Transcript Risk factors for venous thrombosis

Testing for thrombophilia: is it ever
useful?
F.R. Rosendaal, Leiden
ISTH Educational Course on Thrombosis,
Thrombophilia, Thrombolysis and DIC
Moscow, 17-19 September 2014
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Thou art always figuring diseases in me, but
thou art full of error: I am sound
(Shakespeare W. Measure for measure 1604; Act I, Scene II)
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Tests through history
• the very first test....
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Eve tests Adam
(test of faith/love)
Georgio Giulio Clovio
Book of Hours (1546)
Titian (1550)
Judgement of Paris
(test of beauty)
Roman augur
(test for going to war)
Rice water diarrhoea
(test for cholera)
Modern tests
•
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•
Test for clinical disease (e.g. ECG)
Test for early disease (e.g. Pap smear)
Test for risk of disease (e.g. blood pressure)
Test for fetal disease (e.g., amniocentesis)
Test for risk of fetal disease (e.g. carrier testing)
Test for past infection (e.g. Mantoux)
Test for state (e.g. pregnancy test)
• etc
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Not always happy end
Sistine Chapel
Michelangelo (1512)
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Not always a happy end
.. a thousand ships
(film: Troy, 2004)
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Costs and benefits
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medical benefits (NNT, NNS)
medical costs (side effects)
psychosocial benefits (+ Qol)
psychosocial costs (-QoL)
economical benefits (+ €)
economical costs (- €)
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Testing for thrombophilia
• Factor V Leiden worldwide most performed
genetic test
• Often in combination with protein C, protein
S, antithrombin, factor VIII, MTHFR 677T
and homocysteine
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How many tests are done?
• survey over 4 months via large diagnostic center
• 2000 questionnaires to ordering physicians
• response 63% (n=1132)
• extrapolation: 15 000 per year
– EU: 500 000 per year
– USA: 300 000 per year
Population 16 million
(Coppens, J Throm Haemost 2007)
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Indications for testing
• Internal Medicine, Vascular Medicine, Hematology,
Pulmonology, Cardiology, Surgery, Obstetrics,
General Practitioners
family
16%
VT
42%
obstetric
17%
no changes in
management in 24%
(Coppens J Throm Haemost 2007)
arterial
23%
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Indications for testing
• obstetric
• weak relation with pregnancy loss
• no effective treatment
• arterial disease
• weak relation with arterial disease
• no specific treatment
• venous thrombosis
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If testing: for what?
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Confirmed genetic risk factors
patients (%)
AT/PC/PS deficiency
pop. (%)
RR
PAR (%)
3
<1
>10
1
19
3
7.9
17
Factor V Leiden
rs6025
PT 20210A
rs1799963
6
2
2.8
3
FGG C10034T
rs2066865
12
6
2.4
8
71
57
1.8
31
non-00 bloodgroup
FGB his95arg
rs6003
19
14
1.5
7
FXIII leu34val (rec.)
rs5985
96
94
1.4
27
PROC A2418G
rs1799809
22
19
1.3
5
FGA Thr312Ala
rs6050
29
26
1.2
5
FGB 455 G/A
rs1800788
26
21
1.3
6
F11
rs2289252
48
41
1.3
13
F5
rs4524
79
73
1.3
19
GP6
rs1613662
84
82
1.2
11
SERPINC1
rs2227589
17
10
1.3
3
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Testing for genetic variants
• To be discussed
– deficiencies of protein C, S or antithrombin
– factor V Leiden
– prothrombin 20210A
• all others too weak effect
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Testing for genetic variants
• Aim
– prevent thrombosis (death)
• Method
– screening
– intensified treatment or removal risk factors
• Target
– asymptomatic patients (prevent 1st event)
– symptomatic patients (prevent recurrence)
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Major distinction
• unselected individuals
– patients, relatives, non-related
• selected patients (familial thrombophilia)
– patients, relatives
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Unselected individuals
• screening of asymptomatics
– everybody
– prior to risk situations (surgery, OCs)
• all
• relatives of patients
• testing of symptomatics
– prevention of recurrencies
• prolonged anticoagulant treatment
• liberal short-term prophylaxis
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Testing for genetic variants
• Aim
– prevent thrombosis (death)
• Method
– screening
– intensified treatment or removal risk factors
• Target
– asymptomatic patients (prevent 1st event)
– symptomatic patients (prevent recurrence)
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Gene-environment interaction
Absolute risks:
Neither
OC
FVL
Both
35
30
25
0.5 / 10 000
2.0 / 10 000
4.0 / 10 000
14 / 10 000
20
What can be gained
15
10
-10 / 10000 (VT)
- 1 / 10000 (death)
5
0
neither
OC
(Vandenbroucke, Lancet 1994)
FVL
both
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How many to test to prevent one
Risk: 10/10 000
- 1000 with FVL should not take OCs to prevent one VT
- 10000 with FVL should not take OCs to prevent one death
How to find 1000 women with factor V Leiden
- Population (5%) : test 20 000
- Patients’ relatives
- Patients (20%): test 5 to find one with FVL
- Relatives (25-50%): test 2-4 to find one
- to find 1000 women with FVL:
- test 10 000 patients and >2000 relatives
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Costs
• whether patients or asymptomatic women
• we need to test > 10 000 individuals to prevent one VT
• we need to test > 100 000 individuals to prevent one death
• cost per consultation and test: € 150,-
• cost to prevent one VT: 1.5 million euros
• cost to prevent one death: 15 million euros
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Screening asymptomatics
• risk reduction too low to render it costeffective
• not rational
• this includes screening looking for relatives
of patients
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Testing for genetic variants
• Aim
– prevent thrombosis
• Method
– screening
– intensified treatment or removal risk factors
• Target
– asymptomatic patients (prevent 1st event)
– symptomatic patients (prevent recurrence)
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Testing thrombosis patients
• testing of unselected patients
• can only be useful if
– patients with positive test have higher
recurrence risk than those without
– there are ways to reduce this risk with a positive
risk-benefit ratio (side-effects)
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Testing thrombosis patients
• testing of unselected patients
• can only be useful if
– patients with positive test have higher
recurrence risk than those without
– there are ways to reduce this risk with a positive
risk-benefit ratio (side-effects)
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Leiden Thrombophilia Study
• 474 consecutive patients with DVT
– exclusion: malignancy
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prospective follow-up
mean follow-up 7.3 yr (max 12 yr)
90 recurrent thrombotic event
event rate 2.6 percent per year
(Christiansen, JAMA 2005)
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No long-term effect thrombophilia
• abnormalities
PC, PS, AT
FVL, PT20210A
FVIII, FIX, FXI
homocysteine
• HR: 1.4 (CI95: 0.9-2.2)
(Christiansen, JAMA 2005)
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Cambridge study
• N=489
• 2 yr follow-up
• anticoagulant defects
PC, PS, AT
FVL, PT20210A
• HR 1.50 (CI95 0.8-2.8)
( Baglin, Lancet 2003)
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Recurrence risk by defect
RR
CI95
factor V Leiden
1.2
0.7 - 1.9
prothrombin 20210A
0.7
0.3 - 2.0
PC/PS/AT deficiency
1.8
0.9 - 3.7
high FVIII
1.1
0.7 - 1.8
high FIX
0.9
0.5 - 1.7
high FXI
0.6
0.3 - 1.1
hyperhomocysteinemia
0.9
0.5 - 1.6
(Christiansen, JAMA 2005)
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Conclusion
• Effect of laboratory abnormalities on
recurrence small or absent
• Test result does not predict who is at
increased risk
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Testing thrombosis patients
• testing of unselected patients
• can only be useful if
– patients with positive test have higher
recurrence risk than those without
– there are ways to reduce this risk with a positive
risk-benefit ratio (side-effects)
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Prolonged anticoagulation
• idiopathic VT
• N=267
• 3 vs 12 months
• catch-up
• no benefit
(Agnelli, N Engl J Med 2001)
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Conclusion
• Effect of laboratory abnormalities on
recurrence probably small
• No clear strategy to reduce risk except lifelong anticoagulation
– risk of severe hemorrhage 1-2 percent per year
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Real predictors
Relative risk
sex
men vs women
3- to 4-fold
type of first event
idiopathic vs secondary
2- to 3-fold
(Baglin, Lancet 2003; Baglin, JTH 2004; Kyrle, NEJM 2004; Christiansen,
JAMA 2005)
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Unselected individuals
• screening asymptomatic individuals
– risk reduction too low to render it cost-effective
– not rational
• screening symptomatic patients
– does not identify those at high risk of recurrence
– does not open treatment options
– not rational
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Selected individuals
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Familial thrombosis
It is probably more than coincidence when six or more
members of the same family each develop from one to five
thromboembolic conditions and when most of them
eventually die of such conditions (Wright, 1952)
†
†
TE
TE
TE: thromboembolism
†: fatal thromboembolism
†
†
TE
TE
†
TE
TE
TE
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Selected individuals
Age at first thrombosis:
• consecutive patients with 1st VT (N=378)
– protein C deficiency
– no defect found
47 yr
43 yr
• familial thrombophilia (24 families, N=229)
– protein C deficiency
– no defect found
(Lensen, Blood 1997)
35 yr
33 yr
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EPCOT study
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9 centres in Europe
all their patients with clear familial thrombophilia
prospective follow-up (1995-2001)
1626 patients (probands and relatives)
AT/PC/PS deficiency or FVL
(Leiden, Barcelona, Glasgow, Sheffield, Frankfurt, Vienna, Malmö, Bologna,
Paris)
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EPCOT: asymptomatic people
• incidence of venous thrombosis (no AC)
– 0.8 % per year (CI95 0.5-1.2%)
• majority of events spontaneous
• risk not greater than that of anticoagulation
• testing will not affect management
(Vossen, J Thromb Haemost 2005)
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EPCOT: symptomatic patients
• patients with one prior event
• divided in those +/- long-term anticoagulation
• incidence of venous thrombosis
– long term AC: 1.1 % per year
– no AC:
5.3 % per year
• gradient of risk over type of thrombophilia
– AT-def: 10.5%/yr (2.7 on AC), FVL: 3.8%/yr (0.0 on AC)
• incidence of major hemorrhage: 0.6%/yr
(Vossen, Arterioscler Thromb Vasc Biol 2005)
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Familial thrombophilia
• asymptomatic people (relatives)
– no obvious advantage of screening
– no obvious management choices
• symptomatic patients
– suggestive of benefit of long-term
anticoagulation (esp. AT-deficiency)
– no randomised studies
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Testing for genetic variants
• screening in unselected individuals or
patients with thrombosis not indicated
• Screening symptomatic individuals in highly
penetrant familial thrombophilia may be
indicated
– only antithrombin deficiency
– no studies that prove positive benefit-risk-ratio
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Testing in selected patients
• Symptomatic patients with familial
thrombophilia: very small group
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Experimental evidence
• case-cohort study of patients with recurrent VT
• idea: compare patients with recurrence to those
without
• if testing prevents recurrence, more tests in the
latter
• 197 patients with recurrent VT during follow-up
• 324 patients without recurrence
(Coppens, J Throm Haemost 2008)
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No benefit
% tested
OR for recurrent VT
(tested vs nottested)
Recurrent VT
(cases)
No recurrent
VT (controls)
all
35
30
1.2 (0.8-1.8)
women
41
35
1.4 (0.7-2.9)
First VT with
OC use
60
32
3.4 (1.3-8.6)
Positive family
history for VT
47
39
1.5 (0.7-3.1)
(Coppens, J Throm Haemost 2008)
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Psychological impact
(Cohn, J Throm Haemost 2008)
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Impact of testing – my e-mails
“I personally have a chronically elevated factor VIII activity
(186%, 242%, and 192%), an elevated Factor XI
activity (212%), as well as being heterozygous for
MTHFR A1298C. …… After researching the literature
and finding a sparcity of information reguarding my
problem, I believe the only hope for finding advice and
guidance in my care is to personally ask the experts
leading the research in the field of hypercoagulability.
Please attempt to share your wisdom and advice with
me.”
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More consultations
“I recently discovered I am heterozygous for Factor II
G20210A and Factor V Leiden. I have never had a DVT.
…..
I would like to get the best estimate I can of my risk, and how
to monitor and reduce it. ……
My daughter was on birth control because she had an ovarian
cyst. She has tested positive for Factor II and has stopped
birth control—need she do so? Should I have my son
tested?...
From the genomics service, the reported risk of a first DVT
based on my Factor II and V results is 57% over the next 14
years, ie until I turn 74, and the likelihood increases sharply
thereafter with a lifetime estimated risk of 90%. ”
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Conclusion
• our knowledge of genetics has not positively
affected clinical care
• testing seems mainly psychotherapeutic
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studies in patients inconclusive
studies in physicians not performed
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Conclusion: we test too much!
• Seems natural ‘to want to know’
• Wanting to know not always a good idea
(film: Troy, 2004)
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