Heparin-induced Thrombocytopenia Diagnostic Testing Research Articles

Implementation of 4T Score Documentation on PF4 Testing in Patients with Suspected Heparin-Induced Thrombocytopenia

Purpose: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. Diagnosis requires clinical evaluation and laboratory testing. The 4T score is a pretest clinical scoring tool used to determine the probability of HIT. A non-profit health system implemented mandatory documentation of 4T score calculation prior to ordering PF4 tests for suspected HIT patients. The purpose of this performance improvement project is to evaluate the implementation of 4T score documentation on PF4 testing and argatroban utilization. Methods: This was a retrospective, multi-site chart review of patients conducted to assess the impact of mandatory 4T score documentation prior to a PF4 order. The study included adult patients who were admitted to one of the practice sites between January 2020 and November 2022 with a suspicion of HIT and a PF4 order. The primary outcomes included the number of PF4 tests ordered and the percentage of positive PF4 results. Secondary outcomes included number of SRA orders and percentage of positive SRA results, turnaround time for SRA, and the utilization of argatroban. Data collection included baseline demographics, documentation of 4T score, PF4 results, SRA results, documentation of heparin allergy, initial anticoagulant prescribed, platelet trend, ordering provider, and duration of argatroban therapy in patients with a positive PF4 result. The analysis involved using χ2 test and Fisher's exact test for the primary outcomes. Results: Mandatory 4T score documentation significantly reduced PF4 orders by 68% over a two-year period (p<0.0001). It also improved the percentage of positive PF4 results from 12% to 24% (p=0.60) and positive SRA results from 19% to 44% (p=0.35). Notably, after documentation of the mandatory 4T score tool, only 21% of the patients had a PF4 order placed. A total of 42 patients with a positive PF4 test were included to assess argatroban utilization. The turnaround time for SRA in these patients was 3.6 days while duration of argatroban therapy was 6.8 days. Conclusion: Implementation of mandatory 4T score documentation significantly reduced PF4 orders and improved HIT diagnostic testing in a non-profit health system. Challenges remain with SRA turnaround time and corresponding duration of argatroban therapy. The results of this project have demonstrated that standardized documentation is essential for optimizing HIT diagnosis and management protocols. Future efforts will focus on optimizing confirmatory HIT testing and non-heparin anticoagulation therapy.

Clinical decision support to reduce unnecessary diagnostic testing for heparin-induced thrombocytopaenia.

Appropriate evaluation of heparin-induced thrombocytopaenia (HIT) is imperative because of the potentially life-threatening complications. However, overtesting and overdiagnosis of HIT are common. Our goal was to evaluate the impact of clinical decision support (CDS) based on the HIT computerized-risk (HIT-CR) score, designed to reduce unnecessary diagnostic testing. This retrospective observational study evaluated CDS that presented a platelet count versus time graph and 4Ts score calculator to clinicians who initiated a HIT immunoassay order in patients with predicted low risk (HIT-CR score 0-2). The primary outcome was the proportion of immunoassay orders initiated but cancelled after firing of the CDS advisory. Chart reviews were conducted to assess anticoagulation usage, 4Ts scores and the proportion of patients who had HIT. In a 20-week period, 319 CDS advisories were presented to users who initiated potentially unnecessary HIT diagnostic testing. The diagnostic test order was discontinued in 80 (25%) patients. Heparin products were continued in 139 (44%) patients, and alternative anticoagulation was not given to 264 (83%). The negative predictive value of the advisory was 98.8% (95% CI: 97.2-99.5). HIT-CR score-based CDS can reduce unnecessary diagnostic testing for HIT in patients with a low pretest probability of HIT.

A comparative study of platelet factor 4‐enhanced platelet activation assays for the diagnosis of heparin‐induced thrombocytopenia

BackgroundFunctional platelet activation assays, such as the serotonin release assay (SRA), are the gold standard for the diagnosis of heparin‐induced thrombocytopenia (HIT). Recently, platelet activation assays using added platelet factor 4 (PF4) have been described and suggest improved sensitivity. Direct comparisons of these assays have not been performed. ObjectiveWe compare the performance characteristics of three PF4‐enhanced platelet activation assays, the PF4/heparin‐SRA (PF4/hep‐SRA), the PF4‐SRA, and the P‐selectin expression assay (PEA), at a single reference laboratory. MethodsSerum samples from two cohorts of patients were used. The referral cohort (n = 84) included samples that had previously undergone routine diagnostic testing for HIT and tested positive or negative using the SRA. The clinical cohort (n = 101) consisted of samples from patients with clinically confirmed HIT whose serum contained platelet‐activating antibodies. We simultaneously tested all samples in PF4‐enhanced SRA‐based assays (PF4/hep‐SRA, PF4‐SRA) and the flow cytometry‐based PEA. ResultsIn the referral cohort, the three PF4‐enhanced assays identified all samples that were previously determined to be positive in the SRA. However, specificity of the PF4/hep‐SRA was 96.6%, the PF4‐SRA was 84.7%, and the PEA was 67.8%. In the clinical cohort of samples, all SRA‐based assays displayed high performance characteristics (>92.1% sensitivity, >98.4% specificity). Sensitivity and specificity of the PEA was the lowest, 65.8% and 63.5%, respectively; but improved to 92.1% and 96.8% using preselected platelet donors. ConclusionsAll PF4‐enhanced assays demonstrated good performance characteristics when platelet donors were preselected. Further comparisons across multiple laboratories should be conducted for consensus on optimal HIT diagnostic testing.

Evaluation of heparin induced thrombocytopenia using probability scores in a mechanical circulatory support population.

Patients on mechanical circulatory support (MCS) devices carry a high risk for thrombocytopenia and due to the routine use of heparin, heparin induced thrombocytopenia (HIT) is frequently suspected. HIT Expert Panel (HEP) and 4T scoring tools have been validated in the general medicine population to assess the probability of HIT diagnosis, however, these tests have not been validated for use in patients requiring MCS support. The objective of this study was to assess the association of 4T and HEP scores to available assess HIT diagnostic tests in patients requiring MCS. We conducted a retrospective review of patients requiring MCS who had heparin PF4 antibody optical density and/or serotonin release assay results reported. A 4T and HEP score at the time of heparin antibody ordering was calculated. Utilizing previously described ranges for HIT diagnostic tests, patients were categorized into two HIT probability categories: probable and not probable. Descriptive statistics were used for the 4T and HEP scores in both HIT probability categories and t-test and receiver operating characteristic (ROC) analysis were used to determine the association and agreement between each scoring tool and HIT probability. Eighty-five patients were identified who had HIT diagnostic tests ordered while on MCS; 7 patients were classified as HIT probable and 78 patients were classified as HIT not probable. Based on ROC analysis, 4T score and HEP score had an AUC of 0.88 (± 0.06) and 0.96 (± 0.02), respectively demonstrating high predictability of HIT. Utilizing sensitivity and specificity analysis through ROC curves, a cut off score of 3 for 4T score and 1 for HEP score was established. Based on our analysis, both 4T and HEP scores have high predictability of HIT in the mechanical circulatory support population.

A computerized scoring system to improve assessment of heparin‐induced thrombocytopenia risk

Essentials Current risk scores for heparin-induced thrombocytopenia (HIT) are not computer-friendly. We compared a new computerized risk score with the 4Ts score in a large healthcare system. The computerized risk score agrees with the 4Ts score 85% of the time. The new score could potentially improve HIT diagnosis via incorporation into decision support. SUMMARY: Background (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The 4Ts score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation. Objectives Our main objective was to develop an HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified as being at risk for HIT. Methods We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system with that of a clinically calculated 4Ts score. We took a 4Ts score of ≥4 as the gold standard to determine whether HIT diagnostic testing should be performed. Results The best cutoff point of the HIT-CR score was a score of 3, which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% confidence interval0.57-0.81). Ninety percent of patients with 4Ts score of ≥4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT. Conclusion The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT.

The Platelet Factor-4 (PF4)-Dependent p-Selectin Expression Assay (PEA) Is Highly Accurate for the Detection of Pathogenic HIT Antibodies: Results of a 440-Sample Prospective Blinded Study

Introduction: Heparin-induced Thrombocytopenia (HIT) is a potentially life and limb threatening pro-thrombotic syndrome triggered by antibodies to platelet factor 4 (PF4)/polyanion complexes. Commonly used screening tests such as the PF4/Heparin ELISA (PF4 ELISA), while easy to perform in the near-patient setting, are highly non-specific. In contrast, more accurate tests such as the serotonin release assay (SRA) are technically complex, require radioactivity and are performed in only a handful of reference laboratories. These diagnostic challenges lead to both unnecessary anticoagulant use as well as avoidable cases of severe bleeding. Recent reports suggest that a relatively simple three-hour flow cytometry-based test that uses PF4-treated normal platelets, the PEA (PF4-dependent p-selectin Expression Assay), is at least as accurate as the SRA for identifying patients who have HIT (Thromb Haemost. 2015 Nov 25;114(6):1322-3; Chest. 2016 Sep;150(3):506-15; Chest. 2017 Oct;152(4):e77-e80). Here we describe results of a large prospective study designed to compare the accuracy of the SRA and PEA for HIT diagnosis in a clinical setting.Methods: The PEA and SRA were performed on serum samples obtained from adult patients (≥18 yrs.) from 2 large tertiary care academic hospitals from May 2016 to Sep 2017. All inpatients for whom PF4 ELISA testing was ordered were included in the study. The PEA was performed with platelets pretreated with PF4 at 3 concentrations: 30mcg/mL (PEA30), 10mcg/mL (PEA10) and 3mcg/mL (PEA3). Sera were batch-tested in both assays (SRA and PEA) using the same target platelets. The central laboratory was blinded to clinical history and to the results of the PF4 ELISA performed by participating hospitals at the time of diagnosis. Both centers performed IgG-specific PF4 ELISAs and utilized manufacturer-recommended cut-offs for positivity. Predefined “more-stringent” and “less stringent” criteria based on clinical findings (4Ts score) and results of PF4 ELISA testing were used to define the likelihood of a patient having HIT (Table 1A). Receiver Operating Curve (ROC) analysis was performed and Area Under the Curve (AUC) of each assay was calculated to assess their diagnostic accuracy. Since high test specificity was desired, positive cut-offs that maximized the sum of sensitivity and specificity in a specificity range of ≥90% and ≥95% were derived. To evaluate non-inferiority of the PEA to the SRA, we assessed whether the lower limit of the one-sided 95% confidence interval of the ΔAUC (PEA-SRA) was higher than a non-inferiority margin of 5% and 10%.Results: A total of 440 patient samples were tested with both assays. Seventeen and 28 patients were classified as having true HIT based on the use of the more- and less-stringent criteria, respectively. When classified by more-stringent criteria, the AUC was numerically greater for each of the three PEA tests than for the SRA (Table 1B). All tests had excellent accuracy (AUC>0.90, “excellent” by the Traditional academic point system). Using less-stringent criteria, the PEA30 had the highest AUC estimate followed by the SRA (Table 1C). Positive cut-offs generated at test specificities of ≥90% and ≥95% using data classified by more stringent criteria are shown in Table 1D. PEA3 was non-inferior to the SRA at a 5% non-inferiority margin, and all PEA tests were non-inferior at the 10% margin using the more stringent classification for true HIT (Fig 1A). In the less-stringently classified data set, the PEA30 was non-inferior to the SRA at a 10% margin (Fig 1B).Conclusions: The PEA, a 3-hour, non-radioactive functional HIT assay demonstrated high diagnostic accuracy and was non-inferior to the SRA using commonly accepted non-inferiority margins for diagnostic testing (5-10%). The technical advantages of the PEA over the SRA may encourage its widespread adoption as a rapid-turnaround, accurate and near-patient diagnostic for patients with suspected HIT. [Display omitted] DisclosuresJones:BloodCenter of Wisconsin: Patents & Royalties. Curtis:Ionis Pharmaceuticals: Consultancy. Bougie:BloodCenter of Wisconsin: Patents & Royalties. Aster:BloodCenter of Wisconsin: Patents & Royalties. Garcia:Shingoi: Consultancy; Retham Technologies LLC: Consultancy; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Portola: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Boehringer Ingelheim: Consultancy. Padmanabhan:BloodCenter of Wisconsin: Patents & Royalties: Patent/royalties for HIT diagnostic testing; Veralox Therapeutics: Other: Advisory Board; Retham Technologies LLC: Equity Ownership, Other: Retham seeks to develop HITDx(TM), a new assay for HIT diagnosis; TerumoBCT: Consultancy; GE Healthcare: Other: Material support for Clinical Quality Improvement Initiative; Janssen Pharmaceuticals: Consultancy.

Use of Intravenous Immunoglobulin G in HIT: Impact on Thrombosis and Mortality in a Population-Based Study

Introduction: Heparin-induced thrombocytopenia (HIT) is a severe prothrombotic syndrome with a mortality rate of 10% (Lancet Haematol. 2018 May; 5(5):e220-e231). Case reports show that Intravenous Immunoglobulin G (IVIg) can rapidly and durably counteract HIT antibody-mediated platelet activation in the setting of severe persistent HIT (Chest. 2017 Sep;152(3):478-485 and others). While this data supports use of IVIg in severe HIT, it is well documented that “positive result bias” enhances the likelihood of publication of studies that demonstrate salutary effects of interventions. IVIg has a black box warning for thrombosis which lists a number of potential predisposing states for this complication including hypercoagulable conditions (such as HIT). Thus, one concern is that of new/worsening thrombosis in HIT patients treated with this drug, something that is not evaluable with the limited publications in this area. The Nationwide Inpatient Sample (NIS) is the largest publicly available patient discharge database in the US that includes ~7 million discharges per year representative of discharges from all hospital types in the country. The goal of this study was to evaluate thrombosis, bleeding and mortality outcomes associated with IVIg use in HIT using the NIS database.Methods: Hospital discharges with an ICD-9-CM code for HIT (289.84) in the NIS were used to compare outcomes in adult patients (≥18yrs) who did and did not receive IVIg treatment (ICD-9-CM code 99.14) from October 1, 2008 to December 31, 2014. Discharges with diagnoses suggestive of a history of thrombosis (ICD-9-CM codes V12.51, V12.52, V12.55), idiopathic thrombocytopenic purpura (287.31), or secondary thrombocytopenia (287.4) were excluded. Patient characteristics included age, sex, all patient refined diagnosis related groups (APR-DRG) severity index, and APR-DRG mortality index. Outcomes included arterial thrombosis, venous thrombosis, bleeding, mortality, and a composite of all outcomes. Variables were compared by IVIg treatment status using survey weighted Chi-squared tests for categorical variables and ANOVA for continuous variables. Survey weighted multiple logistic regression was used to model each binary outcome by IVIg treatment status while adjusting for age, gender, APR-DRG severity index and mortality index. A matched analysis was performed as a sensitivity analysis for the multiple logistic regression results. Controls were matched with IVIg cases by exact gender, APRDRG severity index, and mortality index. Five matching controls were selected for each case based on nearest age. Conditional logistic regression was used to analyze each outcome using the matched dataset.Results: HIT patients treated with IVIg and those without were no different in age and sex (Table 1). Consistent with the limited published experience of IVIg use in HIT, those who received IVIg had more severe disease with greater likelihood of dying as indicated by their APR-DRG severity and mortality indices (Table 1). Multiple logistic regression showed that the adjusted odds ratio (aOR) was lower for all outcomes except bleeding in the IVIg-treated group, although this did not reach statistical significance (Fig 1; aOR of 0.766, 0.922, 1.049, 0.685 and 0.703 for arterial thrombosis, venous thrombosis, bleeding, death and composite outcome, respectively). Similar results were obtained in conditional logistic regression of matched data (Fig 2).Conclusions: Use of IVIg was not associated with worse thrombotic outcomes or mortality in HIT. On the contrary, results suggest a possible protective effect on these outcomes, but results did not achieve statistical significance possibly due to small numbers of IVIg-treated patients. The aOR was higher (but not significantly so) for bleeding in IVIg-treated HIT patients, however, this finding is consistent with the possibility that IVIg was used more frequently in patients who had more severe disease (and had already hemorrhaged), as suggested by worse APR-DRG severity and mortality indices in IVIg-treated patients. A prospective randomized treatment study may be necessary to provide conclusive data on IVIg efficacy and risk in HIT. [Display omitted] DisclosuresDhakal:Amgen: Honoraria; Celgene: Consultancy, Honoraria; Takeda: Honoraria. Aster:BloodCenter of Wisconsin: Patents & Royalties. Padmanabhan:Janssen Pharmaceuticals: Consultancy; GE Healthcare: Other: Material support for Clinical Quality Improvement Initiative; Retham Technologies LLC: Equity Ownership, Other: Retham seeks to develop HITDx(TM), a new assay for HIT diagnosis; BloodCenter of Wisconsin: Patents & Royalties: Patent/royalties for HIT diagnostic testing; Veralox Therapeutics: Other: Advisory Board; TerumoBCT: Consultancy.

Development of a high-yield expression and purification system for platelet factor 4

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by IgG antibodies bound to complexes of platelet factor 4 (PF4) and heparin. The majority of diagnostic tests for HIT rely on an exogenous source of PF4 to identify anti-PF4/heparin antibodies. These include the PF4-dependent enhanced serotonin release assay (PF4-SRA) among others. Using a bacterial expression system, we developed a novel and efficient method of producing recombinant human PF4 (rhPF4) that is biochemically and antigenically similar to platelet-derived human PF4. rhPF4 was produced using the pET expression system in the BL21(DE3) strain of Escherichia coli. The system was optimized for protein expression using isopropyl β-D-1-thiogalactopyranoside at different induction temperatures and incubation times. rhPF4 solubility was improved by using different detergents during cell lysis and by purifying with heparin affinity and ion exchange chromatography. Biochemical characteristics of rhPF4 were investigated using mass spectrometry, SDS-PAGE analysis, and gel filtration chromatography and compared to platelet-derived PF4. Antigenic and functional characteristics of rhPF4 were studied using the anti-PF4/heparin EIA and the PF4-SRA. Using this method, we could produce 11.4 ± 0.6 mg of pure rhPF4 per liter of bacterial culture. Absorbance readings from the anti-PF4/heparin EIA using platelet-derived and rhPF4 were highly correlated (n = 194; r = 0.9545, p < 0.0001); and functional release of serotonin in the PF4-SRA induced by anti-PF4/heparin antibodies was similar to either platelet-derived or rhPF4 and heparin (r = 0.9597, p < 0.0001). Our method of rhPF4 production is efficient and does not rely on a source of platelets. The rhPF4 purification method described produces greater yields at a lower cost than other current methods. The application of this method can improve the efficiency of biochemical investigations and HIT diagnostic testing by supplying sufficient amounts of PF4.

Heparin Induced Thrombocytopenia: Descriptive Analysis of Diagnosis and Management

Abstract 1168 Introduction:Heparin induced thrombocytopenia (HIT) is a well-recognized serious complication of heparin therapy. A key step in diagnosing HIT is the timing of ordering of the diagnostic tests, ELISA HIT antibody (HIT Ab) and the functional Serotonin release assay (SRA). A pretest clinical score (T score) has been developed and prospectively validated in two centers and includes thrombocytopenia, timing of platelet count fall, presence of thrombosis and other possible causes of thrombocytopenia. Initial positive or negative HIT Ab testing in the absence of accurate clinical suspicion might result in significant morbidity and mortality due either to unnecessary anticoagulation or holding necessary anticoagulation. Methods:To shed more light on this issue and to increase the awareness of established protocols, we reviewed cases in which HIT Ab tests were sent between January 2008 and June 2010 in a tertiary hospital center and did a descriptive analysis according to clinical suspicion based on the T score. Results:A total of 1173 HIT Ab tests were sent between January 2008 and June 2010. 826(70.4%) patients had low clinical score. From these patients, 764(92.4%) had negative HIT Ab test of which 4 patients had SRA checked and all (100%) were negative; 62(7.6%) patients had positive HIT Ab test, of which 11 patients had SRA checked, with 9(81.8%) being negative and 2(18.2%) being positive. 347(29.6%) patients had intermediate/high clinical score. From these patients, 260(74.9%) had negative HIT Ab, of which 6 patients had SRA checked and all (100%) were negative, and 87(24.1%) had positive HIT Ab, of which 18 patients had SRA checked with 4(22.2%) being positive and 14(77.8%) being negative. A total of 97 HIT Ab tests were repeated with 97 %(94 cases) concordance between the results and 3%(3 cases) discordance. Two out of these 3 cases had negative HIT Ab which on repeating turned positive; however, HIT was excluded by a negative SRA in one, and clinically in the other one. A total of 322(27.4%) patients had discordance between clinical score and HIT Ab test, with 96 (29.8%) cases generating a hematology consult, while in the 851(73.6%) concordant cases, 150(17.6%) generated a hematology consult. DTI was started in 20(2%) patients with low clinical score and 78(22%) patients with intermediate/high clinical score. Discussion:This study confirms the importance of following the established protocols of ordering the HIT score only when there is at least an intermediate or high clinical suspicion for diagnosis as only 7.6% of patients with low clinical score had positive HIT Ab test, and even in these patients 81.8% of SRA tests sent were negative, compared to 24.1% positive HIT Ab in patients with intermediate/high clinical score. However, it also shows that the current pretest clinical scores should be improved since in patients with intermediate/high clinical score and positive HIT Ab, 77.8% of SRA tests checked were negative, ruling out HIT, and in patients with low clinical score and positive HIT Ab test, 18.2% of SRA tests checked were positive, confirming HIT. Awaiting improvement in the pretest clinical scores, we feel that SRA should be always sent in positive HIT Ab cases and low/intermediate pretest probability. The study also confirms the high negative predictive value of a negative HIT Ab test as all the SRA sent (100%) were negative even in patients with intermediate/high clinical score. This study also shows for the first time that there is a very high concordance rate between repeated HIT Ab tests (97%), and there is no need to repeat HIT Ab test when positive or negative. The study also revealed a low frequency of hematology consults even with discordant results between clinical score and HIT Ab tests (29.8%) and we feel that a hematology consult can be more helpful in such cases. We also encourage the use of DTI, when possible, in all patients with intermediate/high clinical score while awaiting the HIT diagnostic tests as the study revealed only 22% of patients receiving DTI in this subset of patients. Conclusion:This study confirms the importance of following the established protocols and having an accurate pretest clinical probability for diagnosing HIT, but it also shows that there is a need to improve the current clinical scoring system to avoid unnecessary anticoagulation or holding necessary anticoagulation, and also avoiding repeating HIT Ab tests with its ensuing costs and low benefit. Disclosures:No relevant conflicts of interest to declare.

The Cost-Effectiveness of Argatroban Treatment in Heparin-Induced Thrombocytopenia

A decision-tree analysis was used to estimate the average cost per patient using the direct thrombin inhibitor argatroban for early treatment (<48 hours after thrombocytopenia onset) compared with delayed treatment (> or =48 hours after thrombocytopenia onset) of immune-mediated heparin-induced thrombocytopenia (HIT) with or without thrombosis. Clinical probability data used to populate the model were obtained from argatroban clinical trials and from published clinical literature. Resource utilization data and cost data were also obtained from available literature, the 2003 Physician's Fee Reference, the Healthcare Cost and Utilization Project 2000, the 2003 Drug Topics RedBook, and a modified Delphi panel. The total per-patient cost included hospital days, diagnostic tests, heparin, argatroban, major hemorrhagic events, and patient outcomes (ie, amputation, new thrombosis, stroke, or death), multiplied by the probability of each event. The incremental cost-effectiveness ratio was calculated by dividing the incremental cost between patients with and without argatroban treatment by the incremental effectiveness, or the cost per new thrombosis event avoided. The mean cost per HIT patient without thrombosis who did not receive argatroban was $38,046. The mean cost decreased by 6.85% for patients who were treated earlier with argatroban therapy (average cost, $35,441), representing a $2605 saving per patient compared with those not treated with argatroban. For those receiving delayed argatroban therapy, the mean cost increased by $9024 per patient compared with those receiving early treatment with argatroban. The mean cost for HIT patients with thrombosis who did not receive argatroban was $48,101, which was 9.0% higher than for those receiving early argatroban therapy, representing a $3957 savings per patient. For HIT with thrombosis, mean costs increased by 18.2% in patients whose argatroban was delayed, representing a cost increase of $8020 per patient compared with early treatment (mean cost $44,144 for early treatment and $52,164 for delayed treatment). The results of this analysis support the recommendation to initiate early argatroban treatment upon suspicion of HIT to reduce the thrombotic consequences of HIT and associated healthcare costs. Argatroban therapy should not be delayed pending the results of HIT diagnostic tests.

Evaluation of Diagnostic Tests and Argatroban or Lepirudin Therapy in Patients with Suspected Heparin-Induced Thrombocytopenia

To evaluate diagnostic tests for heparin-induced thrombocytopenia (HIT), a serious drug reaction that can occur in patients receiving heparin, and to evaluate treatment with direct thrombin inhibitors-the only initial drug therapy that decreases the risk of thromboembolism associated with immune-mediated HIT. Retrospective cohort study. University teaching hospital. Patients with HIT treated with argatroban or lepirudin between January 1, 2000, and December 31, 2003. Patients were assessed for dosage and duration of argatroban or lepirudin therapy, HIT diagnostic tests, and clinically significant adverse events. Thirty-four patients received argatroban, 42 received lepirudin. Mean+/-SD doses of argatroban and lepirudin were 1.2+/-0.9 microg/kg/minute and 0.09+/-0.11 mg/kg/hour, respectively; both were 40% lower than the recommended doses. Mean duration of therapy was 10+/-9 days. Supratherapeutic activated partial thromboplastin times were observed in 30 (39%), 10 (13%) , and six (8%) of 76 patients on days 1, 2, and 3, respectively (p<0.0001). Clinically significant bleeding occurred in 6% of patients receiving argatroban and in 5% of those receiving lepirudin (p=0.99); all patients had an activated partial thromboplastin time of longer than 100 seconds. Although platelet-aggregation tests were ordered in 55 (72%) of 76 patients, they were not useful in 16 (29%) because of equivocal or contradictory results. Due to supratherapeutic activated partial thromboplastin times, our patients often required doses of argatroban and lepirudin lower than those usually recommended. Thus, direct thrombin inhibitors should be started at low initial doses and titrated to target activated partial thromboplastin times to achieve appropriate efficacy and to avoid increasing the risk of bleeding. Platelet-aggregation tests were least useful for evaluating HIT. Appropriate diagnostic strategies should be used to avoid unnecessary drug use.

Frequency of heparin-induced thrombocytopenia in critical care patients.

The diagnosis of heparin-induced thrombocytopenia (HIT) in critically ill patients is complicated by lack of information on the frequency of HIT relative to thrombocytopenia from other causes. In addition, results from HIT diagnostic tests have not been clearly evaluated for clinical utility. In this prospective study, we estimated the frequency of HIT and the predictive performance of the heparin-platelet factor 4 enzyme-linked immunosorbent assay (heparin-PF4 ELISA) in 748 consecutive, heparin-treated patients in a combined intensive and coronary care unit. The criteria for diagnosis were as follows: two or more consecutive platelet counts below 150 x 10(3)/mm3 or a 33% or greater decrease in platelet count 5 or more days after beginning heparin, or any time after starting heparin for patients exposed to the agent within the previous 8 weeks; and a positive 14C-serotonin release assay (SRA), the reference standard. Specificity and predictive values for the heparin-PF4 ELISA were estimated in patients who met the clinical criteria for HIT. Of 748 patients, 267 were exposed to heparin for a sufficient length of time to be considered to be at risk for HIT. Forty of these patients (15.0%, 95% confidence interval [CI] 10.7%-19.3%) met the clinical criteria for HIT. Serum samples were available for 32 of these patients, one of whom tested positive by the SRA, yielding a HIT frequency of 0.39% (95% CI 0.01-2.1%). The specificity of the heparin-PF4 ELISA among thrombocytopenic patients with negative SRA results was 71%, and the positive (PPV) and negative (NPV) predictive values of this test were estimated to be 10% and 100%, respectively. The point estimate of the frequency of HIT in critically ill patients was less than 1% in this cohort. The low PPV and high NPV of the heparin-PF4 ELISA suggest that it can be used to exclude HIT as a cause of thrombocytopenia in this patient population.