Choosing Wisely: If, When, What, and Who to Test for Thrombophilia Nicole Dodge Zantek, MD, PhD Medical Director, Special Coagulation Laboratory University of Minnesota
Disclosures Financial interests = ENDO International PLC, Boston Scientific Research Funding = Terumo BCT, Bayer HealthCare, Octapharma Advisory boards = NASCOLA Executive Committee, CAP Transfusion Medicine Resource Committee, ASCP Choosing Wisely Advisory Board
Thrombophilia hereditary or acquired increased risk for thrombosis
Venous Thromboembolism (VTE) Annual incidence rate VTE among persons of European ancestry = 104-183 per 100,000 person yrs Leg DVT = 45-117 per 100,000 person yrs PE ±DVT = 29-78 per 100,000 person yrs ~100,000 deaths per year in US Increases with age Starting in 40 s and further increases in 60 s 25-40% estimated to be unprovoked Heit et al. J Thromb Thrombolysis 2016;41:3-14 Silverstein et al. Arch Int Med 1998;158;585-593 www.cdc.gov/blooddisorders
Predisposing Factors Smoking Immobillization Inherited Causes Age >65 Years Trauma BMI >30 kg/m 2 Surgery Infection PNH VTE Pregnancy- Puerperium Medications Nephrotic Syndrome Antiphospholipid Antibodies Myeloproliferative Neoplasms Post Thrombotic Disorders Varicosis Malignancy Inflammatory States Colucci and Tsakiris. Clin Appl Thromb/Hemost 2017:23:893-899
Heritable Thrombophilia Varies by population studied 4-10% of general population ~50% of patients with VTE Salvagno et al. Blood Transfus 2007; 5: 189 203 Eid and Rihani. Clin Lab Sci 2004; 17: 200 202 Weitz et al. Hematology (Am Soc Hematol Educ Program) 2004; 424 38
Prevalence of Thrombophilia Thrombophilia Prevalence Relative Risk of Initial VTE (Absolute Annualized Risk) Factor V Leiden (FVL) heterozygous 2-7% 3.48-5.51 (0.05-0.2%) FVL homozygous 0.06-0.25% 6.79-19.29 (0.8%) Prothrombin gene mutation (PGM) heterozygous 1-2% 2.25-3.48 (0.13%) PGM homozygous Rare 2.19-20.72 Compound FVL and PGM heterozygosity 0.1% 1.13-5.04 (0.42%) Protein C deficiency 0.2-0.5% 10 (0.4-2.3%) Protein S deficiency 0.1-0.7% 9.6 (0.7-3.2%) Antithrombin deficiency 0.02% 10-30 (1.2-4.4%) Antiphospholipid syndrome 2% 7 Data from several sources summarized by Stevens et al. J Thromb Thrombolysis 2016;41:154-164
To Test or Not To Test?
Cons Inappropriate withholding or provision of anticoagulant High number to test to avoid 1 VTE High number to test to identify 1 thrombophilia Spurious results Misinterpretation of results Patient distress and anxiety Genetic discriminations Spurious results Pros Patient satisfaction of identifying risk factor Improve anticoagulant compliance Stevens et al. J Thromb Thrombolysis 2016;41:154-164 Middeldorp. Hematology Am Socl Hematol Educ Program 2016;2016:1-9
Does testing for thrombophilia Identify an increased risk for recurrent VTE? Guide anticoagulant therapy duration? Identify an increased risk for first VTE?
Recurrence ~30% in the next 10 years Highest incidence within first 6-12 months Higher in unprovoked VTE 10% 1 st year, 40% 5 years Low in provoked VTE 0-0.7% at 2 years post surgical Heit et al. J Thromb Thrombolysis 2016;41:3-14 Prandoni et al. Haematologica 2007;92:199-205 Baglin et al. Lancet 2003; 362: 523-6 Iorio et al. Arch Intern Med 2010;170: 1710-6
Predicting Recurrence Predictors of recurrence = increasing age, body mass, male, active cancer, neurologic disease with leg paresis Prediction scores (DASH, Vienna prediction model, HERDOO2) do not include thrombophilia testing Heit et al. J Thromb Thrombolysis 2016;41:3-14 Tosetto et al. J Thromb Haemost 2012; 10: 1019-25 Eichinger et al. Circulation 2010;121: 1630-6 Rodger et al. CMAJ 2008; 179: 417-26
Follow-Up from LETS Study Recurrence, per 1000 person years (95% CI) Recurrence with thrombophilia, per 1000 person years (95% CI) Recurrence without thrombophilia per 1000 person years (95% CI) Adjusted hazard ratio for thrombophilia (95% CI) Provoked Unprovoked 17.7 (11.9-25.4) 33.2 (25.4-42.6) 20.9 (12.9-31.9) 33.6 (24.3-45.2) 12.6 (5.4-24.8) 32.4 (19.2-51.2) 1.7 (0.7-3.8) 1.2 (0.7-2.2) Adjusted Hazard Ratio for Recurrence - Any abnormality 1.4 (0.9-2.2) - FVL = 1.3 (0.8-2.1) - PGM = 0.7 (0.3-2.0) - Protein C, protein S, antithrombin= 1.8 (0.9-3.8) Christiansen et al. JAMA 2005;293:2352-2361
Addenbrook s Hospital - UK 570 patients Cumulative recurrence rate 11% at 2 years Low recurrence rate in post operative VTE 20% cumulative recurrence risk at 2 years for unprovoked Hazard ratio for presence of thrombophilia 1.50 (95% CI 0.82-2.77) FVL 1.35 (95% CI 0.65-2.80) PGM 1.74 (95% CI 0.54-5.62) Baglin et al. Lancet 2003;362:523-6
Relative Risk of Recurrent VTE Thrombophilia Factor V Leiden (FVL) heterozygous 1.1-1.8 FVL homozygous 1.8 Prothrombin gene mutation (PGM) heterozygous PGM homozygous Compound FVL and PGM heterozygosity Relative Risk of Recurrent VTE 0.7-2.3 Uncertain 2.7 Protein C deficiency 1.8 Protein S deficiency 1.0 Antithrombin deficiency 2.6 Antiphospholipid syndrome 1.5-6.8 Data from several sources summarized by Stevens et al. J Thromb Thrombolysis 2016;41:154-164
Prevalence and Relative Risk Prevalence in general population Prevalence in consecutive patients with VTE Relative Risk for 1 st VTE Relative Risk for Recurrent VTE Antithrombin Deficiency Protein C Deficiency Protein S Deficiency 0.02% 0.2% 0.03-0.13% Factor V Leiden Prothrombin 20210A Mutation 3-7% 0.7-4% 1% 3% 2% 20% 5% 5-10 4-6.5 1-10 3-5 2-3 1.9-2.6 1.4-1.8 1.-1.4 1.4 1.4 Middeldorp Hematology Am Soc Hematol Educ Program 2016;2016(1):1-9 Middeldorp and van Hylckama Vlieg. Br J Haematol 2008;143:321-35
Thrombophilia Testing and Recurrence MEGA study case control substudy 197 with recurrence (case) vs 324 without (controls) Thrombophilia testing 35% case vs 30% control OR for recurrence Testing = 1.2 (95% CI 0.9-1.8) FVL or PGM mutation = 0.8 (95% CI 0.3-2.6) Coppens et al. J Thromb Haemost 2008;6:1474 1477
Randomized Control Trial? No RCT has been completed to evaluate the role of thrombophilia testing with initial VTE NOSTRADAMUS study terminated early due to poor enrollment and lack of funding.
Anticoagulation Provoked VTE low risk of recurrence, complete 3 months anticoagulation Unprovoked VTE extended duration, unless bleeding risk high RCT placebo vs warfarin after 3 months anticoagulation for unprovoked VTE Trial ended early VTE in 27.4% per patient year placebo vs 1.3% per patient year warfarin Kearon et al. Chest 2016;149:315-52 Kearon et al. N Engl J Med 1999;340:901-7 Stevens et al. J Thromb Thrombolysis 2016;41:154-64
Extended Anticoagulation Risk of recurrence vs. bleeding Patient preference Prediction Age, gender, BMI Recurrence predictor scores (DASH, HERDOO2) D-dimer Residual venous occlusion Malignancy Thrombophilia
Family History 314 patients with DVT and/or PE recruited from 3 prospective studies in the Netherlands 190 had full thrombophilia testing 62 (33%) had 1 factor, 5 (3%) had 2 factors Thrombophilia present in 42% with positive vs. 32% with negative family history [likelihood ratio 1.3 (95% CI 0.9-2.1) Family history score correlated with thrombophilia [odds ratio 1.23 per score point (95% CI 1.01-1.48)] chance of inherited thrombophilia is <50% in 97% of cases Sluis et al. J Thromb Haemost 2006;4:2182-7
Family History Increases risk for VTE - odds ratio 2.2 (95% CI 1.9-2.6) When more than 1 relative affected odds ratio 3.9 (95% CI 2.7-5.7) VTE at a young age and unprovoked VTE are independent predictors of VTE in patient relatives Bezemer et al. Arch Int Med 2009;169:610-5 Couturaud Blood 2014;124:2124-30
Thrombophilia Testing and Outcomes No impact on survival in patients with VTE No impact on risk of post thrombotic syndrome Reitter-Pfoertner et al. Thromb Haemost 2013;109:79 84 Rabinovich et al. J Thromb Haemost 2014;12:14 23
Guidelines American College of Chest Physicians Anticoagulation Forum British Committee for Standards in Hematology Choosing Wisely American Society of Hematology, Society for Vascular Medicine, American Society for Clinical Pathology, American College of Medical Genetics and Genomics, American Society for Reproductive Medicine, Society for Maternal Fetal Medicine Choosing Wisely Canada College of American Pathologists Evaluation of Genomic Applications in Practice and Prevention Working Group French Consensus Guidelines International Consensus Statement National Institute for Health and Clinical Excellence (NICE)
Guidelines Guideline Source Provoked VTE Unprovoked VTE Anticoagulation Forum (2016) Do not screen Screen highly select few American College of Chest Physicians (2012/2016) Do not screen Do not screen International Consensus Statement (2013) Selective screening Screen most or all National Institute for Health and Clinical Excellence (2012) Evaluation of Genomic Applications in Practice and Prevention Working Group (2011) Do not screen Do not screen Screen highly select few Do not screen British Committee for Standards in Hematology (2010) Do not screen Do not screen French Consensus Guideline (2009) Do not screen Screen most or all Stevens and Ansell. Semin Respir Crit Care Med 2017;38:107 20
Who to Test Provoked do not test Unprovoked selected patient testing if considering stopping anticoagulant First degree, asymptomatic relatives selected patient testing Primary prevention OCP/HRT Pregnancy
Connors. ThrombophiliaTesting and Venous Thrombosis. N Engl J Med 2017;377:12 Massachusetts Medical Society Reprinted with permission
Testing Issues
What to Test Factor V Leiden gene mutation Prothrombin gene mutation Protein C chromogenic activity (or clot based protein C activity) Protein S free antigen (or clot based protein S activity) Antithrombin chromogenic activity Antiphospholipid antibodies Lupus anticoagulant Beta 2 glycoprotein 1 IgG and IgM Cardiolipin IgG and IgM
What Not to Test Factor VIII Factor IX Factor XI Plasminogen activator inhibitor-1 MTHFR polymorphisms Tissue plasminogen activator
Testing Pitfalls Possible False Diagnosis Thrombophilia frequency in population Reference range Accuracy and precision of assays Methodologic differences Preanalytic issues Timing of testing Anticoagulant Favaloro et al. Semin Thromb Hemost 2009;35:695 710 Favaloro et al. Semin Thromb Hemost 2008;34:612-34
Test Variation Lessons Learned from Proficiency Testing High variation in thrombophilia testing ~5-20% Incorrect diagnosis UK NEQAS thrombophilia exercises (1998-2000) 5.5% for normal plasma 37.8% for FVL homozygous Royal College of Pathologists of Australasia Quality Assurance Program 2-8% Jennings et al. Semin Thromb Hemost 2005;31:66-72 Meijer and Haverkate. Semin Thromb Hemost 2005;31:59-65 Favaloro et al. Semin Thromb Hemost 2005;3149-58 Cunningham et al Arch Pathol Lab Med. 2011;135:227 232 Baron et al Am J Clin Pathol 2012;137:909-15 Smock et al. Thromb Haemost 2016;116:50-7
Methodologic Issues APCR/FVL false decrease in protein S activity in some assays Lupus anticoagulant false elevation of proteins C and S by clot based assays Lupus anticoagulant, factor inhibitor, factor deficiency false APCR results Protein C and protein S antigens may miss some variants detected by activity FVL may be missed in some APCR assays without predilution with Factor V deficient plasma FVL genetics misses other causes of APCR resistance detected by APCR assay Smock et al.thromb Haemost 2016;116:50-7 Favaloro et al. Semin Thromb Hemost 2009;35:695 710 Favaloro et al. Pathology 2002;34:348 55 Favaloro et al. Semin Thromb Hemost 2005;31:49-58
When to Test and Acute Clot Genetic testing unaffected Protein C, proteins S, and antithrombin decreased Lupus anticoagulant may be transiently elevated Moll. J Thromb Thrombolysis 2015;39:367 378
Anticoagulants and Testing Vitamin K Antagonist Unfractionated Heparin Direct Factor Xa Inhibitors Direct Thrombin Inhibitors Lupus anticoagulant Possible false + Possible false + Possible false + Possible false + APCR clot based Variable Possible false Possible false Possible false Antithrombin factor IIa NC NC - # NC False based* Antithrombin factor Xa NC NC- # False NC based Protein C activity * NC NC NC chromogenic Protein C activity clot * Possible false False False based Protein S free protein * NC NC NC S antigen Protein S activity clot * Possible false False False based Protein S total antigen * NC NC NC NC = no change *Expected physiologic response to vitamin K antagonists. # Heparin may cause a physiologic decrease in antithrombin. Goodwin and Adcock. N Engl J Med 2017;377:23 Favaloro and Lippi Blood Transfus 2017;15:491-494 Funk Hematology Am Soc Hematol Educ Program 2012;2012:460-5
Anticoagulants and Testing No Effect Factor V Leiden genetic testing Prothrombin G20210A genetic testing Fibrinogen antigen D-dimer Von Willebrand factor testing Anti-Cardiolipin Anti-Beta2 glycoprotein 1
When to Test Consider 2 stage testing 1 st FVL, PGM, cardiolipin antibodies, β2 glycoprotein 1 antibodies If negative stop anticoagulation for 2-4 weeks 2 nd Protein C, protein S, antithrombin, lupus anticoagulant Stevens and Ansell. Semin Resp Crit Care Med 2017;38:107-20
Inappropriate Testing Somma et al. Am J Clin Pathol 2006;126:120-127 200 consecutive thrombophilia panels 62% ordered during acute thrombotic event 12.5% had abnormal protein C or S results due to warfarin 7.5 % abnormal protein S due to pregnancy/intrauterine fetal demise Shen et al. Plos One 2015:11(5);e0155326 173 patients tested 51% tested within 1 week of index clinical event 34% had appropriate indication: unprovoked venous or arterial thrombosis or pregnancy losses 34% tested while on anticoagulation
Cost In 2014, 280,000 claims were made to Medicare an estimated cost of $300-672 million A single center study Implementation of testing guidelines 84% reduction in testing Projected wastage >$1 million/year Petrilli et al J Hosp Med 2016;11:801-4 Shen et al Plos One 2015:11:e0155326
Two Sides to the Story Many patients with a heritable thrombophilia never develop a VTE. Negative thrombophilia testing does not equal low risk for VTE.
Conclusions Thrombophilia testing should not be routinely ordered for all patients, Testing should only be obtained in selected patients. Testing should only be obtained if it will influence management decisions. Beware of issues with testing, particularly in relation to timing of thrombosis and anticoagulant use.