Thrombophilia
For the Clinician
Dr Cleona Duggan
1
Case Study
24-year-old healthy woman on birth control pills
L>R
by 4 cm
L>R
by 2.5 cm
Reprinted with permission from Moll S. Arterioscler Thromb Vasc Biol. 2008;28:373-379.
2
Natural Anticoagulant System
Normal Factor V
XII
VII
Va
X
506
act. protein C
Protein S
Va
506
act. protein C
Factor V Leiden
Thrombin
Antithrombin
Va
506
Clot
act. protein C
506
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.
3
Factor V Leiden/Prothrombin 20210
Prevalence
Discovered
Factor V Leiden1
Prothrombin 20210
mutation2
Caucasians
African Americans
1994
5%
1.2%
1996
2%
0.5%
1. Ridker PM, et al. JAMA. 1997;277:1305-1307.
2. Varga EA, Moll S. Circulation. 2004;110:e15-e18.
4
Factor V Leiden/Prothrombin 20210
 Prothrombin 20210 = II20210 = G20210A: mutation in
promoter region, leading to increased factor II levels
 Moderate/mild risk factor for DVT/PE
 Only very mild risk factor for recurrent VTE
(FVL OR, 1.41; prothrombin 20210 OR, 1.72)
 Only marginal risk factor for arterial clots
 Mild risk factor for pregnancy loss
Ho WK, et al. Arch Intern Med. 2006;166:729-736.
5
Protein C, S, and Antithrombin Deficiency
Prevalence:
Practical point:
• 1:500 (C and S) to 1:5,000 (AT)
• Always question the diagnosis!
How do you test?
• Activity
• >100 mutations account for each
deficiency; thus: genetic testing
not done in routine practice
How do you treat?
• Consider AT concentrate
• Severe neonatal C deficiency:
protein C concentrate
Acquired deficiency:
•
•
•
•
•
•
Liver disease (C, S, AT)
Warfarin therapy (C, S)
Estrogens, pregnancy (S)
Inflammatory diseases (S)
Heparin therapy (AT)
Acute thrombosis (S, AT)
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
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Other Thrombophilias
• Elevation of factor VIII
• Elevations of fibrinogen, factors II, IX, XI
• Fibrinolysis abnormalities:
– Plasminogen deficiency
– Decreased tPA levels and polymorphisms
– Elevated PAI-1 level and polymorphisms
– Elevated TAFI levels
• Myeloproliferative disorders (JAK-2 mutation)
• Paroxysmal nocturnal hemoglobinuria (PNH)
tPA=tissue plasminogen activator; PAI-1=plasminogen activator inhibitor 1; TAFI=thrombin
activatable fibrinolysis inhibitor.
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.
7
Obesity and Thrombophilia
3.5
Odds ratio
3.0
Obesity is
a risk factor
for VTE
2.5
2.0
1.5
Conclusion:
lose weight
1.0
0.5
0.0
BMI
np
nc
160
256
416
865
817 925 704
1236 1102 626
402
311
190
154
220
133
Reprinted with permission from Pomp ER, et al. Br J Haematol. 2007;139:289-296.
8
Obesity and Thrombophilia
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous
Thrombosis
95% CI
OC use
< 25
No
1
≥ 30
No
3.04
1.66-5.57
≥ 30
Yes
23.78
13.35-42.34
Pomp ER, et al. Br J Haematol. 2007;139:289-296.
9
Obesity and Thrombophilia
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous
Thrombosis
95% CI
OC use
< 25
No
1
≥ 30
No
3.04
1.66-5.57
≥ 30
Yes
23.78
13.35-42.34
< 25
No
1
≥ 30
No
2.48
2.13-2.88
≥ 30
Yes
7.86
4.70-13.15
FVL
Pomp ER, et al. Br J Haematol. 2007;139:289-296.
10
Obesity and Thrombophilia
Combined effect of BMI ≥30 kg/m2 and genetic risk factors for VTE
BMI
Risk Factor
OR for Venous
Thrombosis
95% CI
OC use
< 25
No
1
≥ 30
No
3.04
1.66-5.57
≥ 30
Yes
23.78
13.35-42.34
< 25
No
1
≥ 30
No
2.48
2.13-2.88
≥ 30
Yes
7.86
4.70-13.15
FVL
Prothrombin 20210
< 25
No
1
≥ 30
No
2.45
2.12-2.82
≥ 30
Yes
6.58
2.31-18.69
Pomp ER, et al. Br J Haematol. 2007;139:289-296.
11
Smoking and Thrombophilia
Combined effect of smoking and genetic risk factors for VTE
– Conclusion: stop smoking
Smoking
Risk Factor
OR for Venous
Thrombosis
95% CI
Factor V Leiden
No
No
1
Current
No
1.43
1.26-1.63
Current
Yes
5.05
3.46-7.38
Prothrombin 20210
No
No
1
Current
No
1.41
1.25-1.60
Current
Yes
6.06
2.67-13.76
Pomp ER, et al. Am J Hematol. 2008;83:97-102.
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Contraceptives and Thrombosis1,2
Risk  compared to
women who do not
take OCP
Absolute
risk/year
1
1 : 12,500
2-6x ’d
1 : 3,000
4x ’d
1 : 3,000
20-30x ’d
1 : 500
24x ’d
1 : 500
50-100x ’d
1 : 150
BMI >30 + smoking + OCP
???
???
Homozygous FVL + BMI >30 +
smoking + OCP
???
???
All women of reproductive age
OCP
Hetero FVL
Hetero FVL + OCP
BMI >30 + OCP
Homozygous FVL + OCP
OCP=oral contraceptive; BMI=body mass index.
1. Varga E. J Genet Couns. 2007;16:261-277.
2. Pomp ER, et al. Br J Haematol. 2007;139:289-296.
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Thrombophilia Testing
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Pros and Cons of Thrombophilia Testing
Pros
Cons
1. “Power to prevent clots”
1. Cost
– surgery (red flag)
– birth control pill, pregnancy
2. Explanations
3. Influence on medical treatment
2. Worry
3. Bad medical advice
4. Insurance
implications
– choice of drug (antiplatelet vs
anticoagulation)
– length of warfarin therapy
– intensity of warfarin therapy
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
15
Who Should Be Tested?1-4
General
population
Any
patient
with VTE
Any patient
with
spontaneous
VTE
Younger
patient
with VTE
Ultra-liberal
1.
2.
3.
4.
Grody WW, et al. Genet Med. 2001;3:139-148.
Walker ID, et al. Br J Haematol. 2001;114:512-528.
Nicolaides AN, et al. Int Angiol. 2005;24:1-26.
Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:1281-1295.
5.
Baglin T, et al. Br J Haematol. 2010;149:209-220.
Younger patient
with VTE +
family history
Nobody
Arch-conservative
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Which Patient to Test for Thrombophilia?
Europ Genetics
Foundation,
Mediterranean League
on Thromboembolism,
Internat. Union of
Angiology, etc, 20051
CAP, 20022
Thrombosis Interest
Group of Canada, 20063
Am Coll Med
Geneticists, 20014
Ultra-liberal
Br Committee for
Standards in
Haematol, 20105
Arch-conservative
1. Nicolaides AN, et al. Int Angiol. 2005;24:1-26.
2. Van Cott EM, et al. Arch Pathol Lab Med. 2002;126:1281-1295.
3. The Thrombosis Interest Group of Canada. Available at:
http://www.tigc.org/eguidelines/hypercoagstates.htm.
4. Grody WW, et al. Genet Med. 2001;3:139-148.
5. Baglin T, et al. Br J Haematol. 2010;149:209-220.
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When to Consider Thrombophilia Testing
 VTE occurring at a younger age (ie, <50 years)
 Unprovoked VTE
 Recurrent VTE




Thrombosis at an unusual site (splanchnic, sinus/cerebral, or renal veins)
Unusually extensive spontaneous VTE
Family history of VTE
Asymptomatic individual with family history of strong thrombophilia
–
–
–
–
–
–
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Homozygous factor V Leiden
Homozygous prothrombin mutation
Compound thrombophilias
 Recurrent VTE while adequately anticoagulated
 Unexplained arterial thromboembolism in a young person (ie, no
arteriosclerosis risk factors, no cardio-embolic source)
 ≥3 unexplained pregnancy losses before week 10, or ≥1 loss after week 10
Foy P, Moll S. Curr Treat Options Cardiovasc Med. 2009;11:114-128.
18
Family Implications
of Thrombophilia
19
Why to Test an Asymptomatic
Family Member
1. To put the person on anticoagulants
2. To manage the individual differently:
 Lifestyle changes (obesity, smoking)
 Advice on oral contraceptives, hormone therapy
 Airline travel
 Pregnancy
 Surgery
Moll S. J Thromb Thrombolysis. 2006;21:7-15.
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Key Points About Positive Family History
 Positive family history (1st degree relative) is VTE risk factor
(2.5-4.2 fold increased risk)2
 Risk is independent of presence of known genetic thrombophilias
 Risk is due to unknown risk factor
1. Noboa S, et al. Thromb Res. 2008;122:624-629.
2. Bezemer ID, et al. Arch Intern Med. 2009;169:610-615.
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Strategy for Familial Testing
Proband’s
thrombophilia
Male Family Member Female Family Member
Sons
Brothers
Daughters
Sisters
Hetero FVL or hetero
prothrombin 20210
no
no
no
no
Homo FVL or homo
prothrombin 20210
no
reasonable
no
yes
Double hetero
reasonable
reasonable
yes
yes
C, S, AT
reasonable
reasonable
yes
yes
“Reasonable,” because: consider LMWH with airline travel, cast, non-major surgery; prolonged
after major surgeries.
“Yes,” because: advise against oral contraceptives/hormone therapy; give ante- and postpartum
anticoagulation.
Slide courtesy of Moll S.
22
Lifestyle Changes
1. Lose weight
2. Stop smoking
3. Know the symptoms of DVT and PE
4. Know the risk factors for DVT and PE
5. Know your family history
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