Diagnosis Of Heparin-induced Thrombocytopenia Research Articles

Evaluating Diagnostic Algorithms for Heparin-Induced Thrombocytopenia using Two Combined Automated Rapid Immunoassays.

Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder caused by antibodies against platelet factor 4 (PF4) and heparin complexes. Rapid immunoassays (IAs) for detection of these antibodies mark a milestone in HIT diagnosis, despite a higher false-positive rate compared with functional platelet-activation assays. However, combining different rapid IAs may help to improve their diagnostic specificity. Here, we compared the individual performance of the latex immunoturbidimetric assay (LIA; HemosIL HIT-Ab [PF4-H]; sensitivity 91.7%, specificity 68.4%) and chemiluminescence immunoassay (CLIA; HemosIL AcuStarHIT-Ab [PF4-H]; sensitivity 92.4%, specificity 85.8%) with their combined performance using two unique diagnostic algorithms in a single prospective cohort of suspected HIT patients. Using the simultaneous algorithm adapted from Warkentin et al, the combined LIA-CLIA had a sensitivity of 99.0% and specificity of 64.3%. The sequential algorithm adapted from Rittener-Ruff et al was applied in two theoretical scenarios to reflect real-world circumstances in diagnostic laboratories where access to clinical information is limited: (1) assuming all patients had an intermediate 4Ts score and (2) assuming all patients had a high 4Ts score. This algorithm correctly predicted HIT in 94.5% (high 4Ts) and 96.0% (intermediate 4Ts) and excluded HIT in 82.6% (high 4Ts) and 80.1% (intermediate 4Ts) of patients in either scenario, respectively. Although both combined algorithms improved diagnostic performance of individual IAs, the simultaneous algorithm showed fewer false predictions (7.9%) than the sequential algorithm (intermediate 4Ts: 37.6% and high 4Ts: 41.5%) and proved more practical as it does not rely on physician evaluations. Our findings highlight the importance of accounting for clinician and interlaboratory variability when evaluating diagnostic tests for HIT.

C-reactive protein level at admission is associated with increased mortality in critically ill cardiac patients with heparin-induced thrombocytopenia

Abstract Funding Acknowledgements None. Introduction Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated disorder related to the use of unfractionated heparin or low-molecular weight heparin. As heparin is commonly used in critically ill cardiac patients, HIT consititute a relevant clinical issue in the intensive cardiac care unit. Despite this, there isn't any known factor that could predict mortality in acute cardiac patients with heparin-induced thrombocytopenia. Purpose The purpose of our study was to verify if any clinical or laboratory factor could predict mortality in critically ill cardiac patients with heparin-induced thrombocytopenia. Methods We retrospectively collected data of all patients with HIT who were hospitalized in our intensive cardiac care unit in 2016-2023. We had used functionalized latex immunoassay to confirm the diagnosis of HIT. We performed statistical analysis including clinical and laboratory variables to find any predictor of mortality in critically ill cardiac patients with HIT. Results Among 22 483 patients hospitalized in 2016-2023 in our department of cardiology 12 were diagnosed with HIT. 4 of them died during index hospitalization and 8 survived. Among clinical and laboratory characteristics only C-reactive protein level at admission was associated with increased mortality in acute caridac patients with HIT. Non-survivors had higher CRP levels at admission as compared to survivors, 190 [125-247] mg/l vs. 22 [9-71] mg/l respectively (p = 0,03). Conclusions C-reactive protein level at admission is associated with increased mortality in critically ill cardiac patients with HIT. Initial underlying systemic inflammatory response may constitute the precipitating factor of unfavorouble outcome in acute cardiac patients with heparin-induced thrombocytopenia. Further studies are necessary to confirm these findings.

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice. To evaluate the current diagnostic practice for managing the suspicion of HIT. This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT. Suspicion of HIT. The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests. Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively. In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

A career in solving clinical-pathological conundrums: Heyde syndrome, anti-platelet factor 4 disorders, and microvascular limb ischemic necrosis.

Hematology is a clinical specialty with strong roots in the laboratory; accordingly, the lab can help solve perplexing clinical problems. This review highlights clinical-pathological conundrums addressed during my 35-year hematology career at McMaster University. Heyde syndrome is the association between aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia where the bleeding is usually cured by aortic valve replacement; the chance reading of a neonatal study showing reversible deficiency of high-molecular-weight (HMW) multimers of von Willebrand factor (vWF) following surgical correction of congenital heart disease provided the key insight that a subtle deficiency of HMW multimers of vWF explains Heyde syndrome. The unusual immunobiology of heparin-induced thrombocytopenia (HIT)-a highly prothrombotic, antibody-mediated, anti-platelet factor 4 (PF4) disorder featuring rapid appearance and then disappearance (seroreversion) of the pathological heparin-dependent platelet-activating antibodies-permitted identification of key clinical features that informed development of a scoring system (4Ts) to aid in HIT diagnosis. Atypical clinical presentations of HIT prompted identification of heparin-independent anti-PF4 antibodies, now recognized as the explanation for vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as VITT-like disorders triggered by adenovirus infection. Another unusual feature of HIT is its strong association with limb ischemia, including limb necrosis secondary to deep-vein/microvascular thrombosis (venous limb gangrene). The remarkable observation that supratherapeutic warfarin anticoagulation predisposes to HIT- and cancer-associated venous limb gangrene provided insight into disturbed procoagulant/anticoagulant balance; these concepts are relevant to microvascular thrombosis in critical illness (symmetrical peripheral gangrene), including a pathophysiological role for proximate "shock liver" (impaired hepatic synthesis of natural anticoagulants).

Key considerations in navigating ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays in a landscape of limited data.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. This article discusses key considerations regarding ticagrelor's reported effect on heparin-induced thrombocytopenia functional assays, such as literature gaps and possible management strategies. Limited data indicate that ticagrelor may induce false-negative results in functional assays used in the diagnosis of heparin-induced thrombocytopenia. False-negative functional assays for heparin-induced thrombocytopenia could have catastrophic consequences. The manufacturer labeling of ticagrelor now includes a warning for this potential drug-laboratory interaction. This article suggests areas that would benefit from further research and strategies in navigating this possible interaction. Clinicians should exercise caution when evaluating functional assays for heparin-induced thrombocytopenia in patients receiving ticagrelor. This article offers suggestions for future areas of research and potential management strategies.

Diagnosis and management of heparin-induced thrombocytopenia: Third edition.

Diagnosis and management of heparin-induced thrombocytopenia: Third edition.

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 < 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 > 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 >0.39 with sub classification to low positive 0.4-1, moderate 1-2 and strong if >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 ( > 50% drop in platelet count from baseline, or ≥ 2 consecutive platelet counts < 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 <3 in 90 (57%), Normal platelet count > 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 < 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.

Association of Autoimmune Diseases and Their Effect on Outcomes of Heparin-Induced Thrombocytopenia: An Analysis of the National Inpatient Sample (2016-2020)

Introduction: Heparin-Induced Thrombocytopenia (HIT) is a prothrombotic reaction to heparin exposure caused by antibodies directed towards heparin-platelet protein platelet factor 4 complexes. This thrombocytopenia is associated with and can lead to fatal venous and arterial thrombosis. This study aims to compare outcomes and assess the association of autoimmune diseases with HIT. Methods: A query of the National Inpatient Sample (2016-2020) was performed for index admissions with a principal diagnosis of HIT and concurrent autoimmune diseases using ICD 10 codes. Patient demographics and outcomes were identified. Univariate analysis with t-test or chi-squared was performed where appropriate. A multivariate regression analysis was used to generate adjusted odds ratios (AOR), adjusting for age, race, sex, and Charlson Comorbidity Index (CCI) score. The P-value significance was set at <0.05. All analysis was performed in STATA MP version 14.2. Results: A total of 72,935 patients with HIT met the inclusion criteria, of which, 2.88% had an underlying autoimmune disease. Those with auto-immune disease had a greater proportion of Caucasians, females, and younger patients. While there were no statistically significant differences in mortality, embolic, or bleeding events, patients with autoimmune disease were 43% less likely to become septic (AOR 0.57, p-value 0.006). Additionally, patients with autoimmune diseases had a lower mean hospital services charge and length of stay (p<0.001). Conclusion: Patients with HIT and autoimmune disease showed better outcomes in terms of sepsis, mean length of stay, and hospital services charge without any significant difference in embolic or bleeding outcomes. Underlying autoimmune disease likely does not confer any additional risk to HIT hospitalizations. This might be speculated to be due to the different underlying pathology driving HIT or accompanying immunosuppressants treatment in autoimmune diseases hindering the aggressiveness of immune response.

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.

Heparin-activated procoagulant platelet assay: a flow cytometry-based functional test for heparin-induced thrombocytopenia

BackgroundFunctional platelet activation assays are required for the diagnosis of heparin-induced thrombocytopenia (HIT). Due to their sophisticated methodology, they are only available in reference centers. ObjectivesTo evaluate the diagnostic accuracy of the flow cytometry-based heparin-activated procoagulant platelet (HAPP) assay in the laboratory diagnosis of HIT. MethodsProcoagulant platelets (PCP), defined by the expression of phosphatidylserine and CD62-P, were evaluated by flow cytometry in platelet-rich plasma from healthy donors after incubation with patient sera in the absence and presence of heparin. A sample was considered positive in HAPP assay, if the following 3 criteria were met: 1) the percentage of PCPs was ≥10.3% after incubation with 0.2 IU/mL heparin, 2) the fold increase in presence of 0.2 IU/mL heparin compared with buffer was ≥1.5, and 3) 100 IU/mL of heparin resulted in ≥50% inhibition of PCP. HAPP assay was validated in a prospective cohort (n = 202) of consecutive specimens submitted to our laboratory for serologic diagnosis of HIT. Heparin-induced platelet activation (HIPA) assay was used as the reference standard. ResultsHIT-positive sera induced PCPs in the presence of 0.2 IU/mL heparin, which was inhibited with 100 IU/mL of heparin. In the prospective validation cohort, there were 15 HIPA+ and 187 HIPA- sera. HAPP was positive in 20 samples in this cohort. Using optimized cut-offs, HAPP assay had a sensitivity of 93.3% and specificity of 96.8%. ConclusionHAPP assay is promising as a simple and reliable functional assay for HIT; however, further studies are needed to confirm our results in larger cohorts.

PB0350 Prospective Study to Evaluate the Consolidated Performance of Two Automated Rapid Assays for the Diagnosis of Heparin-Induced Thrombocytopenia

PB0350 Prospective Study to Evaluate the Consolidated Performance of Two Automated Rapid Assays for the Diagnosis of Heparin-Induced Thrombocytopenia

A Functional Assay for the Determination of Heparin-Induced Thrombocytopenia via Flow Cytometry.

Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin therapy (both unfractionated heparin and low-molecular-weight heparin). In our study, we examined a group of 122 patients with suspected HIT. The samples of all patients were analyzed in the first step using an immunoassay (ID-PaGIA Heparin/PF4, Hemos1L-Acustar HIT IgG, ZYMUTEST HIA Monostrip IgG) to detect the presence of antibodies against heparin-PF4 complexes (platelet factor 4). When the immunoassay was positive, the sample was subsequently analyzed for HIT with a functional flow cytometry assay, the HITAlert kit, the purpose of which was to demonstrate the ability of the antibodies present to activate platelets. A diagnosis of HIT can be made only after a positive functional test result. In this article, we present an overview of our practical experience with the use of the new functional method of analysis, HIT, with flow cytometry. In this work, we compared the mutual sensitivity of two functional tests, SRA and the flow cytometry HITAlert kit, in patients perceived as being at risk for HIT. This work aims to delineate the principle, procedure, advantages, pitfalls, and possibilities of the application of the functional test HITAlert using flow cytometry.

How to assess hypercoagulability in heparin-induced thrombocytopenia? Biomarkers of potential value to support therapeutic intensity of non-heparin anticoagulation

BackgroundIn case of heparin-induced thrombocytopenia (HIT), the switch to a non-heparin anticoagulant is mandatory, at a therapeutic dose. Such a treatment has limitations though, especially for patients with renal and/or hepatic failure. Candidate laboratory tests could detect the more coagulable HIT patients, for whom therapeutic anticoagulation would be the more justified.Patients and methodsThis was a monocentre observational prospective study in which 111 patients with suspected HIT were included. Nineteen were diagnosed with HIT (ELISA and platelet activation assay), among whom 10 were classified as HITT + when a thrombotic event was present at diagnosis or during the first following week. Two plasma prethrombotic biomarkers of in vivo activation of the haemostasis system, procoagulant phospholipids (ProcoagPPL) associated with extracellular vesicles and fibrin monomers (FM test), as well as in vitro thrombin potential (ST Genesia; low picomolar tissue factor) after heparin neutralization (heparinase), were studied. The results were primarily compared between HITT + and HITT- patients.ResultsThose HIT + patients with thrombotic events in acute phase or shortly after (referred as HITT+) had a more coagulable phenotype than HIT + patients without thrombotic events since: (i) clotting times related to plasma procoagulant phospholipids tended to be shorter; (ii) fibrin monomers levels were statistically significantly higher (p = 0.0483); (iii) thrombin potential values were statistically significantly higher (p = 0.0404). Of note, among all patients suspected of suffering from HIT, we did not evidence a hypercoagulable phenotype in patients diagnosed with HIT compared to patients for whom the diagnosis of HIT was ruled out.ConclusionThe three tests could help identify those HIT patients the most prone to thrombosis.

The Year in Coagulation and Transfusion: Selected Highlights from 2022

This is an annual review to cover highlights in transfusion and coagulation in patients undergoing cardiovascular surgery. The goal of this article is to provide readers with a focused summary of the most important transfusion and coagulation topics published in 2022. This includes a discussion covering the management of anemia and red blood cell transfusion, the management of factor Xa inhibitors, updates in coagulation testing, updates in the use of factor concentrates, advances in platelet therapy, advances in anticoagulation management of patients on extracorporeal membrane oxygenation and other forms of mechanical circulatory support, and advances in the diagnosis and management of heparin-induced thrombocytopenia.

Heparin Induced Thrombocytopenia - Pathophysiology, Diagnosis and Treatment: A Narrative Review.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated complication following heparin exposure and is considered to be the most severe adverse reaction to heparin treatment that is not associated with bleeding. Development of autoantibodies against platelet factor 4 (PF4) - heparin complex constitutes the basis of the pathophysiological changes in patients suffering from HIT, which then binds to the surface of platelets and monocytes, thus provoking their activation and subsequent aggregation, ultimately leading to the formation of thrombosis. Formation of arterial and venous thrombosis is aggravated by the simultaneous activation of platelets and monocytes with a substantial mortality rate. The incidence of HIT is reported to be significantly lower in pediatric patients compared with adults. Diagnosis of HIT in pediatric population remains a clinical entity supplemented by laboratory evaluation. The positive predictive value of laboratory evaluation is further elevated by the use of scoring systems and predictive models used for hastening the diagnosis of HIT. Use of alternative anticoagulants like direct thrombin inhibitors and factor Xa inhibitors form the mainstay of treatment in cases of HIT, however, more prospective studies would be required in the pediatric population to delineate definitive guidelines for proper management of patients in this age-group. This article delivers diagnostic and treatment approach in case of patients with HIT, wherein the pathophysiology, clinical manifestations, diagnostic approach and the management of patients with HIT has been described.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome in the intensive care unit: a case report

BackgroundVacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the literature. Here, we describe the case of a patient with known Sweet’s syndrome admitted to the intensive care unit and for whom a vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome was diagnosed, allowing for appropriate treatment and the patient’s discharge and recovery.Case presentationA 70-year-old male White patient was hospitalized in the intensive care unit following an intrahospital cardiac arrest. History started a year before with repeated deep vein thrombosis and episodes of skin eruption compatible with Sweet’s syndrome. After a course of oral steroids, fever and inflammatory syndrome relapsed with onset of polychondritis, episcleritis along with neurological symptoms and pulmonary infiltrates. Intrahospital hypoxic cardiac arrest happened during patient’s new investigations, and he was admitted in a critical state. During the intensive care unit stay, he presented with livedoid skin lesions on both feet. Vasculitis was not proven; however, cryoglobulinemia screening came back positive. Onset of pancytopenia was explored with a myelogram aspirate. It showed signs of dysmyelopoiesis and vacuoles in erythroid and myeloid precursors. Of note, new deep vein thrombosis developed, despite being treated with heparin leading to the diagnosis of heparin-induced thrombocytopenia. The course of symptoms were overlapping multiple entities, and so a multidisciplinary team discussion was implemented. Screening for UBA1-mutation in the blood came back positive, confirming the vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome. Corticosteroids and anti-IL1 infusion were started with satisfactory results supporting patient’s discharge from intensive care unit to the internal medicine ward.ConclusionsVacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome should be suspected in male patients presenting with inflammatory symptoms, such as fever, skin eruption, chondritis, venous thromboembolism, and vacuoles in bone marrow precursors. Patients with undiagnosed vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome may present with organ failure requiring hospitalization in intensive care unit, where screening for UBA1 mutation should be performed when medical history is evocative. Multidisciplinary team involvement is highly recommended for patient management, notably to start appropriate immunosuppressive treatments.

Heparin-induced thrombocytopenia: An illustrated review

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect from unfractionated or low-molecular-weight heparin that results in thrombocytopenia and potentially catastrophic thrombosis. HIT occurs due to the development of platelet-activating antibodies against multimolecular complexes of platelet factor 4 and heparin. Given the frequency of thrombocytopenia and heparin use among hospitalized patients, calculation of the 4Ts Score is recommended to identify patients at increased likelihood of HIT and direct further evaluation. In patients with an intermediate or high probability 4Ts Score, an immunoassay and functional assay are recommended to confirm or refute the diagnosis of HIT. Heparin avoidance and initiation of nonheparin anticoagulation are the mainstays of acute HIT management. In this illustrated review, we provide visual summaries of the diagnosis and management of HIT, highlighting connections between pathophysiology and clinical care as well as summarizing efforts in quality improvement in the field. We further emphasize common pitfalls and pearls in diagnosis and management to encourage evidence-based care. We include graphical representation of the unique challenges of HIT with cardiopulmonary bypass and also delineate autoimmune HIT and its subtypes.

Ten questions related to heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially fatal, immune-mediated adverse drug reaction to heparin (both unfractionated and low molecular weight heparin) which is caused by the formation of IgG antibodies against an epitope composed by platelet-derived PF4 and heparin. Binding of IgG to PF4/heparin neoantigen induces platelet activation which may cause venous or arterial thrombosis, associated with thrombocytopenia. HIT diagnosis is based on both pre-test clinical probability evaluation and the detection of platelet activating antibodies. Laboratory diagnosis is based on immunologic and functional assays. When HIT is diagnosed any type of heparin should be stopped immediately and non-heparin alternative anticoagulant must be started in order to halt the pro-thrombotic process. Argatroban and danaparoid are currently the only drugs approved for HIT treatment. Bivalirudin and fondaparinux are also used for the treatment of this rare but severe condition.

Limited concordance of heparin/platelet factor 4 antibody assays for the diagnosis of heparin-induced thrombocytopenia: an analysis of the TORADI-HIT study

BackgroundAnecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited. ObjectivesTo investigate the correlation between widely used assays and examine possible factors contributing to variability. MethodsThis is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman’s correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients. ResultsAmong 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (rs) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients. ConclusionThe correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability.

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.