the usefulness (or lack of it) of thrombophilia testing in...

The usefulness (or lack of it) of thrombophilia testing in women?

GP Education session

April 8th, 2015

Abdul Shlebak

Learning objectives

-Guidelines

-Common scenarios for thrombophilia testing

-International consensus

-Testing pre-contraception

-Testing pre-HRT

-Testing for pregnancy adverse complications (RM, eclampsia etc.)

-The economic impact

BCSH Guidelines If a first-degree relative with VTE

• has not been tested then suggest that women consider an alternative contraceptive or transdermal HRT. Testing for heritable thrombophilia will provide an uncertain estimate of risk and is not recommended (1C).

• has been tested and the result is negative then suggest that a woman

considers an alternative contraceptive or transdermal HRT. Testing for heritable thrombophilia will provide an uncertain estimate of risk and is not recommended (1C).

• has been tested and the result is positive then suggest that women

consider an alternative contraceptive or transdermal HRT before offering testing as a negative test result does not exclude an increased risk of venous thrombosis. Testing for heritable thrombophilia may assist counselling of selected women particularly if a high risk thrombophilia has been identified in the symptomatic relative (C).

British Journal of Haematology Volume 149, Issue 2, pages 209–220, April 2010

http://onlinelibrary.wiley.com/doi/10.1111/bjh.2010.149.issue-2/issuetoc

BCSH Guidelines

• In the asymptomatic pregnant woman with a family history of venous thrombosis, testing is not required if the clinical risks alone are sufficient to result in thromboprophylaxis (2C).

• It is suggested that asymptomatic pregnant women with a family history of VTE be tested if an event in a first-degree relative was unprovoked, or provoked by pregnancy, COC exposure or a minor risk factor (2C). The result will be more informative if the first-degree relative has a known thrombophilia.

• Pregnant women with a previous event due to a major provoking factor, e.g. surgery or major trauma, would not usually require prophylaxis or testing (2B).

• Most pregnant women with a previous unprovoked VTE (1B) or pregnancy or combined oral contraceptive (COC)-related VTE (2C) will qualify for thrombophylaxis on clinical risk alone and so testing for heritable thrombophilia is not required.

• Pregnant women with a previous event due to a minor provoking factor, e.g. travel, should be tested and considered for prophylaxis if a thrombophilia is found (2C).

• Women should be assessed for risk of pregnancy-associated VTE primarily in relation to clinical risk factors (1B).

British Journal of Haematology

Volume 149, Issue 2, pages 209–220, April 2010


BCSH Guidelines

• Antithrombotic therapy should not be given to pregnant women with a history of pregnancy complications based on testing for heritable thrombophilia. Randomised controlled trials with a no-treatment or placebo arm in women with a history of pregnancy complications are in progress. If these studies indicate a benefit in women with pregnancy complications and heritable thrombophilia, as compared with women without thrombophilia, only then would there be a rational basis for recommending that antithrombotic therapy is given to pregnant women with a history of pregnancy complications based on testing for heritable thrombophilia.

• Testing asymptomatic women before assisted conception and those with ovarian hyperstimulation

syndrome is not indicated (1B). • Thrombophilia screening of hospitalised patients to identify patients at risk of hospital-acquired

venous thrombosis is not indicated (1A). • All hospitalised patients should be assessed for risk of venous thrombosis regardless of heritable

thrombophilia based on a clinical risk assessment (1B). The presence of a previously known heritable thrombophilia may influence the assessment of risk.

• Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis (1B).

• It is suggested that testing for heritable thrombophilia is not indicated in children with stroke (2C).

British Journal of Haematology Volume 149, Issue 2, pages 209–220, April 2010


Martinelli, I. et al. (2014) Inherited risk factors for venous thromboembolism doi:10.1038/nrcardio.2013.211

Anticoagulant mechanisms of antithrombin

Anticoagulant mechanisms of the protein C–protein S system

In whom do we consider testing?

• to modify the risk of a first thrombotic event (screening) asymptomatic individuals with a family history. women who wish to use OCP and have a first-degree relative with VTE women who wish to use HRT and have a first-degree relative with VTE

• for patients with first (or subsequent) episode of thrombossis

case finding duration of A/C therapy if they are young. -following 1st unprovoked event recurrent episodes. thrombosis at unusual sites. positive family history.

• for other indications

adverse pregnancy outcome (RPL, IUGR, pre-eclampsia, abruption etc) young stroke family h/o sudden death retinal ischaemia/CRVO other arterial cardiovascular diseases.

Candidates for screening

Stefano 2002

Baglin 2004

Patients with VTE All independent of the age, the circumstances and the severity

Patient presents with first VTE and positive family history

Surgery associated VTE Yes No

Cancer associated-VTE Excluded Excluded

Asymptomatic women with VTE family history pre CHC, HRT or pregnancy

Yes ?

Asymptomatic first degree relative of a diagnosed carrier of a thrombophilic trait

All No clinical utility

Women with pregnancy complications

Yes ?

Thrombophilia testing in VTE Guidelines worldwide

Thrombosis & Haemostasis, 2013

Yes Yes Yes

Yes Yes Yes

Yes Yes

No

No

No

No

No No No

No

No No NA

NA

NA NA NA NA

Asymptomatic relatives

General population

Testing is common in clinical practice

Current practice

42% for VTE (12-16% for asymptomatic individuals)

15-23% for arterial thrombosis

13-17% for obstetrics Coppens et al, Haem & Thomb 2007; Laberge Genet Med 2009

Italian partial survey 2007 (60 million)

22,000 FVL & 20,000 PT20210A

Dallapiccola et al, Analysis 2009

Australian partial survey 2007 (20 million)

20,378 FVL Suthers et al, RCP Aus 2009

Pre-OCP prescribing 15% Gartner et al, Contraception 2008

“Thrombophilia does not increase the risk of death, not even when a personal history of thrombosis is present,”

Extension study of the European Prospective Cohort on Thrombophilia (EPCOT) study. Assessed patient survival or death from 1994 until December 2007. Investigators analyzed 2115 individuals, 1240 patients and 875 controls. Patients Controls

mean age of 41 years, mean age of 43 years

59% females 48% females

55% history of thrombosis 3% history of thrombosis. deaths 5.8% (n=72) deaths 5.1% (n=45)

Overall hazard ratio of 1.09

History of thrombosis had no impact on survival.

Ingrid Pabinger, MD

22nd ISTH

Hormones, pregnancy & VTE

What is the risk of VTE?

Do we know enough about risk in thrombophilic patients/families?

What is the level of evidence?

Risk of unwanted pregnancy?

How can we balance between benefit/risk?

Health-economics for testing?

VTE related M&M in CHC

Women of reproductive age 4-5/10,000 per year Women on hormonal contraceptives 8-9/10,000 (x2) per year (Heinemann and Dinger 2007) Risk of a VTE in pregnancy 29/10,000 (Heit 2005) Peri-partum period 300-400/10,000 (Ros HS 2001, Pomp 2008) The pill reduces rates of unplanned pregnancies decreases the overall rate of VTE (Ory 1983). Fatal pulmonary embolism 1/100 Death associated with pregnancy 8/100,000 Death rate due to oral contraceptive <1/100,000 – similar to the risk of death from other uncommon causes (e.g. falls, drowning, poisoning, domestic violence)

Canadian SOG

VTE incidence/ 100 000 women years

Relative Risk

Non-pregnant non-users 5 -

2ND Generation CHC 15 3-fold

3rd Generation CHC 25 5-fold

Pregnant 60 12-fold

VTE risk and CHC

VTE incidence/1000

Relative Risk

Non-HRT users 1 -

HRT users 3 2-4 fold

VTE risk and HRT

VTE per 100,000 women/yr

0 50 100 150 200 250

No COC

LNG

DSRP

Others

Pregnancy

EURAS

MHRA

Dinger JC et al. Contraception 2007; 75: 344

progestogen Odds ratio

1st generation norethisterone, norethynodrel, lynestrenol, and ethynodiol acetate

3.2 (2.0-5.1)

2nd generation levonorgestrel, norgestrel, and norgestrione.

2.8 (2.0-4.1)

3rd generation desogestrel, gestodene, and norgestimate 3.8 (2.7-5.4)

-30-35mcg ethinylestradiol (EE) and gestodene, desogestrel cyproterone acetate, or drospirenone the RR of VTE were similar (50-80% higher than levonorgestrel). -35mcg EE & norgestimate was associated with a similar risk to COCs with 30mcg EE and levonorgestrel (RR 1.0 [0.7-1.3]).

Meta-analysis: COC and VTE September 2013 VTE incidence in 2 cohorts of non-users was 1.9 and 3.7 per 10,000 woman years1, 5-10 per 100,000 women years2. 1Contraception 2007;75:328-36. 2MHRA 2011

Progestin Rate Ratio of Thrombosis Compared

With Levonorgestrel

Levonorgestrel 1.00

Norethisterone (norethindrone)

0.98 (0.71–1.37)

Norgestimate 1.19 (0.96–1.47)

Drospirenone 1.64 (1.27–2.10)

Desogestrel 1.82 (1.49–2.22)

Gestodene 1.86 (1.59–2.18)

Cyproterone acetate 1.88 (1.47–2.42)

Risks of Thrombosis According to Progestin

Pediatrics. 2011 Feb; 127(2): 347–357.

Effect of the progestogens on risk of VTE

1995- 3 studies reported an increase of thrombosis in women using oral contraceptives containing the newest progestins, ie, desogestrel and gestodene (also known as third-generation progestins). Most subsequent studies confirmed this finding, but some did not. Meta-analysis combining the evidence from all studies found an overall 1.7-fold increased risk. The relative risk was >2-fold increased in studies funded through public agencies but only 1.3-fold in studies sponsored by pharmaceutical companies producing third-generation contraceptives. The risk for third-generation users was higher during the early phases of use but remained 2-fold increased during long-term use.

Rosendal et al, Arteriosclerosis, Thrombosis, and Vascular Biology. 2002; 22: 201-210

Associated with changes in the coagulation system increase in factors II, VII, VIII, and X

decrease in protein S

decrease of fibrinolytic activity (increase of TAFI)

increased resistance to APC (decreases of free protein S

+ desrease in free TFPI)

more pronocned (contain desogestrel,gestodene, drosperidone, or cyproterone as a progestagen)


Mechanism(s) of hormonal related thrombosis

Case 1

• 19-year-old female student referred by her GP pre-OCP thrombophilia testing .

• Healthy and fit.

• Used OCP for few months around age of 17 years.

• TOP 2 years ago.

• Mother had a DVT in her 40s (no thrombophilia results available).

• Smokes 5 per day

• BMI 28

Comparison of Recommendations for Use of CHC

Clinical Situation WHO UKMEC CDC

History of VTE 4 4

4- if higher risk of recurrence of estrogen-associated VTEs, known thrombophilia, active cancer, recurrent VTEs 3- if lower risk of recurrence, no risk factors

History of VTE, currently on anticoagulation therapy (for at least 3 mo)

4 4

4 -if higher risk of recurrence (known thrombophilia, active cancer, history of recurrent VTEs)b; 3- if lower risk of recurrence, no risk factorsb

Acute VTE 4 4 4

First-degree family history of VTE 2 2 (3 if family member was <45 y old) 2

Major surgery with prolonged immobilization

4 4 (suggest COCs be discontinued at least 4 wk before surgery)

4

Major surgery without prolonged immobilization

2 2 2

Known thrombogenic mutations (eg, factor V Leiden, prothrombin mutation, and protein S, protein C, and antithrombin deficiencies)

4 4 4

Obesity 2 2 (BMI < 35); 3 (BMI 35–39); 4 (BMI ≥ 40)

2

Postpartum (nonbreastfeeding) <21 d 3 3 3

Systemic lupus erythematosus with antiphospholipid antibodies

4 4 4

Pediatrics. 2011 Feb; 127(2): 347–357.

Comparison of Recommendations for Use of CHC

Clinical Situation WHO UKMEC CDC

History of VTE 4 4

4- if higher risk of recurrence of estrogen-associated VTEs, known thrombophilia, active cancer, recurrent VTEs 3- if lower risk of recurrence, no risk factors

History of VTE, currently on anticoagulation therapy (for at least 3 mo)

4 4

4 -if higher risk of recurrence (known thrombophilia, active cancer, history of recurrent VTEs)b; 3- if lower risk of recurrence, no risk factorsb

Acute VTE 4 4 4

First-degree family history of VTE 2 2 (3 if family member was <45 y old) 2

Major surgery with prolonged immobilization

4 4 (suggest COCs be discontinued at least 4 wk before surgery)

4

Major surgery without prolonged immobilization

2 2 2

Known thrombogenic mutations (eg, factor V Leiden, prothrombin mutation, and protein S, protein C, and antithrombin deficiencies)

4 4 4

Obesity 2 2 (BMI < 35); 3 (BMI 35–39); 4 (BMI ≥ 40)

2

Postpartum (nonbreastfeeding) <21 d 3 3 3

Systemic lupus erythematosus with antiphospholipid antibodies

4 4 4

Pediatrics. 2011 Feb; 127(2): 347–357.

Benefit outweighs risk

UKMEC-4=Absolute contraindications The risk is unacceptable health risk and should not be used

• < 6 weeks postpartum if breastfeeding

• Smoker ≥ age 35 ≥15 cigs/day

• BP systolic >160 or diastolic ≥95

• Current or past Hx VTE

• Known thrombogenic mutations

• Major surgery with prolonged immobilization

• Systemic Lupus Erythematosus

• Current or past Hx IHD/CVA • Diabetes > 20yrs OR with “opathies” • Complicated valvular heart disease • Migraine aura (“focal”) • Current breast cancer • Liver tumours • Liver disease: active

hepatitis/severe cirrhosis

Evidence based practice

Risk Factor risk estimate

Baseline COCs associated

Factor V Leiden heterozygote 4–8 times 28–35 times

Prothrombin G20210A heterozygote 2–3 times 16 times

Travel 2–4 times 14–20 times

Trauma/surgery 2–5 times 5–12.5 times

Obesity 1.7–2.4 times 10–24 times

Smoking 1.4–3.3 times 8.8 times

Risk estimates for common VTE risk factors

Pediatrics. 2011; 127(2): 347–357.

Martinelli, I. et al. (2014) Inherited risk factors for venous thromboembolism doi:10.1038/nrcardio.2013.211

Risk of VTE among users of OC or HRT with or without inherited thrombophilia

Number of asymptomatic thrombophilic women (or women with a VTE positive FH) who should avoid using OCP to prevent one VTE

Thrombophilia Risk on OCs per Y,

% NNT to prevent

1 VTE No of

female relatives to be tested

AT, PC, PS deficiency -Deficient relatives -Non-deficient relatives

4.3 0.7

28

56

F V Leiden or P 20210A mutation -Relatives with the mutation -Relatives without the mutation

0.5 0.2

333

666

Family h/o VTE -General population, no FH -General population, positive FH

0.04 0.08

3333 1667

? ?

NNT=number not to take OCs Blood, 2011 vol. 2011 no. 1 150-155

http://asheducationbook.hematologylibrary.org/content/2011/1/150/T3.large.jpg

% of unintended pregnancy during the first year of use

Trussell J. In: Hatcher et al. (eds) Contraceptive

Technology (20th Edition). New York, Ardent

Media 2011

Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception Elizabeth F. W. van Vlijmen, Nic J. G. M. Veeger, Saskia Middeldorp, Karly Hamulyák, Martin H. Prins, Harry R. Büller, and Karina Meijer

van Vlijmen E F W et al. Blood 2011;118:2055-2061

Absolute risk of VTE in all 798 female relatives

Defects All female relatives

None Single Combined All women

Total no. 497 251 50

No. with event 17 22 11

Observation period, y 12 908 6234 1175

Incidence rate per 100 person-years (95% CI) 0.13 (0.08-0.21) 0.35 (0.22-0.53) 0.94 (0.47-1.67)

Actual pill use

Total no. 366 171 34


Observation period, pill-years 3211 1218 232

Incidence rate per 100 pill-years (95% CI) 0.19 (0.07-0.41) 0.49 (0.18-1.07) 0.86 (0.10-3.11)

Actual pregnancy

Total no. 364 175 36


Observation period, pregnancy-years 955 507 92

Incidence rate per 100 pregnancy-years (95% CI) 0.73 (0.30-1.51) 1.97 (0.94-3.63) 7.65 (3.08-15.76)

Comparison of VTE outcome in women with single or combined defect

Defects No defects

COC LNG-IUD Copper IUD (380 mm2)

Condom* COC LNG-IUD Copper IUD (380

mm2) Condom*

Incidence of first VTE per 100 pregnancy-years

0.55† 0.25‡ 0.25‡ 0.25‡ 0.19 0.09 0.09 0.09

Cases of VTE per 100 000 pregnancy-years

550 250 250 250 190 90 90 90

Contraceptive failure rate, per 100 women-years§

0.2 0.7 1.4 12 0.2 0.7 1.4 12

Unintended pregnancies per 100 000 pregnancy-years

200 700 1400 12 000 200 700 1400 12 000

Incidence of VTE per 100 pregnancy-years¶

2.8 2.8 2.8 2.8 0.7 0.7 0.7 0.7

Additional cases of VTE 6 20 40 336 2 5 10 84

Total number of VTE 556 270 290 586 192 95 100 174


Conclusions from van Vlijmen E F W et al.

Although the absolute risk is significantly increased during COC use up to 0.86 per 100 pill-years in women with combined defects, the absolute risk during the pregnancy-postpartum period was by far the most important up to 7.65 per 100 pregnancy years. The substantially higher risk during the pregnancy-postpartum period was confirmed by an adjusted HR of 16.0 compared with an adjusted HR of 2.2 for COC use. In line with other publications, the absolute risk of VTE during the pregnancy-postpartum period noted in women without any thrombophilic defect is higher than in COC users (0.73 vs. 0.19 per 100 person-years). These risks were observed in thrombophilic families, the absolute risk during the pregnancy-postpartum period and during COC use in the study was approximately 3.5 to 5 times higher than reported in the general community (incidences of 0.2 per 100 pregnancy-years and 0.06 per 100 pill-years).


• 57-year-old woman referred by her GP for pre-HRT thrombophilia testing.

• Healthy and fit

• Uneventful 2 SVD (children aged 24 & 27 years)

• Took OCP in past for over 10 years

• Sister had an extensive VTE (DVT & PE) following knee arthroscopic surgery

• Family of osteoporosis

• Non-smoker

• BMI 22

Case 2

HRT and VTE

Risk of thrombosis is highest in the first year of use. In some studies, but not in all, the risk was limited to the first year. Oral use and transdermal patches increase the risk of thrombosis. Association with thrombosis has been found for conjugated estrogens as well as for estradiol.


Factor V Leiden, Hormone Replacement Therapy, and Risk of Venous Thromboembolic Events in Women With Coronary Disease David M. Herrington, Eric Vittinghoff, Timothy D. Howard, David A. Major, John Owen, David M. Reboussin, Donald Bowden, Vera Bittner, Joel A. Simon, Deborah Grady, Stephen B. Hulley

VTE -2.0 of 1000 per year in women without the mutation who were taking a placebo -15.4 of 1000 per year in women with the factor V Leiden mutation who were treated with HRT (P 0.0015). -On the basis of these data the estimated number needed to screen for factor V Leiden to avoid an HRT-associated VTE during 5 years of treatment is 376.

Arterioscler Thromb Vasc Biol. 2002;22:1012-1017.

Effect of hormone replacement therapy on CV events in recently postmenopausal women: randomised trial

Schierbeck L L et al. BMJ 2012;345:bmj.e6409 ©2012 by British Medical Journal Publishing Group

Consensus 2013: Venous thromboembolism

The risk of VTE and ischemic stroke increases with

oral MHT but the absolute risk is rare below age 60 years.

Observational studies point to a lower risk with transdermal therapy.

IMS 2013

Health economic implications

Thrombophilia Number to screen

Number to stop OCP

Cost per single thrombosis prevented

1To prevent 1 VTE episode in FVL heterozygous woman

10,000 500 FVL+ to be identified

£ 202,402

2To prevent 1 fatal VTE episode in FVL heterozygous woman

? 92,000 carriers to be identified

> $ 300 M

1Wu et al Br J Haematol 2005, 2Crenin et al Fertil Steril 1999, 3Hoibaraaten et al Thromb Haemost 2000

1&3Screening in unselected women and withholding the prescription in those tested positive

376 (over 5 years of treatment)

Fatality annual risk (HRT & FVL heterozygote) 0.1%

£ 6,824

Date of download: 9/25/2012 Copyright © 2012 American Medical

Association. All rights reserved.

Cost of a typical thrombophilia work-up

Arch Intern Med. 2001;161(20):2433-2439. doi:10-1001/pubs.Arch Intern Med.-ISSN-0003-9926-161-20-ira00051

Costs of Hypercoagulable Workup at the University of Miami

$1873.50

What are the alternatives to HRT?

Herbal medicine – a practice based on the use of plants or plant extracts to relieve symptoms – for example, evening primrose oil or St John’s Wort. Alternative medicine – a range of therapies used instead of conventional medicine, such as acupressure, acupuncture and homeopathy. Complementary therapy – interventions which tend to be used alongside conventional medicine, for example, aromatherapy with HRT. Medical treatments – prescribed by your doctor, such as antidepressants. Overall, alternatives to HRT are much less effective at easing the symptoms of the menopause. The best ones can reduce the severity of symptoms by 50% to 60% (80% to 90% with HRT).

Case 3

• 27-year-old woman, 18 weeks pregnant

• Sister had microgynon associated cerebral venous sinus thrombosis

• Non-Smoker

• BMI 30

• No personal h/o VTE

• Does she need LMWH prophylaxis?

• Does she need testing?

VTE in pregnancy

-RR of antenatal VTE 5-fold -absolute risk remains low 1 in 1000 -The puerperium is the time of greatest risk 20-fold -80% of events occur in the first 3 weeks -Events are spread across the 3 trimesters, with more than 50% of events occurring in the first 20 weeks of pregnancy. -Most events are ileofemoral and left sided.

Ian Greer, asheducation-2012.1.203

OR for risk of VTE in pregnancy

Patient features Adjusted OR 95% CI

Previous VTE 24.8 17.1-36.0

Immobility if combined with BMI > 25

7.7 62

3.2-19.0

Age > 35 Parity > 1 BMI > 30 Weight gain > 21 kg (vs 7-21) Smoking

1.3 1.5 5.3 1.6 2.7

1.0-1.7 1.1-1.9 2.1-13.5 1.1-2.6 1.5-4.9

Antepartum factors Preeclampsia Preeclampsia + fetal GR ART Twin Antepartum haemorrhage

3.1 5.8 4.3 2.6 2.3

1.8-5.3 2.1-16 2.0-9.4 1.1-6.2 1.8-2.8

Postpartum factors Postpartum haemorrhage CS Blood Transfusion

4.1 3.6 7.6

2.3-7.3 3.0-4.3 6.2-9.4

Medical Comorbidity- SLE, cardiac, anaemia, sepsis, VVs

2.0-8.7

Ian Greer, asheducation-2012.1.203

No of asymptomatic thrombophilic women who should use LMWH prophylaxis during pregnancy and/or the postpartum period to prevent

pregnancy-related VTE, and estimated NNT

Thrombophilia VTE risk per Pregnancy, %

Number using prophylaxis to prevent 1 VTE

No of female relatives to be

tested


4.1 0.5

28

56

Heterozygous (FVL or P20210A) -Relatives with the mutation -Relatives without the mutation

0.5 0.2

66

132

Homozygous (FVL or P 20210A) -Relatives with the mutation -Relatives without the mutation

16.0 0.5

6

24


0.5 1.0

200 200

? ?

Blood, 2011 vol. 2011 no. 1 150-155


No of asymptomatic thrombophilic women who should use LMWH prophylaxis during pregnancy and/or the postpartum period to prevent

pregnancy-related VTE, and estimated NNT

Thrombophilia VTE risk per Pregnancy, %

Number using prophylaxis to prevent 1 VTE

No of female relatives to be

tested


4.1 0.5

28 £ 50,904

56

Heterozygous (FVL or P20210A) -Relatives with the mutation -Relatives without the mutation

0.5 0.2

66 £ 119, 988

132

Homozygous (FVL or P 20210A) -Relatives with the mutation -Relatives without the mutation

16.0 0.5

6 £ 10,908

24


0.5 1.0

200 200 £ 363,600

? ?

Blood, 2011 vol. 2011 no. 1 150-155 (40+6X7x2=644 enoxparin injections per pregnancy, £ 3.03 BNF


Health economic implications Thrombophilia Number to

screen Number to stop

OCP Cost per single

thrombosis prevented

1To prevent 1 VTE episode in FVL heterozygous woman

10,000 500 FVL+ to be identified

£ 202,402

2To prevent 1 fatal VTE episode in FVL heterozygous woman

? 92,000 carriers to be identified

> $ 300 M

1Wu et al Br J Haematol 2005, 2Crenin et al Fertil Steril 1999, 3Hoibaraaten et al Thromb Haemost 2000

1&3Screening in unselected women and withholding the prescription in those tested positive

Fatality annual risk (HRT & FVL heterozygote) 0.1%

£ 6,824

1Selective screening and LMWH during pregnancy

£ 81,436 (any adverse pregnancy outcome as an event)

Women with previous VTE

Brill-Edwards et al, N Engl J Med 2000 (n=125)

Pabinger et al, J Thromb Haemost 2005 (n=109)

(n=197 pregnancies)

Design of study -Withheld antepartum prophylaxis -all given post-partum prophylaxis for 6 weeks

-Observed without antepartum prophylaxis

Antepartum VTE Idiopathic Provoked Post-partum

2.4% 5.5% 1.7% 3 recurrences despite prophylaxis

4.1% 0 recurrence 7 recurrences in 72 was OCP related 1 recurrence in 37 women with non-OCP related

Thrombophilia pos Thrombophilia neg

6.2% 10.2%

• VTE recurrence rate in pregnancy is low • To prevent a single VTE episode, the exposure of a large numbers of women to heparin

throughout pregnancy & post-partum.

In women with previous VTE & severe thrombophilia

AT def, Homozygous FVL & FVL/prothrombin double heterozygous

-May have a higher absolute risk of VTE

-Estimates are inconsistent

-AT deficiency, suggested risk of 40% but Friederich et al, Ann Intern Med 1996

followed 13 women (33 pregnancies) and observed only one VTE (3%)

-Martinelli et al, Thromb Haem 2001

3 of 19 (15.8%) with homo FVL & 2 OF 50 (4%) with double hetero

developed VTE

All but one occurred post-partum.

Learning objectives

-Common scenarios for thrombophilia testing

-International consensus

-Testing pre-contraception

-Testing pre-HRT

-Testing for pregnancy adverse complications (RM, eclampsia etc.)

-The economic impact

the usefulness (or lack of it) of thrombophilia testing in...

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