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Use of a Fixed Activated Partial Thromboplastin Time Ratio to Establish a Therapeutic Range for Unfractionated Heparin
Shannon M. Bates, MDCM;
Jeffrey I. Weitz, MD;
Marilyn Johnston, ART;
Jack Hirsh, MD;
Jeffrey S. Ginsberg, MD
Arch Intern Med. 2001;161:385-391.
ABSTRACT
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Background The commonly recommended therapeutic range for patients receiving unfractionated
heparin of 1.5 to 2.5 times the control activated partial thromboplastin time
(aPTT) is not universally applicable. It has been suggested that the therapeutic
range for each aPTT reagent should be based on plasma heparin levels. We sought
to identify an aPTT ratio that corresponds to therapeutic anti–factor
Xa heparin levels for combinations of several reagents and coagulometers that
are commonly used.
Methods Citrated plasma was collected from 126 unselected patients receiving
unfractionated heparin. Four automated coagulometers and 6 commercial aPTT
reagents were used to measure the aPTT. Plasma anti–factor Xa levels
were measured by means of a commercially available assay. The relationship
between the aPTT results and anti–factor Xa heparin levels for each
reagent-coagulometer combination was determined by linear regression analysis,
and the aPTT results corresponding to therapeutic anti–factor Xa heparin
levels were calculated.
Results For all reagent-coagulometer combinations studied, an aPTT ratio of
1.5 resulted in anti–factor Xa heparin levels considerably below the
lower limit of the therapeutic range. When the aPTT was performed on any of
the coagulometers assessed with the use of Actin (Dade Diagnostics, Aguada,
Puerto Rico) and IL Test (Instrumentation Laboratories, Fisher Scientific,
Unionville, Ontario) reagents, aPTT ratios necessary to achieve therapeutic
anti–factor Xa heparin levels approximated 2.0 to 3.5.
Conclusion For laboratories that cannot perform heparin levels, the use of less
responsive reagents and any of the coagulometers studied, along with target
aPTT ratio between 2.0 and 3.5, appears to be a reasonable alternative.
INTRODUCTION
ALTHOUGH THE use of low-molecular-weight heparin is increasing, unfractionated
heparin is still widely used to treat venous and arterial thromboembolic disorders.
Because the anticoagulant response to unfractionated heparin varies among
patients1, 2, 3, 4
and its efficacy and safety are thought to be optimal when a target therapeutic
range is achieved,5, 6, 7, 8
laboratory monitoring with dose adjustment is necessary to ensure that an
appropriate level of anticoagulation is given. The activated partial thromboplastin
time (aPTT), a clotting assay that reflects the ability of the heparin-antithrombin
complex to inactivate thrombin, factor Xa, and other coagulation enzymes within
the intrinsic pathway, is the most widely used laboratory test for monitoring
heparin therapy9 because it is widely available,
rapid, easily automated, simple to perform, and relatively inexpensive.
There are, however, several problems associated with the use of the
aPTT to monitor heparin therapy. No aPTT standard exists. Most medical textbooks
and many experts recommend a therapeutic range of 1.5 to 2.5 times the control
value (the mean aPTT obtained by testing a minimum of 20 plasma samples from
healthy persons).8, 10 This recommendation
is based largely on 2 studies. In the first, a prospective cohort study by
Basu and colleagues,8 patients with recurrent
thromboembolism during heparin treatment were more likely to have an aPTT
less than 1.5 times the control value than those without recurrence. The second
study demonstrated that a heparin level range of 0.2 to 0.4 U/mL, as measured
by protamine sulfate titration, was most effective at inhibiting thrombus
growth in an animal model.11 A level of less
than 0.15 U/mL was associated with increased fibrinogen accretion, whereas
a heparin level of greater than 0.5 U/mL was associated with an increased
risk of bleeding.11 This range of heparin level
based on protamine sulfate titration corresponded to an aPTT range of 1.5
to 2.5 times control for the reagent used at that time.8
However, the responsiveness of different commercial aPTT reagents and different
lots of the same reagent is variable,9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
and an aPTT ratio of 1.5 to 2.5 times control is not likely to be universally
applicable.
The potential to inappropriately dose patients with heparin is a consequence
of this variability in responsiveness to heparin. Two strategies have the
potential to solve the problem of variability in therapeutic aPTT ranges for
different aPTT reagents and coagulometers. The first is to abandon the aPTT
and routinely monitor heparin therapy by protamine sulfate titration (therapeutic
range, 0.2-0.4 U/mL)11 or by chromogenic anti–factor
Xa assay (therapeutic range, 0.3-0.7 U/mL).10
Neither method is practical on a routine basis because both are expensive
and many laboratories are not equipped to perform them regularly. The second
solution is to continue using the aPTT, but to establish an accurate therapeutic
range for each reagent and each coagulometer by performing aPTT and heparin
level measurements by anti–factor Xa or protamine sulfate titration
on the plasma of at least 30 heparin-treated patients and, by linear regression,
calculating the aPTT range that corresponds to the heparin level therapeutic
range.15 This, however, is onerous and does
not obviate the need to measure heparin levels. Therefore, to optimize the
monitoring of heparin therapy, a simple means of determining the aPTT therapeutic
range is critically needed.
The purpose of this study was to simplify heparin monitoring. To accomplish
this, citrated plasma was collected from patients receiving unfractionated
heparin and the aPTT was measured by means of commonly used aPTT reagents
and coagulometers. Concomitant anti–factor Xa heparin levels were also
determined so that, for each aPTT reagent–coagulometer combination,
the aPTT values that resulted in therapeutic anti–factor Xa heparin
levels, as well as anti–factor Xa heparin levels corresponding to an
aPTT ratio of 1.5 to 2.5, could be identified. Using this information, we
sought to identify whether the use of certain reagent-coagulometer combinations
would yield a single fixed aPTT ratio that closely approximates the therapeutic
range as established by anti–factor Xa level measurement.
PATIENTS AND METHODS
PATIENTS
Plasma samples were collected from 126 unselected patients at 3 hospitals.
Patients were receiving unfractionated heparin for the treatment of either
venous thromboembolic disease or acute coronary syndromes or for the prevention
of thromboembolism in the setting of atrial fibrillation. None of the patients
was receiving warfarin at the time of blood sampling. Samples for the determination
of control values were obtained from healthy volunteers without known coagulation
abnormalities who were not receiving anticoagulants.
PROCEDURES
Venous blood samples were collected in 5-mL specimen tubes (BD Vacutainers;
Becton Dickinson Co, Mountain View, Calif) prefilled with 0.5 mL of 3.2% (0.105-mol/L)
buffered sodium citrate. After sedimentation of the red blood cells by centrifugation
at 1700g for 15 minutes at 4°C, the harvested
plasma was subjected to a second centrifugation under the same conditions
to ensure complete removal of platelets. Aliquots of platelet-poor plasma
were then pipetted into polystyrene tubes that were maintained at -70°C
until assayed. Four automated coagulation instruments (MLA-700 [Medical Laboratory
Instrumentation, Pleasantvillle, NY], ACL 3000 [Fisher Scientific, Unionville,
Ontario], MDA-180 [Organon Teknika, Durham NC], and STA Compact [Diagnostica
Stago, Asnières, France]) were used for aPTT determinations performed
according to each manufacturer's specifications. Six commercial aPTT reagents
were used (Table 1). Plasma anti–factor
Xa heparin levels were measured by the method of Teien and Lie22
with the use of the ACL 3000 instrument and a commercially available assay
(Stachrom Heparin; Diagnostica Stago). The therapeutic range for unfractionated
heparin with this assay is 0.3 to 0.7 U/mL.10, 23
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Table 1. Properties of Activated Partial Thromboplastin Time Reagents
Used
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ANALYSIS
For each reagent and coagulometer combination, control values were determined
by calculating the mean aPTT results for plasma samples obtained from a minimum
of 20 control subjects. The normal range, corresponding to the control value
± 2 SDs, was calculated for each reagent-coagulometer combination.
The relationship between the aPTT results and ex vivo anti–factor
Xa heparin levels (both derived from aliquots of the same plasma sample) for
each reagent-coagulometer combination was determined by linear regression
analysis. The aPTT results corresponding to anti–factor Xa heparin levels
of 0.3 to 0.7 U/mL were calculated from the ordinate values for the points
on the regression line corresponding to these 2 heparin levels. By dividing
these aPTT results by the reagent's mean control value on that coagulometer,
corresponding aPTT ratios were calculated. The anti–factor Xa heparin
levels corresponding to aPTT ratios of 1.5 to 2.5 were calculated from the
abscissa values for the points on the regression line at these aPTT values.
The Pearson correlation coefficient (r) was used
to assess the extent of linear correlation between the aPTT and anti–factor
Xa heparin level.
RESULTS
Figure 1 shows an example
of a regression line. The y-intercept, slope, and Pearson correlation coefficient
(r) for each regression line are listed in Table 2. The correlation between anti–factor
Xa heparin levels and the aPTT was good (r = 0.64
to 0.95). However, the assumed linear relationship between anti–factor
Xa heparin levels and the aPTT did not always hold true, and, as a consequence,
the y-intercept on occasion differs from the control value. The control values
and normal ranges for each reagent-coagulometer combination are shown in Table 3. The control aPTT values are similar
regardless of the reagent or instrument used.
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Figure 1. Regression line for Thrombosil
I on ACL 3000 coagulometer. The activated partial thromboplastin time (aPTT)
therapeutic range is determined by the points (dashed lines) on the regression
line (solid line) that correspond to anti–factor Xa heparin levels of
0.3 to 0.7 U/mL. See the "Procedures" subsection of the "Patients and Methods"
section and Table 1 for manufacturers
of reagents and coagulometers.
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Table 2. Characteristics of Regression Lines for Reagent-Coagulometer
Combinations Assessed
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Table 3. Activated Partial Thromboplastin Time Control Values and Normal
Ranges
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aPTT RATIOS NECESSARY TO ACHIEVE THERAPEUTIC ANTI–FACTOR Xa HEPARIN
LEVELS
Table 4 shows the aPTT ratios
corresponding to anti–factor Xa heparin levels of 0.3 to 0.7 U/mL for
each reagent-coagulometer combination. The results obtained on the STA-Compact
coagulometer with a second lot of Thrombosil I (lot ITH237) were nearly identical
to those for lot ITH250 (data not shown). The 6 reagents differed in terms
of heparin responsiveness, with Actin, IL Test, and Thrombosil I appearing
less responsive than Actin FSL, Actin FS, and Pathromtin, in terms of the
aPTT ratio necessary to attain a therapeutic anti–factor Xa heparin
level. The variation in aPTT ratios necessary to achieve anti–factor
Xa heparin levels of 0.3 to 0.7 U/mL appeared to be greater when different
reagents were used on the same coagulometer, than when the same reagent was
used with a different coagulometer (Figure
2 and Figure 3). When
the aPTT was performed on any of the 4 coagulometers with the use of Actin
or IL Test, aPTT ratios necessary to achieve therapeutic anti–factor
Xa heparin levels approximated 2.0 to 3.5 (Figure 2 and Figure 3). The aPTT ratios corresponding to therapeutic anti–factor Xa heparin
levels were higher for Actin FSL, Actin FS, and Pathromtin SL on all of the
coagulometers.
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Table 4. Comparison of Therapeutic aPTT Ranges for Various aPTT Reagents*
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Figure 2. Activated partial thromboplastin
time (aPTT) ratios corresponding to therapeutic anti–factor Xa heparin
levels of 0.3 to 0.7 U/mL for various reagents on different coagulometers.
See the "Procedures" subsection of the "Patients and Methods" section and Table 1 and Table 2 for manufacturers of reagents and coagulometers, respectively.
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Figure 3. Activated partial thromboplastin
time (aPTT) ratios corresponding to therapeutic anti–factor Xa heparin
levels of 0.3 to 0.7 U/mL for various reagents on each of the 4 coagulometers
used. See the "Procedures" subsection of the "Patients and Methods" section
and Table 1 and Table 2 for manufacturers of reagents and coagulometers, respectively.
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ANTI–FACTOR Xa LEVELS ACHIEVED WITH aPTT RATIOS OF 1.5 TO 2.5
Table 5 shows anti–factor
Xa heparin levels corresponding to aPTT ratios of 1.5 to 2.5 for the various
reagent-coagulometer combinations. Again, the results obtained on the STA
Compact coagulometer with a second lot of Thrombosil I (lot ITH237) were nearly
identical to those for lot ITH250 (data not shown). With aPTT ratios of 1.5
to 2.5, the therapeutic range used by many laboratories, variable anti–factor
Xa heparin levels were achieved. The variation in ex vivo anti–factor
Xa heparin levels achieved with a ratio of 1.5 to 2.5 appeared to be greater
when different reagents were used on the same coagulometer, than when the
same reagent was used with a different coagulometer (Table 5). For all reagent-coagulometer combinations, an aPTT ratio
of 1.5 corresponded to anti–factor Xa heparin levels considerably below
the targeted lower limit of 0.3 U/mL.
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Table 5. Anti–Factor Xa Heparin Levels Attained With aPTT Range
of 1.5 to 2.5 s*
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COMMENT
Our results suggest that, with currently available reagents and coagulometers,
the aPTT ratio that corresponds to an anti–factor Xa heparin level of
0.3 to 0.7 U/mL is highly variable. As such, the common practice of recommending
a single "therapeutic" aPTT ratio provides no assurance that target anti–factor
Xa heparin levels will be achieved. This study also confirms the observation
made by Brill-Edwards et al15 that a therapeutic
range with a lower limit set by an aPTT ratio of 1.5 consistently results
in subtherapeutic heparin levels. In addition, our data demonstrate that this
observation holds true regardless of the coagulometer used.
The previously offered solution of establishing a therapeutic range
for aPTT results for each reagent with the use of anti–factor Xa or
protamine sulfate titration heparin levels as a reference standard15 is impractical for most individual laboratories,
as they are not equipped to perform these assays and do not have access to
plasma samples from at least 30 heparin-treated patients. Ideally, manufacturers
should provide a therapeutic range based on anti–factor Xa or protamine
sulfate titration heparin levels for their reagent with commonly used coagulometers,
much the same way as International Sensitivity Indexes are provided for thromboplastin
reagents. Failing that, central reference laboratories with access to patient
plasma could provide individual laboratories with therapeutic ranges based
on their reagent-coagulometer combination. Third, laboratories could choose
to use less heparin-responsive reagents, such as Actin or IL Test. With these
reagents, an aPTT ratio of 2.0 to 3.5 appears to encompass therapeutic anti–factor
Xa heparin levels with the use of several coagulometers. The use of this aPTT
ratio with more responsive reagents would be expected to result in subtherapeutic
anti–factor Xa heparin levels, and for these reagents the therapeutic
range would need to be established by means of ex vivo anti–factor Xa
heparin levels from heparinized patients as a reference standard.
Previous work has indicated that the sensitivity of an aPTT reagent
to heparin depends both on its phospholipid content and on the nature of the
activator present.19, 24, 25
The concentration of total phospholipid in the aPTT reagent is known to govern
the sensitivity of the assay to the presence of nonspecific inhibitors.26, 27, 28 In general, the less
heparin-responsive reagents for which an aPTT ratio of 2.0 to 3.5 encompasses
therapeutic anti–factor Xa heparin levels are relatively insensitive
to lupus anticoagulants. Consequently, laboratories that use one of these
reagents may need to use a different reagent for heparin monitoring than that
used for lupus anticoagulant screening.
This study has limitations. Data supporting the clinical relevance of
a therapeutic range for heparin therapy based on either protamine sulfate
titration or anti–factor Xa heparin levels are based on only a very
small number of animal and clinical studies.8, 11, 29
Most of these studies have used heparin levels from protamine sulfate titration 8, 11; not all authors have found anti–factor
Xa heparin levels of 0.3 to 0.7 U/mL to be equivalent to protamine sulfate
titration levels of 0.2 to 0.4 U/mL.18 However,
in a randomized controlled trial, the incidences of recurrent thrombosis and
bleeding were not significantly higher in patients whose dose of heparin was
adjusted to maintain an anti–factor Xa heparin level of 0.3 to 0.7 U/mL
than they were in those whose heparin dose was adjusted to maintain an aPTT
equivalent to a protamine sulfate titration heparin level of 0.2 to 0.4 U/mL,29 suggesting that these 2 ranges are equivalent. Variability
in heparin responsiveness among different lots of the same aPTT reagent is
well documented.9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
However, unless major differences exist among the lots, this variability is
unlikely to have a major impact on our findings. In support of this statement,
no difference was seen between the 2 lots of Thrombosil I tested. Given the
small number of reagents used in this study, it is not possible to state with
certainty that all lupus anticoagulant–insensitive reagents will have
the same responsiveness to heparin. Only 6 aPTT reagents were studied, and
it is possible that those selected may not be representative of all reagents.
Those chosen are, however, widely used.
Differences in the heparin responsiveness of aPTT reagents increase
the difficulty and expense of determining the therapeutic range for heparin
therapy. Therapeutic ranges for various aPTT reagent–coagulometer combinations
could be provided by reagent manufacturers or central reference laboratories.
Alternatively, the use of less heparin-responsive reagents, such as Actin
and IL Test, and a therapeutic range corresponding to 2.0 to 3.5 times the
control aPTT value might simplify the procedure in institutions that cannot
measure anti–factor Xa or protamine sulfate titration heparin levels
or in those where access to plasma samples from patients treated with heparin
is limited.
AUTHOR INFORMATION
Accepted for publication September 21, 2000.
Dr Bates is a recipient of a Research Fellowship from the Heart and
Stroke Foundation of Ontario, Toronto. Drs Weitz and Ginsberg are recipients
of Career Investigator Awards from the Heart and Stroke Foundation of Ontario,
Ottawa. This work was supported in part by the Thrombosis Interest Group,
Mississauga, Ontario.
We thank Patrick Brill-Edwards, MD, and Jim Julian, PhD, for helpful
comments and suggestions.
From the Department of Medicine, McMaster University (Drs Bates, Weitz,
Hirsh, and Ginsberg), and Hamilton Civic Hospitals Research Centre (Drs Weitz,
Hirsh, and Ginsberg and Ms Johnston), Hamilton, Ontario.
Corresponding author and reprints: Shannon M. Bates, MDCM, Thromboembolism
Unit, HSC 3W15, McMaster University Medical Centre, 1200 Main St W, Hamilton,
Ontario, Canada L8N 3Z5 (e-mail: batesm{at}mcmaster.ca).
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