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Heparin-induced thrombocytopenia and cardiac surgery
Jerrold H. Levy and Anne M. Winkler
Emory University School of Medicine, Atlanta, Georgia,
USA
Correspondence to Jerrold H. Levy, MD, Emory
University School of Medicine, 1364 Clifton Road,
Atlanta, GA 30322, USA
Tel: +1 404 778 3934; fax: +1 404 778 5194;
e-mail: [email protected]
Current Opinion in Anaesthesiology 2010,
23:74–79
Purpose of review
Heparin-induced thrombocytopenia (HIT) is an important, increasingly recognized
antibody-mediated complication of heparin therapy occurring in approximately 0.5–5%
of patients receiving heparin for at least 5 days. HIT is a prothrombotic disorder that
typically presents with a 50% platelet count drop, thrombotic event manifesting usually
5–14 days after starting heparin, or both. HIT antibodies usually decrease to negative
titers/levels within 3 months. When there is clinical suspicion of HIT, heparin should be
discontinued and alternative anticoagulation should be considered, as well as laboratory
evaluation for HIT.
Recent findings
HIT immunoassay results should be used for clinical decision-making about initial
anticoagulation management. Recent data reevaluate the importance of absolute titers
of HIT antibodies as a risk factor for clinical occurrence. Although laboratory assays are
routinely used, current data suggest that increasing optical densities are more likely
associated with a positive 14C-serotonin release assay and HIT. HIT is also associated
with a greater risk for adverse events, so even though alternative anticoagulation is used,
clinicians should be aware of this hypercoagulable syndrome.
Summary
For patients with HIT, alternative anticoagulation is available, but for cardiovascular
surgery, if the operation cannot be delayed until HIT antibodies have become negative,
alternative anticoagulation strategies are recommended, although patients with HIT are
at a greater risk for adverse outcomes.
Keywords
anticoagulation, cardiac surgery, heparin-induced thrombocytopenia, hypersensitivity,
thrombosis
Curr Opin Anaesthesiol 23:74–79
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907
Introduction
Heparin-induced thrombocytopenia (HIT) is an
immune-mediated prothrombotic event resulting from
platelet activation by an antibody formed during heparin
therapy. Clinically, HIT manifests as an unexplained
more than 50% decrease in the platelet count, often to
less than 100 109/l that can be associated with thrombosis [1,2,3,4]. When heparin is administered perioperatively, the incidence of HIT is the highest. When
HIT is strongly suspected, heparin should be stopped
and suitable treatment should be started immediately,
even before laboratory confirmation, especially if a postoperative thrombotic event occurs. This review will discuss the pathophysiology, diagnosis, and treatment of
HIT, in addition to alternative anticoagulation strategies.
Pathogenesis/frequency
HIT is mediated by antibodies that develop to a complex
of heparin–platelet factor 4 (PF4), a basic protein stored
0952-7907 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
in platelet alpha granules. Heparin–PF4 antibodies are
generated when heparin and PF4 bind, creating a conformational change on PF4 that exposes new antigenic
binding sites called epitopes [4]. The antibody producing HIT is an immunoglobulin (Ig)G antibody that
binds heparin–PF4 complexes on platelet surfaces to
form immune complexes. The platelets in turn are
activated by the Fc domain of the IgG via FcgIIa
receptors. Consequently, platelets release membrane
fragments (microparticles) that are prothrombotic and
promote thrombin generation/platelet activation. HIT
antibodies also activate monocytes, bind to endothelial
cells, and further augment the procoagulant state. About
7–50% of heparin-treated patients form heparin–PF4
antibodies; however, HIT occurs in approximately 1–5%
of patients receiving unfractionated heparin and
less than 1% of patients receiving low-molecularweight heparin [3,5]. Cardiac transplant/neurosurgical
patients have an increased risk of developing HIT (11
and 15%, respectively) [6,7]. Cardiovascular surgery
patients are especially at risk of producing the antibodies
DOI:10.1097/ACO.0b013e328334dd2f
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HIT and cardiac surgery Levy and Winkler 75
[8]. HIT antibodies circulate only temporarily (half-life
3 months) [9]. The presence and the level of the
antibodies, irrespective of thrombocytopenia, are associated with increased adverse events in different groups of
patients from acute coronary syndromes to cardiovascular surgery [10,11,12]. HIT increases the risk of thrombosis (odds ratio 37), and the overall thrombotic risk with
HIT is 38–76% [13,14]. Thrombosis appears coincident
with, or slightly before, the decline in platelet count
[13].
an ELISA OD of more than 1.40 units – weak positive
results (0.04–1.00 OD) excluded a diagnosis of HIT in
most cases [23]. Further, ‘high-titer negative’ ELISA
results may become positive on retesting after several
days. Functional tests include the SRA and heparininduced platelet activation test. These tests detect
heparin-dependent, platelet-activating antibodies and
are considered the gold standard for the laboratory diagnoses of HIT because of high sensitivity/specificity but
require specialized laboratories [19,20,21,22].
Diagnosis
Treatment
HIT should be suspected if the platelet count drops by
50% or new thrombosis occurs 5–14 days after initiating
heparin therapy [1,2]. Thrombocytopenia due to other
causes, including an intraaortic balloon pump with mechanical destruction, sepsis, or other drug-induced causes of
thrombocytopenia, should be excluded [4]. In cardiac
patients, IIb/IIIa platelet inhibitors are important causes
of drug-induced thrombocytopenia [4]. Other confounding issues include cardiopulmonary bypass (CPB)
in which a 40–60% decrease in platelet count occurs
because of dilution and consumption. HIT after CPB
often has a biphasic pattern that decreases after CPBrelated thrombocytopenia corrects or a persistently low/
decreasing platelet count more than 4 days postoperatively [15,16]. HIT can manifest with a ‘rapid onset’
within minutes to hours of heparin exposure associated
with systemic responses caused by preexisting antibodies
due to prior exposure [17]. These reactions manifest as
hypersensitivity/anaphylaxis and include hypotension,
pulmonary hypertension, tachycardia 2–30 min after
heparin bolus [4], or all. HIT can also occur days to
weeks after exposure (delayed onset HIT) in patients
presenting with thrombosis [18].
The recommended treatment for patients with strongly
suspected or confirmed HIT is discontinuation of heparin
and beginning of a nonheparin, alternative anticoagulant
such as a direct thrombin inhibitor (e.g. lepirudin, argatroban, and bivalirudin) or danaparoid [1,2]. In addition,
documentation of the patient’s HIT status including a
sign on the patient’s bed chart stating ‘No heparin: HIT’,
or both, may help prevent unintended heparin exposure.
Different direct thrombin inhibitors are approved in the
United States for use in HIT patients without thrombosis
(argatroban), HIT patients with thrombosis (lepirudin
and argatroban), and patients with or at risk of HIT
undergoing percutaneous coronary intervention (PCI)
(argatroban and bivalirudin). Lepirudin and argatroban
are also available in some other countries for use in
patients with HIT in the noninterventional setting.
The direct thrombin inhibitors do not resemble heparin,
do not cross-react with heparin–PF4 antibodies, and
cannot promote HIT. Danaparoid, a heparinoid with
minimal cross-reactivity with heparin–PF4 antibodies,
was one of the first agents approved but was widely
unavailable. Fondaparinux is a selective factor Xa inhibitor with a low risk for antibody formation; however,
fondaparinux has not been prospectively studied in
HIT, and data are limited.
Laboratory confirmation
Laboratory testing for HIT includes antigen assays and
functional platelet activation assays [19,20,21,22]. Antigen assays such as the ELISA and rapid particle gel
immunoassay detect polyclonal antibodies to complexes
of PF4 and heparin or complexes of PF4 and other
polyanions [19,20,21,22]. The most commonly used
commercial ELISAs detect IgG, IgM, and IgA antibodies, and are sensitive for detection of heparin–PF4
antibodies but are not specific for HIT. However, newer
commercial assays have been developed that detect
IgG antibodies, thus increasing clinical specificity
[19,20,21,22]. Although ELISA results can be reported
as positive or negative, optical density (OD), antibody
titer based on the OD, or all are important for clinical
decision-making. The likelihood of a positive 14C-serotonin release assay (SRA) increases proportionally with
increased ODs – most cases of HIT were associated with
Managing HIT should include stopping heparin and continued alternative anticoagulant coverage to prevent
thrombotic complications [1,2,3]. However, the risk
of excessive bleeding especially recently after cardiac or
other surgery should be carefully considered, as bleeding is
also associated with adverse outcomes. Low-molecularweight heparins should be avoided because they crossreact with heparin–PF4 antibodies and worsen HIT
[1,2,3]. Heparin should be avoided, at least as long as
heparin–PF4 antibody testing is positive [1,2,3,4].
The British Committee for Standards in Haematology
recommends the use of a heparin alternative for most
patients needing anticoagulation with previous HIT
[24]. Avoiding heparin is feasible in many patients but
may be challenging in a few clinical situations, for example
cardiovascular surgery (discussed below). For patients with
current or previous HIT who need cardiac surgery, the
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76 Cardiovascular anesthesia
surgery should be delayed, if possible, until heparin–PF4
antibodies are negative [1,2]. If heparin use is unavoidable or planned, the heparin exposure should be limited
to the surgery itself, with alternative anticoagulation
used preoperatively and postoperatively as needed
[1,2,3,4].
Preoperative and postoperative alternative
anticoagulation therapies: lepirudin
Lepirudin, a recombinant form of hirudin, is the most
potent agent with side effects that include an 18% incidence of major bleeding and potential for anaphylactic
reactions on reexposure [25–27]. Bleeding risk is related to
serum creatinine levels, and dosing adjustments should be
made with renal dysfunction [24]. Recommended lepirudin dosing is a 0.4 mg/kg initial bolus, followed by a
0.15 mg/kg/h infusion (reduced in renal injury) adjusted
to keep an activated partial thromboplastin time (aPTT)
1.5–2.5 times baseline. A lower first infusion of 0.1 mg/kg/h
without a bolus may reduce the bleeding risk.
Preoperative and postoperative alternative
anticoagulation therapies: desirudin
Desirudin, another recombinant hirudin, has been extensively studied in orthopedic and cardiac settings [28]. As a
prophylaxis in patients undergoing hip replacement
surgery, desirudin was significantly more effective in
reducing the incidence of deep vein thrombosis than
either unfractionated or low-molecular-weight heparin.
The two recombinant hirudins for clinical use include
desirudin and lepirudin. Desirudin is approved for thrombosis prophylaxis following orthopedic hip replacement
surgery and lepirudin for anticoagulation in patients with
HIT and thromboembolic complications [29]. Both compounds differ from each other in their N-termini; desirudin possesses a valine–valine and lepirudin possesses a
leucine–threonine structure. Otherwise, the desirudin
and lepirudin are similar, with molecular weights of
6.96 and 6.98 kDa, respectively [29].
Preoperative and postoperative alternative
anticoagulation therapies: argatroban
Argatroban is a hepatically metabolized, small molecule
(molecular weight 526 Da) developed from L-arginine.
The small size minimizes the risk for antibody formation.
The recommended initial dose is an infusion of 2 mg/kg/
min (0.5 mg/kg/min if hepatic impairment), adjusted to
achieve an aPTT 1.5–3 times baseline. However, a lower
dose (0.5 mg/kg/min) should be considered in patients with
heart failure, multiple organ system failure, or fluid overload, but dose adjustment for renal failure is not required
[30,31]. Although argatroban is also approved for use in
patients with or at risk of HIT undergoing PCI, most
clinicians now use bivalirudin (see below). Direct thrombin inhibitors, particularly argatroban, prolong the international normalized ratio (INR), and methods for monitoring the argatroban-to-coumarin transition using the INR or
chromogenic factor Xa assay should be followed [32].
Preoperative and postoperative alternative
anticoagulation therapies: bivalirudin
Bivalirudin is a low-molecular-weight protein developed
by adapting hirudin that is cleared by renal elimination
and by circulating proteases. Bivalirudin is used extensively in the cardiac catheterization setting and in
patients with or at risk of HIT during PCI. Bivalirudin
was evaluated in an open-label, prospective study of 52
patients with or at risk of HIT [33]. The primary endpoint of major bleeding occurred in one (2%) patient.
Clinical success, defined as a lack of death, emergency
bypass surgery, or Q-wave infarction, occurred in 48
(96%) of 50 evaluable patients. The recommended dose
is a 0.75 mg/kg initial bolus followed by an infusion of
1.75 mg/kg/h (reduced in renal impairment). Notable
added experience exists with this drug in non-HIT
patients, and it is the agent most extensively studied
and used in cardiac surgery (see below).
Preoperative and postoperative alternative
anticoagulation therapies: danaparoid
Danaparoid is a glycosaminoglycan used since 1982 for
patients with HIT and is the only alternative anticoagulant evaluated in a randomized controlled trial in HIT
that included dextran 70 as the comparator, which is now
considered inappropriate therapy [34]. In 1478 clinical
experiences with danaparoid in HIT, event rates were
16.2% for mortality, 9.7% for thrombosis, and 8.1% for
major bleeding [35]. Other studies report its use, but it is
currently unavailable for clinical use.
Preoperative and postoperative alternative
anticoagulation therapies: fondaparinux
Fondaparinux is a synthetic pentasaccharide with minimal in-vitro cross-reactivity with HIT sera [36]. It is
approved in the United States and elsewhere for prophylaxis and treatment of venous thromboembolism. Prospective, controlled studies in HIT with small numbers
have been reported [37]. In addition, there are a few
reports of HIT associated with fondaparinux and minimal
approaches to reverse its bleeding effects.
Managing heparin-induced thrombocytopenia
patients for cardiovascular surgery
If patients are HIT positive based on current criteria, and
based on recent understanding about antibody titers, and
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HIT and cardiac surgery Levy and Winkler 77
cardiac surgery cannot be delayed, nonheparin anticoagulation during the surgery is recommended [1,2,
3,4]. A previous clinical report [4] included a review
of danaparoid or heparin with the short-acting platelet
inhibitors epoprostenol, iloprost, or tirofiban as alternative agents. A retrospective analysis [38] of 57 patients
with HIT for cardiovascular surgery with CPB was
reported using lepirudin anticoagulation. Lepirudin
0.20 mg/kg was added to the priming solution. A
0.25 mg/kg intravenous bolus followed by continuous
infusion of 0.5 mg/min was started before cannulation.
During CPB, lepirudin was monitored using the ecarin
clotting time. Target values were 350–400 s. Fifty-four
(95%) patients fully recovered without evidence of
thromboembolism. Four (7%) patients, each with renal
impairment, had excessive bleeding associated with prolonged lepirudin elimination. Argatroban has been
reported during cardiac surgery, on the basis of a retrospective analysis of 21 published adult cases with a
history of HIT, heparin allergy, or antithrombin
deficiency [39]. Other studies have reported its use for
cardiovascular surgery, but bivalirudin has been more
extensively studied for this application as noted below.
Bivalirudin
Bivalirudin has become the agent most used to replace
heparin in patients with HIT requiring cardiac surgery. An
early case series [40] reported four patients with suspected
HIT who underwent coronary artery bypass grafting using
CPB and bivalirudin anticoagulation. Patients received a
1.5 mg/kg loading dose before cannulation and continuous
2.5 mg/kg/h infusion during CPB. Anticoagulation was
monitored using activated clotting times with a target of
500 s. Anticoagulation during CPB was effective, and total
operating times were acceptable. One patient experienced
excessive postoperative bleeding.
using CPB [41] or undergoing coronary artery bypass
grafting without CPB [42]. Bivalirudin was administered
to 206 patients, providing anticoagulation with a safety
profile similar to that of heparin. Bivalirudin dosing in
surgery without CPB is similar to that used in PCI.
Cautions when using this agent include intraoperative
techniques to prevent blood from being stagnant when
using bivalirudin, which is metabolized by enzymes
present in blood exposed to wound or foreign surfaces.
Therefore, direct retransfusion of shed pericardial/mediastinal blood into the cardiotomy container should be
avoided with the use of bivalirudin to avoid systemic
activation and circulation of thromboemboli. Alternatively, shed pericardial blood can be processed via cell
salvage systems when using bivalirudin.
Antibody negative
If heparin–PF4 antibodies are negative after a HIT
episode, guidelines recommend heparin over nonheparin anticoagulants during cardiac surgery [1,4].
The risk of complications, including bleeding associated
with nonheparin anticoagulants, during cardiac surgery
may exceed the risk of recurrence of HIT with brief
heparin reexposure [1,2,3,4]. Added concerns with
alternative anticoagulants for cardiac surgery include
limited experience and the lack of a reversal agent
[1,2]. Heparin use should be confined to the intraoperative period, with alternative anticoagulation used
preoperatively and postoperatively as needed [1]. As
previously discussed, heparin–PF4 antibodies are transient. In one study [9] of 144 patients with HIT, the
median time to a negative antibody result after an initial
positive result was 50 days by activation assay and 85 days
by antigenic assay.
Conclusion
Larger, prospective studies compared bivalirudin with
heparin in non-HIT patients undergoing cardiac surgery
HIT is an antibody-mediated prothrombotic disorder
that should be considered if a patient experiences a
Table 1 Direct thrombin inhibitors for clinical use
Drug
Dose
Bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/h
infusion for the duration of PCI, with 0.3 mg/kg
based on ACT; cardiothoracic surgery dosing
depends on on vs. off pump
[40,41,42]
Argatroban 2 mg/kg/min initial infusion adjusted to
10 mg/kg/min when aPTT is 1.5–3
baseline (HIT); 25 mg/kg/min infusion
and 350 mg/kg bolus until ACT > 300 s
Lepirudin 0.4 mg/kg bolus dose and 0.15 mg/kg
infusion to target aPTT of 1.5–2.5 times
Desirudin 15 mg subcutaneously q12 h (orthopedic)
Availability
Indications
Monitoring
Available in the United States,
Europe, and Canada
PCI or in patients with HIT
ACT
Available in the United States
Prophylaxis and treatment of
thrombosis in HIT and
PCI in patients with HIT
aPTT and
ACT (PCI)
Available in the United
HIT and prevention of further VTE aPTT
States and Europe
Approved in the United States
Total hip arthroplasty (HIT)
None
and Europe for hip arthroplasty
ACT, activated clotting time; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary
intervention; VTE, venous thromboembolism.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
78 Cardiovascular anesthesia
platelet count drop of 50% thrombosis occurring 5–14
days after the start of heparin, with other diagnoses
excluded. Heparin should be discontinued if HIT is
suspected, confirmatory laboratory testing performed,
and parenteral alternative anticoagulation should be considered if there is a thrombotic risk. HIT antibodies are
transient, and heparin should be avoided as long as the
antibody test is positive. In patients with HIT who need
cardiac surgery, the surgery should be delayed, if
possible, until HIT testing is negative. Alternative anticoagulation should be used perioperatively as needed.
HIT is a prothrombotic disease that even with alternative
anticoagulation is associated with a significant risk of lifethreatening morbidity and death. Table 1 summarizes
the direct thrombin inhibitors used in HIT.
13 Greinacher A, Farner B, Kroll H, et al. Clinical features of heparin
induced thrombocytopenia including risk factors for thrombosis. A
retrospective analysis of 408 patients. Thromb Haemost 2005; 94:
132–135.
An important study linking antibodies to adverse outcomes in cardiac surgery.
Acknowledgements
20 Warkentin TE, Sheppard JA. Testing for heparin-induced thrombocytopenia
antibodies. Transfus Med Rev 2006; 20:259–272.
Dr Levy receives research support from Eisai, Lilly, Novo Nordisk, and
Schering Plough.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 118–119).
14 Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia and cardiac
surgery. Ann Thorac Surg 2003; 76:2121–2131.
15 Pouplard C, Couvret C, Regina S, Gruel Y. Development of antibodies
specific to polyanion-modified platelet factor 4 during treatment with fondaparinux. J Thromb Haemost 2005; 3:2813–2815.
16 Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for
heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb
Haemost 2004; 2:1882–1888.
17 DeEugenio DL, Ruggiero NJ, Thomson LJ, et al. Early-onset heparin-induced
thrombocytopenia after a 165-day heparin-free interval: case report and
review of the literature. Pharmacotherapy 2005; 25:615–619.
18 Rice L, Attisha WK, Drexler A, Francis JL. Delayed-onset heparin-induced
thrombocytopenia. Ann Intern Med 2002; 136:210–215.
19 Warkentin TE. Confirmatory procedure and other maneuvers to assess
pathogenicity of platelet factor 4 (PF4)-dependent antibodies: distinguishing
‘signal’ from ‘noise’. Thromb Haemost 2008; 100:523–524.
21 Warkentin TE, Sheppard JA, Moore JC, et al. Studies of the immune response
in heparin-induced thrombocytopenia. Blood 2009; 113:4963–4969.
Recent understanding of the immunogenicity of heparin.
22 Warkentin TE, Sheppard JA, Moore JC, et al. Laboratory testing for the
antibodies that cause heparin-induced thrombocytopenia: how much class
do we need? J Lab Clin Med 2005; 146:341–346.
23 Warkentin TE, Sheppard JI, Moore JC, et al. Quantitative interpretation of
optical density measurements using PF4-dependent enzyme immunoassays.
J Thromb Haemost 2008; 6:1304–1312.
An important study that correlates antibody titers with the gold standard test in HIT,
the SRA by Dr Warkentin.
1
24 Keeling D, Davidson S, Watson H. The management of heparin-induced
thrombocytopenia. Br J Haematol 2006; 133:259–269.
2
25 Lubenow N, Eichler P, Lietz T, Greinacher A. Lepirudin in patients with
heparin-induced thrombocytopenia: results of the third prospective study
(HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb
Haemost 2005; 3:2428–2436.
Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention
of heparin-induced thrombocytopenia: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;
133:340S–380S.
Recent guidelines on the management, and an important review.
Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia.
N Engl J Med 2006; 355:809–817.
3 Greinacher A. Heparin-induced thrombocytopenia. J Thromb Haemost 2009;
7 (Suppl 1):9–12.
An important review of this topic by one of the world experts.
Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the
perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 2007; 105:570–582.
An extensive review article with information and individual therapies.
4
5
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with
unfractionated and low-molecular-weight heparin thromboprophylaxis: a
meta-analysis. Blood 2005; 106:2710–2715.
26 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108:2062–2065.
27 Tardy B, Lecompte T, Boelhen F, et al., for the GEHT-HIT study group.
Predictive factors for thrombosis and major bleeding in an observational study
in 181 patients with heparin-induced thrombocytopenia treated with lepirudin.
Blood 2006; 108:1492–1496.
28 Matheson AJ, Goa KL. Desirudin: a review of its use in the management of
thrombotic disorders. Drugs 2000; 60:679–700.
29 Greinacher A, Eichler P, Albrecht D, et al. Antihirudin antibodies following lowdose subcutaneous treatment with desirudin for thrombosis prophylaxis after
hip-replacement surgery: incidence and clinical relevance. Blood 2003;
101:2617–2619.
6
Hourigan LA, Walters DL, Keck SA, Dec GW. Heparin-induced thrombocytopenia: a common complication in cardiac transplant recipients. J Heart Lung
Transplant 2002; 21:1283–1289.
7
Hoh BL, Aghi M, Pryor JC, Ogilvy CS. Heparin-induced thrombocytopenia
type II in subarachnoid hemorrhage patients: incidence and complications.
Neurosurgery 2005; 57:243–248; discussion 243–248.
8
Everett BM, Yeh R, Foo SY, et al. Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery. Ann Thorac Surg 2007; 83:592–597.
31 Tang IY, Cox DS, Patel K, et al. Argatroban and renal replacement therapy in
patients with heparin-induced thrombocytopenia. Ann Pharmacother 2005;
39:231–236.
9 Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocy topenia. N Engl J Med 2001; 344:1286–1292.
An important evaluation of IgG changes and temporal relationships.
32 Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to
warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl
Thromb Hemost 2005; 11:279–287.
10 Williams RT, Damaraju LV, Mascelli MA, et al. Antiplatelet factor 4/heparin
antibodies: an independent predictor of 30-day myocardial infarction after
acute coronary ischemic syndromes. Circulation 2003; 107:2307–2312.
33 Mahaffey KW, Lewis BE, Wildermann NM, et al. The anticoagulant therapy
with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study:
main results. J Invasive Cardiol 2003; 15:611–616.
11 Kress DC, Aronson S, McDonald ML, et al. Positive heparin–platelet factor 4
antibody complex and cardiac surgical outcomes. Ann Thorac Surg 2007;
83:1737–1743.
An important study linking antibodies to adverse outcomes in cardiac surgery.
12 Bennett-Guerrero E, Slaughter TF, White WD, et al. Preoperative anti-PF4/
heparin antibody level predicts adverse outcome after cardiac surgery.
J Thorac Cardiovasc Surg 2005; 130:1567–1572.
An important study linking antibodies to adverse outcomes in cardiac surgery.
30 Levine RL, Hursting MJ, McCollum D. Argatroban therapy in heparin-induced
thrombocytopenia with hepatic dysfunction. Chest 2006; 129:1167–
1175.
34 Chong BH, Gallus AS, Cade JF, et al. Prospective randomised open-label
comparison of danaparoid with dextran 70 in the treatment of heparin-induced
thrombocytopaenia with thrombosis: a clinical outcome study. Thromb Haemost 2001; 86:1170–1175.
35 Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of
1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from
1982 to mid-2004. Thromb Haemost 2006; 95:967–981.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIT and cardiac surgery Levy and Winkler 79
36 Savi P, Chong BH, Greinacher A, et al. Effect of fondaparinux on platelet
activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood 2005; 105:
139–144.
40 Dyke CM, Koster A, Veale JJ, et al. Preemptive use of bivalirudin for
urgent on-pump coronary artery bypass grafting in patients with potential
heparin-induced thrombocytopenia. Ann Thorac Surg 2005; 80:299–
303.
37 Efird LE, Kockler DR. Fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia. Ann Pharmacother 2006;
40:1383–1387.
41 Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin
with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg
2006; 131:533–539.
A study reporting use of bivalirudin in cardiac surgery.
38 Koster A, Hansen R, Kuppe H, et al. Recombinant hirudin as an alternative for
anticoagulation during cardiopulmonary bypass in patients with heparininduced thrombocytopenia type II: a 1-year experience in 57 patients.
J Cardiothorac Vasc Anesth 2000; 14:243–248.
39 Martin ME, Kloecker GH, Laber DA. Argatroban for anticoagulation during
cardiac surgery. Eur J Haematol 2007; 78:161–166.
42 Smedira NG, Dyke CM, Koster A, et al. Anticoagulation with bivalirudin for off
pump coronary artery bypass grafting: the results of the EVOLUTION-OFF
study. J Thorac Cardiovasc Surg 2006; 131:686–692.
A study reporting use of bivalirudin in cardiac surgery.
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