THROMBOPHILIA TESTING: PROS AND CONS SHANNON CARPENTER, MD MS CHILDREN S MERCY HOSPITAL KANSAS CITY, MO

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1 THROMBOPHILIA TESTING: PROS AND CONS SHANNON CARPENTER, MD MS CHILDREN S MERCY HOSPITAL KANSAS CITY, MO

2 DISCLAIMER I m a pediatrician I will be discussing this issue primarily from a pediatric perspective with some comments on adult approaches thrown in

3 OBJECTIVES Identify risk factors for thrombosis (in children) Define thrombophilia testing Discuss pros and cons of testing Identify pitfalls of testing if performed

4 PRE-TEST AND POST-TEST QUESTIONS From your laptop or tablet, please go to Pollev.com/HTRS2016WS From your smartphone, text HTRS2016WS to ONCE, then A, B, C, D or E

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8 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

9 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.

10 OBJECTIVE #1 What puts a child (or other person) at higher risk of a thrombosis

11 AGE AND GENDER Esmon CT. Blood Rev 2009

12 PATHOPHYSIOLOGY OF THROMBOSIS Esmon CT. Blood Rev 2009

13 PATHOPHYSIOLOGY OF THROMBOSIS Mammen EF, Chest 1992

14 HYPERCOAGULABILITY Goldenberg and Bernard. Hematol Oncol Clin N Am 2010

15 HYPERCOAGULABILITY Congenital Factor V Leiden Prothrombin mutation Protein C deficiency Protein S deficiency Antithrombin deficiency Acquired Anti-phospholipid antibodies Cancer Congenital heart disease Infection Central venous catheter Elevated factor VIII Elevated factor IX

16 OBJECTIVE #2 What constitutes a thrombophilia work-up?

17 CONGENITAL PROTHROMBOTIC DISORDERS Van Ommen, Middeldorp. Semin Thromb Hemost 2011 Young, et al. Circulation 2008 Disorder Prevalence (heterozygous) Risk of Thrombosis OR (95% CI) Factor V Leiden 5% Caucasians 3.56 ( ) Prothrombin % Europeans 2.63 ( ) Protein C deficiency 0.2% 7.75 ( ) Protein S deficiency % 5.77 ( ) Antithrombin deficiency 0.02% 8.73 ( ) 2 Genetic Traits 8.89 ( )

18 CONGENITAL PROTHROMBOTIC DISORDERS Anticoagulant deficiency Protein C Protein S Antithrombin III Genetic mutations Factor V Leiden Prothrombin A Approximately 40-50% of those with VTE will have a thrombophilia

19 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.

20 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)

21 ACQUIRED DISORDERS: ANTIPHOSPHOLIPID ANTIBODIES Lupus anticoagulant and anticardiolipin antibodies Associated with many systemic disorders Endocarditis Chorea Recurrent fetal loss Livedo reticularis

22 OBJECTIVE #3 Why do you test?

23 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

24 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 )

25 Coppens, et al. JTH 2008

26 Coppens, et al. JTH 2008

27 CAN THROMBOPHILIA PREDICT RISK OF RECURRENCE IN CHILDREN? Young, et al. Circulation 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

28 Young, et al. Circulation 2008

29 OBJECTIVE #4 When is the best time to test?

30 AGE-RELATED VARIABILITY Reverdiau-Moalic, et al. Blood 1996

31 CLINICAL SETTINGS THAT AFFECT ANTICOAGULANT LEVELS 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

32 BONUS Who should you test?

33 THOSE WITH VTE Unprovoked VTE < 50 years of age associated with increased risk of thrombophilia Dalen JE, Amer J Med 2008

34 FAMILY MEMBERS: TO TEST OR NOT? Lijfering WM, et al. Blood 2009

35 FAMILY MEMBERS: TO TEST OR NOT? Tormene D, et al. Blood 2002 Prospective cohort study of children with thrombophilia 1 st 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

36 FAMILY MEMBERS: TO TEST OR NOT? Holzhauer S, et al. Blood 2012

37 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

38 BONUS #2 What do you do with the results?

39 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?

40 OTHER MARKERS D-dimer Factor VIII

41 PUBLISHED GUIDELINES

42 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

43 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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47 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

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