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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
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190 Anticoagulation Therapy
Life-threatening or bleeding that may
lead to death, damage of a vital organ;
active bleeding or presumed bleeding
with hypotension, tachycardia, hematoma,
swollen joints, other signs or symptoms
that suggest immediate consequences;
may include selected emergent invasive
procedures where immediate reversal is
Plan for emergent invasive medical
procedure causative of bleeding.
Moderate bleeding with time to manage.
Presence of bleeding issues that create
some clinical concerns; however, there may
be sufficient time to address co-morbid
ICH: intracranial hemorrhage
Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice
considerations.
2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved.Adapted with permission.
https://t.me/med1917
Anticoagulant effects may outlast
the reversal therapy and rebound.
Very high levels of an anticoagulant
may persist for days.
High: Minimize with repeat doses of
rapid shorter-acting reversal agent
and consider combining with agents
2
with prolonged action (e.g., vitamin
K for warfarin).
Moderate: Reversal should cover
duration of risk window such as
procedure duration and removal of
invasive devices.
degree for reversal and amount of
Moderate or low: Depends on the
reversal therapy administered.
achieved rapidly and sustained until
bleeding stabilized.
Minutes to hours Onset within minutes to hours for emergent
Urgency Syndrome or Indication Timeline Hemostatic Goal Rebound Risk
TABLE 9-2: Assessment of the Bleeding versus Thrombosis Risk
Urgent
lower usually in 12–72 hr; reserve reversal
for patients with notable risk factors for
bleeding or any shortly planned procedure
Hours Therapeutic anticoagulation level or
necessary.
Semi-urgent
reversed if risk is very high or planned
procedure shortly pending. As with urgent
and semi-urgent bleeding, hemostatic
goals may be achieved by gradually
titrating the hemostatic agent to effect by
using low doses, with the option to repeat,
is high risk for bleeding.
Hours to days Anticoagulation may be partially or fully
conditions.
Non-urgent
to minimize the overall dose necessary
to reach goals and risk for subsequent
thrombosis if time permits.
Am J Health-Syst Pharm.
Source:
ANTICOAGULATION REVERSAL: PART II 191
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anticoagulant effect. This can be validated
by checking the amount of clotting factor II
or X present.
Direct thrombin inhibitor or oral anti-factor Xa antago-
nists
Especially if higher or excessive serum concen-
trations are present
Heparin in absence of a neutralization step by the
laboratory
Hepatic failure
Is there a false activated partial prothromboplastin time (aPTT)
elevation? (see Table 21-7)
Sampling technique
Is there a false anti-factor Xa activity level elevation?
Was the test calibrated to the agent that is being
measured?
Does clinical urgency allow time to recheck the
questioned value prior to implementing a reversal plan?
Are there residual effects from other anti-factor Xa inhibi-
tors (e.g., direct-acting oral anticoagulants [DOACs])?
Can an alternative test confirm the observation?
Heparin: Anti-factor Xa activity, aPTT, activated clotting
time (ACT)
Warfarin: Factor II or Factor X
Direct thrombin inhibitor (DTI): Thrombin time, INR, or aPTT
Anti-factor Xa antagonist: Anti-factor Xa activity
3. Consider clinical reason for reversal and timeline assessment for new goal levels
Have you determined the appropriate approach for the current
issue? (see Table 8-1)
If the patient is bleeding, what is the acute bleeding issue?
What drivers for bleeding are present, and can they be
eliminated or managed?
What is assessment of thrombosis risk with loss of anticoagulation
vs. bleeding concerns? (see Table 9-2)
How fast must the anticoagulant effects be reversed? (see Tables
9-2, 9-3, and 9-4)
If the bleeding event or risk with the procedure is life-
threatening (i.e., intracranial hemorrhage) or capable
of causing permanent disabling consequences (ocular
bleeding), is immediate/urgent reversal necessary?
4. If major bleeding, but not life-threatening bleeding (i.e., drop in hemoglobin, see
Appendix F) is occurring, immediate reversal may or may not be needed depending on the clinical situation and options available to support the patient’s needs.
192 Anticoagulation Therapy
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What degree of reversal is necessary (complete, partial, or bringing
excessive effects back into a safe value)? (see Tables 9-3, 9-4, and 9-5)
Is complete reversal desired if major bleeding is occurring or is
anticipated to occur (during high-risk planned procedure)?
Is partial reversal to be considered (i.e., INR <2 or <1.5) when
bleeding concerns are present, but not high enough when balanced
with thrombosis concerns to warrant full reversal (common when
using reversal to facilitate lower bleeding risk related procedures)?
Does the intervention require sustaining some bleeding
to identify and repair the source?
Are values excessive, suggesting an undesirable higher level of
anticoagulation present and a need to lower (here, the goal may
be to drop the INR, aPTT, or ACT) back into the target range faster
than would occur simply by holding the agent? (see Figure 9-1)
Reversal Plan Considerations
The reversal should consider the immediate and long-term effects of the
management process. The agent(s) involved, urgency, need for an invasive
procedure, potential risks, and need to re-initiate anticoagulation should be
coordinated from the beginning and communicated.
•
Anticoagulant involved: Selected laboratory assays along with review of the
medical record, including medication history, should be completed. If the oral
agent is unknown, then selected assessment tools should be considered to
narrow down to the most likely class of agent involved (Figure 9-3).
FIGURE 9-3. Considerations for the Identification and Reversal
of Oral Anticoagulation (see next page)
a
For PCC in warfarin, the actual body weight (ABW) is used up to 100 kg. For reversing
the DOAC’s, what weight to use has not been determined. Consider that ABW up to
100 kg or IBW as data is emerging that a lower dose strategy (< 20 units/kg) may be an
effective approach.
ABW: actual body weight, aPTT: activated partial thromboplastin time, DOAC: directacting oral anticoagulant, INR: international normalized ratio, FEIBA: anti-inhibitor
anticoagulant complex, IV: intravenous, PO: by mouth, TDC: tunneled dialysis catheter,
TT: thrombin time
• Assay errors during collection or measuring can
occur. Single critical values could be misleading
compared to values observed with a supporting
trend from previous measurements. If the clinical
presentation does not support the laboratory
measurement, consider rechecking the value prior
to implementing a different management plan.
Adding an alternate confirmatory test may be
considered in selected situations.
ANTICOAGULATION REVERSAL: PART II 193
y
g
Urgent reversal
1.4 or higher)
Vitamin K IV 2–10 mg
PCC dosed on
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No
Is this paent on an oral ancoagulant?
or topical hemostac agents
based on bleeding risk assessment
Exit algorithm
Hold ancoagulant
An-Factor Xa Antagonist
Dabigatran
a
PCC or aPCC
Andote if available,
Measured an-factor Xa is elevated
elevated
Thrombin (TT)
normal
8 to 50 units/kg ABW
Consider acvated charcoal orally (within a few hours of ingeson),
IV if life threatening bleed
a
Idarucizumab 5 gm IV
(Lower doses with the opon to repeat if necessary
Consider FEIBA 8 to 50 units/kg
Exit algorithm
may be an opon if me permits)
Hemodialysis: (FEIBA 8 units/kg IV just prior to TDC placement)
No
Exit algorithm
Does the paent need an invasive procedure?
h with excessive DOAC levels
Unclear
Medicaon History
be hi
TT, aPTT, INR, an-factor Xa acvity
Note: INR and aPTT ma
No
(Non-Urgent)
Reversal in 24 hours
(Semi-Urgent)
Reversal in hours
Yes
Hold ancoagulant, consider supporve
Hold ancoagulant, consider andote, reduced dose
reversal strategies and other supporve management
Yes
Is the paent severely
FIGURE 9-3. (Continued)
reversal?
Yes
bleeding and needs urgent
Hold ancoagulant
-minutes
Warfarin
INR not elevated Thrombin (TT)
INR Elevated
ABW (up
to 100 kg)
(e.g.,
194 Anticoagulation Therapy
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REVERSAL PLAN
TABLE 9-3: Considerations for Urgent Reversal of
Anticoagulation Effects
Goal: Minimal active anticoagulation by returning anticoagulation indices to baseline for major
or life-threatening hemorrhage.
•
If an immediate surgical procedure associated with a high risk of bleeding complications
or life-threatening bleed, which cannot delay therapy, the choice of reversal and/or
hemostasis therapy with effects in minutes is ideal. This may include both therapy for
emergent reversal, and prevention of rebound of anticoagulant effect.
• The dose of reversal therapy may be adapted to the current intensity of anticoagulation
level if a desire is to avoid prolonged reversal effects when continued concerns for
thrombosis are present; replacement of impaired coagulant factors if necessary for
incomplete reversal with antidotes; for instance, use of rFVIIa, fresh frozen plasma (FFP),
or PPC for emergent hemostasis (not drug antidote) plus 2–10 mg IV vitamin K to prevent
rebound effects in warfarin-induced life-threatening hemorrhage. For DOACs, an antidote
can be considered.
Generally the goal of reversal is at least 24–72 hours, but as long as life-threatening
•
bleeding issues are present, long-term anticoagulation may not be an immediate concern.
For instance, with warfarin vitamin K IV 2–10 mg (similar degree of reversal, but longer
effects with the higher doses); reversal may be repeated if necessary; for sub-Q LMWH or
sub-Q UFH, prolonged infusion of protamine may be necessary.
FFP: fresh frozen plasma, IV: intravenous, LMWH: low molecular weight heparin, PCC:
prothrombin complex concentrates, rFVIIa: activated recombinant factor VII, sub-Q: subcutaneous
Note: In the setting an intracranial hemorrhage (ICH) or gastrointestinal (GI) bleed with warfarin
used for stroke prevention in AF or history of VTE, reinitiating warfarin within 1 month has been
associated with a net positive benefit. Bridging (Chapter 10) with a LMWH, while transitioning
back to warfarin in AF, for most situations may not be necessary (see Figures 9-4 and 9-5).
ANTICOAGULATION REVERSAL: PART II 195
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TABLE 9-4: Considerations for Semi-Urgent Reversal of
Anticoagulation Effects
Goal: Lower end of target range for minimally invasive procedure to subtherapeutic goal for
highly invasive, bleeding-inducing procedures; for patients with high bleeding risks (see below),
intensity of new goal may be adjusted to a lower target during the period of increased bleeding
concern. For instance, INR reversal from 6 may be reduced to 2.5–3.5 for patient goal without
other risks, but to perhaps 2–2.5 or lower for the procedure if patient has additional risk factors
for bleeding. This should be balanced with the risk for thrombosis.
• Low-risk procedure or high risk for bleeding: Lower goal range but not complete reversal
of anticoagulant effect; relatively lower dose of reversal therapy and selection of therapy
where rebound effects acceptable.
• Administering rapid-onset agents too far in advance may have minimal reversal effect
secondary to decline in effects and subsequent rebound in level of anticoagulation; for
instance, a common mistake in the use of FFP for a procedure like a pacemaker lead
placement is to infuse until the desired INR is obtained but then have a significant delay
from that time until the procedure occurs, allowing for the INR to rebound (increase).
This can be avoided by initiating FFP or PCC within 4–6 hours prior to the procedure and
continuing it up to the time of the procedure if necessary.
FFP: fresh frozen plasma, INR: international normalized ratio, PCC: prothrombin complex
concentrates
Source: Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding
and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst
Pharm. 2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All
rights reserved.Adapted with permission.
TABLE 9-5: Considerations in Non-Urgent Reversal of
Anticoagulant Effects
• Generally therapeutic level is the goal with minimal intervention (e.g., holding the
anticoagulant; oral vitamin K reversal plus holding the anticoagulant for a short period).
Generally holding therapy for 3–4 half-lives, accounting for any organ clearance
•
compromise; for warfarin therapy, holding for 1–2 days and restarting at a lower dose
depending on the initial level of anticoagulation and revised target goals during period
targeting a lower level of anticoagulation.
• Monitor pertinent laboratory tests or clinical features of bleeding; reassess further need for
reversal.
• Decline in anticoagulant effects may be relative to the anticoagulant dose. Patients
receiving higher anticoagulant doses with the same (measured) goal level may be able to
clear out the anticoagulant faster than those on lower chronic doses at the same measured
effect.
Source: Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding
and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst
Pharm. 2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All
rights reserved.Adapted with permission.
196 Anticoagulation Therapy
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FIGURE 9-4. Survival Rates with or without Restarting Warfarin
Anticoagulation in AF Patients Post ICH
49
FIGURE 9-5. Resuming Warfarin in AF Patients After a
Gastrointestinal Bleed
50
ANTICOAGULATION REVERSAL: PART II 197
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Monitor for Bleeding or Recalcitrant Bleeding
TABLE 9-6: Considerations for Monitoring the Impact of the
Reversal Approach
Factor Monitoring Considerations
Bleeding Vital signs, hematocrit or hemoglobin, platelets
Intensity of anticoagulation Agent specific measurements: aPTT, anti-factor Xa activity
Impaired drug elimination Organ function studies consistent with prolonged
ACT: activated clotting time, aPTT: activated partial thromboplastin time, CT: computer
tomography, DOAC: direct-acting oral anticoagulant, INR: international normalized ratio, LFTs:
liver function tests, LMWH: low molecular weight heparin
Signs of bleeding: Physical assessment, wound sites, urine,
and stool for occult blood
CT scan, colonoscopy, etc.
(calibrated to agent when possible), INR, ACT, DOAC
drug levels, thrombin time, platelet count, and fibrinogen
(patients with serious bleeding); other tests may be available
depending on the setting and anticoagulant agent (see
Chapter 21).
Some antidotes in development may have limitations on
our ability to detect if the anticoagulant effects have been
removed. Alternative approaches not influenced by the
reversal agent may need to be considered.
Assess potential impact should rebound in anticoagulant
effect occur if using a reversal strategy that has a shorter
duration of effect than the anticoagulant being reversed.
anticoagulation effects after holding because of a reduction
in elimination (LFTs, renal function, cardiac output). For some
agents (warfarin, LMWH, fondaparinux, DOACs, argatroban),
effects can last for days.
198 Anticoagulation Therapy
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TABLE 9-7: Factors Impacting Extent and Speed of Reversal
Factors Consideration
Assessment of risk for
thrombosis
Requirement of bridge
therapy prior to a procedure
when thrombosis concerns
are notable
Patient risk factors for
continued or worsening
bleeding (not reversal)
angina/ACS, altered
mental status, pulmonary
insufficiency, dialysis efficacy
Magnitude/intensity of
current anticoagulation
effect
•
Thrombotic event (TE) history, number, location, and
severity of the event(s)
•
Recent TE event (provoked versus unprovoked)
Hereditary risk factors/hypercoagulable state
•
•
Risk score (example: CHADS2, CHADS-VASC2) for stroke-
related risk in AF (see Chapter 14)
•
Mechanical devices (ECLS, LVAD) may require continuous
anticoagulation effects
• Ability to provide a bridging agent should be assessed (see
Chapter 10)
Ability to afford bridging agent and desired duration
•
Safety of the therapy or related risks
•
•
Ability to provide follow-up management
Patient ability to administer
•
•
Dose adjusted for organ function
Bleeding risk with continued anticoagulation effect at time
•
of the procedure
• Additional invasive procedures
•
Continuous presence of independent drivers for bleeding
Additional complications may be a concern should
•
continued bleeding or drop in Hgb/Hct occur
•
Current intensity of anticoagulant effects
Degree of reversal (Figure 9-1)
•
•
Return super therapeutic to target goals
• Goal below target or return to baseline
Dose of anticoagulation
agent
Estimation of patient’s
ability to eliminate the
anticoagulant
Higher doses of the anticoagulant required to maintain typical
therapy targets may drop faster (possible increase in clearance);
e.g., the INR may drop faster in patients requiring higher weekly
warfarin dosing than those on low weekly doses (Figure 9-2).
3
• Pharmacokinetics of the anticoagulant
• Note: In acute or chronic illness, advanced age, etc., the
elimination half-life may be notably longer than reported
in prescribing information typically derived from a healthier
population.
• Presence of organ dysfunction
• Ability to expedite reversal
Antidote (protamine, vitamin K, idarucizumab)
Hemofiltration (bivalirudin, dabigatran)
Caution with charcoal if risk for aspiration early
4-8
9-10
post-ingestion
(continued)
TABLE 9-7: (Continued)
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Factors Consideration
ANTICOAGULATION REVERSAL: PART II 199
Predictability of reversal
agent effects
ACS: acute coronary syndrome, ECLS: extra corporeal life support, Hct: hematocrit, Hgb:
hemoglobin, INR: international normalized ratio, LVAD: left ventricular assist device
•
Route of administration
Bioavailability
•
• Dose–response relationship
TABLE 9-8: Considerations for Measuring and Reversing
Parenteral Anti-Factor Xa Agents
Anticoagulant Examples of
Unfractionated
heparin
LMWH Anti-factor Xa
Laboratory Assays
to Consider
aPTT or anti-factor
Xa (UFH calibrator)
typically drawn 4
hr post dose in
selected situations
(LMWH calibrator)
Pharmacologic
Reversal Agents
Protamine For urgent situations: Effects
Protamine Partial reversal of effects
Comment
of heparin dissipate several
hours after holding. Post
cardiopulmonary bypass,
an aPTT rebound may be
detected up to 6 hours out
requiring an additional dose
of protamine (~25 mg).
with protamine. Degree of
reversal and ability to reduce
bleeding is unclear.
Fondaparinux Anti-factor Xa has
aPCC: activated prothrombin complex concentrates, aPTT: activated partial thromboplastin
time, FDA: U.S. Food and Drug Administration, LMWH: low molecular weight heparin, rFVIIa:
recombinant activated factor VII
been proposed,
but no known effect
on outcomes. Not
recommended
at this time.
(No current
FDA-approved
fondaparinux
calibrator)
Unclear One in vitro assessment
showed a greater impact with
an aPCC compared to rFVIIa.
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