1. Regional Anesthetics and Anticoagulation Marie Sankaran Raval M.D. Boston Medical Center Department of Anesthesiology Nina Zachariah M.D.

2. Objectives Coagulation Cascade Coagulation Cascade Thromboembolic Disorders During Pregnancy Thromboembolic Disorders During Pregnancy Guidelines for regional anesthetics and anticogulation Guidelines for regional anesthetics and anticogulation

3. Coagulation Cascade

4. Conditions Warranting Anticoagulation During Pregnancy Mechanical prosthetic valve Mechanical prosthetic valve Inherited deficiency of naturally occuring anticoagulant: Inherited deficiency of naturally occuring anticoagulant: Factor V LeidenFactor V Leiden Protein C deficiencyProtein C deficiency Protein S deficiencyProtein S deficiency Antithrombin III deficiencyAntithrombin III deficiency Prior episode of venous thromboembolism Prior episode of venous thromboembolism Acute deep venous thrombosis or pulmonary embolism during pregnancy Acute deep venous thrombosis or pulmonary embolism during pregnancy Antiphospholipid antibody syndrome Antiphospholipid antibody syndrome

5. Mechanical Prosthetic Valves Pregnant women with a prosthetic valve are at high risk for thromboembolic phenomena, valve failure and bacterial endocarditis. Pregnant women with a prosthetic valve are at high risk for thromboembolic phenomena, valve failure and bacterial endocarditis. Complications from anticoagulation include fetal teratogenicity, and maternal and fetal hemorrhage Complications from anticoagulation include fetal teratogenicity, and maternal and fetal hemorrhage All pregnant women with a prosthetic valve require anticoagulation All pregnant women with a prosthetic valve require anticoagulation

6. Mechanical Prosthetic Valves Warfarin crosses the placenta and has been associated with fetal malformations and hemorrhage. Warfarin crosses the placenta and has been associated with fetal malformations and hemorrhage. The teratogenic effects of warfarin are limited to the first trimester. It may be used in the second and third trimester, but must be discontinued prior to delivery. The teratogenic effects of warfarin are limited to the first trimester. It may be used in the second and third trimester, but must be discontinued prior to delivery.

7. Mechanical Prosthetic Valves Heparin does not cross the placenta, but can still cause maternal hemorrhage. Heparin does not cross the placenta, but can still cause maternal hemorrhage. Low molecular weight heparin has also been used safely in pregnancy as it does not cross the placenta. Low molecular weight heparin has also been used safely in pregnancy as it does not cross the placenta.

8. Factor V Leiden Factor V Leiden is a mutated form of Factor V that is resistant to the effects of activated protein C Factor V Leiden is a mutated form of Factor V that is resistant to the effects of activated protein C Patients with FVL are at increased risk for deep vein thrombosis. Patients with FVL are at increased risk for deep vein thrombosis. Women with FVL are treated with heparin during pregnancy. Women with FVL are treated with heparin during pregnancy.

9. Protein C Deficiency Protein C is produced in the liver, requires Vitamin K for synthesis Protein C is produced in the liver, requires Vitamin K for synthesis It acts by inhibiting activated factors V and VIII It acts by inhibiting activated factors V and VIII Incidence – 1:15,000 Incidence – 1:15,000 Levels of Protein C normally increase by 35% in pregnancy Levels of Protein C normally increase by 35% in pregnancy In patients with Protein C deficiency, thrombosis occurs in 25% of pregnancies, unless anticoagulation is administered. In patients with Protein C deficiency, thrombosis occurs in 25% of pregnancies, unless anticoagulation is administered. Heparin is administered during the 1 st and 3 rd trimesters and heparin or warfarin during 2 nd trimester and post-partum. Heparin is administered during the 1 st and 3 rd trimesters and heparin or warfarin during 2 nd trimester and post-partum.

10. Protein S Deficiency Protein S is produced by the liver and requires Vitamin K for synthesis Protein S is produced by the liver and requires Vitamin K for synthesis Protein S is a cofactor for Protein C Protein S is a cofactor for Protein C The levels of Protein S normally decrease during pregnancy The levels of Protein S normally decrease during pregnancy Heparin is administered in the 1 st and 3 rd trimester and warfarin or heparin during the 2 nd trimester and postpartum Heparin is administered in the 1 st and 3 rd trimester and warfarin or heparin during the 2 nd trimester and postpartum

11. Antithrombin III Deficiency Synthesized by liver and endothelial cells Synthesized by liver and endothelial cells It inactivates thrombin and factors IXa, Xa, XIa and XIIa. It inactivates thrombin and factors IXa, Xa, XIa and XIIa. Incidence – 1:5000 Incidence – 1:5000 Risk of thrombosis iin pregnancy is 55% – 68% in untreated patients. Risk of thrombosis iin pregnancy is 55% – 68% in untreated patients. Anticoagulation or antithrombin III replacement is required in pregnancy Anticoagulation or antithrombin III replacement is required in pregnancy Heparin during 1 st and 3 rd trimester and heparin or warfarin during he 2 nd trimester and postpartum Heparin during 1 st and 3 rd trimester and heparin or warfarin during he 2 nd trimester and postpartum

12. Venous Thromboembolism Includes Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Includes Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) Incidence of DVT - 0.02% to 0.36% of all pregnancies Incidence of DVT - 0.02% to 0.36% of all pregnancies Incidence of PE - 0.05% of all pregnancies Incidence of PE - 0.05% of all pregnancies Treatment options should take the following into consideration: Treatment options should take the following into consideration: (1) the safety of the drug for both the fetus and mother(1) the safety of the drug for both the fetus and mother (2) the efficacy of the regimen(2) the efficacy of the regimen (3) dose regimens for acute and secondary treatment and during delivery and after childbirth.(3) dose regimens for acute and secondary treatment and during delivery and after childbirth.

13. Venous Thromboembolism Patients can be effectively treated with Heparin or LMWH. Patients can be effectively treated with Heparin or LMWH. Warfarin should only be used in the 2 nd trimester or during the postpartum period. Warfarin should only be used in the 2 nd trimester or during the postpartum period. Heparin and LMWH should be discontinued 24 hours prior to elective induction of labor to avoid an unwanted anticoagulant effect during delivery. Heparin and LMWH should be discontinued 24 hours prior to elective induction of labor to avoid an unwanted anticoagulant effect during delivery.

14. Venous Thromboembolism Postpartum heparin therapy should be restarted within 12 hours of delivery. Postpartum heparin therapy should be restarted within 12 hours of delivery. Warfarin can be started at the same time with a goal INR of 2.0 or greater. Warfarin can be started at the same time with a goal INR of 2.0 or greater.

15. Venous Thromboembolism Anticoagulants should be given for at least 4 weeks following delivery. Anticoagulants should be given for at least 4 weeks following delivery. If the DVT or PE was diagnosed during pregnancy, anticoagulants should be continued for a minimum of 3 months. If the DVT or PE was diagnosed during pregnancy, anticoagulants should be continued for a minimum of 3 months. Inferior vena cava filters are indicated in patients with a contraindication to anticoagulants. Inferior vena cava filters are indicated in patients with a contraindication to anticoagulants.

16. Antiphospholipid Syndrome Presence of 2 autoantibodies, lupus antioagulant and anticardiolopin antibody Presence of 2 autoantibodies, lupus antioagulant and anticardiolopin antibody Patients are at risk for venous and arterial thrombotic events Patients are at risk for venous and arterial thrombotic events Mechanism is unknown but related to enhanced platelet activity, inhibition of protein C and elevated factor VIII activity Mechanism is unknown but related to enhanced platelet activity, inhibition of protein C and elevated factor VIII activity Fetus at high risk for death in utero due to placental infarction Fetus at high risk for death in utero due to placental infarction Studies have showed improved fetal outcome when affected pregnant women are treated with prednisone, heparin or aspirin. Studies have showed improved fetal outcome when affected pregnant women are treated with prednisone, heparin or aspirin.

17. Guidelines for Regional Anesthesia while on Anticoagulation Subcutaneous Heparin Subcutaneous Heparin Intravenous Heparin Intravenous Heparin Low Molecular Weight Heparin Low Molecular Weight Heparin Coumadin Coumadin Antiplatelet Medications Antiplatelet Medications

18. Subcutaneous Heparin During administration of subcutaneous heparin, there is no contraindication to neuroaxial techniques During administration of subcutaneous heparin, there is no contraindication to neuroaxial techniques For patients receiving mini dose heparin for ≥ 4 days, reassess platelet count prior to neuroaxial block or removal of catheter. For patients receiving mini dose heparin for ≥ 4 days, reassess platelet count prior to neuroaxial block or removal of catheter.

19. Intravenous Heparin Should be avoided in patients with concomitant coagulopathies Should be avoided in patients with concomitant coagulopathies Heparin administration should be delayed for 1 hour after needle placement Heparin administration should be delayed for 1 hour after needle placement

20. Intravenous Heparin Indwelling neuraxial catheters should be removed 2-4 hours after the last heparin dose and reevaluation of the patient's coagulation status has occurred. Indwelling neuraxial catheters should be removed 2-4 hours after the last heparin dose and reevaluation of the patient's coagulation status has occurred. Re-heparinization should occur one hour after catheter removal. Re-heparinization should occur one hour after catheter removal.

21. Low-Molecular Weight Heparin (LMWH) Monitoring of anti-Xa level is not recommended as it is not predictive of the risk of bleeding. Monitoring of anti-Xa level is not recommended as it is not predictive of the risk of bleeding. Antiplatelet or oral anticoagulant medications administered in combination with LMWH may increase the risk of spinal hematoma. Antiplatelet or oral anticoagulant medications administered in combination with LMWH may increase the risk of spinal hematoma. Traumatic needle or catheter placement may signify an increased risk of spinal hematoma and initiation of LMWH therapy in this setting should be delayed for 24 hours. Traumatic needle or catheter placement may signify an increased risk of spinal hematoma and initiation of LMWH therapy in this setting should be delayed for 24 hours.

22. Low-Molecular Weight Heparin (LMWH) In patients receiving LMWH for DVT prophylaxis prior to surgery, needle placement should be delayed at least 10-12 hours after the administration of LMWH. In patients receiving LMWH for DVT prophylaxis prior to surgery, needle placement should be delayed at least 10-12 hours after the administration of LMWH.

23. Low-Molecular Weight Heparin (LMWH) In patients receiving higher doses of LMWH (1 mg/kg every 12 hours or 1.5 mg/kg daily), needle insertion should be delayed for 24 hours. In patients receiving higher doses of LMWH (1 mg/kg every 12 hours or 1.5 mg/kg daily), needle insertion should be delayed for 24 hours.

24. Low-Molecular Weight Heparin (LMWH) Twice daily dosing The first dose of LMWH should be started no earlier than 24 hours postoperatively and surgical hemostasis has been achieved. The first dose of LMWH should be started no earlier than 24 hours postoperatively and surgical hemostasis has been achieved. Indwelling catheters should be removed prior to initiation of LMWH thromboprophylaxis. Indwelling catheters should be removed prior to initiation of LMWH thromboprophylaxis. If a continuous technique is selected, the epidural catheter may be left indwelling overnight and removed the following day, with initiation of LMWH occurring at least two hours after catheter removal. If a continuous technique is selected, the epidural catheter may be left indwelling overnight and removed the following day, with initiation of LMWH occurring at least two hours after catheter removal.

25. Low-Molecular Weight Heparin (LMWH) Single daily dosing The first postoperative LMWH dose should be administered 6-8 hours postoperatively and the second dose should be given at least 24 hours after the first dose. The first postoperative LMWH dose should be administered 6-8 hours postoperatively and the second dose should be given at least 24 hours after the first dose. Indwelling catheter should be removed at least 10-12 hours after the last dose of LMWH. Indwelling catheter should be removed at least 10-12 hours after the last dose of LMWH. Further LMWH dosing should occur ≥ 2 hours after catheter removal. Further LMWH dosing should occur ≥ 2 hours after catheter removal.

26. Warfarin In patient’s receiving chronic anticoagulation, warfarin should be discontinued at least 4-5 days before procedure. In patient’s receiving chronic anticoagulation, warfarin should be discontinued at least 4-5 days before procedure. The PT/INR should be evaluated prior to any neuroaxial technique. The PT/INR should be evaluated prior to any neuroaxial technique. In patients with an epidural receiving low dose warfarin therapy, the PT/INR should be monitored on a daily basis, and checked before catheter removal. In patients with an epidural receiving low dose warfarin therapy, the PT/INR should be monitored on a daily basis, and checked before catheter removal.

27. Warfarin Indwelling catheters can be removed when the INR is less 1.5 Indwelling catheters can be removed when the INR is less 1.5 In patient’s with an INR >3, the warfarin dose should be held or decreased. In patient’s with an INR >3, the warfarin dose should be held or decreased. No definitive recommendation for removal of neuraxial catheters in patients with therapeutic levels of anticoagulation.No definitive recommendation for removal of neuraxial catheters in patients with therapeutic levels of anticoagulation. Neurologic testing should be performed routinely during epidural analgesia and should be continued after catheter removal for at least 24 hours. Neurologic testing should be performed routinely during epidural analgesia and should be continued after catheter removal for at least 24 hours.

28. Antiplatelet Medications NSAIDs, NSAIDs, Thienopyridine derivatives Thienopyridine derivatives Ticlopidine and ClopidogrelTiclopidine and Clopidogrel Platelet GP IIb/IIIa antagonists Platelet GP IIb/IIIa antagonists Abciximab, Eptifibatide and TirofibanAbciximab, Eptifibatide and Tirofiban

29. Antiplatelet Medications NSAIDs do not represent added significant risk for the development of spinal hematoma in patients having epidural or spinal anesthesia. NSAIDs do not represent added significant risk for the development of spinal hematoma in patients having epidural or spinal anesthesia. The actual risk of spinal hematoma with ticlopidine and clopidogrel and the GP IIb/IIIa antagonists is unknown The actual risk of spinal hematoma with ticlopidine and clopidogrel and the GP IIb/IIIa antagonists is unknown The suggested time interval between discontinuation of thienopyridine therapy and neuraxial blockade is 14 days for ticlopidine and 7 days for clopidogrel.The suggested time interval between discontinuation of thienopyridine therapy and neuraxial blockade is 14 days for ticlopidine and 7 days for clopidogrel.

30. Antiplatelet Medications GP IIb/IIIa inhibitors exert a profound effect on platelet aggregation. GP IIb/IIIa inhibitors exert a profound effect on platelet aggregation. Platelet aggregation returns to normal after 24-48 hours for abciximab and 4-8 hours for eptifibatide and tirofiban. Platelet aggregation returns to normal after 24-48 hours for abciximab and 4-8 hours for eptifibatide and tirofiban. Neuraxial techniques should be avoided until platelet function has recovered. Neuraxial techniques should be avoided until platelet function has recovered.

31. Conclusions The decision to perform spinal or epidural anesthesia/analgesia and the timing of catheter removal in a patient receiving anticoagulation should be made on an individual basis. The decision to perform spinal or epidural anesthesia/analgesia and the timing of catheter removal in a patient receiving anticoagulation should be made on an individual basis. The patient's coagulation status should be optimized at the time of spinal or epidural needle/catheter placement. The patient's coagulation status should be optimized at the time of spinal or epidural needle/catheter placement.

32. Conclusions The level of anticoagulation must be carefully monitored during the period of epidural catheterization. The level of anticoagulation must be carefully monitored during the period of epidural catheterization. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation.