4T Score Research Articles

7762 A Unique Case Of Sepsis-Driven Bilateral Adrenal Hemorrhages In A Patient With HIT

Abstract Disclosure: A. Siddiqui: None. B. Shalit: None. H. Nadeem: None. Z. Khan: None. D. Pinkhasova: None. Introduction: Bilateral adrenal hemorrhages, commonly seen in the setting of sepsis as Waterhouse Friderichsen syndrome, is a rare life-threatening condition. This process is driven by the release of bacterial endotoxins leading to the activation of coagulation, fibrinolysis, and proinflammatory pathways. It is by a similar process that now non-septic hypercoagulable states, including heparin-induced thrombocytopenia (HIT), factor V Leiden and protein C resistance are also being recognized as etiologic for bilateral adrenal hemorrhaging. The following case demonstrates a combination of the two etiologies leading to adrenal insufficiency from bilateral adrenal hemorrhages. Clinical Case: A 48-year-old male presented to the emergency department with right upper quadrant pain, dyspnea, and a low-grade fever. Laboratory results indicated leukocytosis with a predominance of neutrophils. Initial computed tomography imaging revealed a 4 x 3.5 cm right lower lobe multi-loculated lung abscess and multiple right lower lobe segmental/subsegmental pulmonary emboli. The patient was started on a heparin drip and empiric antibiotics. Infectious disease was consulted to help determine the etiology of the lung abscess. Extensive workup including sputum, blood, fungal cultures, and acid-fast bacillus smear testing were negative. The patient improved on routine broad-spectrum antibiotics and was planned to be transitioned to a direct oral anticoagulant until serial imaging revealed incidental bilateral 4 cm adrenal hemorrhages. Endocrinology was emergently consulted; a random cortisol level was drawn and found to be low at 2.7 (3-17 µg/dL) with an elevated Adrenocorticotropic hormone (ACTH) level of 114 (6 - 50 pg/mL) indicative of primary adrenal insufficiency. The patient subsequently became hypotensive and was started on stress-dose steroids. Upon further investigation, the patient was found to be thrombocytopenic, and hematology was involved. Based on his 4T score of 5, concern was raised for HIT and argatroban was initiated. Moreover, the patient was eventually stabilized for discharge with close follow-ups with endocrinology, infectious disease, and hematology as an outpatient. Conclusion: There have been 17 reported cases of bilateral adrenal hemorrhaging in the setting of HIT uniformly presenting with complete hemodynamic collapse. This case serves as even more unique given the added component of sepsis. Both sepsis and HIT respectively have been well established to pose individual risk for developing bilateral adrenal hemorrhages. Hence, we hope to highlight the importance of exploring all potential causes of adrenal insufficiency in the setting of bilateral adrenal hemorrhaging and emphasize the harms of anchoring to a single etiology. Presentation: 6/3/2024

A-166 Performance verification of a polyclonal anti-PF4 immunoassay in evaluation of Heparin Induced Thrombocytopenia (HIT)

Abstract Background Heparin-induced thrombocytopenia (HIT) is a severe complication of exposure to heparin that occurs in a small percentage of patients in anticoagulation therapy. HIT could happen regardless of the dose, exposure, schedule, or route of administration. HIT results from an autoantibody directed against endogenous platelet factor 4 (PF4) that forms complex with heparin. This antibody activates platelets and can cause life threatening arterial and venous thrombosis. Untreated HIT has a mortality rate as high as 20%. However, with appropriate screening, diagnosis and early intervention, mortality rates have been reported to be below 2%. The laboratory evidence in evaluating patients for HIT is crucial for early intervention. There are several assays available to diagnose Heparin Induced Thrombocytopenia (i.e., immunoassay and/or functional assay for HIT antibodies; serotonin release assays). The purpose of this study is to establish the measurement criteria and verify performance characteristics of a polyclonal anti-PF4 immunoassay. The test of interest (anti-PF4 immunoassay) is intended for the qualitative detection of the anti-heparin-platelet factor 4 antibodies in plasma or serum by ELISA. Methods The ASSERACHROM Assay (Diagnostica Stago, Inc. USA) was implemented in the automated Dynex DS2 ELISA Processing System (Dynex Technologies Inc USA). Two Dynex DS2 instrument comparisons along with precision, accuracy and measurement range for qualitative positive and negative results were studied. The reference method comparisons with serotonin release assay and other monoclonal anti-PF4 immunoassays were performed. To evaluate performance of the assay, we conducted precision, accuracy, and qualitative method comparison. We compared the assay of interest with two reference lab immunoassays and the gold standard reference method (serotonin release assay). The statistical analysis was carried out in EP Evaluator and GraphPad Prism. Results The negative control precision demonstrated CV of 9.2% (N=20, mean= 0.11, SD= 0.01). The analyte measurement is expressed as optical density (OD). The positive control precision characteristics showed CV of 8.1% (N=20, mean= 1.62, SD= 0.13). The threshold was defined as reference reagent absorbance (R6OD) times the variance factor divided by 100 ((R6OD* variance factor)/100= threshold (X)). This is used for positive (>the X) and negative (< the X) absorbance cut off for patient samples. The R6 reference material precision study resulted in a CV of 7.95% (N=20, mean= 2.1, SD= 0.17). The R6 variance factor per precision statistics at 3SD level was 23.85%. This is comparable to peer group variance provided in the assay package insert (23.5%). The polyclonal anti-PF4 immunoassay versus a reference monoclonal method (N=40) demonstrated agreement of 90.9% with positive agreement of 100% and negative agreement of 89.5%. When compared with gold standard serotonin release assay (N=40), the assay demonstrated agreement of 75% with positive agreement of 90% and negative agreement of 60%. The two instruments demonstrated agreement of 97.5% with positive agreement of 100% and negative agreement of 93.3% (Cohen's Kappa 94.6%; with Kappa > 75% indicates “high” agreement). Conclusions This anti-PF4 immunoassay is precise, accurate and comparable with three different reference methods. The test is best utilized when 4T score based clinical algorithm is used for evaluation of HIT.

Clinical and economic implications of false-positive heparin-induced thrombocytopenia immunoassays: utility of the 4T score.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition induced by platelet-activating IgG antibodies that recognize PF4/heparin complexes. Diagnosis of HIT relies on enzyme immunologic assays (EIAs) and functional assays [serotonin release assay (SRA)]. Our institution uses a latex immunoturbidimetric assay (LIA), which has shown a positive-predictive value (PPV) of 55.6%, and a negative-predictive value (NPV) of 99.7%. The low PPV of EIAs/LIAs, in combination with the clinical delay in obtaining results of a SRA, commonly leads to a false-positive diagnosis of HIT and inappropriate treatment. We performed a single-institution retrospective study at a large tertiary center to assess patient management decisions and economic costs following a false-positive HIT (LIA) test. This study found an 89.5% incidence of false-positive HIT (LIA) tests. 97.4% of patients underwent anticoagulation changes. 69.6% of patients were switched to argatroban. Of patients with a false-positive HIT immunoassay (LIA), 42 (40.7%) patients were on a prophylactic dose of anticoagulation at the time of HIT (LIA) positivity, of which 22 (52.4%) were switched to full anticoagulation with either argatroban or fondaparinux. Of the 22 patients switched to full anticoagulation, 15 (68%) had low-probability 4T scores. Seven (8.8%) of patients had bleeding events after HIT (LIA) positivity. All seven patients were switched to argatroban from a full-dose heparin anticoagulation. Five of the seven patients were considered major bleeds. Utilization of argatroban incurred substantial costs, estimated at approximately $73 000 for false-positive HIT cases. False-positive HIT (LIA) tests contribute to unwarranted anticoagulation changes, increased bleeding risks, and substantial healthcare costs. Incorporating the 4T score into diagnostic algorithms may help mitigate these risks by guiding appropriate clinical decisions. Future research should focus on refining diagnostic approaches and standardizing management strategies to improve patient outcomes and cost-effectiveness in HIT diagnosis and management.

Heparin-induced thrombocytopenia after cardiac surgery. A single-center, retrospective cohort study

BackgroundCardiac surgery is a high-risk setting for heparin-induced thrombocytopenia (HIT). However, large differences in its incidence, rate of thrombotic complications, and mortality have been reported in this context. Few studies address the pharmacologic management of HIT specifically in this setting. ObjectivesTo describe the incidence, outcomes, and management of patients with HIT in our cohort and to compare them with patients presenting platelet factor 4/heparin antibodies but without platelet-activating capacity. MethodsA retrospective observational study was conducted over a period of 10 years and 6 months on 13,178 cardiac operations in a single high-volume cardiac surgery center. ResultsHIT was diagnosed in 0.22% of patients. HIT with associated thromboembolic complications occurred in 0.04% of cases. Two deaths at 30 days were registered, both in patients with associated thrombosis. The 4T score showed a 99.9% negative predictive value. The immunoglobulin G-specific chemiluminescence test positivity rate was highly predictive of HIT. Warfarin was often started early after surgery, and although it was rarely stopped when the diagnosis of HIT was made, no new thromboembolic complications subsequently occurred. Thrombocytopenia appeared to be a poor prognostic sign, whatever the cause. ConclusionAlthough rare, HIT is characterized by high mortality in this setting, especially if thrombotic complications occur. Large multicentric studies or an international registry should be created to enhance the scientific evidence on HIT diagnosis and management in this context.

Electronic alerts to improve management of heparin-induced thrombocytopenia

BackgroundHeparin-induced thrombocytopenia (HIT) is a difficult clinicopathologic diagnosis to make and to treat. Delays in identification and appropriate treatment can lead to increased morbidity and mortality. ObjectivesTo use electronic health alert interventions to improve provider diagnosis and management of heparin-induced thrombocytopenia through guideline-based, accurate care delivery. MethodsThis quality improvement initiative developed 3 electronic health record-based interventions at our 750-bed academic medical center to improve the initial management of suspected HIT between 2018 and 2021: 1. an interruptive alert to recommend discontinuation of active heparin products when signing a heparin-platelet factor 4 test (PF4) order, 2. integrated 4T score calculation in the heparin-PF4 test order, and 3. interruptive alert suggesting not to order heparin-PF4 tests when the 4T score is <4. Changes in practice were assessed over defined time periods pre and post each intervention. ResultsIntervention 1 resulted in heparin discontinuation in more patients, with 65% (191 heparin orders/293 heparin-PF4 enzyme-linked immunosorbent assay tests) of cases continuing heparin prealert and only 54% (127 heparin orders/235 heparin-PF4 enzyme-linked immunosorbent assay tests) postinterruptive alert (95% CI 2.3-19.9; P = .015). Intervention 2 increased appropriate heparin-PF4 test ordering from 40.4% (110/272) preintervention to 79.1% (246/311) (95% CI 30.9-46.4; P < .00001) postintervention, with inappropriate PF4 ordering defined as testing when 4T score was <4. Intervention 3 did not lead to reduction in heparin-PF4 testing in the control group (96 inappropriate orders/402 total orders, 24%) compared to the randomized alert group (56 inappropriate orders/298 total orders; 19%) (95% CI −1.2 to 11.5; P = .13). ConclusionImplementation of unique electronic health record interventions, including both diagnostic and management interventions, led to improved guideline-based, accurate care delivery with 4T score calculation and cessation of heparin for patients with suspected HIT.

Factors Affecting Heparin Induced Thrombocytopenia: A Case Series Study

Heparin-induced thrombocytopenia (HIT) is a condition that can affect patients who are exposed to heparin across a variety of disease states. A case series study was conducted to evaluate the effect of patient age, unfractionated heparin dose and nadir platelet count on the 4T score in a multiple regression analysis. The number of cases selected was ten. The regression analysis showed that patient age and nadir platelet count were statistically significant (P&lt;.05) and the R-squared value was 0.7. A Pearson correlation coefficient analysis also revealed a low positive correlation between heparin dose and platelet count (r = 0.3). These findings add to the body of knowledge encompassing unfractionated heparin which remains a widely used anticoagulant for patients with thrombotic disease and other conditions and procedures. Future studies should continue to evaluate factors that affect HIT including outcomes between Type I and Type II HIT.

Anticoagulation management in patients tested for heparin-induced thrombocytopenia in the cardiothoracic intensive care unit diverges from expert guidelines

Abstract Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening complication in patients receiving heparin products. Clinical scoring tools, such as the ‘4T’ score, aim to help identify patients at risk for HIT and are recommended by expert guidelines. For example, the American Society of Hematology (ASH) recommends that patients with an intermediate or high-risk 4T score are presumptively treated for HIT by withdrawing heparin and starting an alternative anticoagulant. At our institution, laboratory HIT testing involves an in-house latex immunoassay (LIA) that, if positive, reflexes to a send-out serotonin release assay (SRA) at the Blood Center of Wisconsin. This confirmation may take several days to result, underscoring the importance of presumptive treatment. Anecdotally, we have observed that clinicians have expressed reservations about the use of the 4T score in the cardiothoracic intensive care unit (CTICU). These reservations may lead to increased HIT testing in patients with low 4T scores and delays in the initiation of alternative anticoagulants. We set out to objectively determine if clinical practice in the CTICU is aligned with ASH guidelines. To do so, we used anticoagulant usage as a proxy for medical decisions made at the time of order for HIT laboratory testing. Data was extracted from the electronic medical records of all patients who were admitted to the CTICU between 5/2018 and 7/2022 and administered a heparin product (n = 1,602). Patients that were not tested for HIT (n = 1,449) were excluded. The remaining patients’ (n = 153) medication record timings were normalized such that the time of their first LIA was set to zero to allow for relative comparisons. 25 (16%) of the LIAs were positive, of which 5 (20%) were confirmed by SRA. Of the 153 patients, 136 (89%) received heparin within 24 hours prior to LIA order, while 6 (4%) were already on alternative anticoagulation (bivalirudin). Of the patients on heparin prior to LIA, 18 (13%) were switched to bivalirudin upon LIA order, 66 (49%) had heparin discontinued without an alternative, and 52 (39%) were continued on heparin. Our results suggest that the prevalence of HIT in this cohort is 3.3% by SRA, much lower than the expected pretest probability estimated for intermediate- and high-risk 4T scores in published meta-analyses. In addition, the observed anticoagulation practices varied widely and diverged from ASH guidelines, where only 17% of patients were on alternative anticoagulation when the testing was ordered. Future work will investigate these patterns across LIA positivity and 4T scores while attempting to address the clinical outcomes of these treatment decisions.

Low Inter-Rater Reliability of Calculating the 4T's Score for Heparin Induced Thrombocytopenia

Introduction Heparin induced thrombocytopenia (HIT) is an immune-mediated drug reaction that can cause thromboembolism in the setting of thrombocytopenia following heparin exposure. The “4T's score” has been validated to determine the pre-test probability of HIT and to assist in decision making around ordering testing for HIT. The 4T's scoring system requires an individual clinician to determine each component of the score. The objective of our study is to investigate the inter-rater reliability of calculating the 4T's score among clinicians. Methods Through retrospective query of Northwestern Enterprise Data Warehouse, we identified patients who had a HIT antibody (Ab) test ordered between 10/2019 and 10/2022 after implementation of a clinical decision support (CDS) tool that asked clinicians to calculate a 4T's score as part of HIT PF-4 Ab orders. From this cohort, an independent clinician randomly selected 15 patients. Four raters, including an attending hematologist, a hospital medicine attending, a hematology/oncology fellow, and an internal medicine resident, performed manual chart review of the randomly selected subjects to calculate a 4T's score. Data collected for each case included individual components of the 4T's score and overall 4T's score from each rater. In addition, we compared raters' scores to the 4T's score entered by the ordering clinician for the patient. We then categorized the numerical scores into validated pre-test probability categories: 0-3 as low, 4-5 as intermediate, and ≥6 as high. Inter-rater reliability for the categories was calculated using the Fleiss kappa statistic. Our study was approved by the Northwestern University Institutional Review Board. Results Of 15 cases selected, 5 each were scored as low, intermediate, and high probability 4T's scores by the ordering clinician (associated with the HIT Ab order). The overall agreement between the score categories for the 5 clinicians (4 raters and the ordering clinician) was 50.7%, with a Fleiss Kappa statistic of 0.26 (95% CI [0.07-0.45]), indicating poor inter-rater reliability (Figure 1). Excluding the ordering clinician, the overall agreement in score category between the 4 raters was 58.9%, with a Fleiss Kappa statistic of 0.38 (95% CI [0.14-0.62]). The same 4T's score pre-test probability category was calculated by the 4 raters in 5 cases, with only one case in which all four raters calculated the same numerical 4T's score. There was one case in which all 5 clinicians calculated the same 4T's score probability category, but none with the same numerical 4T's score. The hematology/oncology fellow had highest inter-rater agreement with the original clinical (Kappa 0.30 [-0.09-0.69]), whereas the internal medicine attending and resident had the lowest (both with Kappa 0.00 [-0.37-0.37]). Of the 15 4T's scores, 12/15 ordered by the hematology attending, 5/15 by the internal medicine attending, 12/15 by the hematology/oncology fellow, and 11/15 by the internal medicine resident were lower than those calculated by the original ordering clinicians. Conclusion Our study demonstrates poor inter-rater reliability of HIT 4T's score calculation, across levels of training and specialty. Importantly, poor inter-rater reliability was seen across 4T's categories, which has implications for clinical management of patients undergoing evaluation for HIT. This suggests that different strategies are necessary to help clinicians better use the 4Ts score.

Comparison of Interobserver Agreement between the 4T and the HIT Expert Probability (HEP) Scores: We Agreed Not to Agree

Background: Diagnosis of heparin induced thrombocytopenia (HIT) is challenging. The 4T score is the principal scoring system for HIT. The HIT Expert Probability (HEP) score, based on expert opinion, was proposed in 2010. Both scores have a very high sensitivity, being capable of ruling out HIT in low-risk individuals. However inter-observer agreement (IOA) of HEP score in comparison to the 4T score remains uncertain. Aim: This study aimed to compare IOA between the 4T and the HEP score among hospitalized patients. Specific objectives: Comparison of IOA between the 4T and the HEP score in the 1-whole cohort 2-non-ICU 3- ICU Identify which item of the score have the lowest IOA (magnitude of thrombocytopenia, timing of thrombocytopenia, existence of other causes of thrombocytopenia, presence of thrombosis) Methods: Patients: This is a retrospective study at a single tertiary hospital. All inpatients 16 years or older who have been tested for HIT between June 2019 to end of June 2021 were included. Patients were excluded if the reason for sending HIT was a repeat test. Data were collected retrospectively by manual chart review. Assessment of HEP score and 4Ts score: Two hematologists rated the HEP score and 4Ts score independently for every patient. The score's calculation was blinded between observers and, they were blinded to the HIT Eliza result. Low 4Ts score is defined as score less than 4 and for HEP score if less than 3. HIT test was done using Stago Asserachrom HPIA-IgGAM ELISA with level of &amp;lt; 0.4 considered negative. Statistical analysis: Continuous variables are reported as mean ± standard deviation (SD) or median (interquartile range; IQR), as appropriate. Categorical variables are reported as frequency and percentage. The Kappa coefficient (к) with 95 % confidence interval (CI) was used to assess the IOA of 4T score and HEP score, it was calculated for the individual risk categories - low vs high score in: 1-the whole patients 2-ICU 3- non-ICU We also calculated the IOA for each item of the score, magnitude of thrombocytopenia, timing of thrombocytopenia, existence of other causes of thrombocytopenia, presence of thrombosis (as total score). A P-value less than 0.05 was considered significant. Statistical analyses were performed using SAS version 9.4 (SAS institute, CARY, NC, USA). The study was approved by the local ethical board. Informed consent was waived. Results: After exclusion of the repeat test (13), 302 patients were included in this study. Median age 66 years old. Most common reason for request was thrombocytopenia 288 (95%). HIT ELISA ≥ 0.4 in 34 (11%). Inter-observer agreement: All patients: We found similar IOA between the 4T score and the HEP score к (95 % CI) of 4T score was .14(-0.13-0.41, P &amp;lt; 0.01), compared 0.17(-0.16-0.5, P &amp;lt; 0.01) in the HEP score. Non-ICU patients: The IOA was similar between the 4T score and the HEP score, к of 4T score was 0.24(0.11-0.38, P &amp;lt; 0.01) compared 0.17(0.03-0.31 P &amp;lt; 0.01) in the HEP score. ICU patients: The IOA of 4Tscore was lower than HEP score к of 4T score was -020(-0.20.16, P = 0.83) compared 0.16(-0.037-0.37, P = 0.86) in the HEP score. Among the four individual items of 4T score, “existence of other causes of thrombocytopenia” achieved the lowest к with 0.03 and 0.1 in 4Tscore and HEP score respectively. Conclusion: In this retrospective study, we found a lower interobserver agreement of the 4T score compared to the HEP score in ICU patients. The poor IOA of the 4T score in ICU patients is attributed to worse agreement in (existence of other causes of thrombocytopenia item). Ascertaining the cause of thrombocytopenia in ICU patients is challenging and the 4T score seems to depend on physician gestalt rather than objective points. Our data suggests that the HEP score is the preferred score in in patients with critical illness.

When HIT Testing Hurts- the Financial and Clinical Repercussions of Heparin Induced Thrombocytopenia Testing: A Single Center Analysis

Introduction: Thrombocytopenia is a common inpatient hematologic concern. Most often, thrombocytopenia is a multifactorial phenomenon, without one clear cause. Heparin Induced Thrombocytopenia (HIT) is a rare but serious hematologic consequence of exposure to heparin. In many hospitalized patients, heparin is routinely used as venous thromboembolism (VTE) prophylaxis or for therapeutic anticoagulation. The incidence of HIT is approximately 0.5-1.0% in patients exposed to unfractionated heparin (UFH). Though rare, there seems to be over-testing of HIT antibody in the inpatient setting. As such, there is potential for high cost with low yield and false positives that alter patient management, resulting in prolonged hospital stays and further complications in patient care. Methods: This was a retrospective, observational study reviewing the indications, results, and patient characteristics of cases in which HIT testing was ordered. Indications for testing and influence of results on management were determined based on clinical documentation. The tests of interest included HIT antibody testing and Seratonin Release Assay (SRA). We analyzed how many times a HIT antibody was positive with a negative result in the SRA. We also determined whether there was an increased length of stay in patients who had HIT testing ordered. The study population included patients who were admitted to University of Florida Shands Medical Center, an academic institution in Jacksonville, FL in 2022. All patients were &amp;gt;18 years of age. Results: 190 patients were identified, for whom 190 HIT antibody tests were ordered and 75 SRAs. All patients who had a SRA performed had exposure to low dose heparin or therapeutic high dose heparin. Out of 190 patients, HIT testing was positive in 30 patients (15.8%). SRA testing was performed on 75 patients despite only 30 positive HIT tests. The true positives were 10 patients who had positive SRA confirmatory testing out of 190 patients with suspected HIT. Based on the results of confirmatory testing, the false positive fraction of HIT testing was 66%. When analyzing the 190 patients who underwent HIT testing, the average length of stay was 14 days. On average, a hospital stay in the US is 5.5 days and evaluation of HIT results in 8.5 additional days of hospital admission at our institution. The prolonged length of stay for HIT testing is likely impacted by awaiting SRA results along with other factors. Conclusion: This analysis examines the relative over-testing for HIT at a single institution. Compared with the known incidence of positive HIT tests, there is a significant number of positive HIT antibody tests at our hospital. The data further reveals a high probability of a false positive HIT antibody test results in the hospitalized patient, possibly due to immune reactivity. Of 190 patients suspected with HIT, only 10 patients had a positive confirmatory SRA, indicating that only 5% of suspected patients truly had HIT. This demonstrates that 95% of the time HIT assays ordered did not provide clinically useful information. From the time work up was initiated to the time of discharge, the average stay length was 14 days in a patient suspected with HIT. Cost burden of HIT testing was evaluated. Each HIT panel is $153.83 and each confirmatory SRA test is approximately $250, at a commercial laboratory. Taken together, the total average cost per patient with suspected HIT is $413.83 in diagnostic testing. Prolonged hospital stay contributes to approximately $25,000 increase in hospital stay per patient being evaluated for HIT. This does not include the cost of further work up or interventions. Changing to an alternate anticoagulant such as Argatroban increased costs by nearly $1,500 per case and this number increased further when adding the daily coagulation panel required while on this drug. In other studies, this cost has been estimated to add $90,000 to the hospital stay. Prolonged hospital stays are also associated with unintended incidents such as GI bleeding leading to blood transfusions, invasive testing (such as endoscopy/colonoscopy) and increased morbidity to the patient. We will use this information to implement a tool in our Electronic Medical Record (EMR) that will require answering the 4T score in order to establish high pre-test probability, prior to ordering HIT antibody testing at the University of Florida in Jacksonville.

The Impact of Laboratory Sample Request Evaluation and the Use of Probability Testing for HIT By Trained Physician on the Decrease of Unnecessary Tests and Increase the Likelihood of Positivity

Introduction: Heparin-induced thrombocytopenia (HIT) is an extremely serious and potentially fatal condition that can develop in patients taking heparin-based medications, such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The laboratory tests for diagnosis of HIT is expensive and time consuming. Clinical assessment (4Ts) followed by testing for Heparin/platelet factor 4 antibody in intermediate and high risk patients is the standard algorithm of pretest for (HIT) which can be later confirmed by serotonin releasing assay if available. Materials and methods: We conducted a retrospective analysis of laboratory practice of pretest evaluation of samples submitted for HIT testing in a cohort of patients treated in a tertiary hospital in Saudi Arabia who had a clinical suspicion of HIT. The 4 T score was a pretest requisite to proceed for electronic request for HIT. It had to be performed by the requesting physicians of different medical specialties. The request then been evaluated by hematopathologist before proceeding. The test will be cancelled if: the 4T score calculated by attending physician is &amp;lt; 4 or if platelet count is normal with no evidence of significant drop in the last 4 days from request or the test was performed at least 2 days before the new request. Additional exercise was performed by two physicians in training after train them to standardize the calculation of the 4T scores without re evaluation by the hematopatologist. The sample proceeded for testing if it met the testing criteria of 4T score &amp;gt; 3 and passed the evaluation by the hematopathologist. All tested sample were performed by immunoglobulin G (IgG) antibodies via an ELISA (Asserachrom HPIA-IgG, Stago Diagnostica STA®) and Optic density ( OD) and was evaluated and considered positive if OD &amp;gt;0.39 with sub classification to low positive 0.4-1, moderate 1-2 and strong if &amp;gt;2. Over a period of 2 years, we received 449 samples for patients who were admitted to our hospital, received prophylactic or therapeutic doses of LMWH or UFH, and underwent an HIT test due to clinical suspicion ( &amp;gt; 50% drop in platelet count from baseline, or ≥ 2 consecutive platelet counts &amp;lt; 150,000 per mm 3 and was defined as possible HIT). The 4 T score was calculated in the hospital system by attending physicians referred to as (system 4T score) and recalculated by trained two physicians and referred to (re calculated 4T score). Descriptive statistics, paired samples statistics, correlations, and analysis of variance (ANOVA) were performed. Results: The test was labeled by the laboratory physician ( hematopathologist ) as not indicated and test was not performed in 156 (35%) for various reasons including low 4 T score &amp;lt;3 in 90 (57%), Normal platelet count &amp;gt; 150 at time of test ( and wrong calculated 4T score) in 28 (18%), duplication of test order in 10 (6.4%%), There was clear other cause of thrombocytopenia in 15 (10%), Bad sample quality 5 (3.2%%) and 8 (5%) for other reasons. The samples for HIT test were for 231(51%) males and 220 (49%) females with mean age 56.3 (1-102) years. The mean platelet count at time of request was 82.9 (2-384) per mm 3. Out of the total cohort 422 (95.1%) patients had received UFH and only 22 (4.9%) received LMWH. There is only 69/449 (15.4%) agreement between the two calculations (system and re calculated score) . Out of the tested samples 293, total positive tests 19 (6.5%), were 11 (3.8%) had low positive for HIT test, moderate positive in 6 (2%) and only 2 strongly positive for HIT. The calculated (system 4T score) of &amp;lt; 4 were 142 (32%) samples while the (re calculated 4T score) were 136 (30%) of which 60 ( 38%) of the cancelled tests by hematopathologist, of which 68 (23%) of tested samples were negative and 7 (37%) of positive tests could have been missed based on this calculation. There were 12 out of 19 had moderate and high score by calculation and positive HIT while there were 17 out of 19 had moderate and high score by system calculation. Conclusion: We are reporting improved detection of HIT and confirmed the value of applying the 4 T score for HIT testing with added value of pre test screening to exclude low probability and cancel samples with no clear indication of HIT due to presence of other causes of thrombocytopenia.The retrospective re calculation even with more trained physicians did not add a value compared to pretest evaluation and screening by hematopathologist which had resulted in cancelation or more than third of the requested tests.

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&amp;lt;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.

3Ts Score, an Attempt for Less Testing in Thrombocytopenia Patients with Suspected Heparin Induced Thrombocytopenia (HIT): Retrospective Analysis in a University Hospital Setting

Background: Heparin-induced thrombocytopenia (HIT) is a prothrombotic and potentially fatal adverse drug reaction mediated by platelet-activating antibodies against multimolecular complexes of platelet factor 4 (PF4) and heparin. The 4Ts is a pretest scoring system for HIT that was developed to improve and standardize clinical diagnosis. The strength of the 4Ts score lies in the negative predictive value of a low pretest probability score. Those with a 4T score ≥4 is considered to have moderate to high probability of HIT and should undergo confirmatory laboratory test. Delays in treatment are associated with risk of thrombosis. Immediate cessation of heparin and initiation of a non-heparin anticoagulant is therefore standard of care. Method: This is a single institutional retrospective study. We reviewed the charts of 219 patients with thrombocytopenia with suspected HIT to evaluate the appropriateness of ordering the HIT testing based on the pretest probability of the 4Ts scoring system. All patients had enzyme linked immunosorbent assay (ELISA) test for HIT antibodies (the screening test). We studied tests that were sent from 03\16\2021 through 07\03\2023. The serotonin release assay (SRA) which is the confirmatory test for HIT was only sent for patients who had a positive ELISA test. 4T scores were calculated retrospectively using chart's information available to clinicians at the time of the HIT tests were sent. Results: Out of the 219 patients, 80(36.5%), 120(54.7%) and 19(8.6%) patients had a low, intermediate and high pretest probability respectively. The HIT ELISA test was positive in 33 (15.7%) patients and 196 (84.9%) patients had negative results. HIT ELISA had 100% and 93.5% sensitivity and specificity respectively while the positive and negative predicative values were 60% and 100% respectively. A positive SRA test was reported in 23 patients (10.5% of the total study population). Seventy-nine patients (36% of our total sample) scored 4 points which represents intermediate pretest probability. Out of these 79 patients only 6 (11.3%) patients had a positive ELISA test, and 5 (6.3%) patients had a positive SRA test. Aiming to minimize the HIT over testing we examined the increase in the cutoff point of the intermediate pretest probability from 4 points to 5 points which resulted in significant increase in the sensitivity and positive predictive value of the intermediate pretest probability (75.4% and 21% versus 39% and 12.9% respectively). However, the sensitivity dropped from 90% to 65%. The 4th part of 4Ts score gives points based on the probability of HIT versus other pathology as a cause of the thrombocytopenia. Most of the patients with suspected HIT will score one point out of the 4th part of 4Ts score which makes this part of the score is less helpful in distinguishing between patients with suspected HIT and will result in higher overall pretest probability and more testing. We studied the 3Ts score (the 4Ts scoring system after elimination of the 4th part) effect on the intermediate pretest probability. The cutoff points for the 3Ts score are 1-3, 4-5 and 6 for low, intermediate and high pretest probability respectively. The 3Ts score model resulted in significant increase in the specificity and the positive predictive value (76% and 21.7% versus 39.2% and 12.9% respectively) however the sensitivity dropped from 90% to 65%. The average turnaround time for HIT ELISA test and the SRA test was 2.3 days and 4.4 days respectively. Fifteen patients (21% out the patient had low pretest probability on the 4Ts score), 41 patients (59% of the patient who had an intermediate pretest probability on the 4Ts score) and 13 patients (18.8% of the patients who had high pretest probability on the 4Ts score) started on non-heparinoid anticoagulation meanwhile awaiting on the HIT testing result. Conclusion: Over testing of HIT is common secondary to underuse of 4Ts scoring system. Multicomponent educational interventions to increase the awareness and utility of the 4Ts score in addition to implantation of clinical decision support based on HIT computerized score will help to reduce unnecessary diagnostic testing of HIT in patients with low pretest probability. Increasing the cutoff point of the intermediate pretest probability or applying the 3Ts score model resulted in significant increase in the specificity and the positive predictive value of the 4Ts scoring system on expense of the scoring system sensitivity.

Heparin-induced thrombocytopenia associated with low-molecular-weight heparin: clinical feature analysis of cases and pharmacovigilance assessment of the FAERS database.

Background: Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are commonly used anticoagulants for the management of arterial and venous thromboses. However, it is crucial to be aware that LMWH can, in rare cases, lead to a dangerous complication known as heparin-induced thrombocytopenia (HIT). The objective of this study was to evaluate the pharmacovigilance and clinical features of HIT associated with LMWH, as well as identify treatment strategies and risk factors to facilitate prompt management. Methods: We extracted adverse event report data from the FDA Adverse Event Reporting System (FAERS) database for pharmacovigilance assessment. Case reports on LMWH-induced thrombocytopenia dated up to 20 March 2023 were collected for retrospective analysis. Results: Significantly elevated reporting rates of HIT were shown in adverse event (AE) data of LMWHs in the FAERS database, while tinzaparin had a higher proportional reporting ratio (PRR) and reporting odds ratio (ROR) than other LMWHs, indicating a greater likelihood of HIT. Case report analysis indicated that a total of 43 patients showed evidence of LMWH-induced thrombocytopenia with a median onset time of 8days. Almost half of the events were caused by enoxaparin. LMWHs were mainly prescribed for the treatment of embolism and thromboprophylaxis of joint operation. Patients with a history of diabetes or surgery appeared to be more susceptible to HIT. Clinical symptoms were mostly presented as thrombus, skin lesion, and dyspnea. Almost 90% of the patients experienced a platelet reduction of more than 50% and had a Warkentin 4T score of more than 6, indicating a high likelihood of HIT. In all patients, LMWHs that were determined to be the cause were promptly withdrawn. Following the discontinuation of LMWHs, almost all patients were given alternative anticoagulants and eventually achieved recovery. Conclusion: LMWH-induced thrombocytopenia is rare but serious, with increased risk in patients with diabetes or a surgical history. Prompt recognition and management are crucial for the safe use of LMWHs.

Reducing Inappropriate Simultaneous Ordering of Heparin Antibody and Serotonin Release Assays.

A 4T score with intermediate or high probability of heparin-induced thrombocytopenia prompts ordering of anti-platelet 4 heparin complex. If positive, a serotonin release assay (SRA) is recommended to confirm diagnosis. Despite these recommendations, overtesting of both anti-platelet 4 and SRA is highly prevalent. This was a quality improvement initiative using two forms of clinical decision support across 11 acute care hospitals. First, a 4T calculator was incorporated into anti-platelet 4 orders. Second, a Best Practice Advisory fired when anti-platelet 4 and SRA were ordered simultaneously, prompting the provider to remove the SRA order. Data were analyzed by a quasi-experimental interrupted time series linear regression comparing weekly average laboratory tests per 1,000 patient-days pre- and postintervention. Average ordering frequency of anti-platelet 4 changed from 0.508 to 0.510 per 1,000 patient-days (0.5%, p = 0.42) without significant slope or level differences. Average ordering frequency of SRA decreased from 0.430 to 0.289 per 1,000 patient-days (32.8%, p < 0.001) with a significant level difference of -0.128 orders per 1,000 patient-days (-31.2%, p < 0.05). A simultaneous Best Practice Advisory was effective in reducing SRA orders, but not anti-platelet 4 orders.

Analysis of heparin-induced thrombocytopenia diagnostic and management strategies in individuals with inconclusive antibody optical densities.

Heparin-induced thrombocytopenia (HIT) is an uncommon but serious complication of exposure to heparin. Antibody optical densities (ODs) used to diagnose HIT exceeding 2 are highly suggestive of disease, whereas ODs less than 0.5 often 'rule out' HIT. Variation in the clinical care of patients with inconclusive ODs between 0.5 and 2 is likely. This single-centre, retrospective analysis evaluates the diagnosis, management and outcomes of those with antibody ODs between 0.5 and 2. We queried our institution's Healthcare Enterprise Repository for Ontological Narration (HERON) database to identify individuals with antibody ODs between 0.5 and 2. Chart review was completed to calculate 4T scores, corroborate diagnosis codes with documented information in our electronic health record (EHR) and evaluate the diagnosis, management and outcomes of these individuals. These data were evaluated using descriptive and univariate statistics. Among individuals evaluated for HIT between November 2007 and July 2020, we identified 302 individuals with ODs between 0.5 and 2. Serotonin release assays (SRAs) were assessed in 55% (165/302) and were positive in 12% (20/165). In those with available data, 96% with low 4T scores had negative SRAs and 4% had positive SRAs. As 4T scores and antibody ODs proportionally increased, SRA positivity also increased. Clinical management varied widely; however, 4T scoring remains a valuable assessment in this cohort. In those with HIT antibody ODs between 0.5 and 2, true positives were uncommon, and their clinical management varied widely. Fortunately, 4T scoring is a useful prognostic tool that improves the diagnosis and management among those with inconclusive HIT.

Optimization of laboratory diagnosis of heparin-induced thrombocytopenia using HemosIL-AcuStar-HIT-IgG assay.

The aim of this study was to determine an optimal cutoff value for the newly available HemosIL-AcuStar-HIT-IgG assay (AcuStar) for the diagnosis of heparin-induced thrombocytopenia (HIT). We evaluated the performance of AcuStar using serotonin release assay (SRA) as the gold standard and incorporated 4T score calculation in a cohort of suspected HIT cases. Statistical analysis was performed to determine optimal cutoff value for the diagnosis of HIT. A diagnosis of HIT can be excluded with a platelet factor 4 (PF4) value of <0.4 U/mL by AcuStar and 4T score in the low-risk category (≤3). All other cases will require confirmation with a functional test. Our study resulted in the implementation of a diagnostic algorithm for laboratory diagnosis of HIT, which incorporates pretest calculation of 4T score and AcuStar as a screening test, with reflex confirmation by SRA. This new algorithm resulted in extended hours of test availability and a more rapid turnaround time in reporting PF4 results.

Cerebral venous sinus thrombosis associated with SRA-negative heparin-induced thrombocytopenia: case report

BackgroundThere are very few documented reports in literature of cerebral venous sinus thrombosis (CVST) caused by immune-mediated heparin-induced thrombocytopenia (HIT). Further, there are very few reports of false negative serotonin release assays (SRAs) when testing for immune-mediated HIT.Case presentationWe present a case of a 60- year-old male with recent unfractionated heparin administration for venous thromboembolism prophylaxis, an elevated 4T score of 5 and acute CVST in which immune-mediated HIT was suspected. The enzyme-linked immunosorbent assay (ELISA) screening assay was positive for PF4 antibodies and subsequent reflexive SRA testing was negative. However, given the clinical picture, a false-negative SRA was suspected (and eventually confirmed), prompting use of the alternative PF4-dependent p-selectin expression assay (PEA) which was confirmed to be positive. The patient was successfully managed with a bivalirudin infusion and eventually transitioned to apixaban.ConclusionIt is uncommon for immune-mediated HIT with thrombosis to manifest as CVST. Similarly, false-negative SRA is uncommon in immune-mediated HIT. Take-away lessons from our case report include considering HIT in CVST patients with an elevated 4T score and considering the entire clinical picture and degree of suspicion for HIT when interpreting negative HIT testing results. The PEA, in conjunction with the 4Ts score, may be considered as an alternate diagnostic assay for HIT.

Increased hs-CRP and Sepsis Influence the Occurrence of Thrombocytopenia in Severe and Critically Ill COVID-19 Patients Receiving Anticoagulants

BACKGROUND: Despites its benefits, as one of COVID-19 principal treatments, anticoagulant raises a significant concern regarding the anticoagulant-related thrombocytopenia. However, up to date, there is lack of study examining anticoagulantinduced thrombocytopenia during COVID-19, hence this study was conducted to determine the factors inducing anticoagulant-induced thrombocytopenia in COVID-19 patients.METHODS: An observational cross-sectional study of 106 anticoagulant-treated COVID-19 subjects was conducted. Blood serum was drawn from subjects, then platelets, prothrombin time (PT), activated partial thromboplastin (aPPT), international ratio (INR), D-dimer, ferritin, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP), were measured. For thrombocytopenia risk assessment, the 4T score was calculated. To assess the risk of thrombocytopenia. Statistical analysis using Chi-square and Mann-Whitney U test were performed and followed by multivariate analysis to examine the correlation among the thrombocytopenia risk factors.RESULTS: Significant differences were identified in the length of stay (LOS) (p=0.04), disease severity (p=0.021), sepsis (p=0.006), hs-CRP (p=0.003), and mortality rate (p=0.028) between thrombocytopenia and nonthrombocytopenia groups. A multivariate analysis through linear and logistic regression disclosed an increase in hs-CRP (OR=-0.29; p=0.045) and sepsis (OR=4.32; p=0.03)that precipitate the thrombocytopenia events.CONCLUSION: In severe and critically ill COVID-19 patients, the occurrence of thrombocytopenia was followed by an increase in inflammatory parameters such as D-dimer, fibrinogen, ferritin, hs-CRP and prolonged coagulation. The increase in hs-CRP and sepsis may raise the risk of thrombocytopenia, especially in severe and crtically ill cases of COVID-19.KEYWORDS: COVID-19, anticoagulant, thrombocytopenia, inflammation, infectious disease

Implementation of Electronic Alerts to Improve Clinician Management of Heparin Induced Thrombocytopenia

Introduction: Heparin induced thrombocytopenia (HIT) is often a difficult clinicopathologic diagnosis to make, which can result in poor patient outcomes due to delays in identification and treatment. Platelet factor 4 (PF4) antibody ELISA tests are routinely used to diagnose HIT. PF4 ELISAs have high sensitivity but low specificity; therefore, to guide appropriate ordering of PF4 tests ASH guidelines recommend calculating a 4T score to assess the pre-test probability, but this is not always done. We implemented and studied the impact of three electronic health record (EHR) based strategies to improve diagnosis and treatment of HIT at our institution. Methods: At Brigham and Women's Hospital, we created 1. an interruptive alert to recommend discontinuation of active heparin products when signing a PF4 order (Figure 1), 2. integrated 4T score calculations with PF4 test ordering, and 3. through randomization, investigation of the efficacy of an interruptive alert advising clinicians not to order the PF4 test if the 4T score was low. Pre and post implementation groups for each intervention were identified and compared. The heparin discontinuation alert went live on December 20, 2018; the pre-intervention group included patients with PF4 tests in the previous 12 months, and the post-intervention group for 12 months following. The 4T score elements were integrated into the PF4 ELISA order on August 31, 2020; the pre-intervention group included patients with PF4 tests ordered 9 months prior and the post-intervention for 9 months following. In the pre-intervention group, we performed chart review to assess whether the ordering provider documented a 4T score; if a 4T score was not documented in the EHR, it was calculated retrospectively by the research team. Groups were compared to determine the proportion of appropriate PF4 orders (4T score > 3), and the efficacy of the randomized alert recommending no PF4 ordering if the 4T score was < 4. For both alert-based interventions, Chi-squared analysis was performed to determine statistical significance between defined groups. Results: 1. Heparin discontinuation: For the heparin discontinuation alert analysis, of 781 orders for PF4 tests in the pre-heparin discontinuation alert group, 293 eligible orders were used, and of 708 orders in the post-alert group, 235 orders were included. Eligible orders were those that had heparin ordered at the time of PF4 testing and those that were not cancelled. Implementation of the heparin discontinuation alert increased heparin discontinuation from 35% to 46 % (p = 0.015) (Figure 2). 2. 4T Score Documentation and Associated PF4 Appropriateness: Of the patient charts reviewed prior to integration of the 4T score elements into the PF4 order, only 31% (85/272) had a 4T score documented in the EHR. Of the 547 patients post-intervention, by design 100% had a documented 4T score. In the pre-intervention group, of those with calculated 4T scores before PF4 test ordering, 69.4% (59/85) were appropriate, while for those without a 4T score calculated just 27.2% (51/187) were appropriate based on retrospective 4T calculation, for a composite 40.4% appropriate pre-intervention PF4 test ordering, as compared to 79.1% (246/311) appropriate PF4 test ordering post-intervention (p <0.00001). Subspecialties with the highest inappropriate ordering of PF4 tests were: Surgical ICU (32.3%), Oncology (25.6%), the Cardiac Critical Care Unit (24.5%), and Adult Medicine (23.8%). 3. Alert to Not Order PF4 With Low 4T Score: Rates of appropriate PF4 ordering were similar between the group randomized to see the interruptive alert advising clinicians not to order the PF4 test if the 4T score <4 (242 appropriate orders/ 298 completed orders, 81%) and the control group that did not see the alert (306 appropriate orders/ 402 completed orders, 76%; p=0.13). Conclusions: Heparin product continuation can be life-threatening in patients with HIT. Implementation of electronic decision support significantly increased discontinuation of heparin products in patients in whom HIT was suspected. Forced calculation of the 4T score resulted in increased appropriateness of PF4 test orders by 40%. The impact of randomized guidance not to order a PF4 test when the 4T score was low was not as successful. Overall, the EHR interventions resulted in improved patient care for those suspected of having HIT at our institution. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal