Full text of DOI:10.1191/0267659103pf637oa

Perfusion 2003; 18: 47]53
/
Diagnosis and treatment of heparin-induced
thrombocytopenia
William J DeBois, Junli Liu, Leonard Y Lee, Leonard N Girardi, Charles Mack, Anthony Tortolani,
Karl H Krieger and O Wayne Isom
New York-Presbyterian Hospital, New York Weill Cornell Center, New York, USA
Heparin-induced thrombocytopenia (HIT) is a major side
effect secondary to the administration of heparin. This
syndrome is serious and potentially life threatening. This
response is the result of antibodies formed against the
platelet factor 4 (PF4)/heparin complex. The incidence of
this immune-mediated syndrome has been estimated to
used to support the diagnosis, the negative predictive
value of these tests is generally less than 50%. In contrast,
although non-functional antibody detection assays are
more sensitive, they have a low specificity. HIT can be
treated in several ways, including cessation of all heparin
and giving an alternative thrombin inhibitor, platelet
inhibition followed by heparin infusion, and the use of
low molecular weight heparins. In this presentation, the
pathology and current diagnostic tests, as well as the
successful management of patients with HIT undergoing
CPB at New York Presbyterian Hospital, are reviewed. -
be 1 3% of all patients receiving heparin therapy. The
/
]
occurrence of HIT in patients requiring full anticoagula-
tion for cardiopulmonary bypass (CPB), therefore, pre-
sents a serious challenge to the cardiac surgery team. The
diagnosis of HIT should be based on both clinical and
laboratory evidence. While functional assays, platelet
aggregation tests, and the serotonin release assay can be
Perfusion (2003) 18, 47]53.
/
Introduction
patients with a history of HIT during cardiac
surgery.
Heparin-induced thrombocytopenia (HIT) is defined
as a decrease in platelet count induced by the
administration of heparin for therapeutic purposes.
Pathology
The first symptoms of the immune-mediated HIT
generally occur between four and 14 days after
exposure to heparin, but they may be seen within
hours in patients with previous exposure to he-
1
Mild thrombocytopenia, which occurs within four
days of starting heparin, is the result of a direct
agglutination effect of heparin on platelets. It is not
associated with thrombosis and resolves within a
4
parin. Recent evidence suggests that this syndrome
is initiated by a heparin-platelet-antibody interac-
1
3
couple of days. The immune form of HIT, which is
tion.
associated with both arterial and venous thrombo-
It has been shown that the platelet aggregating
factor in HIT sera is immunoglobulin G (IgG).
2
5
sis, is serious and life threatening. The incidence of
immune-mediated HIT in cardiac surgical patients
can be as high as 1.9%, and late recognition with
continued exposure to heparin can result in bleed-
Current evidence supports a mechanism by which
heparin binds to platelet factor 4 (PF4), a protein
normally found in the alpha granule of platelets, to
form a strongly antigenic hapten on the platelet
3
ing, thromboembolic complications, and death.
5
,6
Early diagnosis, treatment, and proper management
of patients with HIT during cardiac surgery present
a formidable challenge for the surgical team. The
purpose of this paper is to provide an in-depth
review of the pathology, diagnosis, and treatment of
HIT, as well as the anticoagulation management of
surface, which induces the production of specific
IgG antibodies. On re-exposure to heparin, these
specific IgG antibodies react with heparin/PF4
complexes and bind to the carboxy terminal receptor
6
7
(
Fc receptor) of circulating platelets. This anti-
body-receptor interaction initiates signal transduc-
tion and cell activation. Platelet activation caused
by HIT antibodies results in the translocation of
Address for correspondence: William J DeBois, New York-
Prebyterian Hospital, New York Weill Cornell Center, 525 East
Presented at the Annual Seminar of the American Academy of
6
8th Street, Greenberg Pavilion 3-153, New York, NY 10021, USA.
Cardiovascular Perfusion, Fort Lauderdale, Florida, 26]
/
28
E-mail: wdebois@nyp.org
January 2002.
#
Arnold 2003
10.1191/0267659103pf637oa
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Diagnosis and treatment of HIT
WJ DeBois et al.
4
8
anionic phospholipids from the internal to the
external leaflet of the platelet membrane.
up by the platelet membrane. After washing, the
platelets are mixed with the serum to be tested and
with heparin. In the presence of HIT, the release of
1
Activation of platelets results in their lysis and
agglutination. PF4 can also bind to heparin-like
molecules on the endothelial surface to provide
3
,16
serotonin is increased.
Optimal sensitivity and
specificity with either assay are obtained by using
3
17
targets for antibody binding and local injury.
washed platelets rather than platelet-rich plasma.
Patients who produce such antibodies are at risk
Functional assays give a high rate of false negative
results, since these assays require fresh donor
platelets and not all platelets are reactive to HIT
of developing venous or arterial thrombotic compli-
8
cations. The risk for these new thrombotic events is
1
8
enhanced by the interaction of the antigen/antibody
sera. The test should be performed at high and low
5
9
17
complexes with platelets and endothelial cells,
heparin concentrations to optimize specificity.
which result in the release of platelet microparticles,
thromboxane, and massive thrombin generation.
In contrast to the functional assays, the immuno-
7
logic assays detect the binding of antibodies to
1
9
The thrombosis is typically characterized by the
immobilized heparin/PF4 complexes. These as-
says are much more sensitive but have low specifi-
city. Negative enzyme-linked immunosorbent assay
(ELISA) results have been obtained in patients with
clinically apparent HIT and a positive serotonin
1
0
presence of white clots rich in platelets.
The clinical manifestations of HIT include local
skin lesions, venous thrombosis, arterial thrombosis,
1
1
and end organ failure. Erythematous plaque and
localized skin necrosis are two well known but
relatively uncommon early manifestations of HIT
that may precede the development of hematological
2
0
release test result. However, ELISA appears to
detect antibody development in some patients who
do not develop thrombocytopenia or other manifes-
1
2
22
abnormalities. The incidence of venous thrombo-
sis exceeds arterial thrombosis fourfold in HIT and
most often involves the proximal deep vein of the
lower extremities. Arterial occlusion of small and
medium-sized vessels is a classic complication of
tations of the syndrome. At least 50% of patients
exposed to heparin develop detectable antibodies by
2
1
ELISA without the development of HIT.
Recently, several flow cytometric methods have
been described that may approach the level of
1
1
14
HIT.
The morbidity and mortality of HIT have been
sensitivity obtained with the C-serotonin release
2
3
assay. A potential advantage of this development
1
3
reported as high as 23]
/
61% in early studies. Early
is the ability to distinguish antibodies capable of
2
4
diagnosis and prompt treatment have reduced mor-
causing immune HIT from non-immune HIT.
1
4
/
tality to 1.1]7.4%.
Treatment
Diagnosis
If there is a strong suspicion of immune HIT,
therapeutic management should be started immedi-
ately, which consists of two steps: (1) removal of the
immune stimulus by discontinuing heparin therapy,
including heparin line flush; (2) inhibition of
thrombin, either directly or by blocking the genera-
The diagnosis of immune HIT should be considered
in any patient who develops a 50% reduction of
platelet count while on heparin treatment. It is
recommended that the platelet count is measured
twice weekly in the first week or two of heparin
treatment to detect the development of HIT early,
2
5
1
5
tion of new thrombin.
and thus prevent thrombosis.
The laboratory diagnosis of HIT is made function-
To inhibit the generation of thrombin, an alter-
native anticoagulation should be started. This antic-
oagulation (Table 2) could be in the form of
nonsensitive low molecular weight heparin
1
6
ally and serologically. Functional assays (Table 1)
1
4
include the C-serotonin release and platelet ag-
1
7
gregation assays. In the platelet aggregation test,
platelet-poor plasma from the patient is mixed with
normal donor platelets and heparin. Plasma with
HIT causes activation and aggregation of platelets. In
(
LMWH), heparinoids, direct thrombin inhibitors,
1
,16,25
and platelet function inhibitors.
LMWHs, such as enoxaparin and dalteparin, have
1
6,26
1
4
been used in the treatment of HIT in the past.
the C-serotonin release test, healthy donor plate-
1
4
However, it has been found that the cross-reactivity
between LMWH and heparin-associated antiplatelet
antibodies from patients receiving unfractionated
lets are incubated with C-serotonin, which is taken
Table 1 Summary of diagnostic procedures for patients with HIT
2
7
heparin is 34% with enoxaparin and 25.5% with
dalteparin. LMWHs should not be used unless
Functional assays
Immunologic assays
2
8
antibody cross-reactivity is excluded.
C-serotonin release
Platelet aggregation
Negative ELISA
Platelet function inhibitors, such as aspirin and
dipyridamole, protect patients with heparin-asso-
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Diagnosis and treatment of HIT
WJ DeBois et al.
4
9
3
5
Table 2 Pharmacological alternatives for patients with HIT
1
998 for patients with HIT. Lepirudin binds to
9
clot-bound thrombin as well as soluble thrombin. It
has been reported that the incidence of the com-
bined endpoint death, amputation, or new throm-
boembolism was significantly reduced in patients
Pharmacological agent
Considerations
LMWH
Enoxaparin
Dalteparin
Difficult to monitor effect on coagula-
tion. Cross-reactivity with heparin. No
antidote. Potential for increased blood
loss postoperatively.
3
4
treated with lepirudin. The aPTT should be used
to monitor treatment, aiming for an aPTT ratio of
Glycoprotein IIb/IIIa
inhibitor
Blocks potential platelet aggregation.
Need thrombin inhibition as well, i.e.,
heparin.
1
2.5. The drug is renally cleared. Lepirudin has a
short circulating half-life of 1.3 hours in patients
9
with normal renal function. Dose adjustments need
Thrombin inhibitors
Recombinant hirudin
Difficult to monitor effect on coagula-
tion. No antidote. Potential for
increased postoperative blood.
to be made for patients with renal insufficiency. One
problem that occurs with lepirudin is that antihir-
udin antibodies develop in about 40% of patients
treated with lepirudin. In some patients, this can
result in an increased anticoagulant effect due to
delayed renal elimination of active lepirudin/anti-
(
lepirudin)
Bivalirudin
Argatroban
3
6
hirudin complexes.
ciated antiplatelet antibodies (HAAbs) from throm-
boembolic complications during brief exposures to
heparin, but not from thrombocytopenia.
Bivalirudin is a synthetic hirudin-based 20 amino
acid peptide that binds to both the anion-binding
exosite and enzyme catalytic site of thrombin. In
contrast to lepirudin, bivalirudin is a reversible
thrombin inhibitor, which may account for the
lower rate of hemorrhage observed with bivalirudin
2
9
The
glycoprotein IIb/IIIa inhibitor abciximab inhibits
HAAb-induced platelet aggregation, but the glyco-
protein IIb/IIIa inhibitors have not been shown to
provide adequate anticoagulation in patients with
3
0
15
HAAbs. Therefore, these agents cannot provide
adequate therapeutic effects as sole agents in pa-
tients with HIT.
compared with hirudin.
Argatroban is a synthetic L-arginine derivative
that exerts its anticoagulant effects by competitively
and reversibly inhibiting thrombin. It is a small
compound, which binds directly to the catalytic site
of thrombin, independently of antithrombin III (AT
Danaparoid is a mixture of heparin sulfate, der-
3
1
matin sulfate, and chondroitan sulfates. Cross-
reactivity with heparin-dependent antibodies from
patients with HIT can be demonstrated by in vitro
3
7
III). It showed comparable in vitro efficacy against
3
8
assays in 10]40% of patients tested, but this is
/
both fibrin-bound and soluble thrombin.
This
3
2
usually clinically insignificant. Moreover, throm-
bocytopenia might be resolved during danaparoid
treatment even when cross-reactivity is present.
Platelet counts recover during treatment in approxi-
mately 90% of patients. Danaparoid is, therefore, a
useful substitute for heparin, particularly in patients
with a previous history of HIT who require antith-
rombotic prophylaxis. Treatment can be monitored
by anti-Xa activity. Danaparoid has a long half-life of
plasma anti-Xa activity of approximately 24 hours
and is renally cleared, so it must be used cautiously
property would, theoretically, make argatroban
more efficient than unfractionated heparin in mana-
ging patients who present in late stages of thrombo-
tic events. Under its investigational name MD-805, it
has been used in Japan since the early 1980s and
1
,31
3
3
received approval for the treatment of patients with
39
HIT.
It was evaluated in a multicenter trial
comparing treatment in 160 patients with HIT and
44 with heparin-induced throbocytopenia and
1
thrombosis with a group of historical controls
treated in different ways. Argatroban reduced the
number of thromboembolic complications and re-
lated deaths, with no increased risk of major bleed-
3
1 ] 33
in patients with renal insufficiency.
The acti-
vated partial thromboplastin time (aPTT) is not
sensitive to the antithrombotic effect of danaparoid.
In addition, danaparoid is not neutralized by prota-
mine sulfate.
1
,40
ing.
The aPTT is used for monitoring its
therapeutic effects. The PT is also prolonged in
patients on argatroban, which can complicate the
initiation of warfarin in these patients, since war-
farin alone prolongs PT. Argatroban is hepatically
metabolized and can be used with renal insuffi-
ciency. Dose adjustments may be needed in patients
Thrombin inhibitors chemically unrelated to he-
parin are now available. Heparin-dependent anti-
bodies have no cross-reactivity with these agents.
These agents offer the patient adequate anticoagula-
tion with no risk of cross-reaction with their
3
4,35
16
HAAbs.
with hepatic failure. In patients with normal liver
Recombinant hirudin (lepirudin) is a direct
thrombin inhibitor. It received FDA approval in
function, the half-life of argatroban has been esti-
mated to range between 39 and 51 minutes.
4
1
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Diagnosis and treatment of HIT
WJ DeBois et al.
5
0
Management of patients with HIT requiring a
heart operation
pus’ tissue-stabilizing device. By the sixth day
postsurgery, the patient was discharged home safely
without any complications.
Heparin is the principle drug used for anticoagula-
tion during cardiac surgery because it is effective,
immediately reversible, inexpensive, and generally
Danaparoid has also been used as a heparin
4
3
alternative during cardiac surgery. Most of these
patients survived their operations, although a large
portion of them had excessive postoperative bleed-
ing. In a report by Magnani and colleagues, 53
patients received danaparoid for CPB; clots were
observed in either the CPB circuit or the operative
field in 38% of the patients. Fifty-five percent of
these patients required more than eight units of
4
2
well tolerated.
Managing patients who require
cardiac surgery and have a previous history of HIT
is a therapeutic challenge (Table 3).
LMWH has been documented as an alternative of
unfractioned heparin on patients with HIT for
4
3
cardiopulmonary bypass (CPB). In 1983, the first
successful use of nadroparin for CPB in a 66-year-
old man with HIT undergoing an emergency pul-
4
7
postoperative blood products.
4
4
monary thrombectomy was reported. In another
case report, enoxaparin was used for anticoagulation
during CPB on a patient with HIT undergoing heart
Theodore and coworkers reported the successful
use of danaparoid anticoagulation for off-pump
4
8
coronary artery bypass grafting. In this case, CPB
standby was available if required, with sufficient
danaparoid.
4
5
transplantation. In this case report, the patient
manifested important blood loss and significant
hypotension. A surgical revision was performed for
significant blood loss. This result suggested ineffec-
tiveness of activated clotting times (ACT) as a sole
measurement in providing a precise monitoring of
anticoagulation.
In 1989, Zulys et al. reported the use of ancrod for
CPB in a pilot study of 20 patients undergoing
4
9
elective coronary artery bypass graft operations.
Ancrod is a defibrinogenating agent derived from
the Malayan pit viper. It produces a rapid decrease
in plasma fibrinogen concentration following its
thrombin-like action to cleave fibrinopeptide A
Argatroban has been reported to substitute un-
fractionated heparin during cardiac procedures on
patients with HIT. In one case report by Arnoletti
and colleagues, on a 51-year-old man with an
ejection fraction (EF) of 15% who presented with
an acute myocardial infarction with a history of
5
0
from fibrinogen. All patients survived their opera-
tions and none had neurologic complications or
delayed wound healing. However, these patients
required significantly more intra- and postoperative
blood products. Subsequent successful uses of
ancrod for CPB have been documented. For in-
stance, Robitaille et al. showed that a successful
CPB case was performed on a HIT patient with the
4
6
HIT, argatroban at a rate of 3 lg/kg pre minute
replaced unfractioned heparin for anticoagulation.
aPTT was maintained between 1.5 and three times
baseline. Bypass surgery was scheduled for this
patient who was diagnosed with 2-vessel disease.
The argatroban infusion was discontinued 30 min-
utes prior to surgery in anticipation that the antic-
oagulant effects would last throughout the surgery.
Anticoagulant therapy was not administered intrao-
peratively. Surgery was performed using an ‘octo-
5
0
use of ancrod as anticoagulant.
Hirudin has been used as an alternative antic-
oagulant for CPB in patients with HIT by several
4
6,51,52
centers.
No clots were observed in any patient
during CPB and no patient had a thromboembolic
complication. In a subsequent study performed by
Koster and coworkers, 21 patients undergoing dif-
ferent complex cardiovascular procedures using
recombinant hirudin as the anticoagulant for CPB
Table 3 Recommendations for HIT patients requiring cardiac
surgery
5
2
were investigated. They concluded that, if recom-
binant hirudin is used as the anticoagulant for CPB
in patients with HIT and impaired renal function,
the risk of postoperative bleeding is increased.
Although the above cases have shown that several
heparin alternatives can be used as anticoagulants
during cardiac surgery, all of these agents have their
significant limitations. The cross-reactivity of HIT
antibodies with an LMWH may be found in approxi-
mately 90% of patients with HIT, making LMWHs
a potentially dangerous alternative to unfractioned
heparin in these patients. In addition, no current
coagulation assay or set of assays has been shown to
Intervention
Considerations
Heparin alternatives
All these drugs have potential for
significant blood loss due to lack of
antidote.
Platelet inhibitors and full Data support this technique, how-
heparinization
ever, there is little experience. Mini-
mal blood loss in these case reports.
This is a good option if there are no
antibodies present at time of surgery.
Requires some heparin alternative.
Can use aPTT, which is a readily
performed coagulation test. Off-
Full heparinization
Off-pump procedure
3
2
pump only good for coronary artery
bypass surgery, not valvular surgery.
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Diagnosis and treatment of HIT
WJ DeBois et al.
5
1
indicate whether satisfactory CPB anticoagulation
has been achieved with any LMWH. Danaparoid
does not affect the ACT or aPTT, requiring antifactor
Xa determination. With lepirudin, the aPTT may be
should be restricted to the operative period. Post-
operative anticoagulation should be achieved with
alternative anticoagulants.
5
7
Selleng reported a successful conduction of emer-
gency coronary artery bypass surgery with the use of
heparin as anticoagulant on a patient with a history
5
3
used to monitor patients who receive small dose.
However, the levels of r-hirudin recommended for
anticoagulation during CPB exceed those that can be
5
8
of HIT. This case demonstrates that short-term re-
exposure to heparin is possible in patients with a
history of HIT. Short-term re-exposure to heparin in
patients who do not have circulating HIT antibodies
should be safe as long as heparin is strictly avoided
before and after heparin administration.
5
4
effectively monitored with either the aPTT or ACT.
The ecarin clotting time assay, a clot-based method
that uses a prothrombin-activating snake venom
derivative and can be measured with a TAS instru-
ment (Cardiovascular Diagnostics, Raleigh, NC),
produced adequate dose]response curves with r-
/
The combination of hirudin, platelet inhibitor,
and heparin has been used for anticoagulation
during CPB in patients with HIT and renal impair-
5
4
hirudin in patients during CPB, but is not widely
available. In addition, ecarin clotting time can be
substantially prolonged by hemodilution or CPB-
related reductions in procoagulant proteins. More-
over, the lack of antidotes for these agents means
59
ment. In this investigation, the 10 patients en-
rolled were anticoagulated with r-hirudin to an
aPTT of 40]
tion during CPB was achieved with a bolus of
00 lg/kg unfractioned heparins after a bolus of
short-acting plate glycoprotein IIb]IIIa antagonist
/
60 seconds preoperatively. Anticoagula-
5
5
that severe postoperative bleeding can occur.
Compounds that allow easy monitoring and re-
versibility are greatly needed. Another approach for
CPB on patients with a history with HIT is to use a
brief intraoperative exposure heparin. The theory
underlying this option is that during secondary
immune responses, the concentration of antibody
in the serum begins to increase no earlier than three
4
/
tirofiban 10 lg/kg followed by an infusion of tirofi-
ban at a rate of 0.15 lg/kg per minute until one hour
before conclusion of CPB. Coagulation was moni-
tored by an abciximab-modified TEG and the
adenosine diphosphate stimulated platelet aggrego-
metry. Postoperative antithrombotic therapy was
started immediately with r-hirudin anticoagulation
5
6
days after the challenge. Moreover, in the absence
of heparin, HIT antibodies are not thrombogenic.
Thus, it has been postulated that in patients with a
history of HIT who are challenged with heparin, the
HIT antibody concentrations should start to increase
only after the heparin is completely cleared from the
circulation.
to an activated partial thromboplastin time of 40]60
/
seconds. No patients needed re-exploration and in
no patient was there clinical evidence of thrombosis
or embolism in the postoperative period.
In summary, patients with acute HIT who require
heart operations have options. One option is to wait
for the HIT antibodies to become undetectable and
then to operate using a brief intraoperative exposure
to heparin. This approach is not suitable for an
unstable patient, however, as it might take several
months for antibody levels to decline sufficiently. A
second option is to perform heart operations using
heparin substitutes. The relative appropriate agents
should be selected according to patient’s specific
medical condition, such as renal or liver function,
and the availability of the proper monitoring tech-
niques.
This theory was tested by Potzsch and Klove-
5
7
korn. In their investigation, on 10 patients with a
history of acute HIT who required CPB, heparin was
used. During the acute episode, all patients had
detectable HIT antibodies on the heparin-induced
platelet-aggregation assay. At the time of surgery, all
patients were negative for these antibodies. CPB was
performed with the use of heparin without any
problems. None of the 10 patients had prolonged
thrombocytopenia. They concluded that antibody-
negative patients with a history of HIT who undergo
CPB should be treated according to established
heparin protocols. However, the use of heparin
References
1
Baglin TP. Heparin induced thrombocytopenia throm-
bodies improves diagnosis of heparin-induced throm-
bosis (HIT/T) syndrome: diagnosis and treatment. J
bocytopenia. Br J Haematol 2001; 113: 886]90.
3 Follis F, Schmidt CA. Cardiopulmonary bypass in
patients with heparin-induced thrombocytopenia and
/
Clin Pathol 2001; 54: 272]
/
74.
2
Lindhoff-Last E, Gerdsen F, Ackermann H, Bauersachs
R. Determination of heparin-platelet factor 4-IgG anti-
thrombosis. Ann Thorac Surg 2000; 70: 2173 ]81.
/
Downloaded from prf.sagepub.com at Univ of Connecticut / Health Center / Library on May 17, 2015

Diagnosis and treatment of HIT
WJ DeBois et al.
52
4
5
6
Kleinschmidt S, Seyfert UT. Heparin-associated throm-
bocytopenia (HAT): still a diagnostic and therapeutical
tion on the risk for heparin-induced thrombocytope-
nia. Blood 2000; 96: 1703 ]708.
23 Lee DH, Warkentin TE, Denomme GA, Hayward CP,
Kelton JG. A diagnostic test for heparin-induced
thrombocytopenia: detection of platelet microparticles
/
problem in clinical practice. Angiology 1995; 46: 37]
/
44.
Amiral J, Bridey F, Wolf M et al. Antibodies to
macromolecular platelet factor 4-heparin complexes
in heparin-induced thrombocytopenia: a study of 44
using ow cytometry. Br J Haematol 1996; 95: 724]31.
/
24 Jy W, Mao W, Horstman LL, Valant PA, Ahn YS. A ow
cytometric assay of platelet activation marker P-selec-
tin (CD62p) distinguishes heparin-induced thrombo-
cytopenia (HIT) from HIT with thrombosis (HITT).
cases. Thromb Haemost 1995; 73: 21]28.
/
Amiral J, Wolf M, Fisher A, Boyer-neuman C, Vissac A,
Meyer D. Pathogenicity of IgA and/or IgM antibodies to
heparin-PF4 complexes in patients with heparin-in-
duced thrombocytopenia. Br J Haematol 1996; 92:
Thromb Haemost 1999; : 1255 99.
82
]/
25 Spencer FA. Heparin-induced thrombocytopenia: pa-
9
54]59.
/
tient proŽles and clinical manifestations. J Thromb
7
Farner B, Eichler, H, Kroll H, Greimacher A. A
comparison of danaparoid and lepirudin in heparin-
induced thrombocytopenia. Thromb Haemost 2001;
Thrombol 2000; 10: s21]s25.
/
2
2
6 Lanuzzi JL Jr., Jang IK. Heparin induced thrombocyto-
penia: diagnosis and contemporary antithrombin man-
8
5: 950]
Warkentin TE, Kelton JG. A 14-year study of heparin-
induced thrombocytopenia. Am J Med 1996; 101: 502]
07.
/
57.
agement. J Thromb Thrombol 1999; 7: 259]64.
/
8
9
7 Slocum MM, Adams JG Jr., Teel R, Spadone DP, Silver
D. Use of enoxaparin in patients with heparin-induced
thrombocytopenia syndrome. J Vasc Surg 1996; 23:
/
5
Mudaliar JH, Timothy KL, Liem TK, Nichols WK,
Spadone DP, Silver D. Lepirudin is a safe and effective
anticoagulant for patients with heparin-associated
8
39]43.
/
2
8 Kikta MJ, Keller MP, Humphrey PW, Silver D. Can low
molecular weight heparins and heparinoids be safely
antiplatelet antibodies. J Vasc Surg 2001; 34: 17]20.
/
given to patients with heparin]
penia syndrome? Surgery 1993; 114: 705]
9 Laster J, Elfrink R, Silver D. Reexposure to heparin of
/
induced thrombocyto-
10.
1
0 Pifarre R. Anticoagulation hemostasis and blood pre-
servation. In Pifarre R ed. Anonymous cardiovascular
surgery. Philadelphia, PA: Hanley & Belfus, 1993:
/
2
patients with heparin-associated antibodies. J Vasc
1
85]
1 Ali O. Images in heparin-induced thrombocytopenia. J
Thromb Thrombol 2000; 10: s27]s33.
2 Hartman AR, Hood RM. Anagnostopoulos CE. Phe-
nomenon of heparin-induced thrombocytopenia asso-
/
89.
Surg 1989; 9: 677]82.
/
1
1
3
0 Walenga JM, Jeske WP, Wallis DE et al. Clinical
experience with combined treatment of thrombin
inhibitors and GPIIb/IIIa inhibitors in patients with
/
HIT. Semin Thromb Hemost 1999; 25(Suppl 1): 77]81.
/
ciated with skin necrosis. J Vasc Surg 1988; 7: 781]84.
/
3
1 Magnani H. Heparin-induced thrombocytopenia: an
overview of 230 patients treated with orgaran (Org
13 Silver D, Kapsch DH, Tsoi EK. Heparin-induced
thrombocytopenia, thrombosis, and hemorrhage. Ann
1
0172). Thromb Haemost 1993; 70: 554]61.
/
Surg 1983; 198: 301]306.
/
3
2 Newman PM, Swanson RL, Chong BH. Heparin-in-
duced thrombocytopenia: IgG binding to PF4-heparin
complexes in the uid phase and cross-reactivity with
low molecular weight heparin and heparinoid.
1
4 Almeida JI, Coats R, Liem TK, Silver D. Reduced
morbidity and mortality rates of the heparin-induced
thrombocytopenia syndrome. J Vasc Surg 1998; 27:
3
09]
5 Chong B. Heparin-induced thrombocytopenia. Br J
Haematol 1995; 89: 431]39.
6 Ginsberg JA, Crowther MA, White RH, Ortel TL.
Anticoagulation therapy. Hematology 2001; 339]57.
7 Warkentin TE, Chong BH, Greimacher A. Heparin-
induced thrombocytopenia: towards consensus.
/
14.
Thromb Haemost 1998; 80: 292]97.
/
1
1
1
3
3
3
3 Saxon BR, Black MD, Edgell D, Noel D, Leaker MT.
Pediatric heparin-induced thrombocytopenia manage-
ment with danaparoid (orgaran). Ann Thorac Surg
/
/
1
999; 68: 1076]78.
/
4 Greinacher A, Volpel H, Janssens U et al. Recombinant
hirudin provides safe and effective anticoagulation in
patients with heparin-induced thrombocytopenia: a
Thromb Haemost 1998; 79: 1]7.
/
1
8 Walenga J, Jeske W, Wood JJ, Ahmad S, Lewis BE,
Bakhos M. Laboratory tests for heparin-induced throm-
bocytopenia: a multicenter study. Semin Hematol
prospective study. Circulation 1999; 99: 73]78.
/
5 Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz
M. Heparin-induced thrombocytopenia with throm-
boembolic complications: meta-analysis of 2 prospec-
tive trials to assess the value of parenteral treatment
with lepirudin and its therapeutic aPTT range. Blood
1
999; 36 (Suppl I): 22]28.
/
1
9 Arepally G, Reynolds C, Tomaski A et al. Comparison
of PF4/heparin ELISA assay with the 14C-serotonin
release assay in the diagnosis of heparin-induced
2
000; 96: 846]51.
/
thrombocytopenia. Am J Clin Pathol 1995; 104: 648]
/
3
6 Eichler P, Friesen HJ, Lubenow N, Jaeger B, Greinacher
A. Antihirudin antibodies in patients with heparin-
induced thrombocytopenia treated with lepirudin:
incidence, effects on aPTT, and clinical relevance.
54.
2
2
2
0 Walenga J, Jeske W, Fasanella AR, Wood JJ, Ahmad S,
Bakhos M. Laboratory diagnosis of heparin-induced
thrombocytopenia. Clin Appl Thromb Hemost 1999;
5 /
(Suppl 1): s21]s27.
Blood 2000; 96: 2373 ]78.
/
1 Izban K, Lietz H, Hoppensteadt DA et al. Comparison
of two PF4/heparin ELISA assays for the laboratory
diagnosis of heparin-induced thrombocytopenia.
37 Moledina M, Chakir M, Gandhi PJ. A synopsis of the
clinical uses of argatroban. J Thromb Thrombol 2001;
12: 141]49.
/
Semin Thromb Haemost 1999; 25(Suppl I): 51]
/
56.
38 Berry CN, Girardot C, Lecoffre C, Lunven C. Effects of
the synthetic thrombin inhibitor argatroban on Žbrin or
clot-incorporated thrombin: comparison with heparin
2 Warkentin TE, Sheppard JAI, Horsewood P, Simpson
PJ, Moore JC, Kelton JG. Impact of the patient popula-
Downloaded from prf.sagepub.com at Univ of Connecticut / Health Center / Library on May 17, 2015

Diagnosis and treatment of HIT
WJ DeBois et al.
5
3
and recombinant hirudin. Thromb Haemost 1994; 72:
7.
9 Hossmann V, Heiss WD, Bewermeyer H. Antithrombin
III deŽciency in ischemic stroke. Klin Wochenschr
heart transplantation in patients suffering from
1
]/
heparin]
Lung Transplant 2001; 20: 1237 ]
/
induced thrombocytopenia type II. J Heart
40.
3
4
/
51 Latham P, Revelis AF, Joshi GP, DiMaio JM, Jenssen
ME. Use of recombinant hirudin in patients with
heparin-induced thrombocytopenia with thrombosis
requiring cardiopulmonary bypass. Anesthesiology
1
983; 61: 617]20.
/
0 Lewis BE, Wallis DE, Berkowitz SD et al. Argatroban
anticoagulant therapy in patients with heparin-in-
duced thrombocytopenia. Circulation 2001; 103:
2
000; 92: 263]66.
/
1
838 ]43.
/
5
2 Koster A, Pasic M, Bauer M, Kuppe H, Hetzar R.
Hirudin as anticoagulant for cardiopulmonary bypass:
importance of preoperative renal function. Ann Thorac
4
1 Swan SK, Hursting MJ. The pharmacokinetics and
pharmacodynamics of argatroban: effects of age, gen-
der and hepatic or renal dysfunction. Pharmacother-
Surg 2000; 69: 37]41.
/
apy 2000; 20: 318]29.
/
5
3 Nurmohamed MT, Berckmans RJ, Morrien-Salomons
WM et al. Monitoring anticoagulant therapy by acti-
vated partial thromboplastin time: hirudin assessment
4
2 Despotis GJ, Hogue CW, Saleem R et al. The relation-
ship between hirudin and activated clotting time:
implications for patients with heparin-induced throm-
bocytopenia undergoing cardiac surgery. Anesth Analg
]
/
an evaluation of native blood and plasma assays.
Thromb Haemost 1994; 72: 685]92.
/
2
001; 93: 28]32.
/
5
5
4 Potzsch B, Madlener K, Seelig C, Riess CF, Greinache
A, Muller-Berghaus G. Monitoring of r-hirudin antic-
oagulation during cardiopulmonary bypass: assess-
ment of the whole blood ecarin clotting time.
4
3 Frederiksen JW. Cardiopulmonary bypass in human:
bypass unfractioned heparin. Ann Thorac Surg 2000;
7
0: 1434 ]43.
/
4
4 Gouault-Heilmann M, Huet Y, Contant G, Payen D,
Bloch G, Rapin M. Cardiopulmonary bypass with a
low-molecular weight heparin fraction. Lancet 1983; 2:
Thromb Haemost 1997; 77: 920]25.
/
5 Konkle BA, Bauer TL, Arepally G et al. Heparin-
induced thrombocytopenia: bovine versus porcine
heparin in cardiopulmonary bypass surgery. Ann
1374.
4
5 Prifti E, Bonacchi M, Leacche M, Mirald F. Undergoing
cardiopulmonary bypass using enoxaparin only during
a cardiac transplantation procedure. Eur J Cardio-
Thorac Surg 2001; 71: 1920 ]24.
/
5
5
6 Mollison PL, Engelfriet CP, Marcela Contreras. Blood
transfusion in clinical medicine, ninth edition. Ox-
ford, UK: Blackwell ScientiŽc, 1993.
thorac Surg 2000; 17: 760]62.
/
4
6 Arnoletti JP, Whitman GJR. Heparin-induced thrombo-
7 Potzsch B, Klovekorn WP, Madlener K. Use of heparin
during cardiopulmonary bypass in patients with a
history of heparin-induced thrombobytopenia. N Engl
J Med 2001; 343: 515.
8 Selleng S, Lubenow N, Wollert HG, Mullejans B,
Greinache A. Emergency cardiopulmonary bypass in
a bilaterally nephrectomized patient with a history of
heparin-induced thrombocytopenia: successful reex-
cytopenia in coronary bypass surgery. Ann Thorac
Surg 1999; 68: 576]78.
/
4
7 Magnani HN, Beijering RJR. Orgaran anticoagulation
for cardiopulmonary bypass in patients with heparin-
induced thrombocytopenia. In Pifarre R ed. New
anticoagulants for the cardiovascular patient. Phila-
5
delphia, PA: Hanley & Belfus, 1997: 487]500.
/
4
8 Warkentin TE, Dunn GJ, Cybulsky IJ. Off-pump cor-
onary artery bypass grafting for acute heparin-induced
posure to heparin. Ann Thorac Surg 2001; 71: 1041]
/
thrombocytopenia. Ann Thorac Surg 2001; 72: 1730 ]
/
42.
32.
59 Koster A, Kukucka M, Bach F et al. Anticoagulation
during cardiopulmonary bypass in patients with he-
parin-induced thrombocytopenia type II and renal
impairment using heparin and the platelet glycopro-
tein IIb-IIIa antagonist tiroŽban. Anesthesiology 2001;
4
5
9 Zulys VJ, Teasdale SJ, Michel ER. Ancrod as an
alternative to heparin anticoagulation for cardiopul-
monary bypass. Anesthesiology 1989; 71: 870]77.
/
0 Robitaille D, Carrier M, Cartier R et al. Successful
management strategy for mechanical assistance and
94: 245]51.
/
Downloaded from prf.sagepub.com at Univ of Connecticut / Health Center / Library on May 17, 2015