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THROMBOPHILIA TESTING: PROS AND CONS SHANNON CARPENTER, MD MS
CHILDREN’S MERCY HOSPITAL
KANSAS CITY, MO
DISCLAIMER
• I’m a pediatrician
• I will be discussing this issue primarily from a pediatric
perspective with some comments on adult approaches
thrown in
OBJECTIVES
• Identify risk factors for thrombosis (in children)
• Define “thrombophilia testing”
• Discuss pros and cons of testing
• Identify pitfalls of testing if performed
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
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”.
OBJECTIVE #1
• What puts a child (or other person) at higher risk of a
thrombosis
AGE AND GENDER
Esmon CT. Blood Rev 2009
PATHOPHYSIOLOGY OF THROMBOSIS
Esmon CT. Blood Rev 2009
PATHOPHYSIOLOGY OF THROMBOSIS
Mammen EF, Chest 1992
HYPERCOAGULABILITY
Goldenberg and Bernard. Hematol Oncol Clin N Am 2010
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
OBJECTIVE #2
• What constitutes a “thrombophilia work-up”?
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
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
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.
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)
ACQUIRED DISORDERS: ANTIPHOSPHOLIPID ANTIBODIES
• Lupus anticoagulant and anticardiolipin
antibodies
• Associated with many systemic disorders
• Endocarditis
• Chorea
• Recurrent fetal loss
• Livedo reticularis
OBJECTIVE #3
• Why do you test?
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
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)
Coppens, et al. JTH 2008
Coppens, et al. JTH 2008
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
Young, et al. Circulation 2008
OBJECTIVE #4
• When is the best time to test?
AGE-RELATED VARIABILITY
Reverdiau-Moalic, et al. Blood 1996
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
BONUS
• Who should you test?
THOSE WITH VTE
• Unprovoked VTE < 50 years of age associated with
increased risk of thrombophilia
Dalen JE, Amer J Med 2008
FAMILY MEMBERS: TO TEST OR NOT?
Lijfering WM, et al. Blood 2009
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
FAMILY MEMBERS: TO TEST OR NOT?
Holzhauer S, et al. Blood 2012
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
BONUS #2
• What do you do with the results?
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?
OTHER MARKERS
• D-dimer
• Factor VIII
PUBLISHED GUIDELINES
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”.
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