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THROMBOPHILIAS IN PREGNANCY a dangerous pair!

THROMBOPHILIAS IN PREGNANCY a dangerous pair!. Cyndy Krening, MS, RNC-OB, C-EFM Perinatal Clinical Nurse Specialist Denver, CO. OBJECTIVES. Discuss the effects of pregnancy on women with thrombophilias Identify 2 inherited and 2 acquired thrombophilias

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THROMBOPHILIAS IN PREGNANCY a dangerous pair!

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  1. THROMBOPHILIAS IN PREGNANCYa dangerous pair! Cyndy Krening, MS, RNC-OB, C-EFM Perinatal Clinical Nurse Specialist Denver, CO

  2. OBJECTIVES • Discuss the effects of pregnancy on women with thrombophilias • Identify 2 inherited and 2 acquired thrombophilias • Recognize pregnancy complications associated with maternal thrombophilias

  3. DEFINITION Inherited or acquired abnormalities of the coagulation system in which there is a tendency to form clots

  4. INCIDENCE • Incidence of inherited thrombophilias is 15-20% • Enhanced thrombogenic potential during pregnancy causes 50-80% of all maternal thromboembolic events (4-50x higher incidence than non-pg) • VTE complicates 1 in 500-2000 pregnancies

  5. INCIDENCE • Biggest risk for VTE; • Women with inherited thrombophilias • Previous history or first degree relative with a history of thrombosis • 15% of women with a VTE will have a PE • 10-15% of women having a PE will die. PE is the most common cause of pregnancy related death

  6. WHY? • Hypercoagulable state during pregnancy promotes clot; • Formation • Extension • Stability • Stasis in large veins of lower extremities from uterine compression • Vasodilation • Decreased mobility • Delivery

  7. ADDITIONAL RISK FACTORS • Recent surgery (i.e. CS) • Age >35 years • High parity • High body mass index • Smoking • Immobilization • Postpartum state

  8. WHO SHOULD BE TESTED? Pregnant women (or those planning to become pregnant) with a history of; • Venous thromboembolism with nonrecurrent risk factor • Venous thromboembolism or high-risk thrombophilia in first degree relative before age 50 • Poor pregnancy outcomes – no testing recommended (ACOG, 2000)

  9. WHEN SHOULD TESTING OCCUR? • Non-pregnant • Remote from a thrombotic event • Not taking anticoagulants

  10. INHERITED THROMBOPHILIA? Which of the following is NOT an inherited thrombophilia? • Antiphospholipid antibody • Antithrombin III deficiency • Prothrombin mutation

  11. Factor V Leiden Prothrombin mutation Protein S deficiency Protein C deficiency AT III deficiency PAI – 1 MTHFR mutation INHERITED THROMBOPHILIAS

  12. MOST THROMBOGENIC? Which inherited thrombophilia is the most thrombogenic? • Antithrombin III deficiency • Factor V Leiden (heterozygote) • MTHFR mutation

  13. INHERITED THROMBOPHILIAS • Most common; • Factor V Leiden (heterozygote) • Prothrombin mutation (heterozygote) • Most thrombogenic; • Factor V Leiden (homozygote) • Prothrombin mutation (homozygote) • AT III deficiency

  14. INHERITED THROMBOPHILIAS • Factor V Leiden Mutation • Autosomal dominant inheritance • Abnormal Factor V clotting protien leads to ongoing clotting • Present in 1-15% of caucasians, 3% of African Americans • Causes 40% of thromboembolic events in pregnancy

  15. INHERITED THROMBOPHILIAS • Prothrombin Gene Mutation (Factor II) • Present in 3-5% of caucasians • Leads to 200% in circulating levels of prothrombin • Causes 17% of thromboembolic events in pregnancy

  16. INHERITED THROMBOPHILIAS • Combined Factor V Leiden and Prothrombin Gene Mutation (Factor II) • 1:10,000 • Causes synergistic hypercoagulable effect • Heterozygotes have 4-5% risk of VTE in pregnancy

  17. INHERITED THROMBOPHILIAS • Protein C/S Deficiency • Numerous mutations with variable procoagulant sequelae • Difficult to predict patients who will develop thromboembolism • Autosomal dominant inheritance • Risk of thrombosis in pregnancy is 2-20% • Anti-clotting factor deficiency • Associated with risk of stillbirth, preeclampsia, abruption, IUGR

  18. INHERITED THROMBOPHILIAS • 4G/4G PAI –1 Mutation • Causes modestly risk of thromboembolism, fetal loss, IUGR, preeclampsia and preterm birth

  19. INHERITED THROMBOPHILIAS • AT III Deficiency • Most thrombogenic of inherited thrombophilias – risk 60% in pregnancy • Autosomal dominant inheritance • Prevalence 1/2500 • Causes 1-8% of thromboembolic events in pregnancy • Deficit of anti-clotting factor AT III • Rarely causes major pregnancy complications

  20. INHERITED THROMBOPHILIAS • MTHFR Mutation • Autosomal recessive disorder causes abnormal gene or mutation in MTHFR enzyme • Homozygous mutations most common cause of hyperhomocysteinemia (heterozygotes are normal) • Elevated homocysteine is weak risk factor for VTE • Treat with folic acid, B6, B12 • Not recommended as part of thrombophilia workup

  21. ACQUIRED THROMBOPHILIA Antiphospholipid antibody syndrome • Arterial or venous vascular thrombosis (5-12% risk in pg) and/or pregnancy morbidity associated with medium to high titers of antiphospholipid antibodies

  22. ANTIPHOSPHOLIPID ANTIBODIES? Which of the following is NOT an antiphospholipid antibody? • Anti B2 glycoprotein I • Anti-cardiolipin antibody • Anti-Xa level • Lupus anticoagulant

  23. ANTIPHOSPHOLIPID ANTIBODY SYNDROME Incidence • Uncomplicated pregnancies 5% • IVF pregnancies 24% • Women with lupus 37%

  24. ANTIPHOSPHOLIPID ANTIBODY SYNDROME Who should be evaluated? • Vascular thrombosis - > 1 episodes of arterial, venous or small vessel thrombosis • Pregnancy morbidity • > 1 fetal loss >10 wks with normal morphology • Placental insufficiency <34 wks • Severe preeclampsia <34 wks

  25. ANTIPHOSPHOLIPID ANTIBODY SYNDROME Testing; • Lupus anticoagulant activity • False + RPR • Anti-cardiolipin antibody • Anti B2 glycoprotein I antibody Must have + tests on 2 occasions at least 12 weeks apart

  26. PREGNANCY COMPLICATIONS • Studies: Association between thrombophilias and adverse pregnancy outcomes • Insufficient data • Results contradictory • Populations heterogenous • Absolute risk small • Influenced by various confounders

  27. PREGNANCY COMPLICATIONS • Venous thrombosis • Pulmonary embolus • Stroke • Recurrent SABs (late)

  28. PREGNANCY COMPLICATIONS • Placental fibrin deposits, thrombosis, endothelial, trophoblast changes due to hypoxia can cause; • Stillbirth • IUGR • Abruption • Preeclampsia/HELLP syndrome

  29. WHO SHOULD NOTBE TREATED? • No thrombophilia with hx of 1 VTE • Recurrent early first trimester loss • History of poor pregnancy outcome

  30. WHO SHOULD BE TREATED? PROPHYLACTIC, THERAPEUTIC ANTEPARTUM ANTICOAGULATION or surveillance • Individualized based on: • VTE history • Severity of inherited thrombophilia • Additional risk factors: • CS • Prolonged immobility • Obesity • Family hx thrombophilia, VTE

  31. WHO SHOULD BE TREATED? PROPHYLACTIC ANTEPARTUM ANTICOAGULATION or surveillance • Low risk thrombophilia without hx VTE • Factor V Leiden (heterozygote) • Prothrombin Mutation (heterozygote) • Protein C deficiency • Protein S deficiency • Antiphopholipid antibody syndrome without hx of VTE

  32. WHO SHOULD BE TREATED? PROPHYLACTIC ANTEPARTUM ANTICOAGULATION • High risk thrombophilia without hx VTE • Factor V Leiden (homozygote) • Prothrombin Mutation (homozygote) • Antithrombin III Deficiency • Compound factor V Leiden/Prothrombin mutation (heterozygote) • Antiphospholipid antibody syndrome with hx of: • VTE • Recurrent pregnancy loss

  33. WHO SHOULD BE TREATED? PROPHYLACTIC OR THERAPEUTIC ANTEPARTUM ANTICOAGULATION • Low risk inherited thrombophilias with hx 1 VTE (or surveillance) • High risk inherited thrombophilias with hx 1 VTE • Hx > 2 VTE with or without thrombophilia

  34. WHO SHOULD BE TREATED? THERAPEUTIC ANTEPARTUM ANTICOAGULATION • Venous thrombotic event during current pregnancy

  35. WHO SHOULD BE TREATED? POSTPARTUM ANTICOAGULATION • Low risk thrombophilia with hx 1 VTE • No thrombophilia with hx of VTE • High risk thrombophilia with or without hx VTE • Any patient with hx > 2 VTE • Antiphospholipid antibody syndrome with hx of VTE

  36. ANTICOAGULATIONUNFRACTIONATED HEPARIN • Indirect thrombin inhibitor • Safe, successful pregnancy outcomes (category C) • No fetal anticoagulation • Cheap • Aggressive adjusted dosing necessary in pregnancy; 5000-12,000 units sq q 12 hours

  37. PROPHYLACTIC sq q12 hours Adjusted dose to maintain mid-interval heparin level of 0.1-0.2 U/mL OR 1st : 5000-7500 u 2nd : 7500-10,000 u 3rd : >10,000 u THERAPEUTIC sq q 12 hours Adjusted dose to maintain aPTT 6 hours post-injection of 1.5 – 2.5 X control ANTICOAGULATION; UNFRACTIONATED HEPARIN

  38. ANTICOAGULATIONUNFRACTIONATED HEPARIN • Therapeutic anticoagulation; • aPTT at least 2X control • Anti-Xa heparin level 0.35-0.70 U/mL • Side effects; • Thrombocytopenia • Bone demineralization (reversible)

  39. ANTICOAGULANT REVERSAL? What is the reversal agent for anticoagulants? • Calcium Gluconate • Desmopressin (dDAVP) • Protamine sulfate

  40. ANTICOAGULATIONUNFRACTIONATED HEPARIN • Intrapartum • DC heparin at onset of labor or 24 hours before induction • DC heparin 4 hours before CS • Regional anesthesia safe if PTT normal • Postpartum • Restart 6 hours after vaginal delivery if no significant bleeding • Restart 12 hours after CS

  41. BREASTFEEDING ON ANTICOAGULANTS? Which of the following anticoagulants is safe to administer to the woman desiring to breastfeed her infant? • Coumadin • Heparin • Lovenox • All of the above

  42. ANTICOAGULATIONLOW MOLECULAR WEIGHT HEPARIN • Rapid, predictable anticoagulation • Less side effects than unfractionated heparin • Good safety profile, no teratogenicity noted (category B) • Longer half life, so 1X daily dosing • Expensive; $1/mg

  43. PROPHYLACTIC sq q12-24 hours Agent specific dosing i.e: Lovenox 40 mg No monitoring required THERAPEUTIC sq q 12 hours Weight adjusted dose (30-80 mg) to maintain anti-factor Xa assay of 0.5 – 1.2 U/mL 4 hours post-injection ANTICOAGULATION LOW MOLECULAR WEIGHT HEPARIN

  44. ANTICOAGULATIONLOW MOLECULAR WEIGHT HEPARIN • Therapeutic anticoagulation; • Anti-Xa heparin level 0.5-1.2 U/mL • Adjusted dosing necessary due to pregnancy weight gain • Reverse with protamine sulfate

  45. ANTICOAGULATIONLOW MOLECULAR WEIGHT HEPARIN • Change to unfractionated heparin near term due to risk of epidural hematoma (~36 wks) • Postpartum • Restart 6 hours after vaginal delivery if no significant bleeding • Restart 12 hours after CS • Breastfeeding OK

  46. ANTICOAGULATIONWARFARIN • Crosses placenta, so only used after 14 weeks gestation • Postpartum administration, OK in breastfeeding moms • Peak effect begins in 36-72 hours

  47. ANTICOAGULATIONWARFARIN • Administration • Begin Coumadin 5 mg/day • Continue heparin for 5 days, then until INR is 2-3 for 48 hours, then DC heparin • Continue Coumadin for 6 weeks to 6 months

  48. MATERNAL/FETAL CARE • Patient education regarding s/s clots • Platelet count q week X3 • Monitor for preeclampsia • Serial US for fetal growth • NST/BPP in 3rd trimester • Umbilical artery doppler flow if IUGR • Early delivery if deterioration • SCDs if on bedrest, during labor, CS

  49. CASE STUDY #1 • MT, G1P0, 23 6/7 weeks gestation • Presents with PPROM, category II FHR tracing, BPP 4/8, fetus IUGR, EFW 600 gms • Pt and husband opted for urgent CS • Delivered male, 585 grams, apgars 4/7 • Baby died at 29 hours of life

  50. CASE STUDY #1THROMBOPHILIA PANEL • Factor V Leiden - + (heterozygote) • Factor II – negative • Antithrombin III – 99 (nl 90-120) • Protein C activity – 136 (nl 70-155) • Protein S activity – 53 (nl 62-121) • Dilute Russel Viper Venom time – 33 (nl <42) • Cardiolipin AB IgM - <10 (nl <10) • MTHFR – negative • Homocysteine – 2.2 (nl 5.4 – 11.9)

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