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