LA APLA 1 3 ACA Anti-ß2-GP I 2 45 Thrombophilia Stephan Moll, MD Medicine, Heme-Coag UNC Chapel Hill, NC GASCO Atlanta Sept 8 th, 2017 Disclosures Conflicts of interest: NONE Off-label product use discussion: NONE 1
Topics Introduction Whom to Test What to Test When to Test My Choosing Wisely Suggestions 1 2 3 4 5 6 7 Introduction 2
e-mail Recurrence Triangle 3 months Long-term VTE due to major transient risk factor Woman with VTE on hormones Non-major transient risk factor Woman with unprovoked VTE DVT PE Man with unprovoked VTE DVT PE - D-dimer + Strong Thrombophilia [Choosing Wisely ; Hicks LK, et al. Hematology Am Soc Hematol Educ Program. 2014;2014: 599-603] ACCP, AHA, ISTH, BJH 3
Strong Thrombophilias 1. APLA syndrome 2. Antithrombin deficiency 3. Protein C deficiency 4. Protein S deficiency 5. Homozygous factor V Leiden 6. Homozygous II20210 mutation 7. Heterozygous FVL plus heterozygous II20210 Yes yes / no unknown yes / no [Segal J et al. JAMA 2009; 301:2472-85] [Lijfering WM et al. Circulation 2010;121:1706-12] [Garcia D et al. Blood 2013;122:817-824] Recurrence Triangle Cumulative VTE Recurrence Rate 1 year 5 years 3 months Long-term VTE due to major transient risk factor Woman with VTE on hormones Non-major transient risk factor Woman with unprovoked VTE DVT PE Man with unprovoked VTE DVT PE 1 % 3 % 6 % * 5 % 15 % 10 % 30 % [Kearon C et al. Blood 2014;123:1794-1801] *[Douketis J et al. BMJ 2011;342:d813] 4
Downsides of Thrombophilia Testing Take-home point 1. Don t over-focus on the thrombophilia Clinic Patient 39 year old woman Proximal arm DVT and PE 4/2016 VTE risk factors: (a) hetero FV Leiden, (b) hetero II20210 mutation. FH: Parents with VTE. Neither one of them has factor V or factor II. 5
Clinic Patient Mother Father 100051316642 Downsides of Thrombophilia Testing 1. Don t over-focus on the thrombophilia 2. Caveat: Wrong test ordered 3. Caveat: Misinterpretation of tests 6
Decision Making Based on Thrombophilia 62 year old proximal leg DVT 3 weeks after hip replacement surgery APLA testing positive = life-long anticoagulation Downsides of Thrombophilia Testing 1. Don t over-focus on the thrombophilia 2. Caveat: Wrong test is ordered 3. Caveat: Misinterpretation of tests 4. Caveat: Wrong/questionable decision making based on test result 7
Cost $ 398.00 $ 632.00 $ 226.00 $ 356.00 $ 221.00 $ 772.00 $ 2,681.00 Cost $ 772.00 8
Downsides of Thrombophilia Testing 1. Don t over-focus on the thrombophilia 2. Caveat: Wrong test is ordered 3. Caveat: Misinterpretation of tests 4. Caveat: Wrong decision making based on test result 5. Be aware of cost of testing 1 2 3 4 5 6 7 What to Test? Whom to Test? 9
Inherited and Acquired Thrombophilias Most common Classics Acquired Others Factor V Leiden Prothrombin 20210 Protein C deficiency Protein S deficiency Antithrombin deficiency Antiphospholipid antibodies (ACA, LA, anti-β 2 -GPI) Homocysteine, MTHFR Fibrinogen, factor VIII, IX, XI PAI-1, tpa levels and polymorphisms CBC, CD55/59, JAK-2 + CALR Whom to Test Controversial Guideline in development: ASH 2015, ongoing Terminology used: testing can be considered benefit of testing unclear lack of evidence that testing impacts clinical outcomes 10
Whom to Test for Thrombophilia? Everybody Any pt Any pt with Young pt Young pt Nobody with VTE spontan. VTE with FHx Ultra-liberal Nihilist In Whom I Consider Testing 1 2 3 4 5 DVT/PE, intermediate risk recurrence VTE in unusual locations, unprovoked Arterial thrombosis, unexplained VTE: Patient requests testing Family members (if strong thrombophilia in index pt) No Pregnancy loss(es), unexplained 11
Recurrence Triangle 3 months Long-term VTE due to major transient risk factor Woman with VTE on hormones Non-major transient risk factor Woman with unprovoked VTE DVT PE Man with unprovoked VTE DVT PE - D-dimer + Strong Thrombophilia [Choosing Wisely ; Hicks LK, et al. Hematology Am Soc Hematol Educ Program. 2014;2014: 599-603] ACCP, AHA, ISTH, BJH Recurrence Triangle In VTE patients: In intermediate risk-of-recurrence patients I consider testing 12
Risk of 1 st VTE with thrombophilias Relative risk increase for first VTE No thrombophilia Reference group II20210, hetero 3.8 (95% CI 3.0-4.9) FVL, heterozygous 4.9 (95% CI 4.1-5.9) II20210, homozygous Insufficient data FVL, homozygous 18 (95% CI 4.1-41) Hetero II20210 PLUS 20 (95% CI 11.1-36.1) hetero FVL Protein S deficiency 30.6 (95% CI 26.9-55.3) Protein C deficiency 24.1 (95% CI 13.7-42.4) Antithrombin deficiency 28.2 (95% CI 13.5-58.6) [Moll S. J Thromb Thrombolys 2015; ;39(3):367-78] Risk of Recurrent VTE with Thrombophilias 1 II20210, hetero: 1.45 FVL, hetero: 1.56 (95% CI 0.96-2.21) (95% CI 1.14-2.12) [Segal J et al. JAMA 2009; 301:2472-85] 2 FVL, homo: 2.65 (95 % CI 1.18-5.97) FVL, homo: 1.2 (95 % CI 0.5-2.6) [Segal J et al. JAMA 2009; 301:2472-85; meta-analysis] [Lijfering WM et al. Circulation 2010;121:1706-12] 3 FVL + II2010: 4.81 (95 % CI 0.50-46.3) FVL + II2010: 1.0 (95 % CI 0.6-1.9) [Segal J et al. JAMA 2009; 301:2472-85; meta-analysis] [Lijfering WM et al. Circulation 2010;121:1706-12] 4 II20210, homo: insufficient data 13
Risk of Recurrent VTE with Thrombophilias 5 Protein C Protein S Antithrombin 2.8 (95 % CI 2.0 4.0) [Lijfering WM et al. Circulation 2010;121:1706-12] 6 APLA: 1.41 ACA: 1.53 LA: 2.83 (95 % CI 0.99-2.00) (95 % CI 0.76-3.11) (95 % CI 0.83-9.64) [Garcia D et al. Blood 2013;122:817-824] APLA syndrome: 2.0 [Kearon C et al; Chest 2012;141:e419S-494S] Protein C, S and Antithrombin Deficiency How do you test? C, S, AT activity free S antigen >100 mutations Acquired deficiency: Liver disease (C, S, AT) How do you treat? Consider AT concentrate Severe neonatal C deficiency: protein C concentrate Warfarin therapy (C, S) Estrogens, pregnancy (S) Inflammatory diseases (S) Heparin therapy (AT) Acute thrombosis (S, AT) 14
Antiphospholipid Antibodies APLA I) Antibody test (ELISA) LA ACA anticardiolipin anti-ß2-glycoprotein I antiphosphatidylserine antiphosphatidylcholine antiphosphatidylethanolamine Anti-ß2-GP I II) Functional test lupus anticoagulant (inhibitor) [Sapporo criteria: Miyakis S. J Thromb Haemost. 2006;4:295-306] APLA: Sapporo/Sydney Criteria Updated Sapporo Criteria for APS (2006): Clinical criteria: Vascular thrombosis Pregnancy morbidity Laboratory criteria*: Anticardiolipin antibodies (IgG or IgM) (medium or high titer: >40 GPL/MPL or >99th percentile) Anti-β 2 -glycoprotein I antibodies (IgG or IgM) (>99th percentile) LA *2 or more occasions, >12 wks apart. [Miyakis S, et al. J Thromb Haemost. 2006;4:295-306] [J Thromb Haemost. 2014 May;12(5):792-5] 15
APLA: Risk for 1 st Thrombosis Conclusions: 1. LA stronger and more definitive risk factor for thrombosis than ACA. 2. Risk for thrombosis is highest if positive APLA by multiple assays. [Galli M, et al. Blood. 2003;101:1827-1832; Ruffatti A, et al. Thromb Haemost. 2006;96:337-341] Are APLA a Risk Factor for Recurrent VTE? Systematic Review 8 eligible studies All had important methodologic limitations. We judged the overall quality of the evidence as very low. Conclusion Although it appears that pos. APLA predict d risk of VTE recurrence, the strength of this association is uncertain. [Garcia D et al. Blood 2013;122:817-824] 16
Risk for Recurrent VTE 1. Are APLA a risk factor for recurrent VTE? They appear to be! [Garcia D et al. Blood 2013;122:817-824] Risk for Recurrent VTE 2. Which of the APLA best predicts recurrent VTE? LA ACA [Garcia D et al. Blood 2013;122:817-824] 17
APLA: Practical Points APLA syndrome : question the diagnosis moderately high titers of ACA ( 40 U/mL) Include anti-β 2 -GP-I antibody testing Test outside the acute event Repeat APLA testing (3 months apart) Know the LA tests and their interpretation Role of IgA antibodies unclear Homocysteine, MTHFR MTHFR C677T, homozygous TT, or A1298C May have higher homocysteine levels Not a risk factor for thrombosis or pregnancy complications Practical point: Don t Test for MTHFR. Practical point: Test for homocysteine? no good indication. MTHFR=methylenetetrahydrofolate reductase [den Heijer MJ. Thromb Haemost. 2005;3:292-299] [Klerk M. JAMA. 2002;288:2023-2031] [Rey E. Lancet. 2003;361:901-908 [ACOG Bulletin #124, 2011] 18
Factor VIII Factor VIII NOT a useful clinical tool to predict recurrent VTE 1 2 3 4 5 6 7 Arterial thromboembolism 19
Unexplained Arterial Thrombosis 1. Arteriosclerosis documented or risk factors present? 2. Cardioembolic source? 3. Other causes (hormones, cocaine, vasculitis, etc?) 4. Thrombophilia? [Moll S. J Thromb Thrombolys 2015; ;39(3):367-78] Arterial Thrombosis FVL: OR 1.21 (95% CI, 0.99-1.49) II20210: OR 1.32 (95% CI, OR 1.03-1.69) [Kim RJ et al. Am Heart J 2003;146:948-957] Protein C and S deficiency <55 yrs: 4.7-fold (95 % CI 1.5-4.2) >55 yrs: 1.1-fold (95 % CI 1.1-18.3) Antithrombin deficiency Not a risk factor Mahmoodi BK, et al. Circulation. 2008;118:1659-1667] 20
Unexplained Arterial Thrombosis How to best treat (secondary prevention)? 1. Anti-platelet therapy? 2. Anticoagulant? 3. Both together? 1 2 3 4 5 6 7 When to Test? 21
Influence of Anticoagulants on Thrombophilia Tests [Moll S. J Thromb Thrombolys 2015;39:367-378] When To Test $ 632.00 22
1 2 3 4 5 6 7 Which Family Members to Test for Thrombophilia Multi-factorial Nature of VTE Fam H/o VTE Thrombophilia (mild, strong ) Hormones Body mass index Smoking What is this ASYMPTOMATIC family member s ABSOLUTE risk for VTE? Previous surgeries, fractures, pregnancies, hormone use WITHOUT VTE [Noboa S, et al. Thromb Res. 2008;122:624-629] 1. [Bezemer ID, et al. Arch Intern Med. 2009;169:610-615] 23
Which Family Members to Consider for Thrombophilia Screening? Proband s thrombophilia Male Family Member Female Family Member Sons Brothers Daughters Sisters Hetero FVL or hetero prothrombin 20210 no no no no Homo FVL or homo prothrombin 20210 no reasonable no yes Double hetero reasonable reasonable yes yes C, S, AT reasonable reasonable yes yes Reasonable reasonable because: consider LMWH with airline travel, cast, non-major surgery; prolonged after major surgeries. yes Yes because: advise against estrogen contraceptives/hormone therapy; give anteand postpartum anticoagulation. 1 2 3 4 5 6 7 Pregnancy Loss and Other Poor Pregnancy Outcomes 24
Pregnancy Loss / Complications [Skeith L et al. Blood 2016;127:1650-5] Pregnancy Loss / Complications All trials Multicenter trials only [Skeith L et al. Blood 2016;127:1650-5] 25
1 2 Pregnancy loss + thrombophilia (other than APLA): LMWH treatment NOT indicated. Pregnancy loss: thrombophilia testing NOT indicated (other than APLA) ACOG [Obstet Gynecol 2013 Sep;122(3):706-17] 1 Inherited thrombophilias Testing NOT recommended for recurrent pregnancy loss, placental abruption, IUGR or preeclampsia 2 APLA Testing may be appropriate for women with fetal loss 26
1 2 3 4 5 6 7 My Choosing Wisely Suggestions My Choosing Wisely Suggestions My 15 Choosing Wisely Suggestions a) For health care professionals b) For clinical laboratories c) For hospital systems 27
My Choosing Wisely Suggestions Thrombophilia Testing Do NOT test. 1. during an acute thrombotic episode. 2. a hospitalized patient. 3. while patient is on an anticoagulant. 4. if not able to interpret the test or don t know what to do with the results. 28
Summary 1 Often little/no evidence of benefit of testing 2 Whom to test? 1... 2. Unexplained unusual venous thrombosis 3. Unexplained arterial clot in the young 3 When to test: NOT acutely, NOT inpatient, NOT on anticoagulation. Summary Inherited and Acquired Thrombophilias Most common Classics Acquired Others Factor V Leiden Prothrombin 20210 Protein C deficiency Protein S deficiency Antithrombin deficiency Antiphospholipid antibodies (ACA, LA, anti-β 2 -GPI) Homocysteine, MTHFR Fibrinogen, factor VIII, IX, XI PAI-1, tpa levels and polymorphisms CBC, CD55/59, JAK-2 (exon 12, CALR) 29
30