Transcript Thrombophilias

Thrombophilias
Sharon Sams
Objectives
 Overview of etiology of hypercoagulability
 Available tests
 Clinical correlation or “What do I do with
these results?”
 Inconclusive conclusions: To test or not to
test…
Risk Factors: Acquired
 Age: largest gradient of risk
 Malignancy: prevalence ranges from 3-18%
 Surgery:
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Orthopedic surgery:30 - 50%
Abdominal surgery: 30%
With anticoagulants: 18%
 Major trauma: 50-60%
 Immobilization
Risk Factors: Acquired
 Oral contraceptives: 4 X increase in risk
 Hormonal replacement therapy: 2-4 X
increase
 Pregnancy and post-partum: 10 X increase
 Antiphospholipid antibodies: 10 X increase
Genetic causes of Thrombosis
 Deficiencies of natural coagulation inhibitors
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Antithrombin, protein C, and Protein S
deficiencies; < 1% of the population
Quantitative (type I): normal protein but
reduced quality
Qualitative (Type II): Normal amounts of a
defective protein
Heterozygote: Increased risk 10 X
Homozygote: purpura fulminans
Genetic Causes: Factor V Leiden
 Most common genetic defect causing
thrombosis among Caucasians
 Prevalence of carriers: 5 %
 Found in 15 % of patients with venous
thrombosis
 Causes thrombosis via resistance to activated
Protein C
 Heterozygote: Increased risk 3-8 X
 Homozygote: Increased risk 50-80 X; Found
in 1 per 5000 people in general population
Genetic causes of Thrombosis
 Prothrombin G20210A Mutation
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Prevalence: 3% of Caucasians
Increased risk 3 X
 ABO Blood Group
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Non-O blood groups: 2-4 X increased risk
Higher von Willebrand factor levels and higher
factor VIII levels
Plasma Abnormalities
 Hyperhomocysteinemia
 Homozygous deficiency of cystathionine beta-synthase
(CS): Homocystinuria→ atherosclerosis, arterial
disease and venous thrombosis
 Mildly elevated homocystine: 5-10% of the population;
Increased risk 2 X; usually due to low intake of folate,
B6 or B12
 High levels of clotting factors
 Elevated levels (above 90th percentile) of prothrombin,
Factor VIII, Factor IX, and Factor XI: Increased risk: 24x
Multi-Casual Model
 The thrombotic event is the result of gene- gene
interaction and/or gene-environment interaction.
Variable
Normal
Hyperhomocysteinemia
Prothrombin G20210A
Oral contraceptives
Factor Leiden heterozygote
OCT and Factor Leiden
Factor Leiden homozygote
RR
1
2.5
2.8
4
7
35
80
Annual Incidence%
0.008
0.02
0.02
0.03
0.06
0.3
0.5-1
Lab evaluation
 Timing:
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Acute thrombotic event or anticoagulation
therapy will affect the parameters of functional
assays.
Wait 6 months after acute event
10 days after the discontinuation of oral
anticoagulation therapy
Lab testing: APC Resistance
 APC Resistance
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Factor Leiden V: DNA analysis via PCR is the
gold standard
Acquired APC: Paired PTT’s performed in the
presence and absence of exogenous activated
Prot C; →dilute patient plasma with Factor V
deficient plasma: specificity and sensitivity
approach 100%
Lab Testing: Protein C, Protein S and
Antithrombin
 DNA testing not available
 Functional assay to measure protein activity is the
initial screen– low specificity
 Antigenic assays are immunoassays that measure
the quantity of the protein
 Conditions that affect assay:
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Negative influence: Oral anticoagulants, Vitamin K
deficiency, liver disease, recent thrombosis, surgical
procedures, DIC, L- Asparaginase therapy, oral
contraceptives, estrogen replacement therapy, pregnancy,
elevated acute phase reaction, heparin and nephrotic
syndrome
Lab Testing:
 Prothrombin (G20210A) Mutation
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DNA test via PCR
 Homocysteine
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Immunoassay methods
 Coagulation Factors
Lab testing: Antiphospholipid
antibodies
 Low specificity: clinical correlation required
 Solid phase antiphospholipid antibodies
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Anticardiolipin
Antibeta2glycoprotien I
 Lupus anticoagulants
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Clotting time based assays such as Russell
viper venom test, kaolin clotting time, or PTT
Improved sensitivity by use of two screening
tests
Current Treatment
 Acute events: Management of acute
thrombosis is the same for patients with and
without inherited thrombophilia
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Anticoagulation with warfarin for 3-6 months
 Secondary prophylaxis:
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No controlled trials have evaluated the
duration of anticoagulation in pts with
hereditary thrombophilias thus no standard
protocols.
Treatment Proposal I
Risk Classification
Management
High Risk
Indefinite Anticoagulation
 Two or more spontaneous events
 One spontaneous life-threatening event
 One spontaneous event is association with
the antiphospholipid syndrome, antithrombin def
or more than one genetic or allelic abnormality
Moderate Risk
Vigorous prophylaxis in highrisk setting
 One event with a known provocative stimulus
 Asymptomatic
Association Studies
 In patients presenting with a first venous
thrombosis (adults)
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5% have a deficiency of a natural
anticoagulant by phenotypic testing
15% Factor Leiden V deficiency
3-5% Prothrombin G20210A Mutation
>70% have no inheritable abnormality
Risk of Reoccurrence
 Two year cumulative incidence of recurrent
thrombosis ~ 15%
 Five year cumulative incidence of recurrent
thrombosis ~ 25%
 Early studies: 2-4 X increase in risk in Factor
V Leiden carriers
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However these studies were small in number
and retrospective
Cambridge Venous Thromboembolism
Study (CVTE) (2003)
 Two year Prospective Study:
 570 patients
 Recurrence rate was 11%
 Lowest incidence after surgery related VTE (0%)
 Highest incidence with unprecipitated VTE (19.4%)
 85% of patients were tested for heritable thrombophilic
defects→ recurrence rates were not related to
presence or absence of heritable thrombophilia.
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CONCLUSION: Thrombophilia testing had no
predictive value for reoccurrence (hazard ration 1.5
[95% CI 0.82-2.77]; p=0.187)
Baglin et al. Incidence of recurrent venous thromboembolism in relation to clinical and
thrombophilic risk factors: prospective cohort study. The Lancet 2003, (362):523-526.
Leiden Thrombophilia study (LETS)
JAMA 2005
 Prospective follow up study of LETS pts
 447 patients followed for a mean of 7.3 years
 Incidence rate of recurrence was highest during the
first two years: annual rate of 3.2%; cumulative
recurrence of 12.4% at 5 years
 Risk of recurrence was 2.7 x higher in men than
women (95% CI , 1.8-4.2)
 Higher risk of recurrence with idiopathic initial VTE
 Lower risk of recurrence with provoked initial VTE
 OCT use during follow up had a higher recurrence rate
(28 per 1000 pt-yrs vs 12.9 per 1000 pt-yrs)
Recurrence Rates by Sex and Type of First Thrombotic Event
Christiansen, S. C. et al. JAMA 2005;293:2352-2361.
Copyright restrictions may apply.
Recurrence Rates by Oral Contraceptive Use in 215 Women Between 16 and 55 Years
Christiansen, S. C. et al. JAMA 2005;293:2352-2361.
Copyright restrictions may apply.
Recurrence Rates for Prothrombotic Laboratory Abnormalities in 474 Patients
Christiansen, S. C. et al. JAMA 2005;293:2352-2361.
Copyright restrictions may apply.
Leiden Thrombophilia study (LETS)
JAMA 2005
 Conclusion:
 Hazard ratios calculated for reoccurrence
according to individual defect → no defects
were associated with a statistically significant
hazard ratio
 Clinical factors (male sex, use of OCT’s,
idiopathic initial VTE) have a more significant
role in risk of reoccurrence than lab
abnormalities
 Multi-causal disease. Combined defects at
greater risk of reoccurrence?
Candidates for screening
(Stefano et al 2002)
 All patients with venous thromboembolism,
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independent of the age of onset, the circumstances
and the severity
Cancer pts may be excluded
Women with complications of a pregnancy
All asymptomatic individuals who are a first degree
relative of a diagnosed carrier of a thrombophilic trait
Asymptomatic women with a family history of venous
thromboembolism prior to use of oral contraceptives,
HRT or pregnancy
Candidates for screening
(Baglin 2004)
 Patient presents with first thromboembolism
 Family history? If positive, testing is recommended
 Clinical circumstances- surgery or cancer? Testing not
indicated
 Clinical circumstance not associated with surgery or
cancer-acquired antiphospholipid activity is
recommended
 Screening asymptomatic relatives has no clinical
utility
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Annual absolute incidence of venous
thromboembolism was very low
References:
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Baglin T, Management of Thrombophilia: Who to Screen? Pathophysiol
Haemost Thromb 2003/2004;33:401-404
Bauer KA, The Thrombophilias: Well defined risk factors with uncertain
therapeutic implications. Ann Intern Med. 2001;135:367-373
Christiansen et al. Thrombophilia, Clinical Factors, and Recurrent
Venous Thrombotic Events. JAMA 2005;293:2352-2361
Tripodi A, Laboratory diagnosis of thrombophilic states: where do we
stand? Pathophysiol Haemost Thromb, 2002;32:245-248
Bauer et al. Hypercoagulability: Too many test, Too much conflicting
data. Hematology 2002; 353-368
Stefanoe et al. Screeninf for inherited thrombophilia: indications and
therapeutic implications. Haematologica 2002;87:1095-1108
Henry. Clinical Diagnosis and Management by Laboratory Methods.
20th ed. 2001 W.B. Saunders Co. Philadelphia
Baglin et al. Incidence of recurrent venous thromboembolism in
relation to clinical and thrombophilic risk factors: prospective cohort
study. The Lancet 2003, (362):523-526.