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Thrombophilia and Pregnancy An Old Issue Revisited Tripp Nelson, MD Maternal Fetal Medicine Fellow Medical University of South Carolina Objectives • Review coagulation basics and pregnancy influence on clotting • Inherited Thrombophilia – Pregnancy management – Therapy options • Aquired Thrombophilia – Pregnancy management – Therapy options • Anesthesia considerations with thromboprophylaxis Importance • VTE responsible for 20% of pregnancy-related deaths in US • VTE prevalence 1:1600 – 77% DVT – 23% PE • VTE usually a disease of aging – Pregnancy alone increases risk 6x Virchow’s Triad Venous Stasis (Prog vasodilation, pelvic vein compression) Hypercoagulability Vascular Damage (Increase pro-coagulant, decreased natural anticoagulant) (Vessel Distention, Delivery Trauma) Pregnancy Induced Hypercoagulability Pro-coagulants • Increased Fibrinogen • Increased factor levels: – V, VIII, IX, X inc thrombin • Decreased thrombolysis – Increased PAI-1,2 – Decreased tPA activity Anti-coagulants • Protein S activity reduced • Activated protein C resistance increased DVT in pregnancy • 98% involved the lower extremities – 80% left LE • More common antepartum than postpartum – 74% AP – 26% PP – 50% of antepartum DVT detected by 15 weeks – Only 12% detected after 30 weeks PE in pregnancy • More likely diagnosed postpartum – 60.5% • Strongly associated with CD (RR 30.3) Thrombophilia • Inherited – – – – – Protein C/S Deficiency Prothrombin mutation ATIII Deficiency Factor V Leiden Hyperhomocysteinemia • Aquired – APAS Incidence of Inherited Thrombophilia Thrombophilia General population Patients with VTE AT III, Protein C, Protein S 1% 7% Factor V Leiden Caucasian 4-7% Other 0-1% 21% Prothrombin 20210A Caucasian 2-3% Other 0-1% 6% Elevated FVIII:c levels 11% 25% Hyperhomocysteinemia 5% 10% Inherited Thrombophilia: VTE Risk in Pregnancy ACOG Practice Bulletin # 138 Protein C/S Deficiency Diagnosis • Protein C – 55-70% activity = borderline – repeat, family – < 55% = deficiency – False + = liver dz, OCP use, vit K deficiency, DIC • Protein S – < 55% free protein S – False + = liver dz, oral anticoagulants, OCP use, vit K deficiency, pregnancy, nephrotic syndrome – < 30% in pregnancy Hoffman, Hematology 4th Ed 2005 Protein C/S Deficiency Protein C Deficiency • Highly variable phenotype Protein S Deficiency • Highly variable phenotype – 160 possible mutations – 130 possible mutations • Type 1 – reduction in antigen and activity • Type 2 – normal antigen level, decreased activity • Type 1: low levels of total and free protein S • Type 2: Nml total but decrease free protein S • May be associate with RPL, stillbirth, preeclampsia/eclampsia Antithrombin Deficiency • Highly thrombogenic, but RARE • Normal ATIII concentration = 75-120% – No change with pregnancy • 250 associated mutations can cause • Prevalence 1:2,500 • In non-pregnant confers a 25x risk VTE – Pregnancy certainly increases – Although may be lower risk in those without personal or family history of VTE Protein C/S, ATIII First VTE incidence Overall (%/year) 1.5 (0.7-2.8) Surgery/trauma (%/episode) 8.1 (4.5-13.2) Pregnancy (%/pregnancy) 4.1 (1.7-8.3) AT 7.2% 8-13%* During pregnancy 1.2 (0.3-4.2) Puerperium 3.0 (1.3-6.7) OCP use (%/year) 4.3 (1.4-9.7) Coppens, et al 2006; *ACCP Chest, 2012 Factor V Leiden Mutation • Gene defect of clotting factor V – Point mutation – Replacement of arginine by glutamine • In cleavage site for activated protein C (APC) • Results in factor V more resistant to inactivation by APC – APC resistance • Present in 20% of patient with VTE • Present in 5% of caucasian population Factor V Leiden First VTE incidence Overall (%/year) 0.5 (0.1-1.3) Surgery/trauma (%/episode) 1.8 (0.7-4.0) Pregnancy (%/pregnancy) 2.1 (0.7-4.9) 4-16%* During pregnancy 0.4 (0.1-2.4) Puerperium 1.7 (0.7-4.3) OCP use (%/year) 0.5 (0.1-1.4) Coppens, et al 2006, *ACCP Chest, 2012 Relative Risk VTE in pregnancy • Factor V heterozygote – 5.3 (3.7-7.6) • Factor V homozygous – 25.4 (8.8-66) • PT – 6.1 (3.4-11.2) • PT and factor V – 84 (19-369) Prothrombin Gene Mutation • G-A substitution at neucleotide 20210 of PT gene • Result = increased circulating levels of prothrombin – Increased hepatic biosynthesis of PT • Present in 3% of European population • Reported to account for 17% of VTE in pregnancy – Family and personal hx important – No hx of VTE, risk during pregnancy=1% Prothrombin Mutation First VTE incidence Overall (%/year) 0.4 (0.1-1.1) Surgery/trauma (%/episode) 1.6 (0.5-3.8) Pregnancy (%/pregnancy) 2.3 (0.8-5.3) 4-10%* During pregnancy 0.5 (0.1-2.6) Puerperium 1.9 (0.7-4.7) OCP use (%/year) 0.2 (0.0-0.9) Coppens, et al 2006, *ACCP Chest, 2012 Hyperhomocysteinemia/MTHFR • MTHFR mutation is most common reason for hyperhomocysteinemia – MTHFR converts homocysteine to methionine • VTE risk associated with homocysteine levels better than presence of MTHFR mutation • Recent data: – ELEVATED HOMOCYSTEINE LEVELS WEAK FACTOR FOR VTE – NO EVIDENCE TO INCLUDE IN W/U OR TO TREAT Who should I screen? • Controversial • Screening should only be preformed when results of testing would affect management! • Personal History of VTE associated with a nonrecurrent risk factor (surgery, immobility) • First degree relative with history of high risk thrombophilia What about recurrent pregnancy loss? • Not recommended to screen for thrombophilia! – No proven benefit to treating in future pregnancies • Should be screened for APAS! How to screen… Thrombophilia Testing Method Testing reliable Testing reliable during during acute pregnancy? thrombosis? Testing reliable during anticoagulation? FVL Mutation APC ressistance assay (2nd Gen) If abnormal, DNA analysis Yes Yes No Yes Yes Yes Prothrombin G20210A DNA analysis Yes Yes Yes Protein C Def Protein C activity (<60%) Yes No No Protein S Def Functional Assay (<55%) No* No No ATIII Def ATIII activity (<60%) Yes No No Pregnancy Management Pregnancy Management Treatment Definitions Treatment Dose Mini-dose UFH sc, 5000 q 12 hour Moderate-dose UFH sc q 12 hour, Xa adjust Adjusted dose UFH sc q 12 hour, PTT adjust Prophylactic LMWH sc, enoxaparin 40mg/d Intermediate dose LMWH sc, enoxaparin 40mg /12 hr Adjusted dose LMWH sc, enoxaparin 1mg/kg/12h Post partum Warfarin (INR 2-3) Blickstein, 2006 Treatment Definitions • Prophylactic Dose UFH/trimester – First Trimester: 5,000u SQ q12h – Second Trimester: 7,500u SQ q12h – Third Trimester: 10,000u SQ q12h Risk of thromboprophylaxis • Vitamin K antagonist – 2-3% annual incidence of major bleeding • 1% rate of lifethreatening • 0.25% rate of fatal • Osteoporosis (fracture; Monreal, 1994) – UFH 15% (6-30%) – LMWH 3% (0-11%) • UFH – 2% bleeding – HIT – 3% with UFH • Occurs 5-15 days after initiation Need for therapeutic anticoagulation • Acute DVT/PE • Recent DVT/PE on therapeutic anticoagulation prior to pregnancy • Thrombophilia + 2 or more epidodes of VTE – Regardless of whether on lifelong anticoagulation Therapeutic Regimens • Lovenox (LMWH) – 1mg/kg SQ BID – 1.5mg/kg SQ daily – Check Anti-Xa level 6 hrs after most recent dose – Therapeutic window 0.5-1 • UFH – Heparin drip titrated to aPTT of 60-80 Aquired Thrombophilia • Antiphospolipid Antibody Syndrome (APAS) – Multi-functional plasma proteins that have regulatory roles in coagulation, fibrinolysis – Associated with variety of problems: • • • • • • • Arterial thrombosis Venous thrombosis Auto-immune thrombocytopenia Fetal Loss Pre-eclamsia IUGR, placental insufficiency Preterm birth APAS ↑ TX2, PAF, ↓ Protein C ↑ Platelet activation, platelet aggregation, vasoconstriction Decidual vasculopathy Placental thrombosis/infarction APAS Medical Complications • Thrombosis – 2% of VTE – 65-70% venous – Arterial – CVA (MCA); retinal, subclavian, brachial arteries • • • • 25% occur in pregnancy or with OCP APAS = 5-12% risk of VTE in pregnancy 25% recurrence risk in one year Other risks: – Autoimmune thrombocytopenia – Hemolytic anemia APAS Obstetrical Complications • RPL • Pre-eclampsia • IUGR – 15-30% – Associated with increased titers • PTB APAS Diagnostic Criteria Laboratory • +LAC, 2 separate occasions >12 weeks apart • +aCL IgG/M, 2 separate occasions, >12 weeks apart – >40 GPL or MPL – >99% for reference lab • +beta2GP IgG/M, 2 separate occasions, > 12 weeks apart – >99% for reference lab Clinical • Vascular Thrombosis – Arterial – Venous – Small vessel • Pregnancy Morbidity – Stillbirth >10 weeks (nml fetal morphology) – PTB<34 weeks • Due to Pre-eclampsia or IUGR – 3+ RPL < 10 weeks When to test for APAS? • • • • Recurrent pregnancy loss, >3 Unexplained fetal death >10 weeks Severe pre-eclampsia, eclampsia <34 weeks Unexplained thrombotic event – Venous, arterial, CVA/TIA • SLE • Severe IUGR • Auto-immune: thrombocytopenia, hemolytic anemia APAS Pregnancy Management • Treatment goals to improve = – Maternal Outcome – Neonatal outcome • Cases fall into one of two categories: – APAS with prior hx of thrombotic event – APAS with no history of thrombotic event APAS Pregnancy Management • Prior VTE Event – Prophyalctic anticoagulation – UFH – ASA 81mg daily – Continue anticoagulation until 6 weeks postpartum • No hx prior VTE – Less well studied – Expert consensus: • VTE Surveillance + PP prophylactic anticoagulation • OR prophylactic anticoagulation throughout pregnancy and pp In cases of RPL: heparin prophylaxis + ASA daily may reduce pregnancy loss as much as 50%!! Additional Therapies • Steroids – Heparin/LDA superior to LDA alone or prednisone therapy • Empson M, Obstet Gynecol 2002. • IVIG – Most trials evaluating use contained women also treated with combination of heparin/LDA/pred – Small RCT using IVIG + heparin/LDA found no improved outcomes than with heparin/LDA alone • Branch et al, Am J Obstet Gynecol 2000 Antenatal Surveillance with APAS • High potential risk of IUGR, stillbirth • Insufficient data to support/refute specific practice • Recommend developing local protocols: – Serial ultrasonographic assessment of growth – Antenatal surveillance in the third trimester reasonable even if no detection of growth abn Anesthesia Considerations Risk of Spinal / epidural hematoma • With epidural: 1/220,000 • With spinal: 1/320,000 – RR with traumatic tap 11.2 – RR with aspirin use 2.54 • RR heparin after procedure – >1 hr post procedure: 2.18 – <1 hr post procedure: 25.2 Horlocker, Reg Anes Pain Med 2003 Anesthesia - UFH • Duration of heparin >4 days – check plt prior to epidural placement – Goodier, et al. Anesth Analg 2015 • Multicenter retrospective cohort estimation of neuraxial hematoma in parturients plt<100k • 173 pts with spinal or epidural • Risk estimate of epidural hematoma 0-0.6% if plt >80K Anesthesia - UFH • Dose of 5000u BID should not preclude anesthesia • >10,000u BID await normalization of aPTT • Hold IV/SQ for at least 2 hrs prior to epidural insertion or removal • Prophylactic dose heparin may be restarted 12 hrs post cesarean • Therapeutic dose heparin should not be restarted until 24 hrs post cesarean Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010 Anesthesia - LMWH • Plan to convert patients on LMWH to prophylactic or therapeutic UFH at 36 weeks or earlier as indicated • For prophylactic dose LMWH: – Epidural ok 12 hrs after the last dose • For therapeutic dose LMWH: – Epidural ok 24 hrs after the last dose • No benefit to monitor anti Xa levels Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010 Anesthesia - LMWH • For resumption of anticoagulation after therapeutic dosing – Removal of epidural should be 10-12 hrs from the last dose – Subsequent dosing minimum of 2 hrs after epidural catheter removal – If bloody tap, LMWH should be held for 24 hrs Horlocker TT, ASRA and Pain Medicine, 3rd Ed, 2010 Questions?