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180 Anticoagulation Therapy
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ANTIFIBINOLYTIC AGENTS—AMINOCAPROIC
ACID AND TRANEXAMIC ACID
•
Mechanism of action: Inhibits plasminogen activators and to a lesser degree
through antiplasmin activity.
•
Is used prophylactically and therapeutically as a hemostatic agent to control
bleeding and reduce surgical blood loss events including cardiac surgery, hepatic
surgery, postpartum bleeding, knee and hip replacement surgery, sinus, gyneco
logical and prostate surgery, heavy menstrual bleeding, and tooth extraction in
hemophilia patients. Mouthwash formulas have been used for bleeding gums
post-dental procedures.
•
Has prothrombotic risk when administered with other procoagulants (i.e.,
prothrombin complex concentrates, recombinant factor VIIa, anti-inhibitor
concentrates).
Aminocaproic Acid
•
IV dosing: Initial 4–5 gm IV, diluted in 250 mL of D5W or NS, infuse over 1 hour,
followed by 1 g/hour (50 mL/hr) for about 8 hours or until bleeding is controlled.
•
PO dosing: Initial 5 g ORALLY during the first hour, followed by 1 gm per hour
ORALLY for 8 hours or until bleeding is controlled.
•
Contraindications:
Disseminated intravascular coagulation
Tranexamic Acid
•
Dosing: Varies based on indication.
•
Dosing: The CRASH -2 Study34—1 gm IV over 10 minutes, then 1 gm infused
over 8 hours.
Delayed use carries concerns for thrombosis.
•
Contraindications:
Acquired defective color vision, since this prohibits measuring one
endpoint that should be followed as a measure of toxicity.
Subarachnoid hemorrhage—anecdotal experience indicates
that cerebral edema and cerebral infarction may be caused by
tranexamic acid in such patients.
Active intravascular clotting.
Hypersensitivity to tranexamic acid or any of the ingredients.
32
33
32,33
-
Note: Dosing during operative procedures may be different. Combination
with a concentrated
clotting factor may increase the risk for thrombosis.
ANTICOAGULATION REVERSAL: PART I 181
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REFERENCES AND KEY ARTICLES*
*1. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev.
2007;21:37-48.
2. Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex
concentrate (FEIBA) for reversal of warfarin-related bleeding. Am J Emerg Med.
2013;31:1251-1254.
3.
Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic
Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e24S-e43S.
Hiong YT, Tang YK, Chui WH, et al. A case of catastrophic pulmonary vasoconstriction
4.
after protamine administration in cardiac surgery: role of intraoperative
transesophageal echocardiography. J Cardiothorac Vasc Anesth. 2008;22:727-731.
5.
Baker P, Gleghorn A, Tripp T, et al. Reversal of asymptomatic over-anticoagulation by
orally administered vitamin K. Br J Haematol. 2006; 133:331-336.
6. Phytonadione (Vitamin K Injection) Product Information. Lake Forest, Il: Hospira, Inc;
2004 November.
7. Goldstein JN, Rosand J, Schwamm LH. Warfarin reversal in anticoagulated-associated
intracerebral hemorrhage. Neurocrit Care. 2008;9:277-283.
8. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients
treated with vitamin K antagonists. Anesthesiology. 2008;109:918-926.
9. Hellstern P, Beeck H, Fellhauer A, et al. Factor VII and activated-factor-VII content of
prothrombin complex concentrates. The PCC Study Group. Vox Sang. 1997;73:155-
161.
Desmurs-Clavel H, Huchon C, Chatard B, et al. Reversal of the inhibitory effect
*10.
of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res.
2009;123:796-798.
11.
Yasaka M, Oomura M, Ikeno K, et al. Effect of prothrombin complex concentrate
on INR and blood coagulation system in emergency patients treated with warfarin
overdose. Ann Hematol. 2003;82:121-123.
12. Yasaka M, Sakata T, Naritomi H, et al. Optimal dose of prothrombin complex
concentrate for acute reversal of anticoagulation. Thromb Res. 2005;115:455-459.
13. Yasaka M, Sakata T, Minematsu K, et al. Correction of INR by prothrombin complex
concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
Thromb Res. 2003;108;25-30.
14. Markis M, Greaves M, Phillips WS, et al. Emergency oral anticoagulation reversal: the
relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on
correction of the coagulopathy. Thromb Haemost. 1997;77:477-480.
15. van Aart L, Eijkhout HW, Kamphuis JS, et al. Individualized dosing regimen for
prothrombin complex concentrate more effective than standard treatment in the
reversal of oral anticoagulant therapy: an open, prospective randomized controlled
trial. Thromb Res. 2006;118:313-320.
16. Ansell J, Hirsh J, Hylek E, et al. The pharmacology and management of the vitamin K
antagonists: the eighth ACCP conference on antithrombotic and thrombolytic therapy.
Chest. 2008;133(suppl);160S-198S.
182 Anticoagulation Therapy
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17. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal consensus guidelines
on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust.
2004;181:492-497.
Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant
*18.
therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care.
2010;12:403-413.
Boulis N, Bobek M, Schmaier A, et al. Use of factor IX complex in warfarin-related
19.
intracranial hemorrhage. Neurosurgery. 1999;45:1113-1119.
®
20.
Kcentra
(Prothrombin Complex Concentrate [Human]) Product Information.
Kanakee, IL: CSL Behring, LLC; 2014.
®
21. Bebulin
VH (factor IX complex) Product Information. Westlake Village, CA: Baxter
Healthcare; 2012 July.
®
22. Profilnine
SD (factor IX complex) Product Information. Los Angeles: Grifols
Biologicals; 2011 August.
®
23. FEIBA
NF (Anti-Inhibitor Coagulant Complex) Product Information. Westlake Village,
CA: Baxter Healthcare; 2013 November.
®
24. NovoSeven
RT, Coagulation Factor VIIa (Recombinant) Product Information.
Plainsboro, NJ. Novo Nordisk, Inc; 2015 April.
25. Miyaries MA, Davis K. Newer oral anticoagulants: A review of laboratory monitoring
options and reversal agents in the hemorrhagic patient. Am J Health-Syst Pharm.
2012;69:e28-39.
26.
Dager WE, Regalia R, Williamson D, et al. Reversal of elevated international normalized
ratios and bleeding with low-dose recombinant activated factor VIIa in patients
receiving warfarin. Pharmacotherapy. 2006;26:1091-1098.
Ingerslev J, Vanek T, Culic S. Use of recombinant factor VIIa for emergency reversal of
27.
anticoagulation. J Postgrad Med. 2007;53:17-22.
28. Praxbind (Idarucizumab) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT; 2015.
®
29.
Andexxa
(coagulation factor Xa [recombinant], inactivated-zhzo). Product
Information. South San Francisco, CA: Portola Pharmaceutials, Inc.; 2018.
30. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding
associated with factor Xa inhibitors N Engl J Med. 2016;375:1131-1141.
31. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant
effect of edoxaban. N Engl J Med. 2014;371:2141-2142.
32.
Aminocaproic Acid Injection, USP 5 g/20 mL (250 mg/mL) [package insert]. Hospira,
Inc., Lake Forest, IL; 2007.
®
33. Cyklokapron
tranexamic acid injection [package insert]. Pfizer Injectables. Pharmacia
and Upjohn Co. Division of Pfizer, Inc., New York, NY; 2014.
34. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive
events, and blood transfusion in trauma patients with significant haemorrhage
(CRASH-2): a randomised, placebo-controlled trial. Lancet .2010;376 (9734):23-32.
9
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Chapter
ANTICOAGULATION REVERSAL:
PART II—CLINICAL APPLICATION
William E. Dager
INTRODUCTION
Bleeding, or concerns for bleeding during anticoagulation therapy, may at
times create a need to lower or completely reverse the existing intensity of anticoagulation. Besides holding the anticoagulant or managing the bleeding directly,
additional agents may be considered to counter the anticoagulant’s effects.
Such agents may directly reverse the anticoagulant’s pharmacological effects or
independently drive normal coagulation (hemostasis). Several drivers for bleeding or bleeding events may be present and should be identified. Multiple factors
are involved in finding the optimal approach to minimize bleeding consequences
while limiting the risk for a thrombotic event. This chapter will provide insights
into developing a strategy for reversing anticoagulation.
REVERSAL CONSIDERATIONS
Questions to Ask When Deciding the Best Approach to
Reverse the Effects of an Anticoagulant
•
What is the goal with the reversal?
Stop or just slow active bleeding.
Completely reverse or lower the intensity of anticoagulation (see Figure
Prevent a potential bleeding event.
•
What is the risk for thrombosis (surgical procedure, use of hemostatic agents, or initial
reason for anticoagulation)?
•
How long do we need to reverse?
Can we bridge if necessary (i.e., to warfarin)?
Is there an indication suggesting limited break in anticoagulation desired?
•
Is there an active bleed, or high risk situation present?
•
Will the reversal plan create additional challenges?
Restarting anticoagulation.
Prolonged hospital stay.
9-1).
183
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Level
of
Effect
Target Range
Potential Rebound
Time
FIGURE 9-1. Goal Anticoagulation Intensity of Reversal Plan
a
Reversal targets may depend on the current use of anticoagulation, and how far the
reversal and intended level of anticoagulation to achieve is. The goal may be partial—
down to the target range (solid line), or some value below the target range (broken
line). Thus, the amount of reversal may depend on the initial level of anticoagulation and
the final target goal to achieve. A rebound may occur if the duration of effect from the
reversal agent is shorter than the anticoagulant.
a
Considerations During the Development of a Reversal
Plan
End Target Goal
One of the goals of reversal is to not only control and potentially stop the
bleeding, but to also identify and correct the source or cause. In some forms
of bleeding (e.g., gastrointestinal bleeding), full cessation of bleeding using
hemostatic agents may limit the ability to identify and resolve—through other
means—the bleeding source (1) to prevent potential recurrence as well as
(2) to decrease concerns for recurrent events and increase confidence with
re-initiating anticoagulation therapy.
•
Possible goal: Slowing the bleed to identify the source and mechanically correct it.
•
Reversal plans: Should consider the entire process from initiation of reversal and
ability to re-initiate anticoagulation in a manner that avoids any later avoidable
risks to the patient.
Clinician Considerations
•
Pharmacodynamic and pharmacokinetic properties of the anticoagulant and
separately the reversal agent
Onset and offset of effects for each.
Duration of antidote effects shorter than the agent
reversed: Potential for re-bound in anticoagulant effects
(Figure 9-1).
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Duration of antidote effects longer that the agent
reversed: Potential for resistance to any anticoagulant
neutralized by the antidote until its effects are gone.
Alternative anticoagulants may need to be considered
if re-initiating anticoagulation is necessary before the
effects of the antidote wear off.
Broad spectrum antidotes affecting multiple classes
of anticoagulants may diminish options for restarting
anticoagulation until the effects of the antidote have
sufficiently diminished.
Elimination of either anticoagulant or antidote may be longer in
elderly patients, presence of a selected disease state/organ failure,
or a drug interaction.
•
Current degree of anticoagulation
Consider measuring the level of anticoagulation.
Assess the patients’ ability to eliminated anticoagulation effects
from holding alone (Figure 9-2).
•
Presence of other drivers for bleeding (e.g., antiplatelet therapy, history of
bleeding, concurrent clinical conditions such as trauma)
Need for an invasive procedure.
Stopping versus slowing bleeding.
Ability to recognize and manage other drivers for bleeding.
The value of education and preventing both short- and long-term
undesirable situations should not be underestimated.
•
Target level of anticoagulation after reversal
Full or partial reversal (Figure 9-1).
•
Multiple agents possibly used in combination to meet reversal goals
•
Desired timing of the onset of anticoagulation reversal
Determining if a reversal agent has been given.
Ability to measure level of anticoagulation effects post-initiation
of reversal therapy.
Determining if a planned invasive procedure can be undertaken,
and will the reversal therapy last until the bleeding risk has suffi
ciently resolved.
•
Desired duration of anticoagulation reversal
Short term (surgical or invasive procedures with short bleeding
risk period).
Long term (chronic bleeding or bleeding risk/impact higher the risk
for thrombosis for a prolonged period).
•
Desired outcome of the therapy plan versus the risks (i.e., Is the risk of the active
bleeding or prevention of bleeding high enough to risk the use of agents that
could cause embolic complications?)
-
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Rapid
Anticoagulant Effect
Intermediate
Time
Slow
FIGURE 9-2. Drop in Anticoagulant or Antidote Effects Related
to an Individual’s Ability to Store and Eliminate the Agent
This describes the different decay patterns in anticoagulation effects for variations
in pharmacokinetic and pharmacodynamics effects within the population. Individuals
sustaining typical target goals at very low doses of the agent may have poor elimination
and, thus, require a longer duration of time for the effects to cease compared to those
who require very high doses for the same measured effects where more rapid loss of
effects can occur.
Example: A compliant patient on warfarin 1 mg/day with a INR of 2.5 or on DTI infusion
at 2 mg/hour with a aPTT of 65 seconds would be considered low dose. It could take up
to 10 days for the warfarin to see the INR normalize <1.3 or over 8 hours for the effects
of the DTI (aPTT) to wear off. In contrast, a compliant patient on warfarin 10 mg/daily
with an INR of 2.5 may see the INR normalize below 1.3 as soon as 3 days from the last
dose, or effects of a DTI infusion at 15 mg/hour wear off in 4–6 hours.
•
Determine if there is a plan to continue or reinitiate anticoagulation therapy
Has the necessary duration of anticoagulation occurred (e.g., 3
months for a provoked venous thromboembolism [VTE]) where the
potential exists to just end treatment.
•
Options to reestablish anticoagulation with prolonged reversal effects for a
given strategy
Example: Patients with a high risk for thrombosis (cancer with
multiple thromboembolic events), end-stage renal failure, and
excessive reversal (≥10 mg vitamin K in a warfarin patient) may
create challenges in reestablishing anticoagulation, especially if
there is no need for continued hospitalization.
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• Patients who arrive with an oral anticoagulant
on board and bleeding may benefit from
measuring the level of anticoagulation present.
If excessive, potential causes should be identified
and determined if the driver is short- or longterm. If no alteration in the drivers can be
undertaken and the dosing regimen remains
unchanged when restarted, then the same
regimen could result in recurrence of the excessive
level of anticoagulation.
Patient-Specific Considerations
General Considerations for Developing a Reversal Strategy
•
What anticoagulant agents are involved?
•
Is the patient anemic, thrombocytopenic, or bleeding? How low is the Hgb/Hct?
•
Does the patient have risk factors for bleeding?
Are they easy to identify and correct?
•
What is the clinical impact of blood loss?
Is the baseline Hgb/HCT sufficient to minimize consequences of
blood loss?
Is the baseline Hgb/HCT low, or is there a situation present limiting
the ability to transfuse?
Do preexisting disease states (pulmonary or cardiac) create
additional clinical risks from blood loss?
•
Can the patient be transfused or receive the desired intervention?
•
Can the patient handle the transfusion volume (e.g., heart failure patient)?
• In the setting of a bleeding event outside a central
nervous system (CNS) or closed cavity bleed,
one strategy may be to slow and control the
bleeding. Advantages for this include limiting
the amount of concentrated clotting factors and
risk for thrombosis, or allowing the bleeding to
be assessed (e.g., scope the patient) and then
identify the location and mechanically control
(drain placement) and fix the source of bleeding.
This may lead to a higher level of comfort in
restarting anticoagulation therapy at a later
time.
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RISK FACTORS FOR BLEEDING
TABLE 9-1: Risk Factors for Increased Anticoagulant Bleeding
Category Characteristics
Anticoagulation Organ dysfunction (e.g., hepatic failure, renal failure) creating reduced
capacity for hemostasis to occur
Presence of multiple anticoagulants or antiplatelet agents
Prolonged or persistent anticoagulation effects
Quality of therapy (out of range vs. within goal)
Patient Active or prior bleeding
Acute trauma
Age >70 years old
Alcohol abuse
Anemia
Chronic renal insufficiency
Genetic or acquired coagulopathy disorders
Hypercoagulable state
Malignancy
Organ failure reducing anticoagulant clearance
Previous stroke
Reduced platelet count or function
Severe liver impairment
Uncontrolled hypertension
Procedures Anticoagulation required for the procedure (e.g., bypass, vascular
catheterization)
Drains at site
Invasive procedure disrupting vascular integrity
Recent procedure (bleeding risk is higher closer to surgery)
Vascular irregularities (e.g., aneurysm)
1
Considerations for Reversing Anticoagulation During
Invasive Procedures
•
Closed-cavity (pericardial, spinal, CNS, ocular) regions where small amounts of
blood can pool and create notable risk for complications
•
Feasibility to transfuse
•
Presence of drains or ability to intervene to manage bleeding
•
Adequate duration of anticoagulation reversal
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• If use of an anticoagulant is necessary in the
overall management plan (e.g. placement of a
mechanical assist device requiring use of selected
anticoagulants, need to go on cardiopulmonary
bypass), the presence of an antidote may neutralize
or impact necessary laboratory values (for the
anticoagulant) and impair the ability to implement
a critical therapy. The potential for dosing such
procedures emergently should be incorporated into
the management plan and also decisions regarding
reversal and any antidote selection.
REVERSAL OPTIONS
Steps for Developing a Plan to Reverse Anticoagulation
Effects
1. Assess the urgency of the situation (Table 9-2)
Urgent: Reverse immediately.
Semi-urgent: More conservative therapy and titrate to desired
goals.
Non-urgent: Observe, measure, and evaluate. Reverse as necessary
considering titrating to goals.
2. Assess laboratory validity (Do the results accurately describe the situation?)
(see Chapter 21)
Occurrence of an unexpected value (single value not supported by
a trend or clinical explanation).
Does the observed value match the clinical presentation?
Recheck or validate if time permits.
Single unexpected values should be validated.
Consider alternative assays to validate.
Is an interacting factor influencing a result? (see Chapter 21)
Is the value believable? (see Chapter 21)
Dilution of sample
Sample sent or drawn incorrectly (e.g., sample degrada-
tion, alteration)
Is there a false international normalized ratio (INR) elevation? (see
Table 21-7)
Sampling techniques
Lupus anticoagulant
Presence of lupus anticoagulant may falsely
elevate the INR by interfering with the test
and suggest presence of a higher level of
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