Thrombophilia
Steven R. Lentz, M.D. Ph.D.
Carver College of Medicine
The University of Iowa
May 2003
Thrombophilia
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Hereditary and acquired risk factors
for thrombosis
Venous thromboembolism
Arterial thromboembolism
Pregnancy complications
Virchow’s Triad
1850
Vessel Wall
Damage
Factors
Contributing
to
Thrombosis
Altered Blood Flow
(Stasis)
Blood Coagulability
One or more
Inherited
Prothrombotic
Mutation(s)
Factor V Leiden
Prothrombin 20210A
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Thrombosis
Acquired
Prothrombotic
Stimulus
After Schafer
Antiphospholipid antibodies
Malignancy
Immobilization
Surgery
Pregnancy
Estrogen
Hyperhomocysteinemia
Heparin-induced thrombocytopenia
Prevalence of Hereditary Risk Factors
in Venous Thromboembolism (VTE)
Asymptomatic Unselected
Controls
VTE
Mutation (N)
Factor V Leiden (1)
4%
20%
Prothrombin 20210A (1)
2%
6%
Protein C (>160)
0.8%
3%
Protein S (>13)
0.5%
1%
Antithrombin (>80)
0.2%
1%
(All Autosomal Dominant)
Familial
VTE
45%
18%
6%
6%
4%
Factor V Leiden
• Most common hereditary risk factor for
venous thrombosis
• Present in 4% of Caucasian population
• Caused by a point mutation in Factor V
(R506Q)
• Poor anticoagulant response to
activated protein C (APC Resistance)
The Protein C Anticoagulant Pathway
Blood Flow
Protein C
Thrombin
Thrombin
APC
Thrombomodulin
Thrombus
Thrombus
at site of injury
Anticoagulation
downstream
The Protein C Anticoagulant Pathway
Blood Flow
Vai
Factor V Leiden
VIIIai
VIIIa
Va
APC
PS
APC
Thrombus
PS
Activated Protein C Resistance
3
Control
APTT
2
Ratio
1
Factor V Leiden
0
1
2
3
APC (μg/ml)
4
5
Prothrombin Gene Mutation
• Second most common hereditary risk
factor for venous thrombosis
• Present in 2% of Caucasian population
• Caused by a point mutation (G20210A) in
the 3’ UTR of prothrombin gene
• Elevated levels of prothrombin in plasma
Antithrombin Deficiency
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Antithrombin (also called AT III)
inhibits thrombin, factor Xa and other
clotting factors
Activity enhanced by heparin
Risk factor for venous thrombosis,
especially during pregnancy
Influence of Hereditary Risk Factors on
Probability of First DVT or PE
Risk Factor
General population
Heterozygous factor V Leiden
Heterozygous prothrombin 20210A
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Homozygous factor V Leiden
Relative Risk
1
5
5
∼10
∼10
∼20
∼80
Thrombosis-free Survival (%)
Influence of Hereditary Risk Factors on
Probability of First DVT or PE
100
general population (RR=1)
80
heterozygous FVL (RR=5)
60
protein C def (RR=10)
40
antithrombin def (RR=20)
20
homozygous FVL (RR=80)
0
0
20
40
Age (years)
60
80
After Miletich (1998)
Semin Thromb Hemost
Influence of Acquired Risk Factors on
Probability of First DVT or PE
Risk Factor
General population
Hyperhomocysteinemia
Estrogen therapy
Active cancer
Lupus anticoagulant
or antiphospholipid antibody
Relative Risk
1
2
4
~7
~10
Hyperhomocysteinemia
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Elevated level of homocysteine in plasma
Multiple causes
Genetic factors – uncommon
Nutritional factors (folate, B12, B6) – common
Renal dysfunction – common
Cardiovascular disease, stroke, peripheral
vascular disease
Neural tube defects
Dementia
Treatment of
Hyperhomocysteinemia
• Folic acid
• Other B vitamins (B12, B6)
• Methionine restriction
Antiphospholipid Antibodies
Lupus
Anticoagulants
Anticardiolipin
Antibodies
Clinically-Important APLA
Clinically Important
Antiphospholipid Antibodies
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High titer (>30 GPL or MPL)
anticardiolipin antibodies (IgG or IgM)
Lupus anticoagulant
Systemic lupus erythematosus or
lupus-like syndrome
Management of Patients with
Antiphospholipid Antibodies
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Chronic anticoagulation not necessary if no
history of thrombosis
Long-term anticoagulation with warfarin after
first thrombotic event
Target INR 2-3 (hematologists)
Target INR 3-4 (rheumatologists)
Some antiphospholipid antibodies interfere with
INR (may need higher target INR or alternative
method to monitor anticoagulation)
Influence of Combinations of Risk Factors
on Probability of First DVT/PE
Risk Factor
Relative Risk
General population
1
Hyperhomocysteinemia
2
Heterozygous factor V Leiden
5
Hyperhomocysteinemia
and heterozygous factor V Leiden
20
Influence of Combinations of Risk Factors
on Probability of First DVT or PE
Risk Factor
General population
Oral contraceptives
Heterozygous factor V Leiden
Oral contraceptives and
heterozygous factor V Leiden
Relative Risk
1
4
5
35
Thrombosis-free Survival (%)
Influence of Oral Contraceptives and Factor
V Leiden on Probability of First DVT or PE
100
general population (RR=1)
oral contraceptives (RR=4)
pregnancy (RR=10)
90
oral contraceptives and
heterozygous FVL (RR=35)
80
15
20
25
30
Age (years)
35
40
Hereditary Risk Factors and
Arterial Thrombosis (Stroke or MI)
Risk Factor
Heterozygous Factor V Leiden
Heterozygous Prothrombin 20210A
Protein S deficiency
Protein C deficiency
Antithrombin deficiency
Relative Risk
1
1
1
1
1
Possible exception: young patients, especially in
association with smoking or hypertension
Other Putative Risk Factors
(Not Ready for Prime Time)
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Fibrinogen
Lipoprotein (a)
Factor VIII
Von Willebrand factor
Thrombomodulin
Heparin Cofactor II
Factor XII
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GPIa C807T
GPIIIa PLA2
PAI-1 4G/5G
D-dimer
TFPI
MTHFR
Protein Z
Laboratory Testing for Thrombophilia
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Factor V Leiden
Prothrombin 20210A gene mutation
Anticardiolipin antibodies
Lupus anticoagulant workup
Plasma total homocysteine
Antithrombin
(not reliable in patients receiving heparin)
Other Tests to Consider
in Convalescent Period
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Protein C
Protein S
These tests are not reliable in acute
setting or in patients receiving warfarin
Rationale for Thrombophilia Testing
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Prophylactic anticoagulation during high risk
situations (surgery, pregnancy, immobilization)
Extended duration of anticoagulation after a
thrombotic event
Antiphospholipid antibody
Antithrombin deficiency
Two or more thrombophilic alleles
(Factor V Leiden, Prothrombin 20210A,
Protein C deficiency, Protein S deficiency)
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Family genetic counseling
Probability of Recurrence
After First DVT or PE
Relative Risk
Temporary risk factor
1
Heterozygous factor V Leiden
2
Homozygous factor V Leiden
4
Antiphospholipid antibody
4
Unprovoked DVT or PE
8
Recurrent DVT or PE
8
Active Cancer
8
Recurrence after First DVT or PE
30
Recurrent 20
DVT/PE
(%)
10 warfarin
unprovoked
temporary risk factor
100
200
300
Days
Levine et al. Thromb Haemost 1995; 74:606
Duration of Anticoagulation for
First Unprovoked DVT
Recurrence (%)
30
3 months (INR 2-3)
12 months (INR 2-3)
20
Indefinite (INR 1.5-2)
10
Indefinite (INR 2-3)
1
Years
2
3
My Approach to Prevention of
Recurrent Venous Thromboembolism
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Low Risk (anticoagulate for 6 weeks to 3 months)
Superficial venous thrombosis
Secondary DVT or PE
Intermediate Risk (anticoagulate for at least 3 to 6 months;
consider indefinite anticoagulation at INR 1.5-2 or 2-3)
Unprovoked DVT or PE
Unprovoked DVT or PE with one genetic risk factor
High Risk (anticoagulate indefinitely at target INR 2-3)
Recurrent unprovoked DVT or PE
Life-threatening venous thrombosis
Unprovoked DVT or PE with antiphospholipid antibody,
two or more genetic risk factors, or active cancer
References
Kearon et al. Management of patients with hereditary hypercoagulable
disorders. Annu Rev Med 51:169-185, 2000
Kupferminc, et al. Increased frequency of genetic thrombophilia in women
with complications of pregnancy. New Eng J Med 340:9-13, 1999
Gerhardt, et al. Prothrombin and factor V mutations in women with a history
of thrombosis during pregnancy and the peurperium. New Eng J
Med 342:374-380, 2000
Gordy et al. American College of Medical Genetics Consensus Statement
on Factor V Leiden mutation testing. Genetics in Medicine 3:139148, 2001
Ridker at al. Long-term low-intensity warfarin therapy for the prevention of
recurrent venous thromboembolism. New Eng J Med 348:14251434, 2003