Interrater agreement for two systems used to determine the probability of heparininduced. heparin-induced thrombocytopenia CLINICAL REPORT

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1 CLINICAL REPORT CLINICAL REPORT ar Layar Interrater agreement for two systems used to determine the probability of heparininduced thrombocytopenia (HIT) is a rare but serious condition caused by an immune-mediated reaction leading to strong platelet activation and thrombotic complications. The diagnosis of HIT relies on both clinical evaluation and biological or, where available, functional assays. Biological assay methods include testing for anti platelet factor 4 (anti-pf4) antigen by enzyme-linked immunosorbent assay (ELISA), and functional assays include the serotonin-release assay (SRA) and the heparin-induced platelet activation assay. Because of its availability in most health centers, the anti-pf4 assay is often preferred over functional assays. However, despite high sensitivity (>95%), the low specificity (5 89%) of the anti- Maxime Doré, Anne Julie Frenette, Isabelle Chagnon, Nathalie Routhier, and David Williamson Maxime Doré, B.Pharm., M.Sc., is Pharmacist, Department of Pharmacy, Hôpital du Sacré-Coeur de Montréal, Montréal, Quebec, Canada. Anne Julie Frenette, B.Pharm., M.Sc., is Assistant Clinical Professor, Associate Researcher, and Critical Care Pharmacist, Department of Pharmacy and Research Center, Hôpital du Sacré-Coeur de Montréal, and Faculty of Pharmacy, University of Montreal. Isabelle Chagnon, M.D., FRCPC, is Specialist, Internal Medicine, Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and Clinical Professor of Medicine, Faculty of Medicine, University of Montreal. Nathalie Routhier, M.D., M.Sc., FRCPC, is Specialist, Internal Medicine, Department of Medicine, Hôpital du Sacré-Coeur de Montréal, and Clinical Professor of Medicine, Faculty of Medicine, University of Montreal. David Williamson, B.Pharm., M.Sc., BCPS, is Associate Researcher and Critical Care Pharmacist, Department of Pharmacy and Research Center, Hôpital du Sacré-Coeur de Montréal, and Associate Clinical Professor, Faculty of Pharmacy, University of Montreal. Purpose. The interrater reliability of the 4T s method and the HIT expert probability (HEP) score for clinical evaluation of suspected heparin-induced thrombocytopenia (HIT) was investigated. Methods. Patients hospitalized over a three-year period who were tested for HIT via anti platelet factor 4 (anti-pf4) antigen assay were identified using laboratory data; 7 patient cases met the study inclusion criteria. Nine clinical pharmacists with expertise in HIT management evaluated the 7 cases using two pretest scoring systems: the 4T s score and the HEP score. Each case was independently evaluated using both 4T s and HEP scores. The primary endpoint was interrater agreement of overall 4T s and HEP scores and individual item scores. Results. Raw agreement of values assigned by the two raters for each of the four items comprising the 4T s score ranged from.54 to.86, with agreement of.6 for final patient categorizations. Raw agreement of rater weightings of the eight HEP scoring items ranged from.4 to.; for dichotomization of patients at the suggested screening cutoff value (>.), agreement was.65. Kappa coefficients were.5.45 for 4T s item scores and.7.7 for HEP score item scores. With both scoring systems, low rater agreement mainly related to determination of the timing of thrombocytopenia and possible other causes of the disorder. Conclusion. In a retrospective study, interrater agreement in scoring of HIT probability via the 4T s and HEP scoring systems was relatively low. The HEP score did not increase interrater reliability or correlation with anti-pf4 antibodies compared with the 4T s score. Am J Health-Syst Pharm. 4; 7:45-5 Address correspondence to Mr. Doré (maxime.dore@umontreal.ca). Isabelle Boulanger, B.Pharm., M.Sc., Dave Brindamour, B.Pharm., M.Sc., Marie-Christine Champagne, B.Pharm., M.Sc., Émilie David, B.Pharm., M.Sc., Isabelle Larouche, B.Pharm., M.Sc., Karine Wilhelmy, B.Pharm., M.Sc., Nadjib Baki, Pharm.D., Julie Rivard, Pharm.D., and Andrée-Anne Tessier, Pharm.D., M.Sc., are acknowledged for their contributions to this work. Presented as an abstract/poster at the Thrombosis and Hemostasis Summit of North America (THSNA), May 5,, Chicago, IL. The authors have declared no potential conflicts of interest. Copyright 4, American Society of Health-System Pharmacists, Inc. All rights reserved. 79-8/4/-45. DOI.46/ajhp7 Downloaded from by guest on 7 January 9 Am J Health-Syst Pharm Vol 7 Dec, 4 45

2 CLINICAL REPORT PF4 assay can result in overdiagnosis of HIT.,4 The use of optical density values in the anti-pf4 assay and assays specific for immunoglobulin G have improved test performance, but the potential for overdiagnosis remains. 4-6 Overdiagnosis may result in the inappropriate use of alternative anticoagulants, with the potential for an increased risk of bleeding, an increased length of hospital stay, and elevated costs.,6-8 On the other hand, HIT underdiagnosis could be of catastrophic consequence, since thrombotic complications develop in 5% of patients with HIT.,9 Scoring systems have been developed for use in clinically evaluating the probability of HIT before a biological test is ordered. Such pretest scoring systems may serve to limit the use of anti-pf4 assays and the consequent use of alternative anticoagulants that may not be warranted.,- These scoring systems may also potentially help in limiting HIT overdiagnosis. Two principal pretest scoring systems have been developed: the 4T s score and the HIT expert probability (HEP) score (appendix). Another scoring system, elaborated by Lillo-Le Louët et al., applies only to patients undergoing cardiovascular bypass and will not be discussed here. The 4T s score classifies patients as having a low, an intermediate, or a high pretest probability of HIT based on () the degree of thrombocytopenia, () the timing of thrombocytopenia, () the presence of thrombosis, and (4) the presence of other potential causes of thrombocytopenia., Some variations of the 4T s system have also been used.,4 The 4T s score has a high negative predictive value, with the theoretical advantage of making evaluation by assay unnecessary in patients with 4T s scores indicating a low probability of HIT. In an initial evaluation of the 4T s score, good interrater reliability was described by the tool s designers, who reported a weighted kappa value of.84 (95% confidence interval [CI],.75.94). Subsequently, however, discrepancies in interpretations of some components of the test among raters were reported. 5 The HEP score, a pretest probability score based on expert opinion, was published in. The HEP score is based on eight factors: () magnitude of thrombocytopenia, () timing of thrombocytopenia, () nadir of the platelet fall, (4) presence of a thrombotic event, (5) presence of skin necrosis, (6) systemic reaction after heparin administration, (7) presence of bleeding, and (8) presence of other potential causes of thrombocytopenia (appendix). To determine the HEP score, the diagnostic importance of each factor is weighted on a scale ranging from to points (higher and lower values indicate, respectively, that a factor argues strongly for or against a diagnosis of HIT), and the points are tallied to yield a total score. The HEP score was demonstrated to have a sensitivity of. (95% CI,.56.) and a specificity of.6 (95% CI,.45.75) with the use of a screening cutoff value of ; with the use of a cutoff of 5 (a value selected in order to achieve an optimal balance of sensitivity and specificity), the scoring method had a sensitivity of.86 (95% CI,.4.99) and a specificity of.88 (95% CI,.74.96). Good interrater correlation of HEP scores was demonstrated in the initial assessment of the scoring system and in a recently published study.,6 A theoretical advantage of the HEP score over the 4T s score lies in the former system s more extensive definition of scoring criteria. The reliability of the HEP score in comparison to the 4T s score remains understudied, and the HEP score has not been validated in a large prospective study. Pretest scoring systems were developed and first validated by hematology fellows and clinicians with expertise in HIT diagnosis and treatment.,,-6 The systems were also validated by a limited number of investigators and in various clinical settings.,,-6 These pretest scoring systems have not been formally studied in real-world clinical settings with heterogeneous patient populations.,,-6 The primary objective of the study described here was to evaluate the interrater reliability for the 4T s and HEP scoring systems in a pragmatic clinical setting. We also estimated the correlation of 4T s and HEP scores, as well as the rates of agreement of 4T s and HEP scores with the results of the anti-pf4 assay by ELISA. Methods Patients older than 6 years hospitalized at the Hôpital du Sacré-Coeur de Montréal for whom an anti-pf4 assay by ELISA (Diagnostica Stago S.A.S., Asnières-sur-Seine, France) was requested during the period January 8 March were retrospectively identified using the hematology laboratory database. Patient cases were excluded from the study if a requested anti-pf4 assay was performed to search for residual anti-pf4 antibody, if a nonrequested assay was performed in error, if an assay was requested for an outpatient, if a tested patient had no prior exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), or if pertinent information in the medical chart was missing or incomplete. Demographics as well as descriptive data related to admission diagnosis, heparin exposure, and initial platelet counts were collected. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated for patients admitted to the intensive care unit (ICU), and a Charlson Comorbidity Index score was calculated for all patients. Demographics and descriptive data and scoring results were retrieved on a prevalidated data collection form. Downloaded from by guest on 7 January 9 46 Am J Health-Syst Pharm Vol 7 Dec, 4

3 CLINICAL REPORT Each patient case was assigned to two independent raters and successively assessed with both the 4T s and the HEP scores. Raters and their order of assessments were randomly assigned using a computergenerated sequence obtained online ( Randomness and Integrity Services Ltd., Dublin, Ireland). Raters were blinded to the result of the ELISA and to other raters ratings. The raters were nine clinical pharmacists practicing in critical care, cardiology, or internal medicine who had 4 years of experience in the care of patients with suspected HIT (median, 8 years of experience; interquartile range [IQR], years). All the raters had earned a master of science degree, and two had fellowship training in intensive care and cardiology, respectively. The local research and ethics board committee approved the study. Descriptive data are reported as mean ± S.D. values (or medians and IQRs when appropriate) and proportions. Medians are used for the description of nonparametric variables. Interrater agreement was evaluated using raw agreement, the kappa statistic, linear weighted kappa values, and, for comparison of the results of the first and second ratings, the intraclass correlation coefficient (ICC). Interrater agreement was assessed for individual components of the scoring systems; for HIT probability, as determined by the 4T s score (low [score of ], intermediate [score of 4 5], or high [score of 6 8]); and for final HEP scores of > and >5. Interrater agreement according to years of pharmacist experience with HIT cases and certain patient characteristics (e.g., cardiac surgery within days of the anti-pf4 assay, ICU admission) were evaluated in sensitivity analyses. A sample size of 7 patients was needed to achieve an 8% power to detect a kappa value of.6, based on a significance threshold of.5, for agreement of total 4T s and HEP scores. Spearman s correlation coefficient (r) was used to estimate the intrarater correlation between the 4-T s and the HEP scores. Intrarater correlation was calculated for both first and second raters. Finally, we estimated the area under the receiver operating characteristic (ROC) curve to assess the performance of 4T s and HEP scores in predicting anti-pf4 assay results. Sample-size calculation was performed using PASS software (NCSS, LLC, Kaysville, UT), and statistical analyses were performed using SPSS 9. (IBM Corporation, Armonk, NY). Results From January 8 through March, 88 anti-pf4 assays were performed at the hospital; of these, 6 were performed as a patient s first and only postadmission anti-pf4 assay. Seventy-nine patient cases were excluded: 6 because the anti-pf4 assay was requested to detect residual anti-pf4 antibody, because the anti-pf4 assay was performed in error, 6 because the anti-pf4 assay was requested for an outpatient, because the patient had no prior exposure to UFH or LMWH, and 4 because the medical record was incomplete. From the remaining 57 patient cases, 7 were randomly assigned to raters for evaluation, based on the sample-size calculation. Demographic, clinical, and laboratory characteristics of included patients are summarized in Table. Most patients were male, and patients were most commonly admitted to a medical ward or an ICU; their median APACHE II score was 5. Of note, 8.9% of patients had undergone cardiac surgery in the days preceding the anti-pf4 assay. Use of extracorporeal membrane oxygenation (ECMO) was specifically assessed since it is a known trigger for PF4 antibodies; no patient received ECMO during this study. Patients were mostly admitted for infectious diseases, cardiac surgery, cardiovascular diseases, and cancer. The majority of patients (65.4%) received thromboprophylaxis, while the remainder received treatment dosages of UFH or LMWH. UFH was the chosen agent in 78% of patients. The median time from initiation of heparin administration to performance of the anti-pf4 antigen assay was longer than the median time between admission (to our facility) and performance of the anti-pf4 assay; this was because several patients were transferred to our facility after heparin administration was started elsewhere. The results of anti-pf4 assay by ELISA were positive in patients (5.%). Optical density values were available for 84 patients (66.%). Raw agreement between raters for the individual 4T s criteria (timing of thrombocytopenia, degree of thrombocytopenia, presence of thrombosis, and presence of other potential causes of thrombocytopenia) ranged from.54 to.86 (Table ). Raw agreement for the total categorized score (i.e., scores indicating low, intermediate, or high probability of HIT) was.6 (95% CI,.54.7). Kappa coefficients for the four individual criteria ranged from.5 to.45 (weighted kappa values ranged from.9 to.5). The kappa coefficient for the total categorized 4T s score (low, intermediate, or high probability of HIT) was. (95% CI,.4.46); this was mostly due to the low kappa coefficient for the other causes criterion. In general, results of the weighted kappa analysis were consistent with the calculated kappa coefficients. The ICC for true scores was.5 (95% CI,.7.6) for the 4T s score. The eight HEP score criteria were evaluated individually. Raw agreement for individual criteria ranged from.4 to. (Table ). Rater scores for the skin necrosis and systemic reaction criteria were in almost perfect agreement, probably because these events are fairly rare and easily recognized. Consistent Downloaded from by guest on 7 January 9 Am J Health-Syst Pharm Vol 7 Dec, 4 47

4 CLINICAL REPORT with the results of the analysis of the 4T s score, the level of agreement was lowest for the other causes criterion (.4; 95% CI,.6.4). Table. Demographic, Clinical, and Laboratory Characteristics of Study Population (n = 7) a Variable In order to evaluate agreement on total HEP score, we dichotomized the scores at the same two cutoff points used by Cuker et al. For total scores Demographic Data Mean ± S.D. age, yr Female, no. (%) Caucasian, no. (%) Median (IQR) Charlson Comorbidity Index score Median (IQR) APACHE II score (ICU only) Clinical Data Admission diagnosis, no. (%) Infectious diseases Cardiac surgery Cardiovascular diseases Cancer Respiratory diseases Sepsis Thromboembolic diseases Other Cardiac surgery < days prior, no. (%) Anticoagulation, no. (%) UFH LMWH Thromboprophylaxis Type of hospital unit at HIT testing, no. (%) Surgical ward Medical ward Surgical ICU Medical ICU Laboratory Data Result of qualitative anti-pf4 assay or ELISA, no. (%) b Positive Negative Result of quantitative anti-pf4 assay or ELISA, no. (%) c Positive, by range of OD units (nm) < Negative, by range of OD units (nm) < Median (IQR) time from admission to anti-pf4 assay, days Median (IQR) time from heparin initiation to anti-pf4 assay, days Median (IQR) baseline platelet count (x /mm ) Median (IQR) nadir platelet counts ( /mm ) Value 69. ±. 58 (45.7) 69 (89.8). (. 5.) 5. (..) (5.7) 9 (5.) 8 (4.) (.) (8.7) 8 (6.) 7 (5.5) (4.4) 4 (8.9) 99 (78.) 8 (.) 8 (65.4) (9.4) 6 (48.8) 9 (4.9) 4 (6.8) (5.) 95 (74.8) (.) 6 (9.) 57 (67.9) 6 (4) 7 (5) 89 (4 89) 7 (4 9) a IQR = interquartile range, APACHE = Acute Physiology and Chronic Health Evaluation, UFH = unfractionated heparin, LMWH = low-molecular-weight heparin, HIT = heparin-induced thrombocytopenia, ICU = intensive care unit, PF4 = platelet factor 4, ELISA = enzyme-linked immunosorbent assay, OD = optical density. b n = 7. c n = 84. of >, raw agreement was.65 (95% CI,.56.7); for total scores of >5, raw agreement was.77 (95% CI,.69.84). A low kappa coefficient value was obtained for three of the eight individual criteria: thrombosis, bleeding, and other causes of thrombocytopenia. The ICC for true scores was.56 (95% CI,.4.67) for the HEP score. The effect of raters clinical experience on agreement was evaluated in a sensitivity analysis. Of the 7 evaluated patient cases, 6 were evaluated by two raters with at least eight years of experience with HIT cases; for this subgroup, the agreement of categorized 4T s scores and total HEP scores was consistent with that observed for the overall rater sample. Agreement between raters was calculated for the 4 cases in which patients had cardiac surgery within days prior to the anti-pf4 assay and for the 5 ICU admissions. For these cases, agreement statistics were consistent with those for the overall case sample. Because raters were randomly assigned to patient cases and to evaluation order (first or second), the intrarater correlation between 4T s and HEP scores was calculated twice; r was.788 (p =.) for first raters and.757 (p =.) for second raters. The performance of the 4T s score in predicting the anti-pf4 assay result, as determined by the area under the ROC curve, was.687 for first raters (95% CI,.57.8) and.7 for second raters (95% CI,.69.87); the corresponding values for the HEP score were.69 (95% CI, ) and.74 (95% CI,.69.8) for first and second raters, respectively. Discussion HIT is a relatively rare but serious condition that warrants a high level of attention. HIT diagnosis relies on both clinical evaluation and biological assays. However, although biological assays help to rule out HIT, Downloaded from by guest on 7 January 9 48 Am J Health-Syst Pharm Vol 7 Dec, 4

5 CLINICAL REPORT they have their limitations. The anti- PF4 assay has high sensitivity and high negative predictive value but low specificity. 7 Functional assays have high sensitivity and specificity, but they are not widely available because they require specialized equipment and staff. Pretest scoring systems have been developed in order to guide clinicians in identifying patients for whom a biological assay is warranted. When first developed and validated, the 4T s score was demonstrated to have high interrater reliability ; its high sensitivity and high negative predictive value were also highlighted., The simultaneous use of the anti-pf4 assay and 4T s score has effectively contributed to a reduction in the overdiagnosis of HIT. In the study described here, we evaluated interrater agreement in 4T s scoring and found it to be low. Discrepancies between raters resulted Table. Interrater Agreement for Two Systems of Determining the Probability of Heparin-Induced Thrombocytopenia (HIT) in Evaluated Cases (n = 7) a System and Criterion 4T s score Degree of thrombocytopenia Timing of platelet decline Thrombosis Other causes Total categorized score (i.e., low/intermediate/high probability) HIT expert probability score Magnitude Timing Nadir Thrombosis Skin necrosis Systemic reaction Bleeding Other causes Total score Screening cutoff of points Screening cutoff of 5 points a CI = confidence interval. b Not calculated. mostly from variability in the interpretation of the criteria pertaining to the timing of thrombocytopenia and other potential causes of the disorder; previous pragmatic studies have also found interrater disagreement in 4T s scoring, particularly with regard to those two criteria.,5,8,9 The 4T s score was recently evaluated in ICU patients specifically, with reported agreement statistics similar to those documented here. 9 In our study and as previously noted by Strutt et al., 5 scoring discrepancies in the other causes component of the 4T s score are mostly related to the classification of other potential causes of thrombocytopenia as either definite or possible rather than on the presence or absence of any other plausible cause. The lack of a clear definition of these two categories remains a problem.,5 We included a high proportion of critically ill patients in our study. Raw Agreement (95% CI) Kappa (95% CI).69 (.6.76).6 (.5.7).86 (.78.9).54 (.45.6).6 (.54.7).76 (.67.8).6 (.5.7).95 (.9.98).88 (.8.9). (.96.).99 (.95.99).8 (.74.89).4 (.6.4).65 (.56.7).77 (.69.84) Evaluation of other causes of thrombocytopenia in critical care patients is particularly challenging, especially with a retrospective study design, since many causes may be present simultaneously., However, we showed similar agreement between raters for both evaluated pretest scoring systems in ICU patients compared with the overall patient population. Cardiac surgery is a known risk factor for thrombocytopenia, and evaluation of these patients for HIT also represents a challenge; nevertheless, in these subsets of cases, agreement between raters for both pretest scoring systems was consistent with the global results. Determination of the timing of thrombocytopenia was also a source of 4T s scoring discrepancies, as previously reported by other researchers. 5,8 Variation in the availability of the first platelet count at the time of heparin initiation, the use of.45 (..59).44 (..56).4 (.4.66).5 (.). (.4.46).55 (.4.68).48 (.7.6).7 (.48.9). (.7.55)... b....6 (..6).7 (.7.7).9 (..46).8 (.8.58) Linear Weighted Kappa (95% CI).5 (.9.66).44 (..57).8 (.7.59).9 (.6.).5 (..5).6 (.47.7).5 (.8.6).7 (.48.9). (.9.57) (.5.57).7 (.6.7).9 (..46).8 (.8.58) Downloaded from by guest on 7 January 9 Am J Health-Syst Pharm Vol 7 Dec, 4 49

6 CLINICAL REPORT multiple heparin products, multiple discontinuations of heparin therapy, and the presence of thrombocytopenia on admission may partly explain difficulties in assessment. In addition, patients may present with lateonset HIT, a lesser-known condition not taken into account by the 4T s score, ; whether late-onset HIT is more frequent among critically ill patients is unknown. One of the theoretical advantages of the HEP score over the 4T s score is that definition of assessment criteria is more extensive with the former method. We hypothesized that agreement between raters would therefore be higher for HEP versus 4T s scores. However, interrater agreement in the results of HEP scoring was poor, and those results correlated well with the results of 4T s scoring. Despite the more extensive definition of HEP scoring criteria, there is still room for subjective interpretation; particularly in the other causes section, some items are not precisely defined. Differences in clinical training and experience of raters may have influenced the interpretation of this criterion. The HEP score was elaborated and validated in one center, with good interrater agreement reported. Another study observed high interrater reliability (ICC,.88; 95% CI,.79.9) and good correlation between the 4T s score and the HEP score. 6 However, that study (like ours) was retrospective and included only 47 patients and two raters, and heparin therapy was seldom used for thromboprophylaxis, which limited the external validity of the findings. Nevertheless, the correlation between anti-pf4 assay results and HEP scores in our investigation (area under the ROC curve,.69 and.74 for first and second raters, respectively) was similar to the value reported by Uaprasert et al. 6 (.7); those values are both lower than originally reported by the developers of the HEP score (.9). Validation of the HEP score in a large prospective study is warranted before routine use can be recommended in clinical practice. The high negative predictive value of both the 4T s score and the HEP score may help reduce overdiagnosis by limiting biological assays to patients with an intermediateto-high probability of HIT; both methods have therefore been found to have clinical utility. However, in a real-world clinical context, agreement between raters may be lower than previously published data indicate, largely due to subjective interpretation of scoring criteria. Therefore, the diagnosis of suspected HIT and the decision to administer alternative (i.e., nonheparin) anticoagulants cannot rely only on pretest scoring results; clinical judgment remains important. We found that the results of the HEP score correlated well with the 4T s score. However, because the HEP score items cannot be remembered and calculated easily and because the 4T s score is more conveniently determined, we consider the 4T s as the preferred pretest scoring system, particularly with regard to avoiding biological assays in patients at low risk for HIT. The lack of precise cutoffs and clear guidance on the interpretation of the HEP score limits its clinical utility. For the moment, more education could help to improve the reliability of the different pretest scoring systems. Hopefully, highly sensitive and highly specific biological assays will become widely available. New diagnostic tools offer promising results and may overcome the diagnostic problems.,4 Foremost among the limitations of our study was its retrospective design. Missing information or unclear reporting of clinical information in medical charts could have hindered the 4T s and HEP scoring, particularly with regard to the other causes criterion; however, all raters worked with the medical chart as their only tool, limiting variability. In another study limitation, raters were unfamiliar with the HEP score, which could partly explain the differences between our study findings and those of Cuker et al. In another notable study limitation, assignment of both 4T s and HEP scores was particularly challenging in cases involving a low suspicion of HIT. On some occasions during their review of patient cases, raters found that the anti-pf4 assay was not clinically warranted and, therefore, the use of the scoring systems seemed futile. In addition, the heterogeneity of the study population could have contributed to low agreement between raters, although it permitted a useful evaluation of both scoring methods in a pragmatic clinical context. Finally, only anti- PF4 assay results were available for a large majority of patients, and functional tests such as the SRA were not done on a routine basis. The strengths of this study included a large and heterogeneous study population that was representative of the real clinical context. Also, in our study, 4T s scoring and HEP scoring were performed by nine clinical pharmacists experienced with HIT; other studies involving fewer raters have resulted in higher interrater agreement of HIT probability scores but were arguably less representative of actual clinical practice. Conclusion In a retrospective study, interrater agreement in scoring of HIT probability via the 4T s and HEP scoring systems was relatively low. The HEP score did not increase interrater reliability or correlation with anti-pf4 antibodies compared with the 4T s score. References. Saad RA. : pathogenesis and management. Br J Haematol. ; :7-4; author reply, 74.. Otis SA, Zehnder JL. Heparin-induced thrombocytopenia: current status and diagnostic challenges. Am J Hematol. ; 85:7-6. Downloaded from by guest on 7 January 9 5 Am J Health-Syst Pharm Vol 7 Dec, 4

7 CLINICAL REPORT. Cuker A. (HIT) in : an epidemic of overdiagnosis. Thromb Haemost. ; 6: Cuker A, Cines DB. How I treat heparininduced thrombocytopenia. Blood. ; 9: Warkentin TE, Sheppard JI, Moore JC et al. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 8; 6: Warkentin TE, Sheppard JA, Moore JC et al. Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need? J Lab Clin Med. 5; 46: Patrick AR, Winkelmayer WC, Avorn J, Fischer MA. Strategies for the management of suspected heparin-induced thrombocytopenia: a cost-effectiveness analysis. Pharmacoeconomics. 7; 5: Wallis DE, Workman DL, Lewis BE et al. Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med. 999; 6: Jang IK, Hursting MJ. When heparins promote thrombosis: review of heparininduced thrombocytopenia. Circulation. 5; : Lo GK, Juhl D, Warkentin TE et al. Evaluation of pre-test clinical score (4 T s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 6; 4: Cuker A, Arepally G, Crowther MA et al. The HIT Expert Probability (HEP) score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. J Thromb Haemost. ; 8: Warkentin TE. : pathogenesis and management. Br J Haematol. ; : Lillo-Le Louet A, Boutouyrie P, Alhenc- Gelas M et al. Diagnostic score for heparin-induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost. 4; : Bakchoul T, Giptner A, Najaoui A et al. Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 9; 7: Strutt JK, Mackey JE, Johnson SM, Sylvia LM. Assessment of the 4Ts pre-test clinical scoring system as a predictor of heparininduced thrombocytopenia. Pharmacotherapy. ; : Uaprasert N, Chanswangphuwana C, Akkawat B, Rojnuckarin P. Comparison of diagnostic performance of the heparininduced thrombocytopenia expert probability and the 4Ts score in screening for heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis. ; 4: Greinacher A, Juhl D, Strobel U et al. : a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/ heparin antibodies of the IgG, IgM, and Appendix Two systems for determining the probability of heparin-induced thrombocytopenia (HIT) - IgA classes. J Thromb Haemost. 7; 5: Nagler M, Fabbro T, Wuillemin WA. Prospective evaluation of the interobserver reliability of the 4Ts score in patients with suspected heparin-induced thrombocytopenia. J Thromb Haemost. ; : Crowther M, Cook D, Guyatt G et al. in the critically ill: interpreting the 4Ts test in a randomized trial. J Crit Care. 4; 9:47.e7-5.. Williamson DR, Lesur O, Tetrault JP et al. Thrombocytopenia in the critically ill: prevalence, incidence, risk factors, and clinical outcomes. Can J Anaesth. ; 6: Williamson DR, Albert M, Heels-Ansdell D et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. ; 44:7-5.. Linkins LA, Warkentin TE. Heparininduced thrombocytopenia: real-world issues. Semin Thromb Hemost. ; 7: Prechel MM, Jeske WP, Walenga JM. Physiological changes in membraneexpressed platelet factor 4: implications in heparin-induced thrombocytopenia. Thromb Res. ; 5:e Nazi I, Arnold DM, Smith JW et al. FcgammaRIIa proteolysis as a diagnostic biomarker for heparin-induced thrombocytopenia. J Thromb Haemost. ; :46-5. System and Criterion 4T s score a Degree of thrombocytopenia >5% fall in platelet count or platelet nadir of /mm 5% fall in platelet count or platelet nadir of 9 /mm <% fall in platelet count or platelet nadir of 9 /mm Timing of thrombocytopenia Clear onset 5 days after heparin started or within day if previous heparin exposure within days Onset consistent with platelet reduction 5 days after heparin started but unclear (e.g., because of missing platelet counts) or onset after day Fall in platelet count <4 days after heparin started without other recent heparin exposure Thrombosis New thrombosis, skin necrosis, or acute system reaction after i.v. heparin bolus Progressive or recurrent thrombosis, erythematous skin lesions, or suspected but unproven thrombosis None Other causes of thrombocytopenia None Possible Definite Points Downloaded from by guest on 7 January 9 HIT expert probability score b Magnitude of platelet fall (peak to nadir after heparin exposure) <% 5% >5% Continued on next page Am J Health-Syst Pharm Vol 7 Dec, 4 5

8 CLINICAL REPORT Appendix Two systems for determining the probability of heparin-induced thrombocytopenia (HIT) - System and Criterion Timing of platelet fall If typical-onset HIT suspected <4 days after heparin exposure 4 days after heparin exposure 5 days after heparin exposure 4 days after heparin exposure >4 days after heparin exposure If rapid-onset HIT suspected (heparin exposure within days) <48 hr after heparin reexposure >48 hr after heparin reexposure Nadir platelet count /mm > /mm Thrombosis c If typical-onset HIT suspected New venous or arterial thromboembolism after 4 days of heparin exposure Progression of preexisting venous or arterial thromboembolism during heparin exposure If rapid-onset HIT suspected New venous or arterial thromboembolism after heparin exposure Progression of preexisting venous or arterial thromboembolism during heparin exposure Skin necrosis at sites of subcutaneous heparin injection Acute systemic reaction after i.v. heparin bolus Bleeding, petechiae, or extensive bruising Other cause of thrombocytopenia Chronic thrombocytopenic disorder Newly started nonheparin agent known to cause thrombocytopenia Severe infection Severe disseminated intravascular coagulation d Indwelling intraarterial device e Cardiopulmonary bypass within 4 days No other apparent cause a points = low probability of HIT, 4 5 points = intermediate probability, 6 8 points = high probability. b points = high probability of HIT, < points = low probability. c Only one response should be selected. d Fibrinogen concentration of < mg/dl and D-dimer concentration of >5 mg/ml. e For example, an intraaortic balloon pump, ventricular assist device, or extracorporeal membrane oxygenation device. Points Downloaded from by guest on 7 January 9 5 Am J Health-Syst Pharm Vol 7 Dec, 4