Issues in the Investigation and Management of Thrombophilias
Issues in the Investigation and Management of Thrombophilias Michelle Bryson Staff Specialist Haematology Gold Coast Hospital Introduction Background Components of thrombophilia tests Who and when to test
Pitfalls in testing Specific Management issues (contraception/HRT/travel/pregnancy) 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 Incidence of VTE by Age in Community based study, Perth, 2008 Khoon Ho et al MJA 2008 Non-Heritable Risk Factors Surgery/trauma particularly pelvic
Prolonged immobility whatever the cause Malignancy Obesity Pregnancy Hormonal therapy COCP/HRT
Air travel > 4hours Thrombophilia Incidence of first VTE (%/year) Incidenc e of Defect Relative Risk of VTE3 Factor V Leiden 0.1 (0.00.6)1
1.7 (0.83.3)1 0.02%3 25-50 fold Protein S deficiency 0.8 (0.31.9)1 unknown uncertain Protein C deficiency 0.7 (0.31.6)1 0.2-0.3%3
10-15 fold 1. EPCOT study, Vossen et al, J Throm Haem, 2005 2. RCPA Manual, 2004 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 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 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 Pitfalls What do you do with a positive result in an asymptomatic individual with no family history? 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 Implications of Testing Positive in Asymptomatic Individuals Anxiety worried well Over estimation of risk 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) 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 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) Scenario 17 year old attends for COCP FH/ Mother had a DVT at 16/40 in her 2nd pregnancy Mother is heterozygous for FVL Daughter negative for FVL rest of screen
negative What would you do? Prevention of pregnancyassociated 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
Prevention of pregnancyassociated 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 Pregnancy 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 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) What alternatives to use? Barrier contraception Surgical sterilisation
Progesterone only preparations Mirena IUD Gomes et al, Arch Intern Med 2004 WHO Guidance 2009 History History DVT/PTE On established A/C therapy Family History (1st degree relatives) Thrombogeneic mutations POP
Depot Implant s 2 2 2 2 2 2 1 1 1
2 2 2 POP- progesterone only pill 1- A condition for which there is no restriction for the use of contraceptive meth 2- A condition where the advantages of using the method generally outweigh t theoretical or proven risks Pregnancy 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 Pregnancy 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 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 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) Air Travel World Health Organisation Research Into Global Hazards of Travel (WRIGHT study, 2007) Risk Factor
Relative Risk - Travel Relative Risk + Air Travel Factor V Leiden 3.0 13.6 PT 20210A 2.6 7.9 Obesity
1.7 2.6 Short <1.6m 1.0 4.9 Tall >1.9m 1.0 6.8 Height Risk Assessment Very high risk previous VTE
some major thrombophilic abnormalities Other risks 1st degree relative with VTE Age > 50 years Recent major surgery Active cancer Oestrogens BMI > 30 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)
Recommendations Moderate Risk Passengers (more than one risk factor) Prophylaxis as above, plus : X- Support stockings (Grade II, fitted, below-knee) NO ROLE FOR APSIRIN not recommended 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 Summary Overview of common heritable thrombophilias Recommendations on testing Management of Contraception Some issues in Management of Pregnancy
Air travel risk and thromboprophylaxis Thank - You Any questions ? 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.
World Health Organisation Research Into Global Hazards of Travel (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.
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