Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate

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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.
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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 [1]. 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: h.a.a.m.van_vliet@ 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) [4]. 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) [2]. 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 [2]. 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) [3]. 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



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