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Thrombophilia Where angels fear to tread Andrew McDonald Division of Haematology GSH

Thrombophilia Where angels fear to tread

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Thrombophilia Where angels fear to tread. Andrew McDonald Division of Haematology GSH. n. CASE 1 40 year old female (physician) 3 years ago: episode of severe diarrhoea / dehydration swollen calf  U/S “calf vein” DVT 2 weeks full dose clexane, then nothing no further events - PowerPoint PPT Presentation

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Page 1: Thrombophilia Where angels fear to tread

ThrombophiliaWhere angels fear to tread

Andrew McDonaldDivision of Haematology

GSH

Page 2: Thrombophilia Where angels fear to tread

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CASE 1

40 year old female (physician)

• 3 years ago:

episode of severe diarrhoea / dehydration

swollen calf U/S “calf vein” DVT

2 weeks full dose clexane, then nothing

no further events

• Tests herself:

Homozygous Factor V Leiden (FVL)

• Would you anticoagulate her?

• If so, how long?

NO

Not applicable

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CASE 2

52 year old female from a family with VTE history

Heterozygous FVL, no personal history of thrombosis

Asymptomatic daughter tested pre OC use:

– heterozygous FVL positive

Would you have done this?

Do you advise longterm anticoagulation?

She falls pregnant – do you anticoagulate?

Would you test her 2 asymptomatic brothers?

Probably not

NO

NO

NO

Page 4: Thrombophilia Where angels fear to tread

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CASE 2

Her 26 year old bother develops insidious onset dyspnoea

CT shows massive multiple pulmonary emboli

Pulmonary hypertension is present – resolves on anticoagulation

Was the decision not to test him wrong?

How long would you anti-coagulate?

Would you now test him for FVL?

Would you now test the other brother?

NO

Lifelong

NO

NO

Page 5: Thrombophilia Where angels fear to tread

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CLINICAL

Thrombophilia:

“an inherited or acquired disorder which increases the risk of Venous Thrombo-embolism”

VTE is the DISEASE

NOT thrombophilia

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CLINICAL MANIFESTATIONS of THROMBOPHILIA

• Family history of VTE

• Spontaneous VTE at younger age

• Recurrent VTE

• Unusual sites (splanchnic, cerebral venous sinus, upper limb)

• Warfarin skin necrosis

• Neonatal purpura fulminans

• Resistance to therapy

• [Obstetric complications (fetal loss, GPH / HELLP, IUGR)]

• [Arterial thrombosis]

Page 7: Thrombophilia Where angels fear to tread

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CLINICAL RISK FACTORS

ACUTE

• Immobility (>3 days)

• Surgery

• Pregnancy

• Medical diseases (TB)

• Indwelling catheters

• Medical diseases (CCF, Stroke, COPD exacerbation,

HIV)

CHRONIC

• Obesity

• OC and HRT

• Hypertension

• Smoking

• Cancer +/- therapy

Page 8: Thrombophilia Where angels fear to tread

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• nGenetic

AT deficiency

PC deficiency

FVL

Prothrombin 20210A

FV Cam / HK

FV HR2 haplotype

FVII 10976A

FXIII Val34Leu

Fibrinogen mutations

TAFI 438A

TM 127A

ACE intron 16

FSAP 1601A

PAI-1 polymorphisms

tPA intron h

Apolipoprotein E polymorphism

Mixed / Unknown

PS deficiency

APC resistance

FVIII

IX

XI

Fibrinogen

Elevated homocysteine (MTHFR C677T)

Sticky platelet syndrome

Acquired

APLS

PNH

MPD / JAK2V617F

THROMBOPHILIA

Page 9: Thrombophilia Where angels fear to tread

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What is the most prevalent “thrombophilic” risk factor?

Heit et al 2001

Page 10: Thrombophilia Where angels fear to tread

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Relative risk of VTE

TYPE Prevalence in VTE

RR

Anticoagulant deficiencies

5% 3-15

Hetero FVL 15-20% 2.5-8

Homo FVL 0.5-1.0% 10-80

Hetero II 202010A 6-10% 1.5-4

Homo II 20210A 0.1-0.5% 5-15

Raised homocysteine 10-25% 1.5-2.5

Elevated VIII 15-25% 1.5-5

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Absolute risk of VTE in asymptomatic carriers

Type Overall risk %/year

Surgery Trauma

Immobilisation

Pregnancy %/pregnancy

OC %/year of use

Anticoagulant deficiencies

0.4-8.8 8.1 4.1 4.3

FVL 0.1-0.7 1.8-2.4 1.9-2.1 0.5-2.0

Prothrombin 20210A

0.1-0.4 2.0 2.8 0.2

Raised VIII 0.3 1.2 1.3 0.6

Mild hyper-homocysteinemia

0.2 0.9 0.5 0.1

Page 12: Thrombophilia Where angels fear to tread

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EVENTS

VTE event multifactorial:

gene-gene interaction

gene-environment interaction

50-80% “thrombophilic events” have a laboratory abnormality

FVL

FVL + X

X

FVL X

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RISK FACTOR ANALYSIS

ARTERIAL VENOUS

Risk factor predictive of events YES YES

“Exclusion” other causes YES NO

Risk factor modifiable YES NO

Modifies prevention strategy YES ?

Modifies disease therapy YES NO

Page 14: Thrombophilia Where angels fear to tread

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Decision analysis post VTE event

Post first VTE event, does the presence of a thrombophilic defect influence the:

intensity of therapy?

NO

duration of therapy?

NO, except: AT deficiency

homozygous FVL?

APLS ??

Page 15: Thrombophilia Where angels fear to tread

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LEIDEN THROMBOPHILIA STUDY

Christiansen et al 2005

Page 16: Thrombophilia Where angels fear to tread

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RISK STRATIFICATION for VTE RECURRENCE

Provoked VTE – 0-1% recurrence Baglin 2003

Stop after 3-6 months (Grd 1A)

Idiopathic VTE

Dfn: No recent surgery (within 3 months)

No plaster cast

No malignancy in past 5 years

No immobilisation for 3/7

Usual therapy with OAC for 6-12 months

Recurrence rates:

5-10% first year

5% second year

2-3% / year thereafter

Page 17: Thrombophilia Where angels fear to tread

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• nBleed Thrombosis

On anti-coagulation

Major 0.9-3% / year

Case fatality rate of 13.7% per major bleed

1-5 major bleed deaths / 1000 / year

1% per year

Case fatality rate of recurrent VTE

~5% (0.5 / 1000 / year)

Off anti-coagulation

0.5-0.8 / 1000 bleed deaths off OAC / year

2.5-16.6 VTE deaths/1000 in 1st

year

Page 18: Thrombophilia Where angels fear to tread

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RISK STRATIFICATION for VTE RECURRENCE

Catch up effect Agnelli 2001

- OAC Rx

- Early stop

- Late stop

Stratify: 3% recurrence risk = acceptable

>9% recurrence risk = unacceptable

Page 19: Thrombophilia Where angels fear to tread

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RISK STRATIFICATION for VTE RECURRENCE

Clinical Decision Rules for stopping therapy

Risk Stratification:

D-dimer – good at PPV, but not NPV Paoreti 2002, 2006

Residual DVT – proven

but difficult Prandoni ISTH 2007

Male gender – OR 1.6 for recurrence

Elevated FVIII

Age

Thrombophilia

Page 20: Thrombophilia Where angels fear to tread

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RISK STRATIFICATION for VTE RECURRENCE

REVERSE [REcurrent VEenous thromboembolism Risk Stratification Evaluation]

Clinical findings of

Hyperpigmentation

Edema

Redness

MEN: HER+ 21% annual recurrence rate,

HER- 7.9% recurrence risk

WOMEN: Also factor in

d-dimer, obesity (BMI>30), age >65 years, ( chol)

HER DOO 0 or 1 score 1.6% recurrence risk (half of all women)

HER DOO 2 or more 14.1% annual recurrence rate

Kovacs et al ISTH 2007

Page 21: Thrombophilia Where angels fear to tread

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Screening Asymptomatic Individuals

Screen first degree family members of an index case?

No evidence for long term prophylaxis prior to VTE

Bleeding risk outweighs incidence rate of VTE events

FATAL 0.25% / year

SERIOUS 1% / year

Short term prophylaxis

Standard indications and strategy similar

? More aggressive prophylaxis in “low risk” situations

Page 22: Thrombophilia Where angels fear to tread

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Family history

Family history:

EDITH study – case control in 1st VTE event

Family history OR for VTE of 2.7 (95%CI 1.8-3.8)

FVL / II 20210A mutation OR 3.6 (1.2-4)

No mutation OR 2.6 (1.7-3.8)

Positive family history increases risk for DVT irrespective of 2 common mutations

Noboa et al 2008

Treat all patients with family history as high risk, irrespective of thrombophilic status

Page 23: Thrombophilia Where angels fear to tread

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Screening Asymptomatic Individuals

Universal screening prior to longer term risk situations?

0

50

100

150

200

250

0*5 11*15 21*25 31*35 41*45 51*55 61*65 71*75 >80

Female

Male

N.Baartman - personal communication 2008

Page 24: Thrombophilia Where angels fear to tread

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OC and Thrombophilia

• OC risk of thrombosis by 3-4x

• Combination with “thrombophilic” defect synergistic

FVL + OC risk ~30x

• Studies confirm increased risk

• No indication to screen general population for thrombophilia (FVL) prior to OC initiation

TREATS

ICER £202 402 for universal screening pre OC

Wu et al 2005

Prevent 1 in 200 000 deaths by screening

Page 25: Thrombophilia Where angels fear to tread

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OC and Thrombophilia

• OR 4.9 (1.92-12.6 95%CI) for VTE event in women with lowest quartile of APC function (all negative for FVL and other mutations) Legnani et al 2004

• Screen first degree relatives of known carriers?

May prevent DVT

BUT consider:

Anxiety

False reassurance of negative test

Other contraceptives not as good

Insurance

Page 26: Thrombophilia Where angels fear to tread

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FVL and Insurance

Asymptomatic FVL+ve

<30 years

75% load re mortality

no income protection / critical illness / lumpsum disability.

>30 years

50% load on mortality

no income protection

Positive VTE and FVL

No cover

O’Mahoney 2008 – personal communication

Page 27: Thrombophilia Where angels fear to tread

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Traveler’s thrombosis:

Duration of flight < 6 hours > 6 hours

No RF General prevention General prevention

One mod RFFVL / PT 20210A

General prevention

consider elastic stockings

General prevention

+ Elastic stockings

? LMWH

One major RFAT, combined,

prev. VTE

2 or > RFOC, other thrombophilia,

pregnancy, night flight, age, recent surgery, obesity

General prevention

consider elastic stockings

? LMWH

General prevention

+ Elastic stockings

LMWH

Page 28: Thrombophilia Where angels fear to tread

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Practical testing tips

• DON’T test functional assays during acute event or inflammatory process

• No antithrombin (and ?LAC) on UF heparin / LMWH

• No Protein C and S (and ?LAC) on warfarin (washout 2-4 weeks)

• Repeat all abnormal functional assays (high cv)

• Serological and clotting assays for APLS

- Repeat positive APLS studies after 12 weeks

• Do ALL appropriate tests

Page 29: Thrombophilia Where angels fear to tread

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SUMMARY

CURRENT

• Utility of thrombophilia testing largely questionable

• Consider cost-benefit ratio

• Do in context of:

Trials

Changing management strategy

FUTURE

• New global coagulation tests for screening?

• Newer anticogulants?