Heparin-induced Thrombocytopenia Laboratory Testing Research Articles

HTRS2023.P4.2 Improving judicious use of heparin induced thrombocytopenia laboratory testing using a clinician decision support tool

HTRS2023.P4.2 Improving judicious use of heparin induced thrombocytopenia laboratory testing using a clinician decision support tool

336: EVALUATION OF A PHARMACY-MANAGED HEPARIN-INDUCED THROMBOCYTOPENIA STANDARD OPERATING PROCEDURE

Introduction: Heparin-induced thrombocytopenia (HIT) is associated with significant morbidity and mortality, necessitating early identification and timely diagnosis. The objective of this study was to evaluate a pharmacy-managed HIT standard operating procedure (SOP). Methods: A retrospective analysis of HIT laboratory testing at Nebraska Medicine before (April 2018 to August 2019) and after (April 2020 to August 2021) SOP implementation was performed on patients admitted to the ICU. Patients were included if an anti-PF4 antibody and/or SRA test was ordered during hospitalization with prior heparin exposure. Exclusion criteria were age < 19, no heparin product exposure prior to HIT laboratory testing, or if lab testing was ordered ≥15 days from receiving heparin. The primary outcome was appropriately documented heparin allergy field in the medical record. Secondary outcomes include false positive anti-PF4 antibody assays, time from heparin initiation to HIT laboratory testing, duration of direct thrombin inhibitor (DTI) use, hospital length of stay, and in-hospital all-cause mortality. Results: 226 patients were evaluated, 110 in the pre- and 116 in the post-cohort. Baseline characteristics demonstrated most patients were male (58.8%), white (81.4%), and were anticoagulated with an indication of VTE prophylaxis (61.1%). Acute trauma/surgical procedure was the most common reason for admission (31%). Appropriate heparin allergy documentation occurred in 95.5% of patients in the pre- and 97.4% of patients in the post- cohort (p=0.528). No difference was found in the incidence of false positive anti-PF4 antibody assays (9.1% vs 8.6%) or time from heparin initiation to HIT laboratory testing (3.2 vs 3.6 days). DTI’s were utilized for a longer duration of time in the pre- cohort compared to the post-cohort (4.9 vs 2.8 days). There was no difference in hospital length of stay (17.9 vs 17.4 days), but in-hospital all-cause mortality was observed more frequently in the post-cohort than the pre-cohort (36.2% vs 23.6%). Conclusions: The implementation of a pharmacist-driven heparin-induced thrombocytopenia standard operating procedure demonstrated a similar incidence of appropriate heparin allergy documentation in the medical record compared to a physician-driven approach.

Laboratory testing for VITT antibodies

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a highly prothrombotic disorder that like heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4). However, unlike HIT-where heparin at low concentrations (0.1-0.5 U/mL) typically enhances antibody-induced platelet activation, platelet activation by VITT sera is usually inhibited by heparin. Further, conventional platelet activation assays for HIT, such as the serotonin-release assay (SRA) and heparin-induced platelet activation (HIPA) test, often yield negative or atypical results when testing VITT sera. Nevertheless, VITT (like HIT) is a "clinical-pathological" disorder whereby laboratory detectability of platelet-activating anti-PF4 antibodies is crucial for diagnosis. VITT antibodies follow 2 fundamental principles of HIT laboratory testing: (1) high probability of a positive PF4-dependent enzyme-immunoassay (EIA), and (2) high probability of a positive platelet activation assay. However, optimal detection of VITT in platelet activation assays requires the addition of PF4, for example, PF4-enhanced SRA (PF4-SRA) and PF4-enhanced HIPA (PIPA). A novel whole blood assay, called the PF4-induced flow cytometry-based platelet activation (PIFPA) assay, exhibits high sensitivity and specificity for VITT. HIT and VITT sera/plasmas differ in their reactivity in rapid HIT immunoassays (90-97% sensitivity for HIT, <25% sensitivity for VITT), consistent with distinct antigen sites on PF4 recognized by HIT and VITT antibodies.

Minimizing cost associated with management of heparin‐induced thrombocytopenia: A cost analysis of various laboratory testing models

Management of patients with suspected heparin-induced thrombocytopenia (HIT) can lead to significant costs. Reported cost-saving initiatives have focused on minimizing inappropriate testing in low-risk patients and optimizing alternative anticoagulant selection. We sought to further investigate how utilizing various HIT laboratory testing models would impact total cost of testing and alternative anticoagulant use. Utilizing a retrospective cohort of adult patients tested for HIT over three years within our institution, we evaluated how utilization of four distinct laboratory models impacted total number of HIT test combinations completed, time to HIT testing finalization, percentage of patients discharged from the hospital prior to HIT testing finalization, total alternative anticoagulant days, and total anticipated major bleed events. Additionally, we calculated cost of laboratory testing and alternative anticoagulant associated with each model. A total of 482 patients were included in our cohort. A laboratory testing model that utilized an in-house platelet factor 4 (PF4)-heparin enzyme-linked immunosorbent assay (ELISA) completed three days weekly, and reflex serotonin release assay (SRA) with a five-day turnaround resulted in the shortest mean time to HIT testing finalization, lowest percentage of patients discharged prior to HIT testing finalization, and lowest total alternative anticoagulant days. Institutions should evaluate current HIT laboratory testing practices and assess for opportunities for optimization. Testing models utilizing a PF4-heparin antibody ELISA with a reflex SRA for positive results may improve testing metrics and lead to lower utilization of alternative anticoagulants.

Integration of a Heparin-Induced Thrombocytopenia Order-Set (HITOS): A Retrospective Study

Introduction: Heparin-induced thrombocytopenia (HIT) may occur after exposure to heparin containing products. When HIT is suspected, early recognition and diagnosis is crucial due to the risk for developing a life-threatening thrombotic event that can lead to substantial morbidity and even death.However, making the diagnosis of HIT is challenging due to a high false positive rate associated with most widely used screening tests for HIT. Therefore, clinical assessment of the likelihood of HIT is essential to help guide the decision to order a HIT laboratory test and to make changes in anticoagulation management. In 2014, we integrated a new custom HIT Order-Set (HITOS) with the EPIC electronic medical record (EMR) system. HITOS requires a clinician seeking to order a HIT laboratory test to input data to calculate a 4Ts pretest likelihood score for HIT. Recommendations are then automatically provided for proceeding or not with the HIT test and for anticoagulant management. Specifically, for patients with a low likelihood of HIT, HITOS recommends continuing heparin without HIT testing. For patients with an intermediate or high likelihood, HITOS recommends discontinuing heparin in favor of an alternative anticoagulant and proceeding with HIT testing. Our study goals were to evaluate the effect of HITOS on patterns of HIT test ordering and on anticoagulation management in patients with suspected HIT.Methods: We performed a retrospective review of all inpatient charts in which an order for the laboratory test for HIT (heparin-PF4 antibody enzyme immunoassay) was recorded at Dartmouth Hitchcock Medical Center from December 2012 to December 2016. HITOS was launched in December 2014. Subjects were excluded from the study if their charts contained incomplete data, external laboratory results, previous documentation of a HIT diagnosis or duplicate testing . Data were extracted from the EMR for each study subject and included demographic information, clinical data, HIT test results and details of anticoagulation management before and after HIT laboratory testing. In the pre-HITOS group, the 4Ts score was applied retrospectively to assess the likelihood of HIT and was calculated independently by two study members. A score of ≤ 3 defined low likelihood for HIT; 4-5 points, intermediate; 6-8 points, high. The 4Ts score was obtained from the EMR in the post-HITOS group. Before and after HITOS comparisons were analyzed using the chi-square test for independence with a = 0.05.Results: A total of 465 EMR were reviewed; 401 subjects were included in the final analysis. The pre and post-HITOS groups included 213 and 189 subjects, respectively, with a similar median age (66 years, range 21 to 94 and 65 years, range 23 to 94). Pre-HITOS, a HIT test was ordered in 54% of low, 39% of intermediate and 7% of high likelihood cases. Post-HITOS, a HIT test was ordered in 30%, 57% and 14% of the respective cases (p <0.001 for each pre/post comparison). When there was at least an intermediate clinical likelihood for HIT, appropriate discontinuation of heparin at time of HIT testing occurred more frequently in the post-HITOS group (74% vs 66 %, respectively; p <0.001), and more patients in the post-HITOS group were accorded a clinical diagnosis of HIT than in the pre-HITOS group (11.1% vs 5.6%, respectively; p <0.05) group.Conclusions: Implementation of HITOS was associated with a decrease in HIT laboratory test ordering if the clinical likelihood for HIT was low and was associated with a higher rate of appropriate heparin discontinuation when the clinical likelihood of HIT was intermediate or high. Our results suggest that integration of HITOS may help refine the diagnostic process in patients with suspected HIT, though additional study will be required to evaluate the cost-effectiveness and effects on morbidity and mortality of this approach. DisclosuresNo relevant conflicts of interest to declare.

Heparin Induced Thrombocytopenia: A Laboratory Comparison of the IgG Specific EIA Vs Polyspecific EIA

Introduction:Heparin-induced Thrombocytopenia (HIT) is a potentially life/limb threatening immune mediated pro-thrombotic syndrome triggered by heparin/platelet factor 4 (PF4) complexes. Based on clinical probability, if indicated, initial laboratory testing for HIT is typically based on enzyme immunoassay (EIA) to detect anti-PF4/heparin(H) antibodies with or without supplemental functional assays, the serotonin release assay (SRA) is considered to be the gold standard. EIAs detect either polyspecific (IgG, IgA, IgM) or IgG specific antibodies, the latter are recommended by ISTH/SSC, and should have optimal performance characteristics (sensitivity/specificity/negative and positive predictive values (NPV/PPV)). Each performing laboratory, however, needs to establish in-house performance characteristics of the assay.Objective:To compare laboratory performance characteristics of IgG specific and polyspecific PF4/H EIAs for a positive SRA.Materials and methods: Between 2013 to 2017, 284 serum samples submitted to our laboratory for clinical HIT EIA testing were studied. IgG specific and polyspecific (Immucor GTI Diagnostics, Inc. Waukesha, WI) assays were performed per the manufacturer's instructions with the exception of performance on a liquid handling instrument rather than manually. The manufacturer assigned optical density (OD) cutoff of ≥0.400 was defined as positive. The SRA, ordered separately by clinicians, were sent out to reference laboratories; criteria for a positive result was ≥20% serotonin release with low dose heparin and <20% release with high dose of heparin. The data were entered into Excel spreadsheet, de-identified and analyzed by Analyse-it (Analyse-it Software, LTD, Leeds, U.K.). We also correlated the SRA positivity with the EIA ODs.Results:Of the 284 serum samples, 112 were positive with IgG specific EIA, 68 (60.7%) of those also had a positive SRA. 172 were negative with IgG specific EIA, 2 (1.2%) of those had a positive SRA. Of the 148 were positive with polyspecific EIA, 69 (46.6%) also had a positive SRA. 136 were negative with polyspecific EIA, 1 (0.7%) had a positive SRA. The performance characteristics are shown in table 1. Compared with the polyspecific EIA, the IgG specific EIA had superior specificity, PPV and positive likelihood ratio (LR); the NPVs and negative LR of both assays were similar. The percent of patients having a positive SRA at different OD cutoffs is illustrated in Table 2.Conclusion: In aggregate the data suggest that the IgG specific EIA had superior performance characteristics in detecting HIT antibodies. Given the high likelihood of a positive SRA for OD >2.0, in the appropriate clinical context, supplemental SRA testing may not be essential. Since the data were de-identified, assay performance for the clinical diagnosis of HIT was not possible. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Striving to HIT the Bullseye When Diagnosing Heparin-Induced Thrombocytopenia

Background: The 4T score is a validated tool to assess the pretest probability of heparin-induced thrombocytopenia (HIT), with the negative predictive value of a low 4T score (≤ 3) reported consistently above 90%. We performed a retrospective data review of patients aged ≥18 years who had heparin/PF4 antibody testing ordered between January and August 2016 at an academic medical center. 4T scores were calculated retrospectively from data in the electronic medical record (EMR). We then prospectively instituted a mandatory data-driven algorithm utilizing an electronic 4T calculator within the EMR prior to heparin/PF4 antibody testing.Aims: To reevaluate the utilization of laboratory testing for HIT after implementation of a data driven algorithm.Methods: In December 2016, 4T score calculation was implemented in the EMR as a requirement prior to ordering heparin-PF4 antibody testing. We then compared the frequency and results of heparin/PF4 antibody testing in adult inpatients aged ≥18 during the post-intervention period (December 2016 to June 2017) with the pre-intervention period (January to August 2016). 4T scores were calculated retrospectively by a hematologist from data in the EMR and compared to the 4T score entered by the ordering provider.Results: During the pre-intervention period, 161 heparin/PF4 antibody tests were performed, of which 131 (81%) were negative (optical density <0.40), 27 (17%) positive and 3 (2%) equivocal. During the post-intervention period, 105 heparin/PF4 antibody tests were performed, of which 86 (82%) were negative (optical density <0.40), 15 (14%) positive and 4 (4%) equivocal. The 4T score was significantly higher in patients with positive/equivocal heparin/PF4 antibody values compared to those with negative values (p<0.0001). ROC curves demonstrated that the 4T score was highly predictive of a positive or equivocal heparin/PF4 antibody value (AUC 0.705, 95% CI: 0.553, 0.857). Intensive care units ordered the majority (65%) of heparin-PF4 antibodies both pre- and post-intervention. The percentage of heparin-PF4 antibodies ordered with a low 4T score (≤3) was 67% pre-intervention and 57% post-intervention, a difference which trended towards, but did not reach statistical significance (p=0.130 by Chi-square test). 4T score calculation was discordant between the ordering provider and hematologist in 67% of patients.Conclusions: Mandating 4T score calculation prior to heparin/PF4 antibody testing did not significantly decrease the number of tests ordered in the setting of a low 4T score within the first 6 months post-intervention. We plan to review additional data over the next several months and will continue education on accurate 4T score calculation and testing for HIT at our academic medical center. DisclosuresNo relevant conflicts of interest to declare.

A multicentre assessment of contemporary laboratory assays for heparin induced thrombocytopenia

Heparin induced thrombocytopenia (HIT) is a rare but potentially fatal complication of heparin therapy. In some patients, HIT causes platelet activation and thrombosis (sometimes abbreviated HITT), which leads to adverse clinical sequalae ('pathological HIT'). The likelihood of HIT is initially assessed clinically, typically using a scoring system, of which the 4T score is that most utilised. Subsequent laboratory testing to confirm or exclude HIT facilitates exclusion or diagnosis and management. The current investigation comprises a multicentre (n=9) assessment of contemporary laboratory testing for HIT, as performed over the past 1-3 years in each site and comprising testing of over 1200 samples. The primary laboratory test used by study participants (n=8) comprised a chemiluminescence procedure (HIT-IgG(PF4-H)) performed on an AcuStar instrument. Additional immunological testing performed by study sites included lateral flow (STiC, Stago), enzyme linked immunosorbent assay (ELISA), Asserachrom (HPIA IgG), PaGIA (BioRad), plus functional assays, primarily serotonin release assay (SRA) or platelet aggregation methods. The chemiluminescence procedure yielded a highly sensitive screening method for identifying functional HIT, given high area under the curve (AUC, generally ≥0.9) in a receiver operator characteristic (ROC) analysis against SRA as gold standard. ELISA testing resulted in lower ROC AUC scores (<0.8) and higher levels of false positives. Although there is clear association with the likelihood of HIT, the 4T score had less utility than literature suggests, and was comparable to a previous study reported by some of the authors.

Pharmacist involvement in clinical assessment and laboratory testing for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare adverse drug reaction. The anti-PF4 antibody assay (ELISA) is utilized to assist in the clinical evaluation of HIT due to its high negative predictability and wide-spread availability. However, it also associated with false positive results. The 4T score can assist in predicting an individual's risk for HIT and the need for further laboratory testing. This was a single-center prospective observational cohort study. Orders for HIT testing were sent via page to a clinical pharmacist to calculate a 4T score. If low risk, the pharmacist contacted the ordering prescriber to recommend discontinuation of laboratory testing. During the study, a clinical support tool was implemented to assist prescribers with ordering HIT tests. The study was divided into a pharmacist intervention group and a control group. A total of 303 pages were received. One hundred nine were missed due to unavailability of the pharmacist at time of page. A pharmacist reviewed 194 pages and intervened on 132. One hundred seven were scored as low risk, 70 as intermediate risk and 9 as high risk. Pharmacist intervention resulted in discontinuing 64 ELISA and 11 serotonin release assay tests. The clinical support tool resulted in a yearly decrease of HIT testing by 27%. Laboratory cost savings totaled $11,000 but did not include avoidance of laboratory technician or drug cost. Pharmacist involvement in the clinical assessment of HIT and the use of a support tool resulted in the reduction of HIT tests in low risk patients.

Maximum 24-Hour Platelet Count Fall Rate As a Predictor of HIT

Background: Heparin-induced thrombocytopenia (HIT) is a high-stakes diagnosis. A delay in initiation of appropriate therapy is associated with a 6.1% daily incidence of thrombosis, amputation, and death (Greinacher et al, Blood 2000). However, misdiagnosis exposes patients without HIT to alternative anticoagulants and their attendant risk of major bleeding. Although a meta-analysis showed that the negative predictive value (NPV) of a low-probability 4Ts score is 99.8%, the positive predictive value (PPV) of the 4Ts score is limited. This is particularly true among individuals with an intermediate-probability score, in whom the PPV is only 14% (Cuker et al. Blood 2012). It has been observed that immune-mediated causes of thrombocytopenia result in a more precipitous fall in the platelet count than other common causes of hospital-acquired thrombocytopenia (e.g. infection, disseminated intravascular coagulation, drug-induced myelosuppression). Nevertheless, the pace of platelet count fall is not currently captured in the 4Ts score or other clinical prediction models for HIT. We hypothesized that rapidity of the platelet count fall could help to discriminate HIT status among patients with an intermediate probability 4Ts score. Methods: In a cohort of 292 patients with suspected HIT and prospectively calculated 4Ts scores, we identified patients with an intermediate 4Ts score (4 or 5). Patients were classified as HIT-positive or HIT-negative by an independent panel of HIT experts as previously described (Pishko et al. Blood Advances 2018). We compared the frequency of scores in each of the 4Ts score categories between HIT-positive and-HIT negative patients using Chi-square analysis. For each day from hospital admission to day of HIT laboratory testing, we extracted the first measured platelet count, exposure to heparin, and platelet transfusions. We also extracted the dates of the following events of interest, as they may be associated with an immediate fall in platelet count: cardiovascular surgery, initiation of extracorporeal membrane oxygenation, intra-aortic balloon pump placement, Impella device placement, and left ventricular assist device implantation. Two reviewers reviewed the platelet count and clinical data for each patient to determine the day on which the platelet count began to decline, excluding platelet count falls 24 hours following one of the aforementioned events of interest. From this date, we calculated the change in platelet count per each 24-hour timeframe, expressed as a percentage of the previous day's platelet count. For each subject, we identified the maximum percentage decrease in platelet count in a 24-hour period (Fallmax). We then compared the Fallmax between HIT-positive and HIT-negative subjects using the Wilcoxon-rank sum test. We assessed the operating characteristics of Fallmax for the diagnosis of HIT at different cut-offs. We selected a cut-off that maximized specificity of the metric while maintaining a sensitivity of ≥95%. Results: Among 292 patients, 158 (54.1%) had a 4Ts score of 4 or 5. Twenty-two (13.9%) were HIT-positive and 136 (86.1%) were HIT-negative. Patient characteristics are listed in table 1. No single item in the 4Ts score exhibited a significant relationship with HIT diagnosis (table 2). The median Fallmax was 49.6% (IQR 42.3-58.9) in HIT-positive patients and 38.5% (IQR 27.8-50.4) in HIT-negative patients (p=0.009). At a Fallmax cut off of ≥ 30%, the sensitivity and specificity of this measure for the diagnosis of HIT was 95.5% (95% CI 77.2%-99.9%) and 29.4% (95% CI 21.9%-37.8%), respectively (table 3). 29.4% (40/136) of the HIT-negative patients had a Fallmax below this cut-off versus only 2.4% (1/22) HIT-positive patients. Conclusion: The maximum percentage decrease in platelet count within 24-hours (Fallmax) was significantly higher in HIT-positive versus HIT-negative patients. A Fallmax ≥ 30% may be a useful metric to discriminate HIT positivity among patients with an intermediate 4Ts score. In this cohort, nearly 30% of HIT negative patients did not meet this cut-off and thus may have been spared alternative anticoagulant exposure. The rapidity of platelet count fall holds promise as a marker for improving the PPV of the 4Ts score, though it requires further evaluation and external validation. Disclosures Cuker: Synergy: Consultancy; Alexion: Other: Institutional funding on author's behalf; Bayer: Other: Institutional funding on author's behalf; Novo Nordisk: Other: Institutional funding on author's behalf; Pfizer: Other: Institutional funding on author's behalf; Spark: Other: Institutional funding on author's behalf. Pishko:Novo Nordisk: Research Funding; Sanofi Genzyme: Research Funding.

The Risk of Major Bleeding in Patients with Suspected Heparin-Induced Thrombocytopenia (HIT)

Introduction: Without prompt treatment, heparin-induced thrombocytopenia (HIT) is associated with a daily rate of life- and limb-threatening thrombosis of 6.1%. Current recommendations are to empirically treat a patient with an intermediate or high pre-test likelihood of HIT with a non-heparin (alternative) anticoagulant while awaiting HIT laboratory test results. The real-world bleeding rates of empiric treatment with an alternative anticoagulant in patients with suspected HIT have not been well-described. We assessed the rates of major bleeding in a prospective cohort of patients with suspected HIT. Because HIT is generally considered a prothrombotic and not a prohemorrhagic disorder, we hypothesized that major bleeding would be less common in alternative anticoagulant-treated patients with HIT than in treated patients who were ultimately determined not to have HIT.Methods: From June 2012 to January 2015, we enrolled 310 patients with suspected HIT at the Hospital of the University of Pennsylvania and an affiliated community hospital. All patients underwent HIT laboratory testing with a poly-specific PF4/heparin ELISA and in-house serotonin release assay. Patients were adjudicated to be HIT-positive or HIT-negative by an independent adjudication panel of HIT experts based on clinical course and results of HIT laboratory testing. We retrospectively reviewed the electronic health record to assess for the presence of a major bleeding event from the time of suspicion of HIT until hospital discharge or death. Major bleeding events were defined by International Society on Thrombosis and Haemostasis (ISTH) criteria (fall in hemoglobin ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, fatal bleed, bleed occurring in a critical organ and/or requiring a repeat surgical intervention). Secondary outcomes of progressive or new thrombosis following suspicion of HIT testing, in-hospital and 30-day mortality were also assessed. Patients were considered to be treated for suspicion for HIT if they received an alternative anticoagulant following a HIT laboratory test order. The demographics and clinical features of patients defined by adjudicated HIT status were compared using the Wilcoxon test and chi-square tests for continuous and for categorical variables, respectively. The proportion of bleeding and thrombotic events were compared between groups using a chi-square test. All analyses were performed using Stata v14.2.Results:The demographics of our cohort by adjudicated HIT status are displayed in Table 1. 44 patients in the cohort were adjudicated to be HIT-positive and 266 were adjudicated HIT-negative. 42/44 (95.5%) HIT-positive patients and 116 of 266 (43.6%) HIT-negative patients received an alternative anticoagulant.Of those who were empirically treated with an alternative anticoagulant, the median duration of treatment was 3 days (IQR 2-5.5) in HIT-negative patients, compared with 11.5 days (IQR 6-16) in the HIT-positive group (p=0.001). The majority of treated patients received argatroban (88.0% of HIT-positive patients and 76.7% of HIT-negative patients). In those patients who received an alternative anticoagulant, a major bleeding event occurred in 40.9% of HIT positive patients and 44.8% HIT negative patients (p=0.45).The majority of major bleeding events met ISTH criteria based on hemoglobin fall or blood transfusion (Table 2). New or progressive thrombosis following suspicion for HIT was more common in HIT-positive patients (35.7%) than in patients who were HIT-negative and treated (15.5%) or not treated (11.3%) (p=0.001) (Table3).Conclusions:Contrary to our hypothesis, HIT was not protective against bleeding. A similar proportion of HIT-positive patients had ISTH major bleeding compared with HIT-negative patients treated with an alternative anticoagulant. The current paradigm for empiric treatment of patients with suspected HIT may need to be reconsidered in light of our findings of greater than expected bleeding associated with treatment. Limitations of our study include relatively small size, recruitment from a single health system, and predominant use of a single alternative anticoagulant (argatroban). Further studies are needed to determine whether our results apply to other centers and other alternative anticoagulants. [Display omitted] DisclosuresPishko:Novo Nordisk: Research Funding. Cuker:Synergy: Consultancy; Genzyme: Consultancy; Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding.

Prospective comparison of the HEP score and 4Ts score for the diagnosis of heparin-induced thrombocytopenia

AbstractThe HIT Expert Probability (HEP) score compared favorably with the 4Ts score in a retrospective study. We assessed the diagnostic accuracy of the HEP score compared with the 4Ts score in a prospective cohort of 310 patients with suspected heparin-induced thrombocytopenia (HIT). A member of the clinical team calculated the HEP score and 4Ts score. An independent panel adjudicated HIT status based on a clinical summary as well as the results of HIT laboratory testing. The prevalence of HIT in the study population was 14.7%. At a cutoff of ≥3, the HEP score was 95.3% sensitive (95% confidence interval [CI], 84.2-99.4) and 35.7% specific (95% CI, 29.8-42.0) for HIT. A 4Ts score of ≥4 had a sensitivity of 97.7% (95% CI, 86.2-99.8) and specificity of 32.9% (95% CI, 27.2-39.1). The areas under the receiver operating characteristic (ROC) curves (AUCs) for the HEP score and 4Ts score were similar (0.81 [95% CI, 0.74-0.87] vs 0.76 [95% CI, 0.69-0.83]; P = .12). The HEP score exhibited a significantly higher AUC than the 4Ts score in patients in the intensive care unit (ICU) (0.86 vs 0.79; P = .03). Among trainee scorers, the HEP score performed significantly better than the 4Ts score (AUC, 0.80 vs 0.73; P = .03). Our data suggest that either the 4Ts score or the HEP score may be used in clinical practice. The HEP score may be preferable in ICU patients and among less experienced clinicians.

HITTING the Diagnosis: Testing for Heparin-Induced Thrombocytopenia in Cancer Patients.

To evaluate the use of a pretest probability score (4Ts score) in cancer patients to guide ordering of laboratory screening tests for heparin-induced thrombocytopenia (HIT). A retrospective chart review was conducted for patients (n = 140) in whom laboratory testing for HIT was requested. 4Ts scores were calculated and correlated with heparin-endogenous platelet factor 4 antibody enzyme-linked immunosorbent assay (ELISA) test results. All patients with a high pretest probability of HIT (4Ts score = 6-7) had positive ELISA results, compared to 26.1% of patients with intermediate (4Ts score = 4-5) and 4.3% of patients with low (4Ts score ≤3) pretest probability. No patients with 4Ts scores of 2 or less had positive ELISA results. HIT can be ruled out in cancer patients (negative predictive value and sensitivity = 100%) with low pretest probability, defined by 4Ts scores of 2 or less, significantly reducing the need for laboratory testing in this patient population.

Diagnostic accuracy of IgG‐specific versus polyspecific enzyme‐linked immunoassays in heparin‐induced thrombocytopenia: a systematic review and meta‐analysis

Background There are conflicting data on whether the IgG-specific or polyspecific antiplatelet factor 4/heparin (PF4/H) enzyme-linked immunosorbent assay (ELISA) is preferred for the laboratory diagnosis of heparin-induced thrombocytopenia (HIT). Objectives To directly compare diagnostic accuracy of IgG-specific versus polyspecific ELISA in HIT. Patients/Methods A systematic search yielded nine studies comprising 1948 patients with suspected HIT tested by both IgG-specific and polyspecific ELISAs and a reference standard against which the diagnostic accuracy of the ELISAs could be measured. Study quality was assessed by QUADAS-2 criteria. Results There was identical sensitivity for IgG-specific and polyspecific ELISAs (0.97; 95% confidence interval (CI), 0.95-0.99) and superior specificity of IgG-specific compared with polyspecific ELISA (0.87 [0.85-0.88] vs. 0.82 [0.80-0.84], respectively). Performance was similar in subgroups using the serotonin release assay and a single commercial ELISA manufacturer. The negative predictive values of IgG-specific and polyspecific ELISA were similarly high (0.99, [0.99-1.00], but the positive predictive value was superior with IgG-specific compared with polyspecific ELISA (0.56 [0.52-0.61] vs. 0.32 [0.28-0.35], respectively). The positive likelihood ratio (LR) was higher in IgG-specific than polyspecific ELISA, although negative LRs were similar. There was high risk of quality concerns in domains of index test and reference standard. Conclusions The superior diagnostic accuracy of IgG-specific ELISA reinforces the ISTH-SSC recommendation for standardization of laboratory testing for HIT. Likelihood ratios of individual assays may be used in combination with clinical scoring systems as part of an integrated diagnostic algorithm for HIT.

Inappropriate documentation of heparin allergy in the medical record because of misdiagnosis of heparin‐induced thrombocytopenia: frequency and consequences

Background It is recommended that heparin be added to the allergy list of patients with heparin-induced thrombocytopenia (HIT). Misdiagnosis of HIT could lead to inappropriate documentation of a heparin allergy and adverse outcomes. Objectives To determine the frequency and consequences of inappropriate documentation of a heparin allergy because of misdiagnosis of HIT. Methods We conducted a cohort study of patients with an inappropriate heparin allergy listed in the electronic medical record (EMR) because of misdiagnosis of HIT. We searched the EMR for patients with a new heparin allergy. Patients were eligible if the reason for allergy listing was suspected acute HIT and laboratory testing for HIT was performed within 60 days. Subjects were defined as 'HIT-negative' if they had a 4Ts score of ≤ 3 or negative laboratory test results. Results Of 239 subjects with a new heparin allergy documented because of concern regarding HIT, 100 (42%) met the prespecified definition of HIT-negative. Sixty-eight (68%) HIT-negative subjects unnecessarily received an alternative parenteral anticoagulant for a median duration of 10.5 days. Among these 68 patients, 45 (66%) met criteria for major bleeding. Sixty-eight (68%) of the 100 HIT-negative subjects had an inappropriate allergy to heparin documented that persisted in the EMR for > 3 years beyond the index hospitalization. Conclusions Inappropriate listing of heparin as an allergy in the EMR because of misdiagnosis of HIT is common, is associated with substantial rates of unnecessary alternative anticoagulant use and major bleeding, and tends to persist beyond the index admission.

Proficiency Testing Results for Heparin-Induced Thrombocytopenia in North America

Between 2010 and 2012, North American Specialized Coagulation Laboratory Association (NASCOLA) distributed five proficiency testing challenges to evaluate laboratory testing for heparin-induced thrombocytopenia (HIT). Results (n = 355) were submitted from 43 unique laboratories for 10 samples (3 positive, 2 weak positive, and 5 negative). The vast majority of results were from commercial enzyme-linked immunosorbent assay (ELISA) methods, predominantly polyvalent assays. Laboratories performed well in the classification of clear negative and positive samples. All results (100%) submitted for the five negative samples (n = 173) and 97% of immunological results submitted for the three positive samples (n = 105) were correctly classified (the incorrect responses were two borderline classifications and, from a gel-agglutination method, one negative classification). There was more difficulty in the classification of the two weak positive samples (n = 70). In one survey, 61% of results from the weak positive sample were classified as positive, while 21% were called negative, 16% were called borderline, and 2% were called inconclusive. In a second survey, 16% of results from the weak positive sample were called positive, while 56% were called negative, and 28% were called borderline. Significant interlaboratory variation was observed for ELISA results, with coefficients of variation of about 20 to 30%. We conclude that there is variability in HIT laboratory testing and that identification of weak positive samples can be challenging.

External Validation Of The HIT Expert Probability (HEP) Score, a Novel Pre-Test Probability Model For Heparin-Induced Thrombocytopenia Based On Broad Expert Opinion

IntroductionThe diagnosis of heparin-induced thrombocytopenia (HIT) is challenging due to the overlap of its clinical features with other entities, variable specificity of ELISA-based tests, poor availability of functional tests such as the serotonin release assay (SRA) and suboptimal positive predictive values of pre-test probability clinical scoring models, such as the 4T and Lillo-Le Louėt models. Improved diagnostic tools are desirable to guide early therapeutic decisions in patients with suspected HIT and to reduce inappropriate use of alternative anticoagulants. The HIT Expert Probability (HEP) Score, a pre-test probability clinical scoring model for HIT based on broad expert opinion, has recently been proposed to improve the diagnosis of HIT compared to the 4T score. We sought to externally and prospectively validate the HEP score. MethodsPre-test probability of HIT was prospectively assessed for 51 consecutive patients referred to the Cleveland Clinic Vascular Medicine Consultative Service for evaluation of possible HIT between August 1, 2012 and February 1, 2013. Electronic medical records were reviewed to obtain clinical, biochemical (including IgG specific HIT ELISA and SRA tests) and imaging data, and two Vascular Medicine fellows independently applied the 4T and HEP scores for each patient. Two independent HIT expert adjudicators rendered a diagnosis of HIT likely or unlikely. Both scorers and adjudicators were blinded to the Results of HIT laboratory testing, consultative service inputs and scores generated by other raters. ResultsThe median 4T and HEP scores were 4.5 [range 3.0, 6.0] and 5 [range 3.0, 8.5], respectively. Interobserver agreement was lower for the HEP Score compared to 4T score, intraclass correlation coefficient: 0.50 (95% CI 0.16–0.85) vs. 0.69 (0.54–0.86). There were no significant differences between area under receiver-operating characteristics curves of 4T and HEP score against HIT ELISA testing (0.62 vs. 0.58, P = 0.62), SRA (0.74 vs. 0.73, P = 0.97), expert panel diagnosis (0.71 vs. 0.79, P = 0.20), concordant HIT ELISA and SRA (0.76 vs. 0.72, P = 0.65), and positive SRA or positive HIT ELSA with HIT likely expert panel diagnosis (0.73 vs. 0.75, P = 0.80). The HEP score model was 100% sensitive and 17% specific for determining the presence of HIT as defined by positive SRA or positive HIT ELISA with HIT likely expert panel diagnosis compared to 4T score (sensitivity, 94%; specificity 38%) (Figure 1, Table 1). [Display omitted] ConclusionThe HEP and 4T scores are excellent screening pre-test probability models for HIT, however, in this prospective validation study, test characteristics for the diagnosis of HIT based on confirmatory laboratory testing and expert opinion are similar. Given the complexity of the HEP scoring model compared to that of the 4T model, further validation of the HEP score is warranted prior to widespread acceptance. Disclosures:Kim:Philips US: Consultancy; GE: Research Funding.

Novel diagnostic assays for heparin-induced thrombocytopenia

AbstractLaboratory testing for heparin-induced thrombocytopenia (HIT) has important shortcomings. Immunoassays fail to discriminate platelet-activating from nonpathogenic antibodies. Specific functional assays are impracticable due to the need for platelets and radioisotope. We describe 2 assays that may overcome these limitations. The KKO-inhibition test (KKO-I) measures the effect of plasma on binding of the HIT-like monoclonal antibody KKO to platelet factor 4 (PF4)/heparin. DT40-luciferase (DT40-luc) is a functional test comprised of a B-cell line expressing FcγRIIa coupled to a luciferase reporter. We compared these assays to polyspecific and immunoglobulin (Ig)G-specific PF4/heparin enzyme-linked immunosorbent assays (ELISAs) in samples from 58 patients with suspected HIT and circulating anti-PF4/heparin antibodies. HIT was defined as a 4Ts score ≥ 4 and positive 14C-serotonin release assay. HIT-positive plasma demonstrated greater mean inhibition of KKO binding than HIT-negative plasma (78.9% vs 26.0%; P < .0001) and induced greater luciferase activity (3.14-fold basal vs 0.96-fold basal; P < .0001). The area under the receiver-operating characteristic curve was greater for KKO-I (0.93) than for the polyspecific (0.82; P = .020) and IgG-specific ELISA (0.76; P = .0044) and for DT40-luc (0.89) than for the IgG-specific ELISA (P = .046). KKO-I and DT40-luc showed better discrimination than 2 commercially available immunoassays, are simple to perform, and hold promise for improving the specificity and feasibility of HIT laboratory testing.

OHP-042 Heparin-Induced Thrombocytopenia (HIT): Pre-Test Clinical Score (4Ts) to Justify Danaparoid Prescriptions? What Else?

BackgroundHIT is a prothrombotic adverse drug reaction caused by heparin and requires an alternative anticoagulant: danaparoid. Because of its cost and the specific indication, the physicians must request two laboratory...

The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion.

The diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. Over-diagnosis and over-treatment are common. To develop a pre-test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. A pre-test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T's). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80-0.93) vs. 0.71 (0.54-0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver-operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T's. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). The HEP Score is the first pre-test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted.