BRIGHAM AND WOMEN’S HOSPITAL A Contemporary Approach to Thrombophilia Testing Gregory Piazza, MD, MS Associate Professor of Medicine Harvard Medical School Staff Physician, Cardiovascular Division HARVARD MEDICAL Brigham and Women’s Hospital SCHOOL TEACHING AFFILIATE December 6, 2019 1 Disclosures • BMS- grant/research support • Daiichi-Sankyo- grant/research support • BSC/BTG- grant/research support • Janssen- grant/research support • Bayer- grant/research support • Portola- grant/research support 2 1
Objectives 1. Review the epidemiology of thrombophilias 2. Highlight the implications of thrombophilia on venous thromboembolism (VTE) risk, women’s health, and disease recurrence 3. Discuss “when, why, and how” to perform thrombophilia testing 3 What Would You Do? • A 21-year-old woman is referred from her college Health Center for evaluation of possible OCP use. • The patient’s mother suffered PE during her first pregnancy and her older sister had a DVT on an OCP. • The patient has never suffered a thrombotic event. • Her mother and sister were never tested for thrombophilias because their physician felt “it would not assist with management of venous thromboembolism.” 4 2
What Would You Do? 1. Order thrombophilia testing initially focused on the highest-yield tests 2. Order every thrombophilia test available 3. Just prescribe a combination OCP because thrombophilia testing won’t impact your decision-making 4. Tell her combination OCPs are contraindicated based on family history alone 5 Thrombophilia: Prevalence Thrombophilia General Patients with Family History 1 st VTE (%) Population (%) of Thrombosis (%) Factor V Leiden 3-7 20 50 Prothrombin Gene Mutation 1-3 6 18 Hyperhomocysteinemia 5-10 10-25 ? Antiphospholipid Antibodies 0-7 5-15 ? Protein C Deficiency 0.2-0.4 3 6-8 Antithrombin Deficiency 0.02 1 4-8 Protein S Deficiency ? 1-2 3-13 Rosendaal FR. Semin Hematol 1997;34:171 6 3
Thrombophilia and Conventional Risk Factors: US DVT Registry 5% 95% Goldhaber SZ and Tapson VF. Am J Cardiol 2004;93:259 7 Thrombophilia Testing in the Real World: Lessons from RIETE • N = 21,367 consecutive patients with symptomatic VTE. 25.8% • Thrombophilia testing was 36.3% performed in 21%. 19.8% 18.1% • Thrombophilia was detected in 32%. • The rate of thrombophilia was similar in patients with idiopathic VTE and those with provoked events. Roldan V, et al. Thromb Res 2009;124:174 8 4
Question No. 1 • Thrombophilia testing is indicated in which of the following clinical scenarios? A. A 82-year-old man with left calf deep vein thrombosis (DVT) after a fall complicated by a right hip fracture B. A 56-year-old woman with pulmonary embolism (PE) following right mastectomy for breast cancer C. A 23-year-old non-smoking woman with right calf DVT following initiation of a combination oral contraceptive pill D. A 22-year-old collegiate baseball pitcher with right upper extremity DVT following spring training sessions 9 Question No. 1 • Thrombophilia testing is indicated in which of the following clinical scenarios? A. A 82-year-old man with left calf deep vein thrombosis (DVT) after a fall complicated by a right hip fracture B. A 56-year-old woman with pulmonary embolism (PE) following right mastectomy for breast cancer C. A 23-year-old non-smoking woman with right calf DVT following initiation of a combination oral contraceptive pill D. A 22-year-old collegiate baseball pitcher with right upper extremity DVT following spring training sessions 10 5
Why Test for Thrombophilias? Determine optimal agent or duration of anticoagulation Predict risk of VTE recurrence Determine optimal intensity of thromboprophylaxis Assess VTE risk with pregnancy or hormonal contraception/replacement therapy Identify at-risk family members 11 A Philosophic Approach to Thrombophilia Testing “Kitchen • Run all available tests Sink” • Obtain only tests that impact Selective therapy OR for which there is intellectual curiosity No • Defer testing because will not Testing impact therapy 12 6
Thrombophilia: the “Big Three” • Activated protein C resistance Factor V Leiden • Genetic test Prothrombin Gene Mutation • Genetic test 20210 • Anticardiolipin antibodies Antiphospholipid • Lupus anticoagulant Antibodies • Anti-beta 2 glycoprotein-1 antibodies • Anti-prothrombin antibody **Can be drawn in the setting of acute thrombosis or anticoagulation. 13 Thrombophilias: High-Yield vs. Low-Yield • Factor V Leiden High- • Prothrombin Gene Mutation • Antiphospholipid Antibodies Yield • Protein C, S, antithrombin Low- • Homocysteine • Factors VIII, IX, and XI Yield • Fibrinogen • PAI-1 • MTHFR gene mutation 14 7
Classifying Major Thrombophilias Piazza G. Circulation 2014; 130:283 15 High-Risk Thrombophilias • Deficiency of antithrombin, protein C, or protein S • Homozygosity for factor V Leiden or prothrombin gene mutation 20210 • Compound heterozygosity for factor V Leiden and prothrombin gene mutation • Elevated antiphospholipid antibodies 16 8
Factor V Leiden • Guanine-to-adenine Normal FV a substitution at nucleotide 1,691 ProC APC results in a Thrombin glutamine instead of Thrombomodulin Ca ++ FV i arginine at amino acid residue 506. Factor V Leiden FV a • Factor V becomes resistant to ProC APC Resistant Thrombin cleavage by Thrombomodulin activated protein C. Ca ++ FV a 17 Distribution of Factor V Leiden Population Rate Caucasian 5.3% Hispanic 2.2% Native American 1.2% African American 1.2% Asian 0.4% Ridker PM, et al. JAMA 1997;277:1305 18 9
Age and Factor V Leiden: Physicians' Health Study * 7.8 VTE Rate Per 2.6 2.0 1.9 1,000 0.7 1.0 ³ Age (years) Ridker PM, et al. Ann Intern Med 1997;126:528 19 Prothrombin Gene Mutation • Guanine-to-adenine substitution at nucleotide 20210 in the 3' untranslated region of the prothrombin gene. • Heterozygous carriers have 30% higher plasma prothrombin levels than normals. • Heterozygotes have a 4-fold increase in the risk of VTE. Emmerich J, et al. Thromb Haemost 2001;86:809 20 10
Homocysteinemia and VTE den Heijer M, et al. N Engl J Med 1996; 334:759 21 Antiphospholipid Antibodies in Patients with VTE Schulman S, et al. Am J Med 1998;104:332 22 11
Antiphospholipid Antibodies in Patients with VTE Schulman S, et al. Am J Med 1998;104:332 23 Thrombophilia and 1 st VTE RR of 1 st VTE Thrombophilia Factor V Leiden 2-10 Prothrombin Gene Mutation 2-6 Factor V Leiden/Prothrombin Gene 20 Mutation (compound heterozygote) Protein C Deficiency 6.5-31 Protein S Deficiency 2-36 Antithrombin Deficiency 5-40 Hyperhomocysteinemia 2-4 Antiphospholipid Antibodies 3-11 http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology -oncology/hypercoagulable-states/#t0010 24 12
Contraception and Thrombophilia • Estrogen-based oral contraceptive pills (OCPs) in patients with thrombophilia are associated with a 20-to-40-fold increase in the risk of VTE. • The increased risk of VTE appears to be highest around the time of OCP initiation and within the first 6 months. Vanderbroucke JP, et al. Lancet 1994;344:1453 Bloemenkamp KW, et al. Arch Intern Med 2000;160:49 25 Interaction of OCPs and Factor V Leiden Vandenbroucke JP, et al. N Engl J Med 2001;344:1527 26 13
Considering VTE Risk When Choosing an OCP 2 nd generation OCPs with low-dose estrogen and • progestins such as levonorgestrel are the safest combination formulations. • Reducing the estrogen component from 50 mcg to 30- 40 mcg reduces VTE risk. • Estrogen dose reduction to 20-30 mcg decreases VTE risk further. • “Morning after” pill: usually progesterone-only; no increased VTE risk. 27 Safe Alternatives to Combination OCPs Progestin-Only Pill • “Mini-pill” • Has not been associated with VTE Progestin-Coated IUD • Releases ~20 mcg of levonorgestrel daily • Has not been associated with VTE Copper IUD • No hormonal component 28 14
Miscarriage and Thrombophilia Thrombophilia Early Late Homozygous factor V Leiden 3-fold 2-fold Heterozygous factor V Leiden 2-fold 2-fold Heterozygous prothrombin gene mutation 2-fold 3-fold Anticardiolipin antibody 3-fold 3-fold Lupus anticoagulant 3-fold 1-fold Antithrombin deficiency 1-fold 8-fold Protein C deficiency 2-fold 3-fold Protein S deficiency 4-fold 20-fold Robertson L, et al. Br J Haematol 2006;132:171 29 Pregnancy and Thrombophilia Marik PE and Plante LA. N Engl J Med 2008;359:2025 30 15
Risk of Pre-Eclampsia and Abruption in Women with Thrombophilia Thrombophilia Pre-Eclampsia Abruption Homozygous factor V Leiden 2-fold 8-fold Heterozygous factor V Leiden 2-fold 5-fold Heterozygous prothrombin gene mutation 3-fold 8-fold Antithrombin deficiency 4-fold 1-fold Protein C deficiency 5-fold 6-fold Protein S deficiency 3-fold 2-fold Robertson L, et al. Br J Haematol 2006;132:171 31 Thrombophilia and Infertility Hypercoagulability Abnormal Implantation Trophoblast Failure Differentiation Abnormal Placentation Bates SM, et al. CHEST 2012;141:e691s Ivanov P, et al. Am J Reprod Immunol 2012;68:189 32 16
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