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160 Anticoagulation Therapy
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8
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Chapter
ANTICOAGULATION REVERSAL:
PART I—PHARMACOLOGY OF
AGENTS USED FOR REVERSAL
Lance J. Oyen and Scott A. Chapman
INTRODUCTION
Uncontrolled bleeding in the setting of therapeutic anticoagulation is a risk
associated with all anticoagulation therapy. In addition to holding anticoagulation
therapy, pharmacologic antidotes to anticoagulants and fresh frozen plasma (FFP)
can be administered to reverse the anticoagulant effect. These reversal agents differ
in terms of their target, onset of action, duration of reversal effect, and adverse
effect profile. Such agents may directly antagonize the anticoagulants’ pharmacological effects or replace normal coagulation factors (return of hemostasis).
Patients who are receiving anticoagulation therapy are either at high risk for
a thromboembolic event or are being treated for a thromboembolic event and
are, therefore, at greater risk for developing a clot. The greatest concern with
reversal of anticoagulation is the potential for creating a prothrombotic state in
the patient, leading to exacerbated thromboembolic complications. Assessment
of the patient’s need for reversal based on the urgency of the clinical situation,
the associated degree of reversal needed, and the degree to which a patient is
anticoagulated at the time of assessment of the need for reversal will dictate the
reversal approach(s) used. This chapter will review the pharmacologic agents
used for reversal of anticoagulation, including dosing, administration, onset
and duration, and adverse effects associated with anticoagulant reversal agents.
Chapter 9 will discuss patient-specific assessments of reversal strategies used in
anticoagulation therapy.
APPROACHES TO REDUCING THE
PHARMACOLOGIC EFFECTS OF
ANTICOAGULATION
When considering the treatment options to reversing anticoagulation through the
use of reversal agents, the approach to selection of the reversal agent(s) needs to
account for balancing two things: (1) the urgency of the bleeding event, and the
associated emergence of the reversal need with the anticipated timing of response
and degree of reversal response (partial versus complete reversal); and (2) the
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onset and offset of the reversal agent administered (see Figure 8-1), and as
the bleeding event is related to the clinical situation and mitigating risks in
therapies on exacerbating clots (Table 8-1). An elevated coagulation effect
beyond the desired target level of anticoagulation without bleeding can be
corrected by simply holding the anticoagulant without administration of any
reversal agent (Table 8-2). However, a patient experiencing a life-threatening
bleeding event (i.e., intracranial hemorrhage) or a bleeding event that has
the potential for resulting in permanent disabling consequences (i.e., ocular
bleeding) may require rapid and complete reversal of the anticoagulant effect.
TABLE 8-1: Approaches to Reversing Anticoagulation Effects
Approach Consideration
Holding the anticoagulant Goal is hours to days, allowing a natural reduction in
Removing drug If before the drug is absorbed, can administer activated charcoal.
Antidote Administration of an agent that directly inhibits the pharmacologic
Establishing hemostasis Administration of an hemostatic agent (i.e., a procoagulant) that
Revision of the
anticoagulation approach
a
Note: Approach may include complete or partial reduction of anticoagulation.
pharmacologic effects.
It depends on urgency to reverse effect and patient’s ability to
eliminate the effects of the agent within the desired time period.
Bivalirudin and dabigatran can be removed by dialysis.
Drug effects may persist if elimination is impaired (organ failure,
drug interactions).
effects of an anticoagulant.
Goal is minutes to hours to reduce pharmacologic effects, usually
when a patient is at high risk of harm or that harm is already
occurring.
promotes normal coagulation.
Goal is to reduce therapy target usually related to changes in risk
acceptance.
Usually does not involve an antidote.
a
ANTICOAGULATION REVERSAL: PART I 165
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INR
FFP
rFVIIa PCC
IV vitamin K
PO vitamin K
Time
FIGURE 8-1. Onset and Offset of Agents to Reverse Warfarin
This figure illustrates the potential rebound in international normalized
ratio (INR) when administering various reversal strategies that have a shorter
duration of effect compared to warfarin. The effects of recombinant factor
VII activated (rFVIIa) and prothrombin complex concentrate (PCC) are rapid;
however, the shorter half-life of clotting factor VII leads to an earlier rebound
compared to PCCs. The hemostatic effects of PCCs may also last more than
a day. rFVIIa may lower the INR slightly further than PCC and is more likely
to get a value below 1.2; however, this may not mean a greater level of
hemostasis. For FFP, there is a delay in the partial effects secondary to the
time to administer and amount given. Rebound from FFP begins shortly after
the end of infusion. For vitamin K, the intravenous (IV) form has an earlier
onset; however, the impact of the oral form begins to catch up at 24 hours.
The degree and timing of rebound may depend on the dose administered
and how high the INR is initially prior to the intervention.
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AGENTS TO REVERSE ANTICOAGULATION
TABLE 8-2: Mechanism/Pharmacology/Pharmacokinetics of
Agents for Anticoagulation Reversal
Reversal
Agent
Protamine Combines
Fresh frozen
plasma (FFP)
Prothrombin
complex
concentrate
(PCC)
Mechanism Pharmacokinetics Dose
chemically
with heparin
molecules to
form inactive
salt.
Contains all
coagulant
factors, including
II, VII, IX, and X
but in diluted
form compared
to other options.
Requires
activation of
factors in vivo.
Contains
coagulant
factors, including
II, IX, and X and
some with VII, in
concentrations
25 x that of FFP.
Requires
activation of
factors in vivo.
Onset within 5
minutes.
Duration is
irreversible and
dose dependent.
Rebound of
anticoagulation
may occur with
subcutaneous
heparin or LMWH
doses.
Onset in 1–4
hr depending
on dose and
magnitude of
anticoagulation.
Duration of effect
6 hr or less.
Onset within
10–15 min.
Duration of effect
12–24 hr.
Used with
vitamin K for
longer reversal of
warfarin.
1,2
(see also Chapter
9)
See Table 9-9 on
use of protamine
for UFH and
LMWH.
10–20 mL/kg IV
(see Table 9-18)
25–50
International
Units/kg IV;
this may vary
between
products (best
to review your
formularyspecific choice
to determine
dosing used in
studies) (Table
9-18).
Rebound of
Anticoagulant
Effects
30 min to 18 hr
after protamine.
Likely with
subcutaneous
dosing
associated with
later delivery but
not related to
loss of effect.
~4–6 hr
~12 hr
Activated
prothrombin
complex
concentrates
Contains mainly
nonactivated
coagulation
factors II, VII,
IX, and mainly
activated
coagulation
factor VII,
Onset within
minutes.
Duration 6–24 hr.
Warfarin:
500 Units INR <5
1,000 Units INR
>5
DOACs
8–50 units/kg
(Tables 9-11,
9-12, and 9-17)
~12 hr
(continued)
TABLE 8-2: (Continued)
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Reversal
Agent
Mechanism Pharmacokinetics Dose
ANTICOAGULATION REVERSAL: PART I 167
(see also Chapter
9)
Rebound of
Anticoagulant
Effects
Coagulation
factor VIIa
(recombinant)
(rFVIIa)
Vitamin K Cofactor
DOACs: direct-acting oral anticoagulants, FFP: fresh frozen plasma, hr: hours; IM : intramuscular,
INR: international normalized ratio, IV: intravenous, LMWH: low molecular-weight heparin, min:
minutes; PO: oral, UFH: unfractionated heparin
Selective
replacement of
rFVIIa, which
activates extrinsic
clotting pathway
resulting in
thrombin
formation
for hepatic
production of
active factors II,
VII, IX, and X
Onset within 10
minutes.
Duration of effect
4–6 hr.
Used with FFP
to limit INR (with
warfarin) rebound
and vitamin K
extends to
>24 hr.
Onset 12–24 hr
with PO or 4–12
hr
Duration
dependent on
warfarin intensity.
INR rebound
occurring in days.
with
IV.
10–40 mcg/kg IV.
No dose
ranging trials
are available in
this setting; low
doses of 1 mg
have normalized
the INR within
15 minutes
(Table 9-17).
Up to 10 mg
IV/PO.
Subcutaneous
and IM routes not
recommended
(as the onset of
effect is faster
with PO) (Tables
9-13, 9-14, 9-15,
9-16, and 9-18).
6–12 hr
Dose dependent
• Doses for use of PCC products for hemophilia
management are based on calculation for each
product and determined by the desired factor IX
level (e.g., 12.5–100 Units factor IX/kg). These
doses are typically larger than those used to
manage anticoagulation reversal (e.g., 25–50
Units factor IX/kg). Thrombosis risk may be
higher in patients receiving these products
for warfarin reversal as compared to young
hemophiliacs because with warfarin, the cause
for the coagulopathy can be eliminated, whereas
in hemophilia the cause for coagulopathy
persists.
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CONSIDERATIONS FOR DRUG
ADMINISTRATION
Protamine
•
Pregnancy Category 3
•
Typically reserved for life-threatening bleeds during unfractionated heparin
(UFH) or low molecular weight heparin (LMWH) therapy or to prevent risks of
bleeding after very large UFH doses.
•
Neutralizes the effects of heparin and partially for low molecular weight heparins.
•
See Table 9-9 for dosing.
•
Infusion rates: 5 mg/min.
•
The activated partial prothromboplastin time (aPTT) (or activated clotting time
[ACT]) can be used to assess the effectiveness of protamine sulfate neutralization.
•
Neutralization of subcutaneous UFH may require a prolonged infusion of
protamine sulfate.
•
Dosage form/storage: 10 mg/mL IV solution. If diluted in 5% dextrose in water
(D5W) or normal saline (NS), it should be used immediately and not stored.
There is no preservative in protamine. For expiration, see above.
•
The risks and adverse effects associated with protamine are listed in Table 8-3.
TABLE 8-3: Risks Associated with Protamine Use
• Angioedema
•
Cardiac effects (hypotension, shock, bradycardia)
Flushing
•
•
Leucopenia
• Pulmonary edema
• Pulmonary hypertension
• Pulmonary vasoconstriction
• Thrombocytopenia
• Urticaria
1,3
1,3,4
Caution: Hypersensitivity reactions are potentially higher in patients with allergy to fish, prior use
of protamine insulin, or prior vasectomy; consider corticosteroids or histamine antagonist to treat
reactions.
Vitamin K (Phytonadione)
•
Pregnancy category C.
•
The liver needs to be capable of producing clotting factors for vitamin K effectiveness.
•
Mechanism of action: Vitamin K (Phytonidione) increases coagulation through
its effects as a cofactor of the microsomal enzyme that catalyzes the activation
of the inactive hepatic precursor of factors II, VII, IX, and X.
ANTICOAGULATION REVERSAL: PART I 169
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TABLE 8-4: Vitamin K Products Commonly Used for Reversal
Dosing Form Administration Considerations Comments
•
Injectable •
Available as 10 mg/mL or 1
mg/0.5 mL concentration.
•
Physically compatible in NS,
D5W, or D5WNS.
Administer under light sensitive
•
conditions (protect from light).
Recommended to infuse at a
•
rate not exceeding 1 mg/min.
Clinical application: Infuse IV in
•
50 mL of compatible fluid over
30–60 min.
Subcutaneous administration
not preferred because of erratic
absorption and delay in onset of
effect compared to IV or PO (see
Table 9-15).
Not recommended as
•
intramuscular administration
because of potential for
hematoma since patient is
anticoagulated.
•
IV doses of 0.1–0.5 mg appear
to be as effective as higher
doses to reduce excessive INR
values into the target range, with
over-reversal less likely with the
lower dose.
• 5–10 mg IV for lifethreatening bleeding where
re-anticoagulation is not an
issue within the next week,
and rebound anticoagulation
presents a significant threat.
•
Anaphylactoid (and rarely
anaphylaxis) reactions can occur
(see Table 8-5).
24
Oral •
D5W: dextrose 5% in water, D5WNS: dextrose 5% in normal saline, INR: international normalized
ratio, IV: intravenous, min: minutes, NS: normal saline, PO: oral
Available as 5-mg unscored
tablet.
•
IV form can be administered
orally (Table 9-13).
Clinical application: To give
•
doses <5 mg, the intravenous
formulation that is diluted
(cherry syrup is one option)
orally to give a more accurate
5
dose.
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