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

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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”.

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