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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Pathology and Molecular Medicine
and the Department of Medicine, McMaster University; and from the
Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences
Corporation, Hamilton, Ontario, Canada.
The frequency of immune heparin-induced thrombocytopenia
(HIT) varies among prospective studies. It is unknown whether this is
caused by differences in the heparin preparations, the patient populations, or the types of serologic assay used to confirm the diagnosis. Seven hundred forty-four patients were studied from 3 different clinical treatment settings, as follows: unfractionated heparin (UFH) during or after cardiac surgery (n = 100), UFH after orthopedic surgery (n = 205), and low-molecular-weight heparin (LMWH)
after orthopedic surgery (n = 439). Both an activation assay and an
antigen assay were used to detect heparin-dependent IgG (HIT-IgG)
antibodies. By activation assay, the frequency of HIT-IgG formation
ranged from a low of 3.2% in orthopedic patients receiving LMWH to a
high of 20% in cardiac patients receiving UFH; by antigen assay, the
corresponding frequencies ranged from 7.5% to 50%. Both UFH use
(P = .002) and cardiac surgery (P = .01)
were more likely to be associated with HIT-IgG formation. However,
among patients in whom HIT-IgG formed and who were administered UFH,
the probability for HIT was higher among orthopedic patients than among
cardiac patients (by activation assay: 52.6% compared with 5%; odds
ratio, 21.1 [95% CI, 2.2-962.8]; P = .001; by antigen assay: 34.5% compared with 2.0%; odds ratio, 25.8 [95% CI,
3.2-1141]; P < .001). It is concluded that there is an
unexpected dissociation between the frequency of HIT-IgG formation and
the risk for HIT that is dependent on the patient population. HIT-IgG
antibodies are more likely to form in patients who undergo cardiac
surgery than in orthopedic patients, but among patients in whom
antibodies do form, orthopedic patients are more likely to develop HIT.
(Blood. 2000;96:1703-1708) Heparin-induced thrombocytopenia (HIT) is an
adverse drug reaction caused by heparin-dependent IgG (HIT-IgG)
antibodies that activate platelets.1-3 The target antigen
consists of multimolecular complexes of platelet factor 4 and
heparin.4-7 The frequency of HIT varies considerably, as
cited by prospective studies.8,9 The reasons for these
variations are unknown but could be related to different heparin
preparations,10 patient population-dependent factors, or
even different laboratory techniques used to detect the antibodies
responsible for HIT.
Two general types of laboratory assay are used to confirm the
diagnosis. Activation assays, such as the platelet serotonin release
assay, detect HIT-IgG on the basis of their ability to activate
platelets.11-13 Antigen assays, such as a solid-phase immunoassay, detect the binding of antibodies to immobilized platelet factor 4-heparin complexes.4-7,14,15 Despite the
increasing use of these assays, few studies have compared their
clinical usefulness in diagnosing HIT. Those
studies14,16-18 comparing activation and antigen assays
typically have been limited to investigating patient samples that were
referred with the clinical suspicion of HIT (high pretest probability).
However, such an approach does not allow the determination of test
specificity. Furthermore, systematic serologic studies of patients
receiving heparin (low pretest probability) have generally been too
small to evaluate sensitivity. In addition, these studies have
generally focused on single patient populations.
In this report, we describe the results of laboratory testing for
HIT-IgG using both activation and antigen assays in 744 prospectively
studied patients. These patients were from 3 different clinical
treatment settings: cardiac surgery patients receiving unfractionated
heparin (UFH), orthopedic surgery patients receiving UFH, and
orthopedic surgery patients receiving low-molecular-weight heparin
(LMWH). The results of this study indicate that there is an unexpected
dissociation between the formation of HIT-IgG and the risk for HIT
among patients in whom antibodies form that is patient population dependent.
Patient populations
The orthopedic-UFH group consisted of a group of 205 patients who
received porcine mucosal UFH (Calciparine; Laboratoires Anglo-French,
Dorval, Quebec, Canada), 7500 IU every 12 hours by subcutaneous
injection for up to 14 days or discharge. These patients had
participated in a randomized clinical trial of UFH versus LMWH given
for antithrombotic prophylaxis after hip arthroplasty surgery (study
A). Primary trial results and a related study of HIT using only the
platelet 14C-labeled serotonin-release assay have been
reported.10,19 In the current study, the patients' plasma
samples were studied using the antigen assay as well.
The orthopedic-LMWH group (n = 439) consisted of patients from 2 studies who received LMWH for antithrombotic prophylaxis after
orthopedic surgery. The first group (study A) consisted of 182 patients
who received LMWH (enoxaparin; Lovenox; Rhône-Poulenc Rorer,
Montreal, Quebec, Canada), 30 mg every 12 hours by subcutaneous injection for up to 14 days or discharge. These patients had also participated in the trial described previously.10,19 The
second orthopedic-LMWH group (study B) consisted of 257 patients who received postoperative LMWH prophylaxis after orthopedic surgery (hip
arthroplasty, n = 105; knee arthroplasty, n = 152). These patients
received 1 of 3 LMWH preparations based on the current hospital
practice at the time of participation in the study The third patient population consisted of a cardiac-UFH group
comprised of 100 patients undergoing elective valve replacement surgery
(69 aortic valve replacement, 29 mitral valve replacement, 2 both).
Porcine mucosal heparin (Hepalean; Organon Teknika, Scarborough, Ontario, Canada), 400 U/kg, was given before cardiopulmonary bypass; additional heparin was given by bolus as needed to achieve and maintain
an intraoperative whole blood activated clotting time of more than 400 seconds. These patients also received subcutaneous heparin (porcine
mucosal heparin; Heparin; Leo), 5000 IU every 8 hours by subcutaneous
injection, until they were adequately anticoagulated with warfarin or
mobilized. Antiplatelet drugs such as aspirin were not routinely given
to this patient population undergoing valve replacement surgery.
These studies were approved by the Institutional Review Board, and
patients gave their informed consent. Laboratory testing for HIT-IgG
was performed after the patients had been discharged from the hospital,
and no results were used to influence clinical decisions.
Activation assay
Antigen assay Patient plasma and serum samples were also evaluated using a platelet factor 4-heparin enzyme immunoassay, as previously described,15 except that an alkaline phosphatase-conjugated goat antibody specific for human IgG (Fc) replaced the conjugated goat antibody for human IgG (heavy and light chain-specific). By measuring IgG antibodies only, we facilitated comparison with the activation assay, which detects platelet activation through IgG antibodies.3 One hundred samples from healthy blood donors were assayed, and the upper limit of the normal range of optical density (OD) was established as the mean + 3 SD (OD = 0.45). Each assay included pooled negative controls (OD 0.2), high-negative control pool (0.2 < OD < 0.45), known negative control, known positive control (OD > 1.5),
and weak positive control (0.45 < OD < 1.5).
Definitions We defined possible HIT as a 50% or greater fall in the platelet count from the postoperative peak that occurred between days 5 to 14 after surgery, unless another cause for the thrombocytopenia was readily apparent (eg, culture-positive septicemia) or the platelet count recovered during continued heparin treatment. This definition of thrombocytopenia has the best correlation with the formation of HIT-IgG20 and is appropriate for a postoperative patient population in whom thrombocytosis commonly occurs between postoperative days 5 to 14. Heparin-induced thrombocytopenia (HIT) was defined when a patient with possible HIT also had positive results of at least one laboratory assay for HIT-IgG (by activation or antigen assay, or both).Comparison of activation and antigen assays Because both diagnostic assays are quantitative measurements, we used receiver operating characteristic (ROC) curve analysis to compare the sensitivity-specificity tradeoff at various diagnostic cutoff points defining negative and positive test results. Sensitivity of each assay was defined as the proportion (in percentage) giving a positive test result among the patients with possible HIT. Specificity of each assay was defined as the proportion (in percentage) of patients who did not meet the study definition for possible HIT and who tested negative for the assay under consideration. The ROC curve analysis was performed only for the orthopedic patients because this patient group had a relatively large number of patients with possible HIT and additional patients with subclinical HIT-IgG seroconversion (see "Results").Our standard antigen assay uses a 1:50 dilution of test serum or plasma. To investigate whether greater sample dilution would improve the sensitivity-specificity tradeoff of the antigen assay, we also performed the assay using the following sample dilutions: 1/50, 1/75, 1/100, 1/150, 1/250, 1/500, 1/750, 1/1000, 1/2500, and 1/5000. After these preliminary studies, we systematically studied the orthopedic patient samples that tested positive in the antigen assay (at 1/50), at the following additional dilutions: 1/100, 1/250, 1/500, and 1/750. The data obtained were used to calculate ROC curves. Thus, we investigated whether there might be a greater likelihood that blood samples from patients with subclinical HIT-IgG formation would test negative on further sample dilution than blood samples from patients with possible HIT. In other words, could the sensitivity-specificity tradeoff be improved on sample dilution? If so, there would be the potential for greater diagnostic specificity for the antigen assay, without significant loss of sensitivity, if the antigen assay was performed at a higher dilution. Statistical analysis Comparisons of proportions between groups were performed using the Fisher exact test.21 An associated method developed by Gart22 was used for computing confidence intervals around the odds ratio. We performed logistic regression analysis23 to determine the impact of either heparin preparation (UFH compared with LMWH) and the type of patient population (cardiac compared with orthopedic patients) with respect to the frequency of HIT-IgG formation and the proportion of antibody-positive patients in whom possible HIT developed. Analyses were performed separately for activation and antigen test results. All quoted P values were 2-sided.
Frequency of possible heparin-induced thrombocytopenia Eighteen of the 744 prospectively studied patients had a 50% or greater decrease in platelet count that began between postoperative days 5 and 14. Fifteen of these patients met the criteria for possible HIT (Table 1). All 15 patients who were identified as possibly having HIT also tested positive for HIT-IgG using both the activation and the antigen assays. The frequency of HIT was highest (4.9%) in the orthopedic-UFH patients and was relatively low in both the orthopedic-LMWH patients (0.9%) and the cardiac-UFH patients (1%). One or more thrombotic events occurred in 9 (60%) of these 15 patients; 7 patients had venous thromboembolism, 1 patient had unilateral adrenal hemorrhagic infarction, and 1 patient had arterial thrombosis.
Three patients whose platelet counts fell by 50% or more between postoperative days 5 to 14 did not meet the criteria for possible HIT. Thrombocytopenia developed in association with colon perforation and septicemia in two orthopedic patients, one treated with UFH and one treated with LMWH. Both died. In both patients, however, platelet counts recovered during continued heparin use. A third patient had a 59% decrease in platelet count in association with pulmonary embolism, but full platelet count recovery during treatment with therapeutic-dose UFH occurred. All 3 patients tested negative for HIT-IgG by activation and antigen assays. Frequency of HIT-IgG antibody formation Figure 1 summarizes the results of the laboratory assays for HIT-IgG among the 3 patient treatment groups studied. With both antigen and activation assays, we observed the highest antibody-positivity rate (by conventional positive cutoff) among the cardiac patients (50% and 20%, respectively), followed by the orthopedic-UFH (14.1% and 9.3%) and the orthopedic-LMWH patients (7.5% and 3.2%). By logistic regression analysis (Table 1), we found that 2 variables were associated with a higher frequency of HIT-IgG formation: cardiac surgery and use of UFH.
We observed dissociation between the frequency of HIT-IgG formation and the risk of HIT that was patient population dependent. Among patients in whom antibodies formed, HIT was more likely to develop in orthopedic patients than in cardiac patients (Table 1). Among patients who tested positive by the activation assay and who received UFH, HIT developed in 52.6% of orthopedic patients but only 5% of cardiac surgery patients (odds ratio, 21.1 [95% CI, 2.2 to 962.8]; P = .001). Among patients who tested positive by antigen assay and who received UFH, HIT developed in 34.5% of orthopedic patients and only 2.0% of cardiac surgery patients (odds ratio, 25.8 [95% CI, 3.2 to 1141]; P < .001). We investigated the duration of heparin treatment as a reason fewer patients with HIT-IgG in the cardiac group had possible HIT. At the time of heart surgery, the cardiac patients received very high doses of heparin. After surgery, both the cardiac and the orthopedic patients who received UFH were given the same dose (15 000 U/d). Although orthopedic patients received UFH for a greater duration than cardiac patients (9.2 ± 2.2 vs 5.1 ± 2.2 days; P < .001), the duration of heparin exposure was not the major reason for the higher frequency of HIT in orthopedic patients. For example, among patients in whom HIT-IgG formed and was detectable by both assays and who received UFH for 5 or more days, there was a greater likelihood of the onset of platelet count decrease by day 5 in the orthopedic patients than in the cardiac patients (5 of 19 compared with 0 of 15; P = .053). A similar trend was noted when the analysis was restricted to patients who received heparin for at least 6 days: 0 of 8 patients in the cardiac group had a platelet count decrease indicative of possible HIT, whereas 7 of 19 orthopedic patients had a platelet count decrease by day 6 (P = .068). This suggests that orthopedic patients are at greater risk for HIT for reasons other than longer duration of UFH use. Indeed, the cardiac surgery patient in whom HIT developed (postoperative day 7, complicated by unilateral adrenal necrosis) received UFH only until the second day after surgery. Diagnostic usefulness of laboratory assays for heparin-induced thrombocytopenia Figure 1 shows that most patients with HIT (indicated by arrows) had strong positive test results for HIT-IgG using either assay: more than 90% serotonin release (activation assay) and greater than 1.0 OD (antigen assay). Figure 2 compares these 2 assays by sensitivity-specificity tradeoff analysis (ROC curve analysis) at various cutoff points between positive and negative results for the orthopedic patients. Because activation and antigen assays were positive at their conventional cutoff points (more than 20% serotonin release and greater than 0.45 OD, respectively) for all 15 patients with possible HIT identified in the prospective studies, the sensitivity of each assay for HIT was high (100%). However, because the antigen assay was more likely to be positive in patients in whom HIT did not develop, the activation assay had superior operating characteristics (ie, greater diagnostic specificity) over all values of the diagnostic cutoff between positive and negative tests. The activation assay remained superior even when the antigen assay was performed at greater dilutions. For orthopedic patients, test specificity (at the conventional cutoff points) for the activation and antigen assays was 97% and 92%, respectively. For cardiac patients, the corresponding specificities were only 81% and 51% because possible HIT developed in fewer cardiac surgery patients, even though HIT-IgG antibodies formed in more.
Immune HIT continues to be one of the most important IgG-mediated drug reactions that physicians must manage. The association between anticoagulant-induced platelet count decrease and unexpected arterial and venous thrombosis represents a paradox of considerable clinical interest. Another confounding factor is the unusual composition of the target antigen of the disorder, which is a stoichiometrically defined complex between a native platelet protein, platelet factor 4, and heparin.4-7 Antibodies against this antigenic complex can be detected using either of 2 classes of assay. One type measures the HIT-IgG antibody-induced activation of platelets in a heparin-dependent fashion,11-13 and the other detects HIT-IgG that recognize immobilized platelet factor 4-heparin antigen.4-7,14,15 Despite these recent insights into the pathogenesis of HIT, there remain important unresolved issues. For example, it is unknown why the frequency of HIT differs among patients in prospective studies.8,9 Explanations include differences in risk for forming, and clinical effects arising from, HIT-IgG antibodies that are patient population dependent. Differences in the diagnostic significance between the 2 different tests for HIT-IgG could also explain differences between studies. For these reasons, we performed both activation and antigen assays on blood samples from 744 patients studied prospectively for HIT who were treated either with UFH or LMWH, after either cardiac or orthopedic surgery. The results of this study indicate a patient population-dependent dissociation between the risk for HIT-IgG formation and the risk for HIT among patients in whom antibodies formed. The highest frequency of HIT-IgG formation occurred after cardiac surgery: 50% of these patients had antibodies detected by antigen assay, and 20% had antibodies detected by activation assay. However, the clinical syndrome of HIT was uncommon in this group. In contrast, only 14.1% and 9.3%, respectively, of patients who received UFH after orthopedic surgery had HIT-IgG detected by antigen and activation assay. Yet this was the patient population in whom HIT was most likely to develop. Fewer orthopedic patients developed antibodies (7.5% and 3.2%, respectively) when treated with LMWH. Logistic regression analysis showed that patient population and type of heparin preparation determined antibody formation (Table 1). Although cardiac surgery patients had the highest frequency of antibody formation, among those patients who developed antibodies, the orthopedic patients were about 20 times more likely (by odds ratio) to have HIT. Other investigators have also shown high frequencies of antibody formation in cardiac surgery patients without associated thrombocytopenia.24-26 In 2 of these studies,24,25 postoperative heparin prophylaxis was not given, so the risk for HIT might have been reduced. In the third study,26 no thrombocytopenia occurred among 16 patients receiving postoperative UFH who had positive antigen assay. Because these studies did not include large comparative patient populations, it was not possible to determine whether there were population-dependent differences in HIT risk. Our study was not designed to determine the explanation for patient population-dependent differences in frequency and clinical significance of HIT-IgG formation. Reasons for the high frequency of antibody formation among cardiac patients could include high doses of intraoperative heparin or the release of platelet factor 4 from platelets during contact between blood and the cardiopulmonary bypass apparatus27,28; together these could increase the risk for antibody formation. Alternatively, various proinflammatory factors associated with orthopedic surgery could influence the pathogenicity of antibodies in this patient population.29 Aspirin use could not have accounted for the differences because the cardiac surgery population underwent valve replacement surgery and was routinely given anticoagulant rather than antiplatelet drugs. We observed that activation and antigen assays are very sensitive for HIT. However, the antigen assay was more likely to detect antibodies that did not cause thrombocytopenia, ie, the diagnostic specificity for clinical HIT was lower. In addition, the operating characteristics of the antigen assay did not improve when performed using samples tested at a greater dilution (Figure 2). This finding, plus the observation that most patients with possible HIT had antibodies that caused strong platelet activation (serotonin release greater than 90%; see Figure 1), suggests that the activation assay may be better able than the antigen assay to detect pathogenic antibodies with potent platelet-activating properties. Indeed, preliminary HIT antibody purification studies by Pouplard et al30 suggest that only a relatively small subset of anti-PF4-heparin antibodies has a potent platelet-activating profile.30 If activation assays are better able to detect clinically significant HIT antibodies, the situation would appear to parallel somewhat that of laboratory testing for the antiphospholipid antibody syndrome: a biologic assay (the nonspecific lupus inhibitor) has greater specificity for thrombosis than the antigen assay (anticardiolipin antibodies).31 Our data also suggest that the patient population influences the diagnostic significance of HIT-IgG test results. For either activation or antigen assay, a positive result in an orthopedic patient may be more specific for clinical HIT. The current study indicates that HIT is a more complicated syndrome than might be expected for a drug-induced, immune-mediated thrombocytopenic disorder. There exist patient population-dependent differences in risk for HIT-IgG formation and in the thrombocytopenic potential of antibodies. There also exist differences in the diagnostic usefulness of the 2 different classes of assays to detect these antibodies. The complex nature of this syndrome may relate to the compound nature of the responsible antigen, in which both drug and autologous protein concentrations could vary in different clinical settings.
We thank Jean I. Russett and Judith Johnson for organizing the collection of plasma samples in these patients, Carol A. Smith for technical assistance with some of the assays, and Prof Robin Roberts for assistance in the statistical analysis.
Submitted November 2, 1999; accepted May 5, 2000.
Supported by operating grants A2449 and B3763 from the Heart and Stroke Foundation of Ontario (T.E.W.) and by a Research Scholarship from the Heart and Stroke Foundation of Canada (T.E.W.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Theodore E. Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences Centre, Hamilton General Site, 237 Barton St East, Hamilton, Ontario L8L 2X2, Canada; e-mail: twarken{at}fhs.mcmaster.ca.
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© 2000 by The American Society of Hematology.
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S. G. Shelat, A. Tomaski, and E. S. Pollak Serologic Results in >1000 Patients With Suspected Heparin-Induced Thrombocytopenia Clinical and Applied Thrombosis/Hemostasis, October 1, 2008; 14(4): 410 - 414. [Abstract] [PDF]
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J. G. Kelton and T. E. Warkentin Heparin-induced thrombocytopenia: a historical perspective Blood, October 1, 2008; 112(7): 2607 - 2616. [Full Text] [PDF]
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M. P. Mullen, D. L. Wessel, K. C. Thomas, K. Gauvreau, E. J. Neufeld, F. X. McGowan Jr, and J. A. DiNardo The Incidence and Implications of Anti-Heparin-Platelet Factor 4 Antibody Formation in a Pediatric Cardiac Surgical Population Anesth. Analg., August 1, 2008; 107(2): 371 - 378. [Abstract] [Full Text] [PDF]
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 T. E. Warkentin, A. Greinacher, A. Koster, and A. M. Lincoff Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 340S - 380S. [Abstract] [Full Text] [PDF]
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J. H. Levy and N. F. Adkinson Jr Anaphylaxis During Cardiac Surgery: Implications for Clinicians Anesth. Analg., February 1, 2008; 106(2): 392 - 403. [Abstract] [Full Text] [PDF]
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 G. B. F. Oliveira, E. M. Crespo, R. C. Becker, E. F. Honeycutt, C. S. Abrams, K. J. Anstrom, P. B. Berger, L. D. Davidson-Ray, E. L. Eisenstein, N. S. Kleiman, et al. Incidence and Prognostic Significance of Thrombocytopenia in Patients Treated With Prolonged Heparin Therapy Arch Intern Med, January 14, 2008; 168(1): 94 - 102. [Abstract] [Full Text] [PDF]
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M.F. Barginear, L. Donahue, S.L. Allen, D.R. Budman, T. Bradley, M. Bhaskaran, and I. Shapira Heparin-Induced Thrombocytopenia Complicating Hemodialysis Clinical and Applied Thrombosis/Hemostasis, January 1, 2008; 14(1): 105 - 107. [Abstract] [PDF]
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S. Suvarna, B. Espinasse, R. Qi, R. Lubica, M. Poncz, D. B. Cines, M. R. Wiesner, and G. M. Arepally Determinants of PF4/heparin immunogenicity Blood, December 15, 2007; 110(13): 4253 - 4260. [Abstract] [Full Text] [PDF]
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T. A. Morris, S. Castrejon, G. Devendra, and A. C. Gamst No Difference in Risk for Thrombocytopenia During Treatment of Pulmonary Embolism and Deep Venous Thrombosis With Either Low-Molecular-Weight Heparin or Unfractionated Heparin: A Metaanalysis Chest, October 1, 2007; 132(4): 1131 - 1139. [Abstract] [Full Text] [PDF]
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J. H. Levy, K. A. Tanaka, and M. J. Hursting Reducing Thrombotic Complications in the Perioperative Setting: An Update on Heparin-Induced Thrombocytopenia Anesth. Analg., September 1, 2007; 105(3): 570 - 582. [Abstract] [Full Text] [PDF]
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H. Tsukui, A. Abla, J. J. Teuteberg, D. M. McNamara, M. A. Mathier, L. M. Cadaret, and R. L. Kormos Cerebrovascular accidents in patients with a ventricular assist device J. Thorac. Cardiovasc. Surg., July 1, 2007; 134(1): 114 - 123. [Abstract] [Full Text] [PDF]
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T. E. Warkentin and J. W. Eikelboom Who Is (Still) Getting HIT? Chest, June 1, 2007; 131(6): 1620 - 1622. [Full Text] [PDF]
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M. A. Smythe, J. M. Koerber, and J. C. Mattson The Incidence of Recognized Heparin-Induced Thrombocytopenia in a Large, Tertiary Care Teaching Hospital Chest, June 1, 2007; 131(6): 1644 - 1649. [Abstract] [Full Text] [PDF]
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D. C. Kress, S. Aronson, M. L. McDonald, M. I. Malik, A. B. Divgi, A. J. Tector, F. X. Downey III, A. J. Anderson, M. Stone, and C. Clancy Positive Heparin-Platelet Factor 4 Antibody Complex and Cardiac Surgical Outcomes Ann. Thorac. Surg., May 1, 2007; 83(5): 1737 - 1743. [Abstract] [Full Text] [PDF]
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B. M. Everett, R. Yeh, S. Y. Foo, D. Criss, E. M. Van Cott, M. Laposata, E. G. Avery, W. D. Hoffman, J. Walker, D. Torchiana, et al. Prevalence of Heparin/Platelet Factor 4 Antibodies Before and After Cardiac Surgery Ann. Thorac. Surg., February 1, 2007; 83(2): 592 - 597. [Abstract] [Full Text] [PDF]
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T. E. Warkentin and M. A. Crowther When is HIT Really HIT? Ann. Thorac. Surg., January 1, 2007; 83(1): 21 - 23. [Full Text] [PDF]
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A. Koster, S. Huebler, E. Potapov, O. Meyer, M. Jurmann, Y. Weng, M. Pasic, T. Drews, H. Kuppe, M. Loebe, et al. Impact of Heparin-Induced Thrombocytopenia on Outcome in Patients with Ventricular Assist Device Support: Single-Institution Experience in 358 Consecutive Patients Ann. Thorac. Surg., January 1, 2007; 83(1): 72 - 76. [Abstract] [Full Text] [PDF]
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S. Schenk, A. El-Banayosy, W. Prohaska, L. Arusoglu, M. Morshuis, W. Koester-Eiserfunke, L. Kizner, E. Murray, P. Eichler, R. Koerfer, et al. Heparin-induced thrombocytopenia in patients receiving mechanical circulatory support J. Thorac. Cardiovasc. Surg., June 1, 2006; 131(6): 1373 - 1381. [Abstract] [Full Text] [PDF]
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B. E. Lewis, D. E. Wallis, M. J. Hursting, R. L. Levine, and F. Leya Effects of Argatroban Therapy, Demographic Variables, and Platelet Count on Thrombotic Risks in Heparin-Induced Thrombocytopenia Chest, June 1, 2006; 129(6): 1407 - 1416. [Abstract] [Full Text] [PDF]
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R. L. Levine, M. J. Hursting, and D. McCollum Argatroban Therapy in Heparin-Induced Thrombocytopenia With Hepatic Dysfunction Chest, May 1, 2006; 129(5): 1167 - 1175. [Abstract] [Full Text] [PDF]
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E. Bennett-Guerrero, T. F. Slaughter, W. D. White, I. J. Welsby, C. S. Greenberg, H. El-Moalem, and T. L. Ortel Preoperative anti-PF4/heparin antibody level predicts adverse outcome after cardiac surgery J. Thorac. Cardiovasc. Surg., December 1, 2005; 130(6): 1567 - 1572. [Abstract] [Full Text] [PDF]
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P. Prandoni, S. Siragusa, B. Girolami, F. Fabris, and for the BELZONI Investigators Group The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a prospective cohort study Blood, November 1, 2005; 106(9): 3049 - 3054. [Abstract] [Full Text] [PDF]
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N. Martel, J. Lee, and P. S. Wells Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis Blood, October 15, 2005; 106(8): 2710 - 2715. [Abstract] [Full Text] [PDF]
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B. V Reddy, E. J Grossman, S. A Trevino, M. J Hursting, and P. T Murray Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia Requiring Renal Replacement Therapy Ann. Pharmacother., October 1, 2005; 39(10): 1601 - 1605. [Abstract] [Full Text] [PDF]
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S. Suvarna, L. Rauova, E. K. E. McCracken, C. M. Goss, B. S. Sachais, S. E. McKenzie, M. P. Reilly, M. D. Gunn, D. B. Cines, M. Poncz, et al. PF4/heparin complexes are T cell-dependent antigens Blood, August 1, 2005; 106(3): 929 - 931. [Abstract] [Full Text] [PDF]
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M. J. Hursting, B. E. Lewis, and D. E. Macfarlane Transitioning from Argatroban to Warfarin Therapy in Patients with Heparin-induced Thrombocytopenia Clinical and Applied Thrombosis/Hemostasis, July 1, 2005; 11(3): 279 - 287. [Abstract] [PDF]
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 I.-K. Jang and M. J. Hursting When Heparins Promote Thrombosis: Review of Heparin-Induced Thrombocytopenia Circulation, May 24, 2005; 111(20): 2671 - 2683. [Full Text] [PDF]
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R. L. Levine Finding Haystacks Full of Needles: From Opus to Osler Chest, May 1, 2005; 127(5): 1488 - 1490. [Full Text] [PDF]
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J. G. Kelton The Pathophysiology of Heparin-Induced Thrombocytopenia: Biological Basis for Treatment Chest, February 1, 2005; 127(2_suppl): 9S - 20S. [Full Text] [PDF]
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T. E. Warkentin New Approaches to the Diagnosis of Heparin-Induced Thrombocytopenia Chest, February 1, 2005; 127(2_suppl): 35S - 45S. [Abstract] [Full Text] [PDF]
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W. H. Matthai Jr Thrombocytopenia in Cardiovascular Patients: Diagnosis and Management Chest, February 1, 2005; 127(2_suppl): 46S - 52S. [Abstract] [Full Text] [PDF]
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 A. T. Gurbuz, W. G. Elliott, and A. A. Zia Heparin-induced thrombocytopenia in the cardiovascular patient: diagnostic and treatment guidelines Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 138 - 149. [Abstract] [Full Text] [PDF]
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P. Savi, B. H. Chong, A. Greinacher, Y. Gruel, J. G. Kelton, T. E. Warkentin, P. Eichler, D. Meuleman, M. Petitou, J.-P. Herault, et al. Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin Blood, January 1, 2005; 105(1): 139 - 144. [Abstract] [Full Text] [PDF]
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L. Rice Heparin-Induced Thrombocytopenia: Myths and Misconceptions (That Will Cause Trouble for You and Your Patient) Arch Intern Med, October 11, 2004; 164(18): 1961 - 1964. [Full Text] [PDF]
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M. A. Smythe, W. E. Dager, and N. M. Patel Managing Complications of Anticoagulant Therapy Journal of Pharmacy Practice, October 1, 2004; 17(5): 327 - 346. [Abstract] [PDF]
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T. E. Warkentin and A. Greinacher Heparin-Induced Thrombocytopenia: Recognition, Treatment, and Prevention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 311S - 337S. [Abstract] [Full Text] [PDF]
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U. Harbrecht, B. Bastians, A. Kredteck, P. Hanfland, T. Klockgether, and C. Pohl Heparin-induced thrombocytopenia in neurologic disease treated with unfractionated heparin Neurology, February 24, 2004; 62(4): 657 - 659. [Abstract] [Full Text] [PDF]
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G. M. Palatianos, C. N. Foroulis, M. I. Vassili, P. Matsouka, G. M. Astras, G. H. Kantidakis, E. Iliopoulou, and E. N. Melissari Preoperative detection and management of immune heparin-induced thrombocytopenia in patients undergoing heart surgery with iloprost J. Thorac. Cardiovasc. Surg., February 1, 2004; 127(2): 548 - 554. [Abstract] [Full Text] [PDF]
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W. E Dager and R. H White Low-Molecular-Weight Heparin-Induced Thrombocytopenia in a Child Ann. Pharmacother., February 1, 2004; 38(2): 247 - 250. [Abstract] [Full Text] [PDF]
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 A. Koster and T. Fischer Management of Patients with Heparin-Induced Thrombocytopenia During Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2003; 7(4): 411 - 416. [Abstract] [PDF]
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T. E. Warkentin and A. Greinacher Heparin-induced thrombocytopenia and cardiac surgery Ann. Thorac. Surg., December 1, 2003; 76(6): 2121 - 2131. [Abstract] [Full Text] [PDF]
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T. E. Warkentin, R. S. Roberts, J. Hirsh, and J. G. Kelton An Improved Definition of Immune Heparin-Induced Thrombocytopenia in Postoperative Orthopedic Patients Arch Intern Med, November 10, 2003; 163(20): 2518 - 2524. [Abstract] [Full Text] [PDF]
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B. E. Lewis, D. E. Wallis, F. Leya, M. J. Hursting, and J. G. Kelton Argatroban Anticoagulation in Patients With Heparin-Induced Thrombocytopenia Arch Intern Med, August 11, 2003; 163(15): 1849 - 1856. [Abstract] [Full Text] [PDF]
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T. E. Warkentin and A. Greinacher Heparin-induced thrombocytopenia and cardiac surgery Ann. Thorac. Surg., August 1, 2003; 76(2): 638 - 648. [Abstract] [Full Text] [PDF]
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B. Girolami, P. Prandoni, P. M. Stefani, C. Tanduo, P. Sabbion, P. Eichler, R. Ramon, G. Baggio, F. Fabris, and A. Girolami The incidence of heparin-induced thrombocytopenia in hospitalized medical patients treated with subcutaneous unfractionated heparin: a prospective cohort study Blood, April 15, 2003; 101(8): 2955 - 2959. [Abstract] [Full Text] [PDF]
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N. Lubenow, S. Selleng, H.-G. Wollert, P. Eichler, B. Mullejans, and A. Greinacher Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use Ann. Thorac. Surg., February 1, 2003; 75(2): 577 - 579. [Abstract] [Full Text] [PDF]
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T. E. Warkentin Pork or beef? Ann. Thorac. Surg., January 1, 2003; 75(1): 15 - 16. [Full Text] [PDF]
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T. E. Warkentin Invited commentary Ann. Thorac. Surg., January 1, 2003; 75(1): 284 - 285. [Full Text] [PDF]
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T. E. Warkentin, W. C. Aird, and J. H. Rand Platelet-Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome Hematology, January 1, 2003; 2003(1): 497 - 519. [Abstract] [Full Text] [PDF]
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B. M. Alving How I treat heparin-induced thrombocytopenia and thrombosis Blood, January 1, 2003; 101(1): 31 - 37. [Full Text] [PDF]
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E. Lindhoff-Last, B. Wenning, M. Stein, F. Gerdsen, R. Bauersachs, and R. Wagnert Risk Factors and Long-term Follow-up of Patients with the Immune Type of Heparin-Induced Thrombocytopenia Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 347 - 352. [Abstract] [PDF]
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W. C. Aird and E. J. Mark Case 15-2002 - A 53-Year-Old Man with a Myocardial Infarct and Thromboses after Coronary-Artery Bypass Grafting N. Engl. J. Med., May 16, 2002; 346(20): 1562 - 1570. [Full Text] [PDF]
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Z. Q. Li, W. Liu, K. S. Park, B. S. Sachais, G. M. Arepally, D. B. Cines, and M. Poncz Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody Blood, February 15, 2002; 99(4): 1230 - 1236. [Abstract] [Full Text] [PDF]
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T. E. Warkentin and J. G. Kelton Delayed-Onset Heparin-Induced Thrombocytopenia and Thrombosis Ann Intern Med, October 2, 2001; 135(7): 502 - 506. [Abstract] [Full Text] [PDF]
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E. Lindhoff-Last, C. Betz, and R. Bauersachs Use of a Low-Molecular-Weight Heparinoid (Danaparoid Sodium) for Continuous Renal Replacement Therapy in Intensive Care Patients Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 300 - 304. [Abstract] [PDF]
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G. M. Arepally and I. M. Mayer Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8 Blood, August 15, 2001; 98(4): 1252 - 1254. [Abstract] [Full Text] [PDF]
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J. Hirsh, S. S. Anand, J. L. Halperin, and V. Fuster Guide to Anticoagulant Therapy: Heparin : A Statement for Healthcare Professionals From the American Heart Association Circulation, June 19, 2001; 103(24): 2994 - 3018. [Full Text] [PDF]
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T. E. Warkentin and J. G. Kelton Temporal Aspects of Heparin-Induced Thrombocytopenia N. Engl. J. Med., April 26, 2001; 344(17): 1286 - 1292. [Abstract] [Full Text] [PDF]
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K. R. McCrae, J. B. Bussel, P. M. Mannucci, G. Remuzzi, and D. B. Cines Platelets: An Update on Diagnosis and Management of Thrombocytopenic Disorders Hematology, January 1, 2001; 2001(1): 282 - 305. [Abstract] [Full Text] [PDF]
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J. A. Ginsberg, M. A. Crowther, R. H. White, and T. L. Ortel Anticoagulation Therapy Hematology, January 1, 2001; 2001(1): 339 - 357. [Abstract] [Full Text] [PDF]
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J. Hirsh, T. E. Warkentin, S. G. Shaughnessy, S. S. Anand, J. L. Halperin, R. Raschke, C. Granger, E. M. Ohman, and J. E. Dalen Heparin and Low-Molecular-Weight Heparin Mechanisms of Action, Pharmacokinetics, Dosing, Monitoring, Efficacy, and Safety Chest, January 1, 2001; 119 (2009): 64S - 94S. [Full Text] [PDF]
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Top
Abstract
Introduction
enoxaparin (Lovenox; Rhône-Poulenc Rorer), 30 mg twice daily by subcutaneous injection, n = 70; tinzaparin (Innohep; Leo, Ajax, Ontario, Canada), 3000 U twice daily by subcutaneous injection, n = 2; or dalteparin (Fragmin; Pharmacia, Mississanga, Ontario, Canada), 3000 U twice daily
by subcutaneous injection, n = 185. For orthopedic patients, heparin
administration was usually started on the first postoperative day and
continued until discharge or full mobilization. Although 3 different
LMWH preparations were used, we made an a priori decision to analyze
all the data as one orthopedic-LMWH group.
70°C before testing. Using a
predetermined algorithm, samples were considered positive if all the
following criteria were met: (1) 20% or greater serotonin release at
0.1 U/mL heparin; (2) at least 50% inhibition of platelet activation by both an Fc receptor-blocking monoclonal antibody (IV.3) and a high
concentration of heparin (100 U/mL); (3) appropriate activation profiles observed with 3 positive controls (including 2 "weak" sera, ie, giving 20%-50% serotonin release) and one negative
control serum.
; thin broken lines indicating higher dilutions
[1/100, 1/250, 1/500, 1/750], as indicated). Although the
sensitivity-specificity trade-off analysis was performed at 0.1-OD
increments, the data points for cutoff of 0.5 or more, 1.0 or more, and
2.0 or more are shown. The ROC curve analysis suggests that both the
activation and the antigen assays are highly informative for diagnosing
HIT in this patient population. For comparison, the inset shows the
full-scale ROC curve analysis for both activation and (at conventional
1/50 dilution) antigen assays together with a (theoretical)
noninformative assay (shown as dashed line). The data indicate that the
operating characteristics of the antigen assay are not improved by
performing the assay using a greater dilution of patient
serum/plasma.