RAPID REVERSAL OF
ANTICOAGULATION IN
TRAUMA PATIENTS
Dalia Elfawy., MD
Lecturer of Anesthesia and ICU
Ain Shams University
2014
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
anticoagulant
effect
that
thru
exerts
binding
its
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
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)
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