2. Introduction  Background  Components of thrombophilia tests  Who and when to test  Pitfalls in testing  Specific Management issues (contraception/HRT/travel/pregnancy)

3. Background Worldwide incidence 1-2 events per 1000 persons/year Australian Incidence  VTE – 0.83 per 1000 persons per year  DVT – 0.52 per 1000 persons per year  PTE – 0.31 per 1000 persons per year  Approx. 17,400 new cases annually In keeping with figures from UK, lower than other areas in Europe Khoon Ho et al MJA 2008

4. Incidence of VTE by Age in Community based study, Perth, 2008Incidence of VTE by Age in Community based study, Perth, 2008

5. Non-Heritable Risk Factors  Surgery/trauma – particularly pelvic  Prolonged immobility – whatever the cause  Malignancy  Obesity  Pregnancy  Hormonal therapy – COCP/HRT  Air travel > 4hours

6. ThrombophiliaIncidence of first VTE (%/year) Incidence of Defect Relative Risk of VTE 3 Factor V Leiden0.1 (0.0-0.6) 1 ~5% 2 3-8 fold (hetero) 80 fold (homo) Prothrombin G2010A~5% 2 3 fold Combined Defects1.6 (0.5-3.7) 1 ???Higher than FVL homozygous Antithrombin deficiency1.7 (0.8-3.3) 1 0.02% 3 25-50 fold Protein S deficiency0.8 (0.3-1.9) 1 unknownuncertain Protein C deficiency0.7 (0.3-1.6) 1 0.2-0.3% 3 10-15 fold 1.EPCOT study, Vossen et al, J Throm Haem, 2005 2.RCPA Manual, 2004 3.Walker et al, 2001, B J Haem, 2001

7. Why are you doing the thrombophilia screen?  Identify those individuals at high risk of first event or high risk of recurrence?  To provide an intervention to reduce risk?  To enable screening of family members?  Ultimately to reduce the incidence and mortality associated with thrombosis

8. When to test?When to test?  At presentation ?  Not recommended  Issues with counselling, and does not impact on duration of treatment  Recommend to perform 4-6 weeks after completion of anticoagulant therapy

9. Pitfalls Free Protein S  falls progressively during pregnancy  Lower in those on COCP and possibly HRT  Leads to over diagnosis of Protein S deficiency Testing in relation to anti-coagulants  Falls in protein C and S on warfarin (6 weeks)  Changes in anti-thrombin on heparin

10. Pitfalls  What do you do with a positive result in an asymptomatic individual with no family history?

11. Who to test?Who to test? Not everyone who has had a thrombosis Not everyone with a positive family history Depends upon  Circumstances of VTE both for individual and family member  Family history-nature of the thrombophilic defect

12. Implications of Testing Positive in Asymptomatic Individuals  Anxiety – worried well  Over estimation of risk

13. Case finding as means to select those for testing NOT RECOMMENDED  Asymptomatic relatives of those with low risk defects (FVL/PT)  Relatives of those with homozygous or compound heterozygotes (very rare) RECOMMENDED  Asymtomatic relatives of those with high risk defects (AT, Protein C and S)

14. Case finding as means to select those for testing  Clinical scenario much more important Family history  82yo grandmother develops DVT following surgery for #NOF  36yo sister has PTE/DVT whilst on the COCP  27yo brother has unprovoked DVT

15. Prevention of VTE associated with Oestrogen-containing preparations  If first degree relative has had VTE whilst on COCP/HRT and not been tested – advice to consider alternatives – testing not recommended  First degree relative with VTE tested and negative – advice to consider alternates – testing not recommened  First degree relative with VTE tested and positive – advice consider alternative before undergoing testing. (May assist in counselling if high risk thrombophilic defect)

16. Scenario  17 year old attends for COCP FH/ Mother had a DVT at 16/40 in her 2 nd pregnancy Mother is heterozygous for FVL Daughter negative for FVL – rest of screen negative  What would you do?

17. Prevention of pregnancy- associated VTE  Rare – but still highest cause of maternal mortality in Developed World  Associated with 5-10 fold increased risk of VTE  100 fold risk if prior VTE

18. Prevention of pregnancy- associated VTE  Testing based upon clinical risk factors  If prior unprovoked, pregnancy or COCP related VTE testing not recommended – does not alter management  Previous major provoking factor related VTE e.g. due to trauma – do not usually require testing or prophylaxis*  Previous minor provoking factor related VTE e.g. travel – consider testing and prophylaxis if defect found  First degree relative who has had unprovoked, or pregnancy/COCP related VTE – testing recommended

19. Pregnancy ComplicationsPregnancy Complications  Association between thrombophilic defects and pregnancy complications  Recent study compared aspirin alone vs aspirin plus heparin in women with unexplained recurrent miscarriage.  No improvement in live birth rate was noted in either arm  No difference between those with thrombophilic defect and those without  At present not enough evidence to support routine thrombophilic testing as no intervention has been established to improve outcomes Kaandorp et al NEJM 2010

20. Contraception  Alternatives to COCP should be sought if:  Personal history of VTE  Family history of COCP/HRT/pregnancy associated VTE  Known thrombophilic defect (evidence strong for FVL and AT, less so for other defects)

21. What alternatives to use?What alternatives to use?  Barrier contraception  Surgical sterilisation  Progesterone only preparations  Mirena IUD

22. Gomes et al, Arch Intern Med 2004

23. WHO Guidance 2009WHO Guidance 2009 HistoryPOPDepotImplants History DVT/PTE222 On established A/C therapy 222 Family History (1 st degree relatives) 111 Thrombogeneic mutations 222 POP- progesterone only pill 1- A condition for which there is no restriction for the use of contraceptive method 2- A condition where the advantages of using the method generally outweigh the theoretical or proven risks

24. Pregnancy - ProphylaxisPregnancy - Prophylaxis  High risk thrombophilic defects Homozygotes/ compound heterozygote for FVL/PT Antithrombin deficiency*  Lower risk defects X Asymptomatic – not indicated Depends upon personal and family history, and other risk factors such as obesity  Previous VTE  Recurrent miscarriages – no role  Adverse pregnancy outcomes – uncertain benefit

25. Pregnancy - ProphylaxisPregnancy - Prophylaxis  When to start? As soon as is practical – events in high risk women are equally distributed throughout gestation  When to interrupt for delivery? As soon as labour starts Day before induction/C-section No epidural/spinal for at least 12 hours post dose  When to stop ? 6 weeks post-partum

26. What to use?What to use?  LMWH – preferred choice  UFH – associated with progressive bone loss  Warfarin – only in post-partum period, but most prefer to continue with LMWH  If tolerated – compression stocking throughout

27. Pregnancy and Anticoagulant Therapy  Access to early pregnancy assessment unit  Early USS – 5-6 weeks  Stop warfarin and switch to LMWH  LMWH requirements increase throughout pregnancy – anti-Xa levels ~4 weekly  Post-partum – re-establish on warfarin (can breast feed)

28. Air TravelAir Travel

29. W orld Health Organisation R esearch I nto G lobal H azards of T ravel (WRIGHT study, 2007) Risk FactorRelative Risk - Travel Relative Risk + Air Travel Factor V Leiden3.013.6 PT 20210A2.67.9 Obesity1.72.6 Height Short <1.6m1.04.9 Tall >1.9m1.06.8

30. Risk AssessmentRisk Assessment  Very high risk previous VTE some major thrombophilic abnormalities  Other risks 1 st degree relative with VTE Age > 50 years Recent major surgery Active cancer Oestrogens BMI > 30

31. Recommendations  Low Risk Passengers (ie most passengers) Exercise legs & calves Keep legs straight: avoid getting legs in fixed position Keep well hydrated Do not drink alcohol (it dehydrates) Consider support stockings (Grade I, fitted)

32. Recommendations  Moderate Risk Passengers(more than one risk factor) Prophylaxis as above, plus : S upport stockings (Grade II, fitted, below-knee ) X - NO ROLE FOR APSIRIN – not recommended

33. Recommendations  High Risk Passengers  Prophylaxis as above, plus the following: Low-molecular-weight heparin: Single subcutaneous injection at prophylactic dose e.g. enoxaparin 40mg, 2-4 hours before travel Patients on Warfarin should know they are in their therapeutic range before flying, Avoid sleeping tablets

34. Summary  Overview of common heritable thrombophilias  Recommendations on testing  Management of Contraception  Some issues in Management of Pregnancy  Air travel risk and thromboprophylaxis

36. References:  Khoon Ho, W., G. Hankey, et al. (2008). "The incidence of venous thromboembolism: a prospective, community-based study in Perth, Western Australia." MJA 189(3): 144-147.  Walker, I., M. Greaves, et al. (2001). "Investigation and Management of Heritable Thrombophilia." B J Haem 114: 512-528.  W orld Health Organisation R esearch I nto G lobal H azards of T ravel (WRIGHT study, 2007)  Kaandorp, S., M. Goddijn, et al. (2010). "Aspirin plus heparin or aspirin alone in women with recurrent miscarriage." NEJM 362(17): 1586-96.  Vossen, C., J. Conard, et al. (2005). "Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prosepctive Cohort on Thrombophilia (EPCOT)." J Thromb Haem 3: 459-464.  Baglin, T., E. Gray, et al. (2010). "Clinical guidelines for testing for heritable thrombophilia." B J Haem 149: 209-220.  WHO (2009). "Medical eligibility criteria for contraceptive use. Fourth Edition." World Health Organisation.  RCOG (2009). "Reducing the risk of thrombsis and embolism during pregnancy and puerperium.." Royal College of Obstetricians and Gynaecologists Green-top guideline No.37.