1. Member of the Executive Board of EBCOG
Decrease the risk for VTE in CHC users: is a general screening for thrombophilia useful?
Prof Johannes Bitzer
Former President of the European Society of Contraception and Reproductive Health
Editor in Chief of the European Journal of Contraception and Reproductive Health Care
Member of the Executive Board of EBCOG

2. Epidemiology
Risk of venous thromboembolism in women of reproductive age
4-5/10,000 per year

3. Epidemiology Risk Age, Years Incidence of VTE/10,000 women-years)
Method of contraception/ Population group
Available literature
Ongoing studies
Reference
≤ 19
20-29
30-39
40-49
15-49
1-2
2-3
3-4
5-7
healthy, non-pregnant women of childbearing age without contraception
non-hormonal methods of contraception
Tubal sterilisation
Condom, spermicides
Behavioural methods
Copper IUDs
Lidegaard 2009 I=3.0 ( ); Ex= TF
Dinger 2007 I=4.4 ( ); Ex=65 TF
Review Heinemann 2007
INAS-OC and INAS-SCORE
(EURAS-type studies, end of 2013/2014)

4. Venous thromboembolism Multifactorial disease
Triggering
factors
Genetic factors
Environmental
factors

5. Example :Age as a risk factor
Age under 20 years: 1:
Age years: 1:
Age years: 1: 1000
>64 years: 1: 100

6. Inherited Risk factors for thromboembolic diseases
Hereditary
Anti-thrombin deficiency
Protein C deficiency
Factor V Leiden mutation
Prothrombin 20210a mutation
Dysfibrinogenaemia
Factor XIII 34val mutation

7. Risk factors for thromboembolic diseases
Unclear
Elevated Factor VIII level
Elevated Factor IX level
Elevated Factor XI level
Increased fibrinogen concentration
Increased concentration of the thrombin-activated fibrinolysis inhibitor
Elevated levels of the "tissue factor pathway inhibitor"
Activated Protein C resistance (without Factor V Leiden mutation)
Hyperhomocysteinaemia
Elevated levels of Protein C inhibitor

8. Frequency and risk of VTE in thrombophilias
Risk of VTE Frequency
in normals
AT deficiency (type II HBS excluded)
FV L ou FII 20210A homozygous
Combined thrombophilias
PC or PS deficiency
FV L ou FII 20210A heterozygous
X 20-50
0.02%
X 7 & 2
5 & 2%

9. Clinical risk factors for venous thromboembolism
Previous history of VTE
Inherited defects in the coagulation system
Older age
Obesity
Certain chronic diseases
Use of steroidal hormones
Pregnancy and the puerperium
Varicose veins
Recent surgery
Air travel
Prolonged immobilization
Trauma
Infection
Hannaford P. Thromb Research 2011

10. Normal COAGULATION FIBRINOLYSIS Fibrinogen t-PA
Platelets Plasminogen
Fibrinogen t-PA
Factors II, VII, VIII, X, …
COAGULATION FIBRINOLYSIS
Inhibitors Inhibitors
AT, PC, PS TFPI PAI
TAFI
Normal

11. Pregnancy PROTHROMBOTIC STATE Fibrinogen Factors II, VII, VIII, X, …
Platelet number, function
Fibrinogen
Factors II, VII, VIII, X, …
HYPERCOAGULATION
Coagulation inhibitors AT PC PS
Pregnancy
PROTHROMBOTIC STATE

12. COC Fibrinogen t-PA Factors II, VII, VIII, X, …
Platelet number, function Plasminogen
Fibrinogen t-PA
Factors II, VII, VIII, X, …
HYPERCOAGULATION HYPERFIBRINOLYSIS
Coagulation inhibitors Fibrinolysis inhibitors AT, PS PAI
TFPI TAFI
COC

13. Haemostasis and EE
EE stimulates plasma coagulation and fibrinolysis factors reduces coagulation inhibitors
Progestogens Antagonistic (esp. with partial androgen effect)

14. Prevalence of hereditary thrombophilia in the population and effect on VTE risk
Risk Factor
Relative risk without oral contraceptives
Relative risk with oral contraceptives
Prevalence (%)
None 1 4
Pregnancy 5 -
0.05
Postpartum phase 25
0.25
Affliction in family history 3 11
APC resistance (Factor V Leiden) 8
30-50
Protein C deficiency 9 15
0.4
Anti-thrombin deficiency 32
Rosendaal ,1997 Anderson 2003

15. “VTE pill risk” in perspective
Adapted from: Maguire K & Westhoff C. Am J Obstet Gynecol. 2011;205(4 Suppl):S4-8

16. Real-life data: Multiple risk factors in COC users experiencing VTE
Retrospective review of risk factors in COC users, aged years, with VTE diagnosis
Of those with VTE, 79% had multiple risk factors %
Chronic illness known to increase VTE risk
Trauma
Hospitalization
Mix of acquired/genetic factors
Adapted from: Westhoff CL, et al. J Womens Health (Larchmt) Aug 28. [Epub ahead of print]

17. Pattern of VTE risk with oral contraceptives
VTE risk with 2nd/3rd generation COCs is highest in the 1st year of pill use (especially during first 3 months)1,2
Adjusted rate ratio
1Herings RM, et al. Lancet. 1999;354:127-8;2van Hylckama Vlieg A, et al. BMJ. 2009;339:b2921; 3Suissa S, et al. Contraception. 1997;56(3):141-6

18. Clinical risk factors for venous thromboembolism: thrombophilia
Mazzolai L et al. Eur J Vasc Endovasc Surg 2007

19. Estimated relative risk of first time VTE in patients with hereditary thrombophilia
Mazzolai L et al. Eur J Vasc Endovasc Surg 2007

20. Clinical risk factors for venous thromboembolism: thrombophilia
There is a strong association between hereditary defects of coagulation, use of combined contraceptives and the risk of venous thromboembolism
Vandenbroucke P et al. N Engl J Med 2001

21. Supra-additive effect in case of thrombophilia
COC +
OR (95%CI)
Factor V Leiden
15,62 (8,66-28,15)
Deficiency of antithrombin
12,60 (1,37-115,79)
Deficiency of Protein C
6,33 (1,68-23,87)
Deficiency of Protein S
4,88 (1,39-17,10)
Elevated levels of F VIIIc
8,80 (4,13-18,75)
FV Leiden + Prothrombin G20210A
7,85 (1,65-37,41)
En una revision sistemática y metaanálisis cuyo objetivo fue el de evaluar el riesgo de TEV en mujeres con trombofilia que están utilizando AHC se identificaron 201 estudios de los que 7 cumplían los criterios de inclusion.
Wu O et al. HTA 2006

22. Clinical risk factors for venous thromboembolism: thrombophilia
The most common defect affecting approximately 5% of white women (but few Asian or African women) is Factor V Leiden mutation
Although the risk estimates among combined contraceptives users with these coagulation defects are high, most women with these deficiencies do not experience a venous thrombosis
Emmerich J et al. Thromb Haemost 2001

23. Which are the problems regarding thrombophilia screening in women before contraception ?
The majority of thormboembolic events occur in wome without genetic risk factors(70%)(sensitivity of risk screening)
Most women with genetic risk factors can use hormonal contraceptives without developping a thrombosis 90% (specificity of the screening)
The negative predictive value is low
The cost effectiveness until now is low. (NNT to avoid one case of VTE)

24. Screening for thrombophilia
Universal or unselected population screening is inappropriate and should be avoided1
However, a targeted selective screening strategy based on specific high-risk patients groups may be of some value2
1 Machin SJ et al. Br J Fam Plann 1995; 2 Martinelli I. J Thromb Haemost 2009

25. Definition of population screening
Public health service in which members of a defined population, who do not necessarily perceive they are at risk of, or are already affected by a disease or its complications, are asked a question or offered a test, to identify those individuals who are more likely to be helped than harmed by further tests or treatment to reduce the risk of a disease or its complications

26. Costs of screening: estimated total costs of detecting one case of thrombophilia
Italy
A prospective cohort of women was screened for APCr, deficiencies of protein C, S and antithrombin III prior to prescribing COC
433 US dollars for detecting one case of APCr
7795 US dollars for detecting one case of protein S deficiency
Palareti G et al. Contraception 1999

27. Costs of screening: estimated total costs of detecting one case of thrombophilia
USA
Estimated costs of screening for FV Leiden prior to prescribing CHC
Over women with FV Leiden would need to be identified and CHC withheld to prevent one VTE related death
Cost: US dollars 300 million
Creinin MD et al. Fertil Steril 1999

28. Costs of screening: estimated total costs of detecting one case of thrombophiliaUK
Screening for all thrombophilic defects in women prior to prescribing CHC would incur an additional £ to prevent one additional case of VTE
Wu O et al. Br J Haematol 2005

29. Clinical risk factors for venous thromboembolism: family history
Family history of VTE is a poor discriminator of those with underlying coagulation problems
Cosmi B et al. BMJ 2001

30. Prevalence of thrombophilia in women with VTE using COCs or HRT
85 women developed a VTE while on COCs or HRT
65 had at least one additional thrombophilia risk factor
20 women had not any thrombophilia risk factor
Estudio retrospective de los casos de TEV referidos a un centro especializado en un period de 4 años.
37% had a positive family history of VTE
Family and personal history of VTE should be carefully evaluated in all women before initiating CHCs
DeSancho MT et al. Blood Coagul Fibrinolysis 2010

31. Testing for heritable thrombophilia Diseases to be investigated
Deficiency of antithrombin, protein C or protein S
Factor V Leiden
Prothrombin G20210A mutation
Antiphospholipid antibodies
Walker D et al. Br J Haematol 2001

32. «Real world» laboratory testing results for patients presenting with VTE
Somma J et al. Am J Clin Pathol 2006

33. Screening for thrombophilia in high-risk situations
*ICER ¼ Dcosts/Dbenefits; i.e. costs (screening ) no screening)/clinical complications prevented (screening ) no screening).
Wu O et al. Br J Haematol 2005

34. Thrombo-embolic risk factors?

35. WHO eligibility criteria

36. I = initiation, C = continuation
CONDITION
CATEGORY
CLARIFICATIONS/EVIDENCE
COC P R
CIC
KNOWN THROMBOGENIC MUTATIONS
e.g. Factor V Leiden, Prothrombin mutation, Protein S, Protein C, and Antithrombin deficiencies 4
Clarification: routine screening is not appropriate because of the rarity of conditions and the high cost of screening
Evidence: Among women with thrombogenic mutations, COC users had a 2 to 22 fold higher risk of thrombosis than non-users
CONDITION
CATEGORY
I = initiation, C = continuation
CLARIFICATIONS/EVIDENCE
Cu-IUD
LNG-IUD
KNOWN THROMBOGENIC MUTATIONS
e.g. Factor V Leiden, Prothrombin mutation, Protein S, Protein C, and Antithrombin deficiencies 1 2
Clarification: routine screening is not appropriate because of the rarity of conditions and the high cost of screening
CONDITION
CATEGORY
I = initiation, C = continuation
CLARIFICATIONS/EVIDENCE
POP
D/NE
LNG/ETG
KNOWN THROMBOGENIC MUTATIONS
e.g. Factor V Leiden, Prothrombin mutation, Protein S, Protein C, and Antithrombin deficiencies 2
Clarification: routine screening is not appropriate because of the rarity of conditions and the high cost of screening

37. Conclusions
Women and their doctors might be aware the use of CHCs increases the risk of experiencing a VTE
The risk of VTE is higher in those women using COCs and having and inherited coagulation defect
The overall risk of VTE among COCs users is lower than the risk of VTE among pregnant women
A family history of VTE could help to identify those women at a high risk of VTE
Testing for thrombophilia could be appropriate in this last group of women