Download - Thrombophilia Where angels fear to tread
ThrombophiliaWhere angels fear to tread
Andrew McDonaldDivision of Haematology
GSH
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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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• n
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
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• n
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
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• n
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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• n
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]
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• n
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
n
• 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
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• n
What is the most prevalent “thrombophilic” risk factor?
Heit et al 2001
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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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• n
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
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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
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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 ??
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• n
LEIDEN THROMBOPHILIA STUDY
Christiansen et al 2005
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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
n
• 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
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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
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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
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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
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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
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• n
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
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• n
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
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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
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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
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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
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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
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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
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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?