Heparin Sensitivity and Resistance:

Management During
Cardiopulmonary Bypass
Alan Finley, MD
Department of Anesthesia and Perioperative Medicine
Medical University of South Carolina
Charleston, South Carolina

the CPB circuit. Heparin has long been the agent of choice
Learning Objectives:
to achieve anticoagulation during bypass surgery. Despite
As a result of completing this activity, the participant
the many advantages of heparin, there remains a concern
will be able to
about the significant variability in its anticoagulant effect
 Define heparin resistance
across patients. When the responsiveness of the anti-
 Discuss the limitations of anticoagulation with
coagulant effect is decreased, the patient is determined to
heparin
be heparin resistant. Unfortunately, there is no universal
 Explain the basics of the activated clotting time
definition of heparin resistance in the literature. Broadly,
and heparin dose response
heparin resistance can be defined as the inability of an
 Explain the various mechanisms of heparin resis-
adequate heparin dose to increase the activated clotting
tance
time (ACT) to the desired level. Alternatively, heparin
 Describe the various treatment options for heparin
resistance can be defined as a decrease in the heparin dose
resistance
response. Depending upon the specific ACT target and
Author Disclosure Information: heparin dose chosen, the incidence of heparin resistance
Dr. Finley has disclosed that he has no financial has been reported to range from 4 to 26% (Supplemental
interests in or significant relationship with any Digital Content 1, http://links.lww.com/ASA/A514).1
commercial companies pertaining to this educational Much of the concern about heparin resistance revolves
activity. around the fact that the minimum ACT to abolish coagu-
lation activation is not known. This is demonstrated by the
wide variability of target ACTs used in clinical practice.2
f utmost importance to successfully placing a patient

O on cardiopulmonary bypass (CPB) is maintaining

the fluidity of blood after it comes in contact with
Because the minimum ACT remains unknown, physicians
have empirically chosen a target ACT much higher than
the theoretical minimum to maintain a margin of safety. At
worst, insufficient anticoagulation will result in the devel-
opment of catastrophic thrombosis in the CPB circuit or
Supplemental Digital Content is available for this article. Direct URL the patient’s end organs. At best, inadequate anti-
citations appear in the printed text and are available in both the HTML coagulation will result in coagulation activation, con-
and PDF versions of this article. Links to the digital files are provided in
the HTML and PDF text of this article on the Journal’s Web site
sumption of coagulation factors, and the development of a
(www.asa-refresher.com). consumptive coagulopathy. Because of these concerns,

58
Copyright r 2015 American Society of Anesthesiologists. All rights reserved.
Heparin Sensitivity and Resistance 59

clinicians often choose interventions with the goal of

improving anticoagulation when the target ACT is not
achieved.

Much of the concern about heparin resistance

revolves around the fact that the minimum
ACT to abolish coagulation activation is not
known.

HEPARIN
Unfractionated heparin has long been used as the anti-
Figure 1. In addition to binding with antithrombin (AT) to facilitate its
coagulant of choice for cardiac surgery because it is effec- anticoagulant effects on factors IIa and Xa, circulating heparin binds to
tive, easy to use, inexpensive, and easily reversed with many substances in the blood including endothelial cells, macrophages,
protamine. Heparin’s primary mechanism of action involves and various heparin-binding proteins. From Finley A, Greenberg C: Heparin
sensitivity and resistance: management during cardiopulmonary bypass.
catalyzing the anticoagulant effects of antithrombin (AT). Anesth Analg 2013; 116(6):1210–22.1 Reused with permission.
AT is a naturally occurring substance known to inhibit fac-
tors in the contact activation pathway, which include achieved after administration. If these substances are ele-
thrombin (factor IIa) and factor Xa. The presence of heparin vated, their interactions with heparin may result in lower
has been reported to accelerate AT inhibition of thrombin than expected heparin concentrations and a decrease in
by 4,000-fold and factor Xa by 1,200-fold.3 Heparin also heparin responsiveness. Heparin metabolism occurs by
has an AT-independent mechanism of action mediated both a rapid saturable and a slower nonsaturable mecha-
through heparin cofactor II.4 When heparin concentrations nism. Rapid metabolism results when endothelial cells and
exceed 1.0 U/mL, molecules greater than 24 saccharide macrophages internalize and metabolize the heparin mol-
units interact with heparin cofactor II in a charge-dependent ecules. Renal elimination is responsible for the slower
manner to inactivate thrombin.4 The clinical relevance of nonsaturable clearance. These two mechanisms result in
this mechanism during cardiac surgery is unclear. heparin having an elimination half-life that is dose de-
Although heparin is the mainstay of anticoagulation pendent. The half-lives of heparin after 25, 100, and
during cardiac surgery, the variability in its anticoagulant 400 U/kg are approximately 30, 60, and 150 minutes, re-
effect continues to be a concern. The variability in response spectively.8–10
can be partially explained by the heterogeneity of heparin. Because of this variability, the United States Pharmaco-
Heparin is purified from either bovine or porcine sources peia has standards in place to ensure that the variability in
and consists of multiple chain lengths with molecular potency is only 710%. Before 2008, the United States
weights varying between 5,000 and 30,000 Da (mean, Pharmacopeia standards were not equivalent to the World
15,000 Da).5 In addition, heparin’s interaction with AT Health Organization standard for heparin potency. This
requires a critical pentasaccharide sequence that is only discrepancy resulted in the heparin available in the United
present on approximately one third of heparin molecules. States having a potency approximately 10% greater than
Although heparin molecules lacking this sequence are un- in the remainder of the world. Since 2008, the United
able to interact with AT, they can still contribute to acute States Pharmacopeia and World Health Organization
hypersensitivity reactions and the development of heparin- standardization processes are similar, resulting in a de-
induced thrombocytopenia.6 Finally, the heparin molecule crease in the potency of heparin available in the United
must be at least 18 saccharides in length to interact with States. This conversion has potentially resulted in an in-
both AT and thrombin to form the AT/thrombin/heparin crease in the incidence of heparin resistance.11
ternary complex.7 Heparin molecules with chain lengths
less than 18 saccharides (i.e., low-molecular-weight hep-
arin) can still inhibit factor Xa if the critical penta-
saccharide sequence is present.
ANTICOAGULATION MONITORING
In addition to the pharmacological reasons, the varia- Because of the large variability in the anticoagulant effect
bility in response is also related to biological factors. After achieved with heparin, monitoring is routinely performed
administration, heparin immediately interacts with many to ensure that therapeutic anticoagulation has been
substances other than AT (Figure 1). These include hep- achieved. The most common method for monitoring
arin-binding proteins, endothelial cells, and macrophages, heparin’s anticoagulant effect during cardiac surgery is the
and can have a direct impact on the heparin concentration ACT. The ACT was adopted in cardiac surgery because it is

Copyright r 2015 American Society of Anesthesiologists. All rights reserved.

60 Finley

easy to use as a point-of-care test and, unlike the activated

partial thromboplastin time, retains the ability to induce
clot formation at the high concentrations of heparin
achieved during cardiac surgery. However, the ACT is a
rather crude test that is not specific to heparin’s anti-
coagulant effect on thrombin.
The ACT involves combining a sample of the patient’s
whole blood with a contact activator (i.e., kaolin or Cel-
ite), warming the sample, and measuring the time elapsed
until a measurable fibrin clot is detected (Figure 2). The
addition of a contact activator mimics the negatively
charged CPB circuit and initiates the intrinsic coagulation
system. As demonstrated in Figure 2, multiple steps sub-
sequently occur before a fibrin clot is formed. Thus, any-
thing affecting a step in the intrinsic coagulation system
will alter the result of the ACT. Unfortunately, many of
these factors are commonly seen during cardiac surgery
and should be kept in mind when considering the anti- Figure 2. The activated clotting time is initiated by adding a contact
coagulation management of a patient (Table 1; Supple- activator, which triggers the intrinsic coagulation pathway. Multiple steps
follow in the time elapsed from initiation to when a fibrin clot is measured.
mental Digital Content 2, http://links.lww.com/ASA/ From Finley A, Greenberg C: Heparin sensitivity and resistance: manage-
A515). Furthermore, many different ACT machines are ment during cardiopulmonary bypass. Anesth Analg 2013; 116(6):
utilized in clinical practice. They can vary in the amount of 1210–22.1 Reused with permission.
whole blood used, the activator (kaolin vs. Celite), tem-
perature, and the method used to detect the presence of a calculated heparin sensitivity and lack of accuracy in esti-
fibrin clot. These differences in testing methodology result mating the patient’s blood volume. In addition, the heparin
in variability in the measured ACTs and do not allow the dose/response curve assumes a linear relationship, which is
tests to be completely interchangeable.12 not the case.14

The ACT is a rather crude test that is not

specific to heparin’s anticoagulant effect on Table 1. Factors Affecting the Activated Clotting
Time
thrombin. Hypothermia
Hemodilution
An alternative method for monitoring heparin’s anti- Medications
coagulant effect is the heparin dose/response curve. This Heparin
curve attempts to quantify the heparin responsiveness of
Warfarin
each individual patient. To plot a heparin dose/response
Aprotinin (Celite more likely than kaolin)
curve, two ACTs need to be performed: a baseline ACT
with no heparin present and an additional ACT after a Platelet inhibitors (therapeutic medications such as cyclooxygenase
inhibitors, IIb/IIIa or ADP inhibitors, or antiplatelet antibodies)
known heparin concentration has been added to an in vitro
Direct thrombin inhibitors (e.g., hirudin derivatives, argatroban)
blood sample (Figure 3). A curve can then be plotted, and
the slope of the curve can be calculated by the equation: Protamine
Thrombocytopenia or thrombocytosis
ðACT after heparinbaseline ACTÞ Factor deficiencies (any contact or common pathway coagulation
Heparin sensitivity ¼
Heparin concentration factor)
Contact factors (factor XII/factor XI, kallekrein) or intrinsic (factor VIII)
Using this curve, the required heparin loading dose can Antithrombin III
be extrapolated. Alternatively, the heparin sensitivity in-
Common pathway (factor V, II)
dex can be calculated following an in vivo heparin bolus by
Fibrinogen
substituting the heparin loading dose for the heparin con-
centration in the above equation. Disease states: anticardiolipin/antiphospholipid antibodies
Although the dose/response curve is an attempt to ADP ¼ adenosine diphosphate.
From Finley A, Greenberg C: Heparin sensitivity and resistance: management
overcome some of the individual variability in heparin re- during cardiopulmonary bypass. Anesth Analg 2013; 116(6):1210–22.1 Reused
sponsiveness, it fails to predict the heparin concentration with permission.

after the loading dose.13 This is likely explained by the

absence of some heparin-binding proteins in the in vitro

Copyright r 2015 American Society of Anesthesiologists. All rights reserved.

Heparin Sensitivity and Resistance 61

might be improved with higher levels of anticoagulation,

minimal evidence exists to prove this notion.

MECHANISM

Antithrombin-dependent Mechanism
Traditionally, heparin resistance has been attributed to AT
deficiency. This seems logical given that heparin exerts its
anticoagulant effect indirectly through AT, and thus a de-
ficiency of AT would diminish heparin’s anticoagulant ef-
fect. AT deficiency can be either congenital or acquired. In
the cardiac surgical population, an acquired AT deficiency
would be much more common. Examples of causes of
acquired AT deficiency include liver failure (reduced
Figure 3. Heparin dose/response curve. ACT ¼ activated clotting time;
C ¼ concentration. From Finley A, Greenberg C: Heparin sensitivity and synthesis), nephropathy (renal losses), an upregulated
resistance: management during cardiopulmonary bypass. Anesth Analg hemostatic system (accelerated consumption), and mechan-
2013; 116(6):1210–22.1 Reused with permission. ical assist devices (accelerated consumption).1 AT concen-
trations can be assessed with either an antigen or a
functional assay and are reported as a percentage (normal,
80 to 120%). Between the two, the functional assay is pre-
MINIMUM ACTIVATED CLOTTING TIME ferred as it will detect abnormalities in both function and
quantity of the AT present.
Despite decades of using the ACT to monitor anti- In vitro evidence has confirmed that an AT concentration
coagulation during CPB, the minimum ACT remains less than 80% will result in decreased heparin responsive-
unclear. Conceptually, the minimum ACT reflects an anti- ness.20 In vivo evidence confirms that an AT concentration
coagulation level required to prevent coagulation from less than 80% does in fact result in a higher incidence of
occurring during CPB. Bull et al.15 reported a minimum heparin resistance.21,22 If AT were the predominant deter-
ACT of 300 seconds on the basis of the absence of visual- minant of heparin responsiveness, one would expect the
izing thrombus in the CPB circuit; they did not, however, correlation between AT concentrations and heparin sensi-
determine the ACT that minimizes coagulation activation tivity to be high. However, Garvin et al.23 demonstrated a
and will prevent the development of a consumptive co- low correlation, even in patients with an AT concentration
agulopathy.16 More recent literature evaluating the less than 80%. In addition, not all heparin-resistant patients
adequacy of anticoagulation has focused on assessing who receive AT concentrate show an increase in heparin
markers of hemostatic activation while on CPB, and has responsiveness.24 Thus, there must also be a non-AT-
shown that even with high doses of heparin, hemostatic dependent mechanism for heparin resistance.
activation is not abolished with ACTs greater than 400
seconds.17,18 Thus, the optimal ACT can be defined as the
Heparin Pretreatment
anticoagulation level at which hemostatic activation is
Heparin pretreatment is a specific cause of acquired AT
minimized.
deficiency that deserves special consideration, as many
cardiac surgical patients receive heparin in the pre-
operative period. Multiple studies have shown an in-
Conceptually, the minimum ACT reflects an creased incidence of heparin resistance when a patient
anticoagulation level required to prevent receives a heparin infusion for 24 to 48 hours.25–27 The
proposed mechanism is an acquired AT deficiency because
coagulation from occurring during CPB. the AT/thrombin complex is rapidly cleared after dis-
sociating from heparin. The reduction in AT during hep-
arin pretreatment has been reported to be approximately 5
This anticoagulation level remains unknown as well. to 7% per day.28 This difference does reach statistical sig-
However, fibrin-bound thrombin is not inhibited at hep- nificance, but there is still concern about whether such a
arin concentrations less than 2.0 U/mL, so one can rea- small drop in AT concentration is clinically significant.
sonably assume that the minimum anticoagulation Furthermore, Shore-Lessersen et al.29 showed no differ-
level requires at least a heparin concentration greater than ence in the high-dose thrombin time—a much more spe-
2.0 U/mL.19 In addition, many institutions use a target cific test for thrombin inhibition—between patients on
ACT of 350 seconds and a heparin concentration of preoperative heparin versus no heparin, whereas the ACT
2.0 U/mL without reports of thrombosis in the CPB circuit was lower in the preoperative heparin group. This finding
or excessive coagulopathies. Although anticoagulation calls into question the validity of using the ACT in this

Copyright r 2015 American Society of Anesthesiologists. All rights reserved.

62 Finley

patient population. Even though the cause of heparin re-

sistance is unclear, the fact remains that heparin-pretreated When faced with heparin resistance,
patients have a higher incidence of heparin resistance. clinicians have four treatment options
Antithrombin-independent Mechanisms available to them: they can administer
Despite AT deficiency being the commonly cited cause of additional heparin, supplement AT with either
heparin resistance, many patients have other potential
contributing factors (Supplemental Digital Content 3, AT concentrate or fresh frozen plasma, or
http://links.lww.com/ASA/A516). Heparin-binding proteins
likely play a large role in AT-independent heparin resistance. commence CPB without further interventions.
When higher than normal concentrations of heparin-bind-
ing proteins are present in the circulation, a heparin bolus
is unlikely to achieve the expected circulating heparin The second treatment option for heparin resistance is
concentration. Thus, the responsiveness is likely to be AT supplementation with FFP. This has historically been
decreased. the source of AT used to treat AT-dependent heparin re-
sistance. However, evidence supporting this treatment op-
tion is lacking, with only case reports and one small
Despite AT deficiency being the commonly retrospective study to support its use.38–42 The standard
dose of FFP for heparin resistance is 2 U (1 U of AT is
cited cause of heparin resistance, many present in 1 mL FFP or B500 U of AT in 2 U FFP), which is
patients have other potential contributing expected to increase the AT by 2 to 3% per unit.43 Al-
though this results in higher AT concentrations, such a
factors. small increase is unlikely to have a clinical impact. During
a trial assessing AT concentrate, Avidan et al.44 ad-
ministered 2 U of FFP to the control group and noted an
Heparin responsiveness in patients having an acute ACT increase in only a small percentage of patients. De-
phase response is also likely to decrease. These patients spite the lack of literature supporting its use, AT supple-
have an elevated factor VIII concentration, which has been mentation with FFP is still an accepted treatment for AT
shown to correlate well with a decrease in heparin re- deficiency. Furthermore, many centers may only have FFP
sponsiveness.30 Multiple case reports support the theory as a source of AT supplementation. Finally, the time delay
that elevated factor VIII concentrations are a risk factor for to thaw FFP and the potential for transfusion-related
heparin resistance.31–35 The contribution of elevated fac- complications should be considered before administering
tor VIII concentrations to heparin resistance in the cardiac FFP for AT supplementation.
surgical population remains unclear. An alternative method of AT supplementation is with AT
concentrates. These are supplied as a sterile, lyophilized
powder that can be rapidly reconstituted. Multiple studies
TREATMENT have demonstrated increased heparin responsiveness after
When faced with heparin resistance, clinicians have four administration of AT concentrate. The concentrate can be
treatment options available to them: they can administer from a human purified or recombinant source, with the key
additional heparin, supplement AT with either AT con- differences outlined in Table 2. Although administration of
centrate or fresh frozen plasma (FFP), or commence CPB AT concentrate for heparin resistance remains off label,
without further interventions. The first option, adminis- multiple studies have demonstrated improved heparin re-
tering additional heparin, is often chosen to account for the sponsiveness as measured by the ACT after its admin-
possibility of excessive heparin-binding proteins. Ideally, istration.14,24,44–50 However, limited evidence exists to
one would be able to monitor point-of-care whole heparin support a reduction in hemostatic activation on CPB, and
concentrations to ensure adequate heparin dosing. Mon- none supports a reduction in thrombotic/coagulopathic
itoring heparin concentrations also has the benefit of complications in the postoperative period.24,25 Fur-
avoiding excessively high concentrations, as heparin con- thermore, the literature is confusing with regard to the AT
centrations greater than 4.0 U/mL are unlikely to greatly concentrate dose used to treat heparin resistance. The tra-
increase the ACT.14 Furthermore, a high heparin concen- ditional dose is B500 to 1,000 U, but many recent studies
tration raises the risk of heparin rebound and increased have used doses as high as 75 U/kg (7,500 U for a 100 kg
bleeding evidenced by higher chest tube output in the patient).24,45 Such high doses complicate the results of these
postoperative period.36,37 The increased risk of heparin studies because they maintain AT concentrations near
rebound should not preclude the use of high heparin con- normal levels throughout CPB. This is a major confounding
centrations, but rather should prompt the clinician to factor when interpreting these studies, as the decrease in
monitor for the presence of heparin rebound in the post- coagulation activation seen during surgery might be related
operative period. to a separate mechanism other than the treatment of hep-

Copyright r 2015 American Society of Anesthesiologists. All rights reserved.

Heparin Sensitivity and Resistance 63

AT concentrate for AT-dependent heparin resistance as a

Table 2. Recombinant AT Concentrate Versus method to decrease FFP transfusion before CPB (Supple-
Human Purified AT Concentrate
mental Digital Content 4, http://links.lww.com/ASA/
Recombinant AT Human Purified AT A517).52 A closer look at the study leading to this recom-
(Atryn)* (Thrombate)† mendation reveals that the study design played a major role
in this conclusion. In the study, heparin-resistant patients
Supplied Sterile, lyophilized Sterile, lyophilized powder
were randomized to receive either AT concentrate or pla-
powder
cebo.44 As has been demonstrated in multiple studies, the
Standardization WHO International WHO International
Standard Standard
AT concentrate group had an increase in their ACT and
thus proceeded with CPB. As one would expect, the place-
Source Goat milk Human plasma
bo group showed no change in ACT and the study protocol
Contraindications Goat milk None
hypersensitivity
dictated that they receive 2 U of FFP. This one difference
accounted for the vast majority of the intraoperative dif-
T12 11.6 h 3.8 d
ference seen in FFP transfusions. More concerning is the
Affinity 4-fold higher —
fact that the AT concentrate group received more FFP in
Supplied B1,750 IU vials B500 IU vials the postoperative period because of more bleeding, as
Cost B$980/vial or B$1,350/vial or $2.71/IU evidenced by increased chest tube output.
$0.56/IU
*rEVO Biologics, Framingham, MA.
†Grifols International, Barcelona, Spain.
AT ¼ antithrombin; T12 ¼ half-life. Despite heparin resistance being a complex
clinical disorder, a rational approach can still
be used in its management.
arin resistance.51 Nonetheless, the Society of Thoracic
Surgeons/Society of Cardiovascular Anesthesiologists
blood conservation guidelines still recommend the use of The last therapeutic option would be to accept the cur-
rent ACT and commence CPB. This option is often not
chosen for fear of inadequate anticoagulation. However,
there is some evidence that clinicians could, in fact, choose
this option in many situations without negative sequelae
for their patients. First, there is wide variability in the tar-
get ACTs used in clinical practice with some institutions
using target ACTs as low as 350 seconds with good re-
sults.2 This suggests that many institutions are using a
target ACT that is higher than necessary to safely conduct
CPB, and heparin resistance may be partially related to
choosing a target ACT goal that is too high. In addition,
the evidence supporting the routine use of ACT monitoring
does not consistently support a benefit with its use.53
Despite heparin resistance being a complex clinical dis-
order, a rational approach can still be used in its manage-
ment (Figure 4). Point-of-care monitoring of whole blood
heparin concentration will ensure that adequate concen-
trations are achieved and avoid excess heparin admin-
istration. In select patient populations, a preoperative AT
concentration will allow for a reduction in empiric AT
supplementation when the AT concentrations are normal.
AT supplementation to supraphysiological concentrations
is unlikely to provide benefit. If the AT concentration is
normal and the heparin concentration is therapeutic, the
Figure 4. A rational approach to the management of heparin resistance. next step in management remains unclear. Options in this
ACT ¼ activated clotting time; AT ¼ antithrombin; CPB ¼ cardiopulmonary scenario include proceeding with CPB with a lower than
bypass; DIC ¼ disseminated intravascular coagulation; DVT/PE ¼ deep vein
thrombosis/pulmonary embolism; ECMO ¼ extracorporeal membrane oxy- target ACT. Many times, this may be appropriate, as the
genation; FFP ¼ fresh frozen plasma; HDR ¼ heparin dose/response; commonly used ACT targets provide a large margin of
IAPB ¼ intraaortic balloon pump; VAD ¼ ventricular assist device. From safety for the patient. In these situations, a fixed heparin-
Finley A, Greenberg C: Heparin sensitivity and resistance: management
during cardiopulmonary bypass. Anesth Analg 2013; 116(6):1210–22.1 dosing regimen may be required. Otherwise, consideration
Reused with permission. should be given to alternative anticoagulants.

Copyright r 2015 American Society of Anesthesiologists. All rights reserved.

64 Finley

CONCLUSIONS 18. Slaughter TF, LeBleu TH, Douglas JM. Jr, Leslie JB, Parker JK, et al.:
Characterization of prothrombin activation during cardiac surgery
Heparin resistance is a complex, multifactorial disorder. It by hemostatic molecular markers. Anesthesiology 1994; 80:520–6.
is complicated by the fact that heparin’s anticoagulant ef- 19. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J: Clot-bound
thrombin is protected from inhibition by heparin-antithrombin III
fect is widely variable and that the monitoring most com- but is susceptible to inactivation by antithrombin III-independent
monly used, the ACT, is not specific to heparin. inhibitors. J Clin Invest 1990; 86:385–91.
Furthermore, the mechanism of decreased heparin re- 20. Despotis GJ, Summerfield AL, Joist JH, Goodnough LT, Santoro
SA, et al.: Comparison of activated coagulation time and whole blood
sponsiveness is multifaceted and not always dependent heparin measurements with laboratory plasma anti-Xa heparin
upon AT. Because of this, clinicians should attempt to use a concentration in patients having cardiac operations. J Thorac
rational approach in management of heparin-resistant Cardiovasc Surg 1994; 108:1076–82.
patients. Much remains unknown about the best strategy 21. Dietrich W, Braun S, Spannagl M, Richter JA: Low preoperative
antithrombin activity causes reduced response to heparin in adult
for managing these patients, and future research is needed but not in infant cardiac-surgical patients. Anesth Analg 2001;
to confirm a clinical benefit of the treatment options often 92:66–71.
chosen. 22. Ranucci M, Isgro G, Cazzaniga A, Soro G, Menicanti L, et al.:
Predictors for heparin resistance in patients undergoing coronary
artery bypass grafting. Perfusion 1999; 14:437–42.
23. Garvin S, Fitzgerald D, Muehlschlegel JD, et al.: Heparin dose
response is independent of preoperative antithrombin activity in
patients undergoing coronary artery bypass graft surgery using low
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