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THROMBOPHILIA TESTING: PROS AND CONS SHANNON CARPENTER, MD MS
CHILDREN’S MERCY HOSPITAL
KANSAS CITY, MO
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DISCLAIMER
• I’m a pediatrician
• I will be discussing this issue primarily from a pediatric
perspective with some comments on adult approaches
thrown in
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OBJECTIVES
• Identify risk factors for thrombosis (in children)
• Define “thrombophilia testing”
• Discuss pros and cons of testing
• Identify pitfalls of testing if performed
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PRE-TEST AND POST-TEST QUESTIONS
• From your laptop or tablet, please go to
Pollev.com/HTRS2016WS
• From your smartphone, text HTRS2016WS to
22333 ONCE, then A, B, C, D or E
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CASE #1
• You receive a phone call from the on-call resident
regarding a 16 year-old male admitted tonight with a
proximal femoral VTE and no known medical history
• The resident has already ordered low molecular weight
heparin, but first dose has not been given
• He wants to know what “labs to draw”
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CASE #2
• You are referred a 12 year-old girl whose grandfather
had a pulmonary embolus.
• The family’s PCP has sent the child to you for a
“thrombophilia work-up”.
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OBJECTIVE #1
• What puts a child (or other person) at higher risk of a
thrombosis
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AGE AND GENDER
Esmon CT. Blood Rev 2009
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PATHOPHYSIOLOGY OF THROMBOSIS
Esmon CT. Blood Rev 2009
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PATHOPHYSIOLOGY OF THROMBOSIS
Mammen EF, Chest 1992
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HYPERCOAGULABILITY
Goldenberg and Bernard. Hematol Oncol Clin N Am 2010
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Congenital Acquired
Factor V Leiden Anti-phospholipid antibodies
Prothrombin 20210 mutation Cancer
Protein C deficiency Congenital heart disease
Protein S deficiency Infection
Antithrombin deficiency Central venous catheter
Elevated factor VIII
Elevated factor IX
HYPERCOAGULABILITY
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OBJECTIVE #2
• What constitutes a “thrombophilia work-up”?
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Disorder Prevalence (heterozygous) Risk of Thrombosis –OR (95%
CI)
Factor V Leiden 5% Caucasians 3.56 (2.57 – 4.93)
Prothrombin 20210 2-4% Europeans 2.63 (1.61 – 4.29)
Protein C deficiency 0.2% 7.75 (4.48 – 13.38)
Protein S deficiency 0.03 – 0.13% 5.77 ( 3.07 – 10.85)
Antithrombin deficiency 0.02% 8.73 (2.12 – 24.42)
≥ 2 Genetic Traits 8.89 (3.43 – 23.06)
CONGENITAL PROTHROMBOTIC DISORDERS
Van Ommen, Middeldorp. Semin Thromb Hemost 2011
Young, et al. Circulation 2008
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CONGENITAL PROTHROMBOTIC DISORDERS
• Anticoagulant deficiency • Protein C
• Protein S
• Antithrombin III
• Genetic mutations • Factor V Leiden
• Prothrombin 20210 A
• Approximately 40-50% of those with VTE will have a thrombophilia
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GAIN OF FUNCTION MUTATIONS
• Factor V Leiden
• Results from a point mutation in gene
• Leads to resistance of the factor to inactivation by protein C
• Accounts for ~ 95% of activated protein C resistance
• Prothrombin 20210A
• Associated with increased levels of prothrombin activity
• Identified as a risk of stroke in childhood in prospective study of 148
patients by Nowak-Göttl et al.
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PROTEIN DEFICIENCIES: ANTITHROMBIN, PROTEIN C, PROTEIN S
• Naturally occurring coagulation inhibitors
• Antithrombin: inhibits serine esterase activity
• Protein C: • in conjunction with protein S degrades factor V and VII
• Forms complexes with plasminogen activator inhibitor-1 (PAI-1)
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ACQUIRED DISORDERS: ANTIPHOSPHOLIPID ANTIBODIES
• Lupus anticoagulant and anticardiolipin
antibodies
• Associated with many systemic disorders
• Endocarditis
• Chorea
• Recurrent fetal loss
• Livedo reticularis
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OBJECTIVE #3
• Why do you test?
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DOES THROMBOPHILIA PREDICT MORTALITY?
• European Prospective
Cohort on Thrombophilia
(EPCOT)
• Followed 1240 individuals
with thrombophilia
• Survival did not differ even
when history of clot was
considered
Pabinger et al. JTH 2012
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CAN THROMBOPHILIA PREDICT RISK OF RECURRENCE?
• Coppins, et al. JTH 2008
• Case control study to determine if testing for thrombophilia reduced
recurrence
• Sub-study of MEGA study
• Perhaps interventions due to thrombophilia would decrease recurrence
• Looked at 197 cases of recurrent thrombosis, compared to 324 controls
• Proximal DVT and PE included
• Recurrence confirmed with objective testing
• Known malignancy excluded
• Found no difference in thrombophilia testing in 2 groups (35% vs. 30%)
• OR for recurrence 1.2 (95% CI 0.9 -1.8)
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Coppens, et al. JTH 2008
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Coppens, et al. JTH 2008
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CAN THROMBOPHILIA PREDICT RISK OF RECURRENCE IN CHILDREN?
• Young, et al. Circulation 2008.
• Meta-analysis of studies looking at impact of inherited
thrombophilia on VTE recurrence in children
• >70% of children had a least one risk factor for VTE
• 11.4% of children developed a recurrence
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Young, et al. Circulation 2008
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OBJECTIVE #4
• When is the best time to test?
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AGE-RELATED VARIABILITY
Reverdiau-Moalic, et al. Blood 1996
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Protein C Protein S Antithrombin
Acute thrombosis ↓ ↓ ↓
Liver disease ↓ ↓ ↓
Consumptive coagulopathy ↓ ↓ ↓
Hemodilution ↓ ↓ ↓
Nephrotic syndrome ↓ ↓ ↓
Asparaginase therapy ↓ ↓ ↓
Pregnancy ↓ ↓
Oral contraceptives ↓ ↓
Vitamin K antagonist ↓ ↓
Vitamin K deficiency ↓ ↓
Heparin Therapy ↓
CLINICAL SETTINGS THAT AFFECT ANTICOAGULANT LEVELS
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BONUS
• Who should you test?
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THOSE WITH VTE
• Unprovoked VTE < 50 years of age associated with
increased risk of thrombophilia
Dalen JE, Amer J Med 2008
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FAMILY MEMBERS: TO TEST OR NOT?
Lijfering WM, et al. Blood 2009
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FAMILY MEMBERS: TO TEST OR NOT?
• Tormene D, et al. Blood 2002
• Prospective cohort study of children with
thrombophilia
• 1st degree relative with VTE
• 81 carriers of inherited defect, 62 normal
• No VTE occurred in either group
• Of note – No episodes of CVL, cancer or CV surgery
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FAMILY MEMBERS: TO TEST OR NOT?
Holzhauer S, et al. Blood 2012
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WHAT ABOUT CONTRACEPTION?
• Combined oral contraceptives increase the risk of thrombosis
• The addition of a thrombophilia compounds that risk
• HOWEVER – absolute risk remains low
• ACOG guidance is to NOT test routinely prior to starting
OCPs
• Estimate need to screen 1 million to prevent 2 OCP-related
thrombotic deaths
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BONUS #2
• What do you do with the results?
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REASONS TO TEST
• Does it change your management of the patient?
• Does it prolong treatment?
• Does it influence use of prophylaxis?
• Does it change management of relative?
• Would you change recommendations regarding birth
control?
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OTHER MARKERS
• D-dimer
• Factor VIII
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PUBLISHED GUIDELINES
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CASE #1
• You receive a phone call from the on-call resident
regarding a 16 year-old male admitted tonight with a
proximal femoral VTE and no known medical history
• The resident has already ordered low molecular weight
heparin, but first dose has not been given
• He wants to know what “labs to draw”
-
CASE #2
• You are referred a 12 year-old girl whose grandfather
had a pulmonary embolus.
• The family’s PCP has sent the child to you for a
“thrombophilia work-up”.
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CONCLUSIONS
• The strongest predictor for thrombosis is a family history of thrombosis
• All thrombophilias are not the same
• Anticoagulant protein deficiencies have a higher risk of thrombus recurrence than gain of
function mutations in coagulant enzymes
• Combined disorders have highest risk
• There may not be a right or wrong answer to testing for thrombophilia
• Adults with unprovoked thrombus likely do not need testing
• Testing in children with unprovoked thrombosis may help determine duration of treatment
• It is most important to know what you will do with the results of the testing if you
choose to test