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Original Research: Antithrombotic Therapy |

The Role for Optical Density in Heparin-Induced ThrombocytopeniaOptical Density: A Cohort Study FREE TO VIEW

Chee M. Chan, MD, MPH, FCCP; Christian J. Woods, MD, FCCP; Theodore E. Warkentin, MD; Jo-Ann I. Sheppard, BSc; Andrew F. Shorr, MD, MPH, FCCP
Author and Funding Information

From the Pulmonary and Critical Care Section (Drs Chan, Woods, and Shorr), MedStar Washington Hospital Center, and Georgetown University Medical Center, Washington, DC; and the Department of Pathology and Molecular Medicine (Dr Warkentin and Ms Sheppard), Hamilton Regional Laboratory Program and McMaster University, Hamilton, ON, Canada.

CORRESPONDENCE TO: Chee M. Chan, MD, MPH, FCCP, Pulmonary and Critical Care Medicine, MedStar Washington Hospital Center, 110 Irving St NW, Washington, DC 20010; e-mail: chee.m.chan@medstar.net


FOR EDITORIAL COMMENT SEE PAGE 1

FUNDING/SUPPORT: Funding support was provided by GlaxoSmithKline plc as an unrestricted grant to the MedStar Washington Hospital Center and to McMaster University.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):55-61. doi:10.1378/chest.14-1417
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BACKGROUND:  Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin utilization. An enzyme-linked immunosorbent assay (ELISA) is usually performed to assist in the diagnosis of HIT. ELISAs tend to be sensitive but lack specificity. We sought to use a new cutoff to define a positive HIT ELISA.

METHODS:  We conducted a prospective observational study of hospitalized patients undergoing ELISA testing. All patients who underwent ELISA testing were eligible for inclusion (n = 496). Irrespective of the results, all subjects had confirmatory testing with a serotonin release assay (SRA). We compared a threshold optical density (OD) > 1.00 to the current definition of a positive ELISA (OD > 0.40) as a screening test for a positive SRA. We used sensitivity, specificity, and area under the receiver operating curve to determine whether an OD > 1.00 would improve diagnostic accuracy for HIT.

RESULTS:  The SRA was positive in 10 patients (prevalence, 2.0%). Adjusting the definition of a positive HIT ELISA to > 1.00 maintained the sensitivity and negative predictive value at 100% in the cohort. The positive predictive value of the higher cutoff OD was more than triple the positive predictive value of an OD > 0.40 (41.7% vs 13.3%). No patient with a positive SRA had an OD measurement ≤ 1.00.

CONCLUSIONS:  Increasing the OD threshold enhances specificity without noticeably compromising sensitivity. Altering the definition of the HIT ELISA could prevent unnecessary testing and/or treatment with non-heparin-based anticoagulants in patients with possible HIT.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00946400; URL: www.clinicaltrials.gov

Figures in this Article

Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin utilization that is strongly associated with venous or arterial thrombosis.1 Despite leading to thrombocytopenia, the generation of heparin-dependent platelet-activating antibodies is the hallmark of HIT.13 Certain types of patients, such as those undergoing major cardiac surgery (MCS) who receive postoperative anticoagulation treatment, face an increased risk for HIT.14

Although multiple guidelines recommend treatment approaches for HIT, the diagnosis remains clinically challenging.5,6 Several risk stratification schemes exist to aid clinicians in evaluating patients for HIT.6,7 Irrespective of the implementation of clinical risk stratification, diagnosing HIT usually requires confirmatory testing to document the presence of heparin-dependent, platelet-activating antibodies.3,8 Two “functional” washed platelet assays exist, the serotonin release assay (SRA) and the heparin-induced platelet activation assay. Each represents a “gold standard” for diagnosing HIT, as washed platelets enhance diagnostic sensitivity and specificity for the detection of pathogenic HIT antibodies.

In the United States, the SRA is available only at a handful of reference laboratories. Most institutions use an “antigen” test such as a commercial enzyme-linked immunosorbent assay (ELISA), which can be readily performed but lacks diagnostic specificity because of its frequent detection of nonpathogenic, non-platelet-activating antiplatelet factor 4/heparin antibodies.9 The prevalence of SRA positivity among those with positive ELISAs ranges from 10% to 50%.13 The risks of clinical decision-making based on a test with limited specificity are not insignificant. Current guidelines recommend initiating a nonheparin anticoagulant if there is clinical suspicion for HIT and a positive ELISA.5,6 Thus, patients with thrombocytopenia are exposed to the risk of full-strength anticoagulation treatment with an expensive alternative to heparin.

Altering the definition of a positive ELISA represents one potential paradigm for addressing the limitations of this assay. Historically, the ELISA is defined as positive when the optical density (OD) exceeds 0.40.13 This threshold was chosen based on control groups composed mainly of healthy blood donors who do not reflect the appropriate comparator population for hospitalized patients. Bakchoul et al10 demonstrated that altering the breakpoint for the ELISA to an OD ≥ 1.00 improved the specificity of the test by nearly 20%. Warkentin et al11 showed that the prevalence of a positive SRA in people with ODs < 1.00 was rare.

Most studies exploring alternative definitions of a positive ELISA are limited because they are either retrospective, focus on a narrow cohort of patients, or include few critically ill subjects, therefore, limiting generalizability. Additionally, the paucity of prospective data are concerning. Therefore, we conducted a prospective observational study of consecutive patients being evaluated for HIT, including those in the ICU and those on the general floors, to assess the utility of adopting a new cutoff for the HIT ELISA.

Study Overview and Subjects

We conducted a prospective observational study of patients (NCT00946400) undergoing HIT ELISA testing at our institution between August 2009 and April 2012. The decision to order the ELISA was determined by the treating clinicians. Documentation of any formal risk stratification prior to ordering the ELISA was not required as this is not done routinely at the host institution. All adult subjects (age ≥ 18 years) were eligible. We excluded subjects with a known prior history of HIT. Either subjects or their surrogates provided written informed consent. The MedStar Washington Hospital Center Human Use Committee approved the protocol (Institutional Review Board No. 2009-202).

Study Objective and Assays

The primary objective was to determine the performance characteristics of an OD > 1.00 for the diagnosis of HIT. We sought to compare a threshold OD > 1.00 to the current definition of a positive ELISA (OD > 0.40, per manufacturer’s recommendation). The diagnosis of HIT was based on confirmatory SRA. All patients underwent SRA testing, irrespective of the results of the ELISA. The HIT ELISA (Genetics Testing Institute Inc) represented a commercially available test performed routinely in the study institution. This assay is a polyspecific assay that detects IgA, IgG, and IgM antibodies. SRAs were conducted by one investigator at a central laboratory (Platelet Immunology Laboratory, McMaster University) with specialized expertise in HIT testing. For the SRA, a < 20% release was classified as a negative result, a 20% to 49.9% serotonin release as a “weak-positive,” and ≥ 50% serotonin release as a “strong-positive.” Testing was performed at two pharmacologic concentrations of heparin (0.1 and 0.3 International Units/mL) and one high dose (100 International Units/mL) in both patient samples and using known strong, weak, and negative controls. SRA results were reported as a positive or negative result with a mean percentage release (at 0.1 and 0.3 Interational Units/mL heparin). For the purposes of analysis, we categorized both the weak and strong release amounts as “positive.” The laboratory technician conducting the SRAs was blinded to the results of each patient’s clinical scenario.

Covariates and Subgroup Analysis

We collected information regarding patient demographics, comorbid illnesses, and acute disease processes. Patients were dichotomized as hospitalized for a medical or surgical reason, and we recorded if there was a history of coronary artery disease, congestive heart failure, hypertension, diabetes mellitus, stroke, or VTE. We also assessed whether the patient had his/her ELISA collected while in an ICU or a general floor. To determine the influence of severity of illness on sensitivity, we repeated our primary analysis in the ICU subgroup. We assessed severity of illness via noting the use of mechanical ventilation. We further conducted a subgroup analysis in persons undergoing MCS (eg, coronary artery bypass grafting [CABG], valve replacement). At our institution, MCS patients routinely receive postoperative low-molecular-weight heparin (LMWH) thromboprophylaxis with enoxaparin until discharge.

Statistics

We completed univariate analyses for parametrically distributed data with the Fisher exact test or Student t test, as appropriate. If the data were not normally distributed, we used nonparametric tests. All analyses were two-tailed, and a P value < .05 was assumed to represent statistical significance. We created a receiver operating curve (ROC) to assess the performance characteristics of the OD from the ELISA and determined the area under this ROC (AUROC). We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of two threshold definitions based on the OD. We explored the ability of a threshold OD of ≥ 0.40 and ≥ 1.00 to correctly classify subjects according to SRA testing.

The final cohort included 496 subjects (mean age, 63.2 ± 16.1 years; 56.0% men; 51.0% medical admissions). Most patients (57.3%) had received or were receiving unfractionated heparin (UFH). Of all heparin use (eg, UFH and LMWH), the majority was for thromboprophylaxis (85.7%). The SRA was positive in 10 patients (prevalence = 2.0%): Nine patients tested strongly positive (≥ 50% serotonin release; mean serotonin release = 91%), whereas one patient tested weakly positive (43% serotonin release). Table 1 reveals the baseline characteristics of the cohort and compares subjects with negative SRAs to subjects with positive SRAs. There were no differences between patients with positive SRAs and negative SRAs with respect to demographics or comorbid diseases. There was no difference in the frequency of SRA positivity between medical and surgical patients. A higher rate of HIT was not observed in MCS compared with noncardiac surgery patients.

Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics

CAD = coronary artery disease; CHF = congestive heart failure; CVA = stroke; DM = diabetes mellitus; HIT = heparin-induced thrombocytopenia; HTN = hypertension; LMWH = low-molecular-weight heparin; SRA = serotonin release assay; UFH = unfractionated heparin.

Figure 1 reveals that the median OD was significantly higher in those with positive SRAs. The median OD measured 2.63 among the SRA-positive cohort vs 0.19 in the SRA-negative group (P < .001). There was no overlap in the distribution of OD values between the two populations.

Figure Jump LinkFigure 1 –  Optical density distribution.Grahic Jump Location

Figure 2 underscores the operating characteristics of the two thresholds as a performance test to define a positive SRA. The AUROC for an OD > 1.00 (0.99; 95% CI, 0.98-1.00) was significantly higher than the AUROC for an OD > 0.40 (0.92; 95% CI, 0.90-0.96). Table 2 presents the specific screening characteristics of the two OD breakpoints. The different definitions had similar sensitivities and NPVs. The specificity of an OD > 1.00 was approximately 10% higher than for an OD > 0.40 (96.8%; 95% CI, 94.7%-98.1% vs 86.5%; 95% CI, 83.1%-89.3%). The PPV of an OD > 1.00 was three times greater than utilizing an OD > 0.4 (38.5% vs 13.2%). There were no false negatives utilizing an OD > 1.00 as the threshold. No patient with a positive SRA and a clinical diagnosis of HIT had an OD ≤ 1.00.

Figure Jump LinkFigure 2 –  Receiver operating characteristics curves. OD = optical density.Grahic Jump Location
Table Graphic Jump Location
TABLE 2 ]  Screening Characteristics of Different OD Thresholds for a Positive SRA

NPV = negative predictive value; OD = optical density; PPV = positive predictive value. See Table 1 legend for expansion of other abbreviation.

Nearly 40% (n = 192) of the cohort had HIT testing performed while they were in the ICU. Two-thirds of the ICU subgroup derived from the surgical ICU while the remaining were in the medical ICU (n = 39) or the cardiac care unit (n = 25). Of the 10 patients with positive SRAs, seven were critically ill. SRAs were more frequently positive in the surgical ICU than in other ICUs (4.7% vs 1.6%) but this difference was not statistically significant (P = .428). As with the entire population, the OD was higher among subjects with positive SRAs than those with negative test results (Fig 3, median OD 2.81 vs 0.18, respectively, P < .001). Adjusting the definition of the ELISA to > 1.00 maintained the test’s sensitivity and NPV at 100% in this cohort. The PPV of the higher cutoff OD was more than double the PPV of an OD threshold of 0.40 (53.8% vs 21.9%).

Figure Jump LinkFigure 3 –  Optical density distribution in patients in the ICU.Grahic Jump Location

Proximate to their evaluations for thrombocytopenia and HIT, 163 patients underwent MCS. The most common types of MCS included CABG (n = 62), valve repair/replacement (n = 58), and CABG with valve replacement (n = 25). Although 16.0% (n = 26) of this subgroup had a positive ELISA based on a cutoff of 0.40, only 3.1% (n = 5) had a positive SRA. Similar to the ICU cohort, the median OD was significantly higher in people with positive SRAs (median OD 2.19 vs 0.16, P < .001). The performance characteristics of the higher OD definition enhanced the specificity and the PPV of the OD (Table 2). The AUROC of the OD > 1.00 as a discriminatory test for a positive SRA measured 0.99 (95% CI, 0.98-1.00).

This large, prospective study of a heterogenous population suspected of HIT reveals that this syndrome remains infrequent. Although using the classic approach of an ELISA OD > 0.40 to reflect a positive assay results in excellent sensitivity, one can enhance the specificity of the ELISA. Increasing the breakpoint to an OD > 1.00 raises specificity and overall accuracy without markedly compromising sensitivity. Altering the definition of a positive ELISA can potentially result in fewer subjects undergoing follow-up SRAs and/or being exposed to empirical anticoagulation treatment with a non-heparin-based agent.

Prior work has addressed the significance of the HIT ELISA OD. Both Zwicker et al12 and Baroletti et al13 observed that higher OD measurements increased the likelihood that a patient would suffer a thrombosis. Neither of these analyses, however, specifically examined the role of the OD as a diagnostic test for HIT.12,13 Janatpour et al14 indicated that the OD correlated with the pretest probability of HIT as measured by either the 4Ts or Chong scores. Unfortunately, these authors provided no data on the actual rate of HIT or the relationship between the OD and eventual outcomes. In a mixed cohort, Whitlatch et al15 studied the nexus between OD and a final diagnosis of HIT. Consistent with our findings, they noted that the median OD was significantly higher in those with HIT than in those without HIT. However, their study was retrospective and they did not specifically comment on the important clinical issue of the performance characteristics of the OD as a test to exclude HIT. Moreover, they did not use an accepted gold standard assay for HIT. They diagnosed HIT based on one investigator’s expert opinion, and this adjudicator was not necessarily blinded to clinical outcomes.13 With respect to people undergoing MCS, both Demma et al16 and Chan et al17 concluded that findings from the OD were generally concordant with the results of SRA testing. These studies, though, suffered from substantial selection bias since they only included patients who had actual SRA results available. Patients in whom the SRA was not performed or lost were excluded. Finally, Warkentin et al11 described the performance characteristics of the OD as compared with an SRA. The proportion of people with SRA-positive results increased significantly when the OD exceeded 1.00. Ninety percent of people with an OD ≥ 2.0 had a positive SRA.11 This association was seen both in MCS and non-MCS subjects.

There is a biologic basis for this discrepancy between the laboratory cutoff of 0.40 and 1.00. Laboratory test cutoff values to distinguish normal from abnormal are routinely determined in healthy subjects. HIT antibody testing is almost always performed in patients who have prior exposure to heparin. Because heparin treatment frequently generates nonclinically relevant antiplatelet factor 4/heparin antibodies that do not cause HIT, it would be logical to determine a threshold value in heparin-exposed patients who did not develop clinical HIT.11

Our efforts expand on this growing literature. We confirm that the prevalence of a positive SRA is low among people with an ELISA OD > 0.40. We show that increasing the breakpoint to 1.00 improves the specificity of the test without appreciably undermining sensitivity. Our study has several unique aspects. First, we examined this issue in a prospective fashion. Prior work has comprised mostly retrospective analyses. Retrospective approaches are prone to multiple forms of bias thereby limiting its ability to correctly determine the discriminatory characteristics of a test. Second, we examined a large cohort of patients. This helps limit the uncertainty surrounding assessments of the AUROC. Thus, this investigation is less likely to be fraught with sampling error. Third, we specifically explored subgroups where the diagnosis of HIT may be more complicated and the consequences of HIT more concerning. Consistencies in our findings in both subjects in the ICU and MCS subjects provide important insights that expand on earlier inquiries into this topic.

There are important implications to our findings. The standard clinical approach to diagnosing HIT includes empirical anticoagulation treatment with a nonheparin agent if the ELISA is positive. The improved diagnostic characteristics of the ELISA by increasing the cutoff value demonstrates that perhaps the ELISA should be reported as a numeric value instead of as a positive or negative value. In conjunction with the appropriate clinical scenario, this will assist in properly diagnosing HIT. As illustrated by the low prevalence of HIT in this population, there may be an overevaluation for HIT. By beginning the testing process with a sensitive but nonspecific assay, such as the ELISA, one minimizes the risk of withholding nonheparin anticoagulation treatment. This necessarily means that some patients will be exposed to full-strength anticoagulation treatment when it is not indicated. This could prove life-threatening, specifically to postoperative patients and/or patients in the ICU, who may be thrombocytopenic and who are already at increased risk of bleeding. These patient types also compose a significant proportion of those undergoing evaluation for HIT. Furthermore, most of the agents used to treat HIT are costly. There is an urgent need for either rapid access to a gold standard test or a screening tool with enhanced specificity but without a decrement in sensitivity. Increasing the OD appears to satisfy these criteria. We estimate that if the OD breakpoint is set at 1.00 rather than 0.40, 50 fewer subjects would be exposed to a nonheparin agent while awaiting SRA results. In terms of direct pharmacy costs, this could have saved our institution over $150,000.

Despite the novel aspects of our project, several significant limitations exist. First, our data derive from a single center, which limits generalizability. We partially address this by reporting subgroup findings in key populations at risk for HIT. Second, the rate of true HIT, as defined by SRA findings, was low at approximately 2%. If the rate were higher we might have identified subjects with mid-range ODs and positive SRAs. Uncertainty remains surrounding our estimate of a zero false-positive rate with an OD threshold of 1.00. Furthermore, the unaltered sensitivity may have been caused by the low prevalence of disease in our cohort rather than a truly unchanged sensitivity. A prior study by Warkentin et al11 demonstrated that the prevalence of HIT in those with an OD value between 0.4 and 1.0 was < 2% but not zero. Thus, we must be cautious about interpreting a lack of compromise in sensitivity in our study. In the same vein, perhaps the OD value should no longer be reported as a positive or negative value when the OD reaches a certain value. A positive or negative value can be misleading as HIT antibodies are often present after heparin exposure but are not actively causing disease. Therefore, it behooves the clinician to incorporate the ELISA OD value with the appropriate clinical context to properly diagnosis HIT. Third, even though our sample size reflects the largest prospective evaluation of a HIT OD value of 1.00 as a diagnostic test, with a larger population or different case mix of subjects we might have seen a different distribution in OD values. Fourth, HIT is usually diagnosed with clinical findings in conjunction with the presence of heparin-dependent platelet-activating antibodies. We decided to use a positive SRA alone to define a diagnosis of HIT given the substantial variability in clinical scenarios that prompted the ordering of an ELISA.

In conclusion, HIT appears infrequent among persons evaluated for this syndrome when a HIT ELISA is defined as positive at a 0.40 threshold. Increasing the cutoff to 1.00 improves the tests operating characteristics without necessarily compromising diagnostic accuracy or patient safety.

Author contributions: C. M. C. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. C. M. C., T. E. W., and A. F. S. contributed to study concept and design, drafted the manuscript, and obtained funding; C. M. C., C. J. W., T. E. W., J.-A. I. S., and A. F. S. contributed to data acquisition, analysis, and interpretation and critically revised the manuscript for important intellectual content; C. M. C. and A. F. S. contributed to study supervision and provided statistical expertise; and J.-A. I. S. contributed administrative, technical, or material support.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Chan has served as a speaker for GlaxoSmithKline plc. Dr Warkentin has served as consultant and/or has received honoraria for speaking on behalf of companies that manufacture LMWH (Pfizer Canada Inc) or heparin-coated grafts (W. L. Gore & Associates Inc). His institution has received funding from the Heart and Stroke Foundation for research related to HIT. He has also received royalties from Taylor & Francis Group, an Informa Business, for a book entitled, Heparin-Induced Thrombocytopenia. He receives compensation for medicolegal testimony regarding thrombocytopenic disorders including HIT. Drs Woods and Shorr and Ms Sheppard have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in drafting the protocol, in data collection, analysis, or interpretation, or in manuscript preparation.

AUROC

area under the receiver operating curve

CABG

coronary artery bypass grafting

ELISA

enzyme-linked immunosorbent assay

HIT

heparin-induced thrombocytopenia

LMWH

low-molecular-weight heparin

MCS

major cardiac surgery

NPV

negative predictive value

OD

optical density

PPV

positive predictive value

ROC

receiver operating curve

SRA

serotonin release assay

UFH

unfractionated heparin

Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2010;24(4):755-775. [CrossRef] [PubMed]
 
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(8):2710-2715. [CrossRef] [PubMed]
 
Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011;9(12):2498-2500. [CrossRef] [PubMed]
 
Lee GM, Arepally GM. Diagnosis and management of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):541-563. [CrossRef] [PubMed]
 
Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of eparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e495S-e530S. [CrossRef] [PubMed]
 
Cuker A, Ortel TL. ASH evidence-based guidelines: is the IgG-specific anti-PF4/heparin ELISA superior to the polyspecific ELISA in the laboratory diagnosis of HIT? Hematology (Am Soc Hematol Educ Program). 2009;:250-252.
 
Chong BH. Heparin-induced thrombocytopenia. J Thromb Haemost. 2003;1(7):1471-1478. [CrossRef] [PubMed]
 
Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. [CrossRef] [PubMed]
 
Pouplard C, Leroux D, Regina S, Rollin J, Gruel Y. Effectiveness of a new immunoassay for the diagnosis of heparin-induced thrombocytopenia and improved specificity when detecting IgG antibodies. Thromb Haemost. 2010;103(1):145-150. [CrossRef] [PubMed]
 
Bakchoul T, Giptner A, Bein G, Santoso S, Sachs UJ. Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). Thromb Res. 2011;127(4):345-348. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304-1312. [CrossRef] [PubMed]
 
Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2004;2(12):2133-2137. [CrossRef] [PubMed]
 
Baroletti S, Hurwitz S, Conti NA, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med. 2012;125(1):44-49. [CrossRef] [PubMed]
 
Janatpour KA, Gosselin RC, Dager WE, et al. Usefulness of optical density values from heparin-platelet factor 4 antibody testing and probability scoring models to diagnose heparin-induced thrombocytopenia. Am J Clin Pathol. 2007;127(3):429-433. [CrossRef] [PubMed]
 
Whitlatch NL, Perry SL, Ortel TL. Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost. 2008;100(4):678-684. [PubMed]
 
Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011;113(4):697-702. [PubMed]
 
Chan CM, Corso PJ, Sun X, Hill PC, Shorr AF. Evaluating the role for the optical density in the diagnosis of heparin-induced thrombocytopenia following cardiac surgery. Thromb Haemost. 2011;106(5):934-938. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Optical density distribution.Grahic Jump Location
Figure Jump LinkFigure 2 –  Receiver operating characteristics curves. OD = optical density.Grahic Jump Location
Figure Jump LinkFigure 3 –  Optical density distribution in patients in the ICU.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics

CAD = coronary artery disease; CHF = congestive heart failure; CVA = stroke; DM = diabetes mellitus; HIT = heparin-induced thrombocytopenia; HTN = hypertension; LMWH = low-molecular-weight heparin; SRA = serotonin release assay; UFH = unfractionated heparin.

Table Graphic Jump Location
TABLE 2 ]  Screening Characteristics of Different OD Thresholds for a Positive SRA

NPV = negative predictive value; OD = optical density; PPV = positive predictive value. See Table 1 legend for expansion of other abbreviation.

References

Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2010;24(4):755-775. [CrossRef] [PubMed]
 
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(8):2710-2715. [CrossRef] [PubMed]
 
Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011;9(12):2498-2500. [CrossRef] [PubMed]
 
Lee GM, Arepally GM. Diagnosis and management of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):541-563. [CrossRef] [PubMed]
 
Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of eparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e495S-e530S. [CrossRef] [PubMed]
 
Cuker A, Ortel TL. ASH evidence-based guidelines: is the IgG-specific anti-PF4/heparin ELISA superior to the polyspecific ELISA in the laboratory diagnosis of HIT? Hematology (Am Soc Hematol Educ Program). 2009;:250-252.
 
Chong BH. Heparin-induced thrombocytopenia. J Thromb Haemost. 2003;1(7):1471-1478. [CrossRef] [PubMed]
 
Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. [CrossRef] [PubMed]
 
Pouplard C, Leroux D, Regina S, Rollin J, Gruel Y. Effectiveness of a new immunoassay for the diagnosis of heparin-induced thrombocytopenia and improved specificity when detecting IgG antibodies. Thromb Haemost. 2010;103(1):145-150. [CrossRef] [PubMed]
 
Bakchoul T, Giptner A, Bein G, Santoso S, Sachs UJ. Performance characteristics of two commercially available IgG-specific immunoassays in the assessment of heparin-induced thrombocytopenia (HIT). Thromb Res. 2011;127(4):345-348. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304-1312. [CrossRef] [PubMed]
 
Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2004;2(12):2133-2137. [CrossRef] [PubMed]
 
Baroletti S, Hurwitz S, Conti NA, Fanikos J, Piazza G, Goldhaber SZ. Thrombosis in suspected heparin-induced thrombocytopenia occurs more often with high antibody levels. Am J Med. 2012;125(1):44-49. [CrossRef] [PubMed]
 
Janatpour KA, Gosselin RC, Dager WE, et al. Usefulness of optical density values from heparin-platelet factor 4 antibody testing and probability scoring models to diagnose heparin-induced thrombocytopenia. Am J Clin Pathol. 2007;127(3):429-433. [CrossRef] [PubMed]
 
Whitlatch NL, Perry SL, Ortel TL. Anti-heparin/platelet factor 4 antibody optical density values and the confirmatory procedure in the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost. 2008;100(4):678-684. [PubMed]
 
Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011;113(4):697-702. [PubMed]
 
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543