higher risk of thrombosis compared with LNG-
without knowledge of the OC used or any other participant’s
characteristics. The samples were analyzed in random order in
Our results conﬁrm that the thrombin generation-based
APC-resistance test discriminates between OC with a high risk
Between July and November 2002, 158 women aged
of thrombosis (CPA, DSG and GTD) and OC with a lower
18–51 years were recruited. We excluded two women, one
thrombotic risk (LNG) . It is therefore an excellent test to
because of a history of diabetes mellitus and one because of
predict the thrombotic safety of OC before women experience
a history of thrombosis. Forty-six women switched OC type
an actual thrombosis. In our study, DRSP-containing OC
of whom 40 returned for a second blood draw. One
users were less sensitive to APC than LNG-containing OC
participant using a CPA pill was erroneously prescribed the
users, which predicts an increased risk of thrombosis. There-
DRSP pill instead of a LNG-containing OC. Five women in
fore, even in the absence of clinical outcome data, we advise not
Table 1 Mean ETP-based nAPCsr in women using oral contraceptives containing diﬀerent kind of progestogens
Ó 2004 International Society on Thrombosis and Haemostasis
to prescribe DRSP-containing combined OC as a ﬁrst choice
1 Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S,
Helmerhorst FM, Bouma BN, Rosendaal FR. Oral contracep-tives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527–
We gratefully acknowledge Frans M Helmerhorst who
2 Rosing J, Middeldorp S, Curvers J, Thomassen MCLG, Nicolaes GA,
Meijers JC, Bouma BN, Buller HR, Prins MH, Tans G. Low-dose oral
initiated the project. We are indebted to Thea C Visser-
contraceptives and acquired resistance to activated protein C: a rand-
Oppelaar, M Christella LGD Thomassen and Elke JP
omised cross-over study. Lancet 1999; 354: 2036–40.
Magdeleyns for performing the laboratory tests and to Ank J
3 Tans G, van Hylckama Vlieg A, Thomassen MC, Curvers J, Bertina
Schreijer and Ingeborg de Jonge for data management. We
RM, Rosing J, Rosendaal FR. Activated protein C: resistance deter-
gratefully thank all women who participated in the study.
mined with a thrombin generation-based test predicts for venousthrombosis in men and women. Br J Haematol 2003; 122: 465–70.
Funding was from Leiden University Medical Center and
4 van Grootheest K, Vrieling T. Thromboembolism associated with the
Cardiovascular Research Institute Maastricht.
new contraceptive Yasmin. BMJ 2003; 326: 257.
5 Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism
with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358:
6 van Hylckama Vlieg A. Causes of Venous Thrombosis: Procoagulant
Jan Rosing: the laboratory of Jan Rosing acts as a reference
Factors and Oral Contraceptives, Dissertation. Leiden: Leiden
laboratory for the ETP-based APC-resistance test in a study
Thalidomide, deep venous thrombosis and vasculitis
M . S I L I N G A R D I , M . I O T T I , C . T R E N T I , C . S A L V A R A N I and I . I O R IDipartimento Area Medical, Az. Ospedaliera S. Maria Nuova, Reggio Emilia, Italy
To cite this article: Silingardi M, Iotti M, Trenti C, Salvarani C, Iori I. Thalidomide, deep venous thrombosis and vasculitis. J Thromb Haemost 2004;
See also Rus C, Bazzan M, Palumbo A, Bringhen S, Boccadoro M. Thalidomide in front line treatment in multiple myeloma: serious risk of venous
thromboembolism and evidence for thrombophrophylaxis. This issue, pp 2063–5.
ial growth factor has been suggested. The role of thrombophilia
Thalidomide has been employed in recent years for its anti-
inﬂammatory and antiangiogenic properties in the treatment of
We describe a case of proximal DVT in a patient with SLE
several conditions including leprosy, systemic lupus erythema-
treated with thalidomide for cutaneous vasculitis.
tosus (SLE), Behcet’s disease (BD) and solid and hematological
A 65-year-old female satisﬁed the American College of
Rheumatology criteria for SLE. Recurrent cutaneous vasculitis
An increased incidence of deep venous thrombosis (DVT)
had been observed during a period of 5 years. Her medical
has been observed in malignancies, especially in multiple
history was remarkable for obesity, varicose veins and venous
myeloma, during treatment with thalidomide combined with
thromboembolism, having suffered of recurrent idiopathic
chemotherapy. Pathogenetic mechanisms of thalidomide asso-
superﬁcial thrombophlebitis of lower limbs in the last 2 years.
ciated DVT have not been clearly assessed. A possible role for
She had been treated with corticosteroids for 3 years.
acquired APC-R, increased levels of factor VIII coagulant
In an attempt to spare corticosteroids, thalidomide (100 mg)
activity, von Willebrand factor antigen and vascular endothel-
was added. Fifteen days later the patient presented right lowerlimb swelling, pain and discomfort. No chest pain, dyspnea orhemoptysis was reported. Venous ultrasonography of the lower
Correspondence: Mauro Silingardi, U.O. Medicina Interna, Centro
limbs was diagnostic for proximal DVT (right superﬁcial
Emostasi e Trombosi, Az. Ospedaliera S. Maria Nuova, Viale
femoral/popliteal vein) associated with recurrence of superﬁcial
Risorgimento,80, 42100, Reggio Emilia, Italy.
thrombophlebitis (great saphenous vein). A perfusional lung
scintigraphy was negative for signs of pulmonary embolism.
The search for antiphospholipid antibodies (lupus anticoagu-
Received 6 May 2004, accepted 25 June 2004
lant, anticardiolipin antibodies, antibeta2-GPI antibodies), FV
Ó 2004 International Society on Thrombosis and Haemostasis
Galambok fertőző náthája. A légzőszervek megbetegedése több kórokozó által okozott,kevert fertőzés következménye. A kóroktani tényezők közé tartoznak az ellenállást csökentő faktorok,köztük a galambdúc nem megfelelő légtere. Kórokozók.: A betegség előidézői közé mycoplasmák,virusok,gombák,és trichomonasok is tartoznak. A felsoroltak csökkentik a galam
“Early stage projects always have a valuation. Possible reasons for the earlier negative NPV” statement, that all early-stage projects when discussing with people from pharmaceutical companies: “Early-stage • Over-conservative sales assumptions. never get to a positive value. Decisions are based on other criteria such as Let’s have a closer look at this: biotech posit