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40 Anticoagulation Therapy
https://t.me/med1917
TABLE 3-4: Evidence Supporting Weight-Based Dosing
Compared to a Preset Bolus and Infusion Rate and the
Importance of Achieving Minimal aPTT Targets
N = 115 (VTE = 80)
a,8
Time Standard UFH
24 hr aPTT
Therapeutic 35% 57% <0.001
Subtherapeutic 58% 15% <0.001
Supratherapeutic 7% 27% <0.001
48 hr aPTT
Therapeutic 44% 65% <0.001
Subtherapeutic 49% 18% <0.001
Supertherapeutic 8% 18% <0.001
Minor/major bleeding
Recurrent VTE (3 months)
a
The key points of this analysis were that using a weight-based approach (using total body
weight) led to a higher incidence of aPTT values within or above the target range in the first
24–48 hours without increasing bleeding instances but decreasing recurrent VTE events five
fold. Some observations have linked increased bleeding to frequent excessive aPTT values or
higher doses during prolonged courses of therapy, suggesting some caution regarding frequent
supratherapeutic values beyond 48 hours.
aPTT: activated partial thromboplastin time, hr: hours, NS: nonsignificant, UFH: unfractionated
heparin, VTE = venous thromboembolism
Bolus: 5,000 units
Continuous Infusion
started at 1,000 units/hr
2% / 1%
8 / 32 (25%)
9,10
Weight-based UFH
Bolus: 80 units/kg
Continuous Infusion
18 units/kg/hr (total
body weight)
2% / 0%
2 / 41 (5%)
P value
NS
0.02
Dose Capping
•
Adjusted and total body weight to a certain maximum dose should be considered to minimize potential excessive anticoagulation. The amount can vary
between indications.
Bolus: Outside of arterial disease or during surgical procedures,
Large bolus doses may not be necessary to get a sufficient antico-
bolus doses beyond 4,000–5,000 units may not add any clinical
benefit and should be avoided.
agulation effect. In one analysis, 3,000 units of heparin prior to
cardiac catheterization produced therapeutic aPTT values, with half
exceeding 140 seconds. Low values were only seen if the dose was
<32 units/kg (weight >92 kg).
11
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TABLE 3-5: Dosing Considerations for the Initiation of UFH
Indication Bolus Dose Maintenance Dose
IV VTE treatment (DVT
or PE)
PCI (with GP IIb/IIIa
inhibitor)
PCI (without GP IIb/
IIIa inhibitor)
Acute STEMI
(patients receiving
full-dose rt-PA)
Acute STEMI
(combination
regimen with rt-PA)
(See Chapter 6)
80 units/kg (or 5,000
units)
Lower doses (e.g.,
2000 units) have been
suggested as an option.
18 units/kg/hr; aPTT range
established by laboratory;
calibrated to correspond to
anti-factor Xa activity of 0.3–0.7
International Units/mL
50–70 units/kg Additional bolus doses
(common target low response
ACT 200–250 sec)
70–100 units/kg Target ACT may depend on
the device and if a high or low
range card is used. Different
tests (e.g., Hemochron,
MedTronic, HemoTec) and card
range will give notably different
values. See Table 3-9.
60 units/kg
Max: 4,000 units
12 units/kg/hr
Max: 1,000 units/hr
(common target aPTT 50–70
a
sec)
for at least 48 hr or until
revascularization
40 units/kg
Max: 3,000 units
7 units/kg/hr
Max: 800 units/hr
(common target aPTT 50–70
a
sec)
1,14-16
STEMI 60 units/kg
Unstable angina or
NSTEMI
Stroke Historically has been
Max: 4,000 units
60 units/kg
Max: 4,000 units
avoided due to
bleeding concerns.
Currently, consensus and
recommendations for
bolus dosing of heparin in
acute stroke are lacking.
12 units/kg/hr (maximum 1000
units) initially, adjusted to
maintain aPTT at 1.5–2 (e.g.,
50–70 sec) times control for 48
hr or until revascularization
12 units/kg/hr
Max: 1,000 units/hr; some
institutions use a higher
threshold to achieve target
ranges earlier
In the early phase of an acute
ischemic stroke, heparinization
or use of anticoagulation is not
generally recommended (Class
III A). Use of heparin should
be avoided for a minimum of
24 hours after thrombolytic
therapy (Class III B). Overall,
use of heparin in acute stroke
has not shown to impact
outcomes. Some potential
exceptions, however, may exist
(see below).
(continued)
42 Anticoagulation Therapy
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TABLE 3-5: (Continued)
Indication Bolus Dose Maintenance Dose
Sub-Q DVT prophylaxis 5,000 units every 8–12 hr
VTE treatment
(DVT or PE, with
monitoring)
VTE treatment
(DVT or PE, without
monitoring)
IM IM administration should be avoided because of frequent hematomas.
a
aPTT range will depend on the reagent’s sensitivity to heparin unique to each laboratory. aPTT
target range selection of VTE treatment may consist of the middle to upper portion of the
anti-factor Xa activity calibration. Anti-factor Xa activity targets with concurrent thrombolytic
therapy or ACS are unclear. See Chapter 6 (Table 6-6) for heparin dosing recommendations when
thrombolytic therapy is used.
ACT, activated clotting time, aPTT: activated partial thromboplastin time, DVT: deep vein
thrombosis, GP: glycoprotein, hr: hour, IM: intramuscular, IV: intravenous, kg: kilogram, NSTEMI,
non-ST elevation myocardial infarction, PCI, percutaneous coronary intervention, PE: pulmonary
embolism, q: every, rt-PA: recombinant tissue plasminogen activator, sec: second, STEMI: ST
segment elevation myocardial infarction, sub-Q: subcutaneous, VTE: venous thromboembolic
event
250 units/kg (or 17,500
units)
333 units/kg 250 units/kg every 12 hr
(Note: q 12 hr dosing intervals
may be considered in low/
moderate risk, elderly, low
weight)
Dose in obesity unknown - See
Chapter 10
250 units/kg every 12 hr
•
Infusions: Depending on the situation, infusions for systemic anticoagulation
are typically initiated at 12–18 units/kg/hr, but may go up to 25 units/kg/hr.
Capping the initial allowed infusion rate, unless otherwise specifically justified,
can avoid unintended or excessive dosing. On occasion, higher infusion rates
adjusted based on aPTT or anti-Xa activity may be needed.
It has been suggested that the risk of bleeding may increase when
In acute coronary syndromes (ACS), daily doses >1,667 units/hr
12
daily doses exceed 31,000 units/day.
13
(>40,000 units/day) may not need to be adjusted upward when
the aPTT remains low if the measured anti-factor Xa activity is at
least 0.35 units/mL. In the American Heart Association non-ST
segment elevation myocardial infarction (AHA NSTEMI) guideline,
the maximum bolus of 60 units/kg is 4,000 units and infusion of
12 units/kg/hr up to 1,000 units is suggested followed by dosing
adjustment per established nomogram.
14,15
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• Setting a maximum “capped” dose for both the
bolus dose and separately the infusion rate may
avoid dosing errors that might occur from an
incorrect weight (or units such as pounds for kg),
or extra digit (500 units intended but 5,000 units
ordered). Capped doses may be different based
on the indicated use. Lower capped doses may
be considered in the setting of ACS compared to
PE. Higher doses may occur in the setting of PE
secondary to enhanced elimination.
•
Common order sets should be considered where
possible, especially if for the same indication. All
areas where adjusted dose heparin is used should
be easy to identify and revised as aPTT assay
reagents change.
When restarting anticoagulation in a patient
•
who recently received UFH, titration difficulties
may be avoided by considering the previous
dose required to reach and maintain therapeutic
values. Acute changes in clinical status, different
therapeutic goals, and safety concerns must also
be carefully assessed.
Fixed-dose UFH subcutaneous for VTE treatment has been explored while
transitioning to warfarin. No heparin-induced thrombocytopenia (HIT) was
observed; however, the course was relatively short.
In the setting of acute stroke, heparinization may not influence outcomes.
But in the following situations, it may be considered:
•
Atrial fibrillation with intracardiac chamber thrombus on echocardiography
•
Cerebral venous sinus thrombosis
•
Presence of artificial valves, thrombus in the left atrium or ventricle, or recent
(past month) myocardial infarction
•
Symptomatic dissection of the arteries providing blood flow to the brain after
CT scan has ruled out central nervous system hemorrhage
•
Symptomatic intracranial or extracranial arteriosclerotic stenosis with crescendo
transient ischemic attacks or early progressive stroke
•
Basilar artery occlusion
•
Presence of established hypercoagulable states (Note: Nongenetic hypercoagulable conditions at the time of the acute event may be misleading.)
44 Anticoagulation Therapy
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TABLE 3-6: Estimating a Subcutaneous Heparin Regimen When
Transitioning from an IV Infusion in Treatment of VTE
• Dose subcutaneously administered q 12 hr = [last IV infusion rate/hr × 24] [1.2] / 2 (for
twice daily – every 12 hour dosing)
•
“[1.2]” reflects the approximately 20% loss of bioavailability with the subcutaneous route.
The common 250 units/kg every 12 hr dose for VTE treatment was determined by this
•
approach; 20% over the common 18 units/kg/hr IV infusion rate used in VTE.
hr: hour, IV: intravenous, VTE: venous thromboembolism, x: times
Transitioning from Intravenous to Subcutaneous UFH
•
Depending on dose, onset of effect occurs within 1–2 hours with peak effect
achieved around 3 hours. Several days may be required to reach steady-state
pharmacodynamics for assessing values when subcutaneous UFH is given in full
therapeutic doses.
•
Due to the lower and variable bioavailability of the subcutaneous route of
administration, higher doses of UFH should be initiated to attain therapeutic
anticoagulation effect quickly.
•
For VTE treatment, target aPTT values (or equivalent anti-factor Xa activity of
0.3–0.7 units/mL) at 6 hours post administration should be considered (Table
16
3-14).
• In selected treatment situations where a low
molecular weight heparin (LMWH) may not be
an available option, UFH can be administered
subcutaneously every 8–12 hours. The dose can
be estimated from the IV infusion rate in Table
3-6. It may take several days for the aPTT
to reach steady state. The risk for HIT with
long-term subcutaneous UFH is not known. If
bleeding at injection sites is observed, consider
checking an aPTT and also checking the size of
the needle used.
• Doses of 5,000 units every 8 hours in elderly,
low-weight individuals may yield aPTT values
close to or in the therapeutic range.
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Use of UFH in Selected Procedures and Weight
Considerations
Dosing heparin in selected procedures is further described in Table 3-7 with
Table 3-8 providing some insights on trials exploring the obese population.
See Tables 3-7 and 3-8 for specific examples of UFH in selected procedures
and weight-based dosing.
TABLE 3-7: Examples of UFH Dosing in Selected Invasive
Procedures for Adults
Indication Initial Bolus Dose Maintenance Dose
IV
administration
CABG 80–350 units/kg Target HR-ACT 250 to >400 sec
On-pump CABG 250–400 units/kg Target HR-ACT 2.5 x baseline or
Off-pump CABG
(with aspirin 600
mg PR)
Vascular
reconstruction
Cardiac AF ablation Heparin bolus
17-20
≥400 sec
180 units/kg 3,000 units every 30 min
100–150 units/kg 50 units/kg every 45–50 min
(50–150 units/kg).
Timing may be
operator preference
but should be
administered prior
to or immediately
following transseptal
puncture in AF.
If on warfarin,
higher heparin
requirements may
occur if INR is below
2 versus above 2.
(target HR-ACT ≥350 sec)
Heparin infusion to sustain an
ACT of 300–400 sec. Target ACT
(low range) 300–350 sec may be
considered with a higher goal to
400 sec if enlarged atria present.
Target range may be ACT range
card and test used dependent
(see Table 3-9). Post-procedure
protamine can be considered—
sheaths may be removed
when ACT below 160–200 sec.
Anticoagulation agent chosen
post-procedure is dependent
on the clinician’s choice. Due to
concerns for bleeding—lower
intensity anticoagulation (e.g.,
enoxaparin 0.5 mg/kg) may
be considered until bleeding
concerns subside.
Dialysis (normal
bleeding risk)
Dialysis (increased
bleeding risk)
50 units/kg 500–1,500 units/hr
(target LR-ACT 80% above
baseline)
10–25 units/kg 250–500 units/hr
(target LR-ACT 40% above
baseline)
(continued)
46 Anticoagulation Therapy
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TABLE 3-7: (Continued)
Indication Initial Bolus Dose Maintenance Dose
Other Impella (see
Chapter 17)
Dialysis (very high
bleeding risk or
active bleeding)
Hypothermia Therapeutic
ACT: activated clotting time, AF: atrial fibrillation, aPTT: activated partial thromboplastin time,
CABG: coronary artery bypass graft, hr: hours, HR-ACT: high range-activated clotting time, IV:
intravenous, kg: kilograms, L: liters, LR-ACT: low range-activated clotting time, min: minutes, mL:
milliliters, PR: per rectum, sec: seconds
May depend on
the device inserted,
and several types
of Impellas are
available.
For insertion on
the left side, the
following has been
suggested:
Inserting
guidewire—ACT
goal >250 sec.
Systemic heparin—
of 160–180 sec
ACT
suggested. For aPTT
monitoring, may
depend on assay
reagent sensitivity.
One approach
suggested an aPTT
60–80 sec using
a 12-unit/kg/hr
infusion rate to start
with a 60-unit/kg
optional bolus.
If receiving a
GP IIb/IIIa agent,
can insert guidewire
at ACT value of 200
sec or higher.
Rinse dialyzer with
5,000–20,000 units
and flush with 0.5–2
L saline.
hypothermia may
slow down the
clotting cascade.
Goals may be
different with
hypothermia during
surgery versus postcardiac arrest.
Purge solution of dextrose
20% and heparin 50 units/mL
is used to locally keep device
from clotting. Adjustments
in purge rate part of device
programming. Higher purge
rates may increase the heparin
delivered and affect concurrent
systemic heparin therapy
requirements.
System infusion rate will need
to account for heparin given
both IV and through the purge
solution.
Lower heparin concentrations
within the purge (12.5 units/
mL or 25 units/mL) can be
employed if aPTT values are
above desired range.
For Impella RP for the
right side of the heart,
a separate approach to
heparinization has been
suggested. See manufacturers’
recommendations. aPTT goals
may not have been assessed
and adjusted for different
reagent sensitivities to heparin.
Rinse dialyzer intermittently with
saline (target blood flow ≥250
mL/min).
In general, protocols or
guidelines for dosing heparin
during hypothermia may
require an adjustment to lower
doses (e.g., ~50% reduction)
depending on the clinical
situation and temperature
goals. The dose may need to
subsequently increase as the
patient is being warmed.
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TABLE 3-8: Weight Considerations for UFH Dosing in Obesity
Source Observation
18
22
23
8
19
anti-factor
21
See Table 3-4 (actual body weight [ABW] used)
ABW more likely to get aPTT in range by 24 hr
Median infusion rate: 13 units/kg/hr
Morbidly obese: potential for severe overdose at 18 units/kg/hr
Max bolus: 10,000 units; Max infusion: 1,500 units/hr
Max weight: 184 kg (this patient therapeutic at 1,700 units/hr)
Loading dose (units): 450 × estimated blood volume (liters)
Initial infusion (units/hr): 344.335 + estimated blood volume
(liters) × 257.962 – (age in years × 4.951)
Estimated blood volume: (liters)
Males: (0.3669 × height m
Females: (0.3561 × height m
3
) + (0.03219 × wt kg) + 0.6041
3
) + (0.03308 × wt kg) + 0.1833
Weight: median 77 kg (range 30 – 184 kg)
Literature review and case report in a 388-kg patient suggests a
dosing weight of IBW + 0.4 [ABW – IBW]
For aPTT similar to anti-factor Xa activity 0.3–0.7 units/mL
BMI ≥40 kg/m
BMI 25–39.9 kg/m
2
: 11.5 units/kg/hr (mean wt 141 ± 32 kg)
2
: 12.5 units/kg/hr (mean wt 89 ± 16 kg)
Normal: 13.5 units/kg/hr (mean wt 62 ± 11 kg)
aPTT targets were achieved faster with heparin infusions based
on adjusted body weight over actual body weight. Use of actual
body weight dosing was associated with higher bleeding rates.
3
: cubic meters, UFH: unfractionated heparin, wt: weight, x: times
Raschke R et al.
Yee W et al.
Rosborough TK
Xa activity monitoring
Myzienski AE et al.
Riney JN et al.
Fan J et al.
ABW: actual (total) body weight, aPTT: activated partial thromboplastin time, hr: hours, IBW: ideal
body weight, kg: kilograms, m
•
The amount of heparin required to maintain a hemodialysis circuit is variable
depending on the approach (e.g., intermittent, extended duration, continuous),
the properties of the dialysis circuit, and the patient.
•
Some hemodialysis machines are programmed to use preselected heparin
concentrations (i.e., 1,000 units/mL) for continuous infusions.
•
Heparin requirements may be lower in extended daily dialysis (~650 units/
hr) compared to continuous renal replacement therapy (approximately 1,100
units/hr).
•
Fewer patients on extended duration dialysis may require heparin compared to
continuous renal replacement therapy (CRRT).
•
Consider using total body weight with a preselected maximum infusion rate cap
(i.e., 2,000 units/hr) that subsequently triggers an additional assessment to limit
unintended excessive dosing.
48 Anticoagulation Therapy
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• Because obesity is a risk factor for VTE, it is
•
As the patient’s weight increases, the amount of heparin
aPTT and anti-factor Xa assay monitor may not
•
important to achieve adequate anticoagulation as
soon as possible. The volume of distribution for
heparin correlates to blood volume and thus creates
a risk for overshooting targets in the very obese
patient (BMI ≥40 kg/m
2
or >200 kg) if weightbased dosing is not capped or adjusted accordingly.
Dosing caps can be considered to reduce the risk of
excessive anticoagulation; however, aPTT (or antifactor Xa activity) should be carefully measured
and infusions promptly adjusted to achieve targets
as soon as possible in the setting of an acute
thromboembolic event. Table 3-8 provides insights
on how to approach heparin dosing in this setting.
required on a unit/kg per body weight may decline.
correlate in obesity.
MONITORING AND DOSING ADJUSTMENTS
Clinical Challenge—Transitioning from an Oral Anti-Xa
Agent to Heparin Infusion
Presence of an oral anti-Xa agent (e.g., apixaban, rivaroxaban, edoxaban,
betrixaban) in the system can elevate the heparin calibrated anti-Xa values. It is
unclear if the total anti-Xa activity with the combined agents provides the same
degree of anticoagulation as each agent individually and carries the potential
for initially under-dosing or down titration of unfractionated heparin in the
first few days of therapy, or at least the need to titrate up the heparin infusion
as the oral agents’ effects wear off. The effects of the oral agents, including
shorter acting apixaban, may last for over 48 hours from the last dose, with
the occasional rare case of longer effects if a long-acting agent, high levels,
or a notable reduction in clearance is present. Consider adding both aPTT
and anti-Xa activity as baseline laboratory assessments prior to starting the
heparin infusion. One option may be manage with the aPTT until the DOAC
effects have dissipated. Presence of a high baseline aPTT and INR may suggest
excessive DOAC effects present. In high thrombosis risk situations (e.g., new
STEMI and post thrombolysis), the risk of bleeding and recurrent thrombosis
should be evaluated. Should heparin be continued (e.g., 2–3 days post lytic)
when an oral anti-Xa agent had recently been administered, anti-Xa values
may be elevated and drive either holding or lowering heparin infusion rate.
Consider using the aPTT to manage the heparin infusion and capping how low
the infusion rate may go and assess for thrombosis or bleeding.
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TABLE 3-9: Laboratory Tests Used in the Monitoring of UFH*
Test Monitoring Considerations
aPTT Target range will vary between assays depending on the lot of each reagent
Anti-factor Xa
activity
Low response
ACT
High response
ACT
Protamine
titration
*See Appendix L: Considerations for Transitioning from aPTT to Anti-Xa to Manage Heparin
Therapy.
ACT: activated thrombin time, aPTT: activated partial thromboplastin time, PCI: percutaneous
coronary intervention, UFH: unfractionated heparin, VTE: venous thromboembolism
used; the aPTT is typically used for lower intensity of heparin anticoagulation
effects such as prophylaxis to VTE treatment; this assay can identify presence
of diminished response to UFH if antithrombin deficiency is present.
aPTT values obtained via central venous access devices may yield higher
values than by venipuncture.
As with the aPTT, anti-factor Xa activity calibrated to heparin is an alternative
assay for measuring lower intensity of heparin anticoagulation effects such as
prophylaxis to VTE treatment; this assay can identify presence of diminished
response to UFH if high factor VIII concentrations are present.
Anti-factor Xa assays may or may not add antithrombin into the process and
potentially yield different results. (See Table 3-10)
Typically used in cardiac interventional procedures such as PCI; measures the
intermediate range of heparin anticoagulation; ACT values may vary between
tests. (Hemochron values yield higher results than MedTronic values in the
upper part of the ACT range.)
Used during high ranges of heparinization such as during cardiopulmonary
bypass; may not detect presence of heparin at concentrations used to treat
VTE.
a
See Chapter 21
a
• Target ACT ranges may depend on the device,
specific test, and if a high or low range card
is used. Different tests (e.g., Hemochron,
MedTronic, HemoTec) and card ranges (high vs.
low) will give notably different values. The ACT
range established for each test specifically should
be used instead of a standard range. See Table
3-9.
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