Rapid Reversal of Anticoagulation in Trauma Patients

1. Rapid Reversal of Anticoagulation in Trauma Patients Dalia Elfawy., MD Lecturer of Anesthesia and ICU Ain Shams University 2014

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 antifactorXa 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/IIIacomplex. • 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 Triflusalirreversibly 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.

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’sdisease. • 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