Scott M. Stevens, MD. Co-Director, Thrombosis Clinic. Associate Professor of Clinical Medicine

Transcription

1 Scott M. Stevens, MD Co-Director, Thrombosis Clinic Intermountain Medical Center Associate Professor of Clinical Medicine The University of Utah School of Medicine No Relevant Financial Relationships Research Contracts with TWINE LLC, Bristol- Myers Squibb No discussion of off-label therapy or devices

2 ANSWER # The Y chromosome #2 Non-O Blood type

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4 Hereditary and Acquired Thrombophilic Conditions FVL (Heterozygous and Homozygous) PGM (Heterozygous and Homozygous) Compound FVL & PGM Heterozygosity Non-O Blood Type MTHFR C677T Hereditary Multiple, Mixed or Uncertain Etiology Antithrombin Deficiency Protein C Deficiency Protein S Deficiency Factor VIII Overactivity Factor IX Overactivity Factor XI Overactivity Dysfibrinogenemia Hyperhomocysteinemia Acquired Diseases with thrombosis as primary manifestation Antiphospholipid Syndrome Disease and conditions associated with thrombosis among other manifestations Myeloproliferative syndromes Paroxysmal Nocturnal Hemoglobinuria Active cancer Nephrotic Syndrome Inflammatory bowel disease Obesity Leg length Age Pregnancy Long distance travel Etc. etc. etc. etc. Stevens S. Journal of thrombosis and thrombolysis. 205:-3 Freyburger G. Thrombosis and haemostasis. 205;3():66-76.

5 The Classic Thrombophilias Hereditary Hereditary/Acquired Acquired Factor V Leiden Prothrombin Gene Mutation Antithrombin Deficiency Protein C Deficiency Protein S Deficiency Antiphospholipid Syndrome Thromb Haemost :

6 PGM FVL

7 AT Def (250 + mutations) Type I - Function / Level Type II - Function / Level PC Def (200+ mutations) Type I - Function / Level Type II - Function / Level PS Def (200+ mutations) Type I - Function / Level Type II - Function / Level Type III - Function / Free Antigen Thromb Haemost :

8 FVL PGM PC Def PS Def AT Def THROMBOSIS Caucasian Common Common Rare Rare Very Rare Thromb Haemost :

9 Caucasian Asian FVL Common Very Rare PGM Common Very Rare PC Def Rare Rare PS Def Rare Rare AT Def Very Rare Very Rare THROMBOSIS Thromb Haemost :

10 Caucasian Asian African FVL Common Very Rare Very Rare PGM Common Very Rare Very Rare PC Def Rare Rare Very Rare PS Def Rare Rare Very Rare AT Def Very Rare Very Rare Very Rare THROMBOSIS Thromb Haemost :

11 ~0 Thrombophilia tests can be performed in a clinical or reference lab. 384 single nucleotide polymorphisms from 64 different genes have been associated with thrombosis risk in exploratory analysis. At least 27 additional genes seem like sure bets. Thromb Haemost : Freyburger G. Thrombosis and haemostasis. 205;3():66-76.

12 Utility Likelihood that testing results in a decision that improves a patient-important outcome Disutility Likelihood that testing results in a decision that worsens a patient-important outcome (causes harm) Waste Utilities Disutilities Neither result occurs

13 Secondary Prevention Primary Prevention Screening following provoked VTE Screening family members without VTE history Screening following unprovoked VTE Screening female family members contemplating estrogen use contemplating pregnancy Relevant Conditions FVL (Heterozygous and Homozygous) PGM (Heterozygous and Homozygous) Compound FVL & PGM Heterozygosity Antithrombin Deficiency Protein C Deficiency Protein S Deficiency Antiphospholipid Syndrome

14 Potential Utility Thrombophilia testing identifies high risk patients who should continue anticoagulation indefinitely Utilities Disutilities Potential Disutility Anticoagulation is unnecessarily continued in patients at low risk for VTE recurrence J Thromb Haemost 6(9): JAMA 293(9): Lancet 362(9383):

15 Selected Guideline Statements on Thrombophilia Screening Secondary Prevention FVL PGM Antithrombin, Protein C, Protein S Antiphospholipid Syndrome Screening Following Provoked VTE ICS 203 ICS 203 ICS 203 ICS 203 FCG 2009 FCG 2009 FCG 2009 FCG 2009 BCSH 200 BCSH 200 BCSH 200 BCSH 200 EGAPP 20 EGAPP 20 EGAPP 20 EGAPP 20 NICE 202 NICE 202 NICE 202 NICE 202 ACCP 202 ACCP 202 ACCP 202 ACCP 202 Color Key Screen Most/All Screen Selected Screen Few/None No Guidance Choosing Wisely - American Society of Hematology Don t test for thrombophilia in adult patients with venous thromboembolism (VTE) occurring in the setting of major transient risk factors (surgery, trauma or prolonged immobility). Stevens S. Journal of thrombosis and thrombolysis. 205:-3 Hicks LK. American Society of Hematology. Education Program. 203;203:9-4.

16 Potential Utility Thrombophilia testing identifies high risk patients who should continue anticoagulation indefinitely Utilities Disutilities Potential Disutility Anticoagulation is improperly discontinued in patients at high risk for VTE recurrence Blood 23(2): Thromb Haemost 6(9): Blood 22(5):

17 Selected Guideline Statements on Thrombophilia Screening Secondary Prevention FVL PGM Antithrombin, Protein C, Protein S Antiphospholipid Syndrome Screening Following Unprovoked VTE ICS 203 ICS 203 ICS 203 ICS 203 FCG 2009 FCG 2009 FCG 2009 FCG 2009 BCSH 200 BCSH 200 BCSH 200 BCSH 200 EGAPP 20 EGAPP 20 EGAPP 20 EGAPP 20 NICE 202 NICE 202 NICE 202 NICE 202 ACCP 202 ACCP 202 ACCP 202 ACCP 202 Screen Most/All Screen Selected Screen Few/None No Guidance Stevens S. Journal of thrombosis and thrombolysis. 205:-3

18 Potential Utility Affected family members may be more likely to employ prophylaxis in high risk situations Utilities Disutilities 2 Reassurance from knowing gene status Potential Disutility Family members testing negative for the gene may forego prophylaxis in high risk situations 2 Anxiety from knowing gene status 3 Genetic discrimination 4 Unwanted genetic disclosures J Thromb Haemost 9(2): J Thromb Haemost 8(6):93 200

19 Selected Guideline Statements on Thrombophilia Screening Primary Prevention FVL PGM Antithrombin, Protein C, Protein S ICS 203 ICS 203 ICS 203 FCG 2009 FCG 2009 FCG 2009 Screening Asymptomatic First Degree Relatives BCSH 200 BCSH 200 BCSH 200 EGAPP 20 EGAPP 20 EGAPP 20 NICE 202 NICE 202 NICE 202 ACCP 202 ACCP 202 ACCP 202 Screen Most/All Screen Selected Screen Few/None No Guidance Stevens S. Journal of thrombosis and thrombolysis. 205:-3

20 Potential Utility Affected family members may change contraceptive or hormone replacement therapy decisions and avoid VTE risk Utilities Disutilities 2 Reassurance from knowing gene status Potential Disutility/Waste Family members testing negative may be falsely reassured about risk 2 Women may overestimate risk Very large number needed to test to avoid a VTE Arch Intern Med 69(6): Postgrad Med J 82(973):

21 Selected Guideline Statements on Thrombophilia Screening Primary Prevention in Females FVL PGM Antithrombin, Protein C, Protein S ICS 203 ICS 203 ICS 203 Screening Asymptomatic First Degree Females considering OCP or HRT Use FCG 2009 FCG 2009 FCG 2009 BCSH 200 BCSH 200 BCSH 200 EGAPP 20 EGAPP 20 EGAPP 20 NICE 202 NICE 202 NICE 202 ACCP 202 ACCP 202 ACCP 202 Screen Most/All Screen Selected Screen Few/None No Guidance Stevens S. Journal of thrombosis and thrombolysis. 205:-3

22 Potential Utility Affected family members can undergo VTE prophylaxis during pregnancy & postpartum Utilities Disutilities Potential Disutility/Waste Many weak cases (requiring no special prophylaxis) identified for each strong case 2 2 Risk:Benefit of antepartum prophylaxis questioned Cost effectiveness uncertain Lancet 384(9955): Thromb Res 3():7 2 Health Technol Assess 0(): 0

23 Selected Guideline Statements on Thrombophilia Screening Primary Prevention in Pregnancy FVL PGM Antithrombin, Protein C, Protein S ICS 203 ICS 203 ICS 203 Screening Asymptomatic First Degree Females considering pregnancy FCG 2009 FCG 2009 FCG 2009 BCSH 200 BCSH 200 BCSH 200 EGAPP 20 EGAPP 20 EGAPP 20 NICE 202 NICE 202 NICE 202 ACCP 202 ACCP 202 ACCP 202 Screen Most/All Screen Selected Screen Few/None No Guidance Stevens S. Journal of thrombosis and thrombolysis. 205:-3

24 Potential Utility Potential Disutility Disease understanding Emotional distress 2 Emotional Reassurance 2 Test misinterpretation 3 High cost 4 Genetic discrimination 5 Inability to predict mortality 6 Questionable ability to predict PTS Semin Thromb Hemost 3():66 72 Thromb Res 3():7 2 Thromb Haemost 09():79 84 J Thromb Haemost 2():4 23.

25 Thrombophilia testing should be employed only with great care, and highly selectively. Be cognizant of the potential harms and wastes of testing Results of an individual thrombophilia test seldom impacts an individual patient s clinical management

26 Know the 4 P s Patient Selection Patient Counseling Proper test interpretation Provision of education and advice Moll S. J Thromb Thrombolysis. 205 Apr;39(3):367-78

27 Don t test while the patient is on anticoagulation Don t test during an acute thrombosis Moll S. J Thromb Thrombolysis. 205 Apr;39(3):367-78

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29 (+) Thrombophilia Test

30 (+) Thrombophilia Test

31 Acquired Thrombiphilia Hereditary Thrombophilia

32 Acquired Thrombophilia Hereditary Thrombophilia Gender Concomitant Diseases Family History Age Understudied Genetic Factors Medications BMI Blood Type Activity Leg Length Pregnancy Unknown Genetic Factors Unknown Acquired Factors Smoking

33 Risk Prediction Models General Models HerDOO2 Vienna Prediction Model DASH Models with Hereditary Thrombophilias MARseilles-NImes prediction model Bruzelius Model CMAJ 79(5): J Thromb Haemost 0(6): Circulation 2(4): Journal of Thrombosis and Haemostasis 2 (2):38-46 Journal of Thrombosis and Haemostasis 205;3: Moll S. Genet Med, 20. 3(): p. 9-20