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Dalia Elfawy., MD
Lecturer of Anesthesia and ICU
Ain Shams University
2014
RAPID REVERSAL OF ANTICOAGULATION IN
TRAUMA PATIENTS
OBJECTIVES
• Basic Knowledge about anticoagulants.
• How to reverse anticoagulation in trauma patients.
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
TYPES OF ANTICOAGULANTS
WARFARIN
• • Most commonly used oral anticoagulant .
• • Its vit K antagonists Inhibits factors II, VII, IX,
and X formation.
• • Best selling drug
• • Underestimated drug
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.
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.
NEWER ANTICOAGULANTS• Direct Thrombin Inhibitors:
• hirudin, lepirudin, desirudin, bivalirudin,
• ximelagatran, Dabigatran
• Xa inhibitors:
• fondaparinux, idraparinux
• Rivaroxaban, Apixaban
ANTIPLATELETSClopidogrel
• 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)
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.
INDICATIONS FOR REVERSAL OF ANTICOAGULANTS
• INR above the target range on warfarin.
• Upcoming invasive procedure:
- Bridging.
• Trauma with massive bleeding.
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.
REVERSAL OF WARFARIN
• Choices of antidote:
- Vitamin K.
- FFP.
- Prothrombin complex concentrate (PCC).
- Recombinant activated factor VII (rFVIIa).
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).
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.
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).
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).
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.
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.
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.
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.
REVERSAL OF IV UFH• Protamine
- Binds heparin chains.
- Administer 1 mg of protamine per 100 U of circulating heparin.
Time Elapsed
Dose of Protamine (mg) to neutralize 100 units of heparin
Immediate 1-1.5
30-60 min 0.5-0.75>2 h 0.25-0.375
REVERSAL OF UFH• Protamine
- Excess amount acts as a mild anticoagulant.
- Risk of infusion reaction:
• Hypotension/circulatory collapse.
• Pulmonary edema.
• Pulmonary hypertension.
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.
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.
REVERSAL OF RIVAROXABAN
• Activated charcoal if ingestion < 2 hours prior.
• 4-factor PCC.
• aPCC: takes long time.
• rFVIIa: partial correction of thrombin
generation.
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).
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.
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.
QUIZ
• Warfarin works mainly through inhibition of thrombin
• True
• False
• Oral administration of vitamin K helps in reversal of warfarin effect within 2 hours
• True
• False
• APCC is useful in clearing Dabigatran• True
• False
• Protamine neutralizes about 60-75% of LMWH activity
• True
• False
THANK YOU