1. Dalia Elfawy., MD Lecturer of Anesthesia and ICU Ain Shams University 2014 RAPID REVERSAL OF ANTICOAGULATION IN TRAUMA PATIENTS

2. OBJECTIVES Basic Knowledge about anticoagulants. How to reverse anticoagulation in trauma patients.

6. WHY PEOPLE ARE ON ANTICOAGULANTS Atrial fibrillation Deep vein thrombosis Mechanical heart valves Stroke prevention Heart attacks Heart failure Pulmonary emboli Angina Stents Orthopedic procedures Wound care

7. TYPES OF ANTICOAGULANTS

8. WARFARIN Most commonly used oral anticoagulant. Its vit K antagonists Inhibits factors II, VII, IX, and X formation. Best selling drug Underestimated drug

9. UNFRACTIONATED HEPARIN (UFH) A glycosaminoglycan that exerts its anticoagulant effect thru binding and potentiation of ATIII. Given sub q, IV infusion. Therapy gauged by PTT or INR which is prolonged. Half-life is 1 hour.

10. LOW MOLECULAR WEIGHT HEPARIN (LMWH) Has 1/3 the molecular weight of heparin. Has more antifactor Xa activity than inhibition of thrombin. Does not prolong PTT (since it does not affect thrombin). Half-life is much longer than heparin and mainly cleared by the kidneys.

11. NEWER ANTICOAGULANTS Direct Thrombin Inhibitors: hirudin, lepirudin, desirudin, bivalirudin, ximelagatran, Dabigatran Xa inhibitors: fondaparinux, idraparinux Rivaroxaban, Apixaban

14. ANTIPLATELETS Clopidogrel It affects the ADP-dependent activation of IIb/IIIa complex. Is used to prevent strokes and heart attacks. Works by keeping platelets from sticking together and preventing clots. Glycoprotein IIb/IIIa receptor antagonists It block a receptor on the platelet for fibrinogen and von Willebrand factor. 3 classes: Murine-human chimeric antibodies (e.g., abciximab) Synthetic peptides (e.g., eptifibatide) Synthetic non-peptides (e.g., tirofiban)

15. ANTIPLATELETS Aspirin and Triflusal irreversibly inhibits the enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane - powerful vasoconstrictor that lowers cyclic AMP and initiates the platelet release reaction). Dipyridamole inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2.

16. INDICATIONS FOR REVERSAL OF ANTICOAGULANTS INR above the target range on warfarin. Upcoming invasive procedure: -Bridging. Trauma with massive bleeding.

17. UNIVERSAL CONSIDERATIONS FOR REVERSAL How urgent is reversal? -Faster methods often have drawbacks. What is the risk of thrombotic event off anticoagulation? - Absolute risk = Rate X Time.

18. REVERSAL OF WARFARIN Choices of antidote: -Vitamin K. -FFP. -Prothrombin complex concentrate (PCC). -Recombinant activated factor VII (rFVIIa).

19. REVERSAL OF WARFARIN Vitamin K - Oral administration results in correction by 24 hours. -IV administration is marginally faster (small risk of anaphylaxis). -SC route is unreliable (poor bioavailability).

21. REVERSAL OF WARFARIN FFP - Each ml contains 1 U of factors II, VII, IX, and X. -Need large volume for meaningful correction: dose = (target factor activity – actual level) X body weight eg: 20% desired increase X 70 kg = 1400 U or 5-6 bags of FFP.

22. REVERSAL OF WARFARIN PCC -3-factor concentrate contains only II, IX and X. -4-factor version was just approved in the USA. At least equivalent of FFP for stopping major bleeding at 24 hours. Superior for INR reduction (<1.3) at 30 min. Less volume (105 mL +/- 37 mL versus 865 mL +/- 269 mL).

23. REVERSAL OF WARFARIN rFVIIa -Approved indications include hemophilia A or B with inhibitor, congenital factor VII deficiency and acquired hemophilia. -“Bypassing” effect helps sustain coagulation in the absence of FVIII or FIX. -Does correct deficit in factors II, IX and X. -Corrects the INR. -Doses used have varied (20-90 mcg/Kg).

24. GUIDELINES FOR WARFARIN REVERSAL ACCP 2012 guidelines for warfarin overanticoagulation (No bleeding): -INR < 4.5 Decrease the dose of warfarin. -INR 4.5 – 10 Hold warfarin Can administer small dose of vitamin K (not routinely) -INR > 10 Administer oral vitamin K.

25. GUIDELINES FOR WARFARIN REVERSAL ACCP 2012 guidelines for warfarin reversal (major bleeding present) -IV vitamin K -First choice for immediate reversal (over FFP): 4-factor PCC.

26. GUIDELINES FOR WARFARIN BRIDGING ACCP 2012 Guidelines - High thrombotic risk (atrial fibrillation CHADS2 score 5 or 6, recent stroke, TIA, Rheumatic valvular heart disease, recent venous thromboembolism, protein C,S deficiency): bridge. - Moderate thrombotic risk ( atrial fibrillation CHADS2 score 3 or 4, old venous thromboembolism, active cancer): use clinical judgment (consider risk of bleeding) - Low thrombotic risk ( atrial fibrillation CHADS2 score 0 to 2, previous venous thromboembolism of more than 12 months): do not bridge.

28. GUIDELINES FOR WARFARIN BRIDGING ACCP 2012 guidelines - Last dose of warfarin 5 days before the surgery. - Parenteral anticoagulant: Last dose of LMWH should be 24 hours before the surgery. Last dose of IV UFH 4-6 hours before the surgery. Restart 24-72 hours. - Restart warfarin 12-24 hours after the procedure.

29. REVERSAL OF IV UFH Protamine - Binds heparin chains. - Administer 1 mg of protamine per 100 U of circulating heparin. Time ElapsedDose of Protamine (mg) to neutralize 100 units of heparin Immediate1-1.5 30-60 min0.5-0.75 >2 h0.25-0.375

30. REVERSAL OF UFH Protamine -Excess amount acts as a mild anticoagulant. -Risk of infusion reaction: Hypotension/circulatory collapse. Pulmonary edema. Pulmonary hypertension.

31. REVERSAL OF LMWH Protamine - Neutralizes about 60-75% of activity - consider half life of enoxaparin Enoxaparin administered < 8 hours prior: give 1 mg of protamine per mg of enoxaparin. Enoxaparin administered >8 hours prior: give 0.5 mg of protamine per mg of enoxaparin.

32. REVERSAL OF DABIGATRAN Activated charcoal if ingestion < 2 hours prior. Hemodialysis can help clear the drug ( low binding to plasma protein) -Useful for patient with renal failure. aPCC: takes long time. rFVIIa: partial correction of thrombin generation.

33. REVERSAL OF RIVAROXABAN Activated charcoal if ingestion < 2 hours prior. 4-factor PCC. aPCC: takes long time. rFVIIa: partial correction of thrombin generation.

34. RECENT ADVANCES Monoclonal antibody directed against dabigatran showed efficacy in murine model. PRT4445 universal reversal agent for Xa inhibitors drug neutalizes the effect of enoxaparin and fondaparinux in rats,rapid (5 min) and sustaned (3 h) effect. PER977 is synthetic molecule binds to NOACs (dabigatran and rivaroxaban).

35. PROTOCOL FOR REVERSAL OF ANTIPLATELETS Patients presenting with an intracranial hemorrhage on ASA alone are given 5 platelet concentrate units upon admission. Patients presenting with an acute ICH on clopidogrel with small hemorrhages an initial transfusion of 10 platelet concentrate units upon admission. Patients with a severe acute ICH on clopidogrel, 10 units of platelets are transfused initially with 0.3µg/kg of desmopressin, and platelets are subsequently transfused every 12 hours for the next 48 hours.

36. DESMOPRESSIN Is a synthetic analogue of antidiuretic hormone. Increasing plasma levels of Factor VIII is beneficial for patients with hemophilia and von Willebrand’s disease. is effective for patients with qualitative platelet defects by reversing the antiplatelet effects of glycoprotein IIb/IIIa inhibitors and aspirin therapy.

37. QUIZ

38. Warfarin works mainly through inhibition of thrombin True False

39. Oral administration of vitamin K helps in reversal of warfarin effect within 2 hours True False

40. APCC is useful in clearing Dabigatran True False

41. Protamine neutralizes about 60-75% of LMWH activity True False

42. THANK YOU