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Dweck B, Pane M, Nguyen V, Sharma S, Monhollen A, Malireddy S, Whiteley A. Clinical and economic implications of false-positive heparin-induced thrombocytopenia immunoassays: utility of the 4T score. Blood Coagul Fibrinolysis 2024; 35:265-270. [PMID: 38874904 DOI: 10.1097/mbc.0000000000001314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
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.
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Warkentin TE. A career in solving clinical-pathological conundrums: Heyde syndrome, anti-platelet factor 4 disorders, and microvascular limb ischemic necrosis. Int J Lab Hematol 2024; 46 Suppl 1:12-26. [PMID: 38432651 DOI: 10.1111/ijlh.14261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/14/2024] [Indexed: 03/05/2024]
Abstract
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).
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Affiliation(s)
- Theodore E Warkentin
- Department of Pathology and Molecular Medicine, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Pelzl L, Uzun G, Marini I, Zlamal J, Trumpp PN, Karakuyu A, Bakchoul T, Althaus K. Heparin-activated procoagulant platelet assay: a flow cytometry-based functional test for heparin-induced thrombocytopenia. J Thromb Haemost 2024; 22:470-479. [PMID: 37838242 DOI: 10.1016/j.jtha.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 09/04/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND Functional 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. OBJECTIVES To evaluate the diagnostic accuracy of the flow cytometry-based heparin-activated procoagulant platelet (HAPP) assay in the laboratory diagnosis of HIT. METHODS Procoagulant 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. RESULTS HIT-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%. CONCLUSION HAPP assay is promising as a simple and reliable functional assay for HIT; however, further studies are needed to confirm our results in larger cohorts.
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Affiliation(s)
- Lisann Pelzl
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
| | - Günalp Uzun
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
| | - Irene Marini
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
| | - Jan Zlamal
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
| | - Pascal N Trumpp
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Aleyna Karakuyu
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Tamam Bakchoul
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany.
| | - Karina Althaus
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
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Morel-Kopp MC. Functional Testing for Heparin-Induced Thrombocytopenia Using Whole Blood Multiplate Impedance Aggregometry. Methods Mol Biol 2023; 2663:417-428. [PMID: 37204727 DOI: 10.1007/978-1-0716-3175-1_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Immune-mediated heparin-induced thrombocytopenia (HIT) occurs when heparin-dependent IgG antibodies bind to heparin/platelet factor 4 (H/PF4) complexes and activate platelets. There is a vast panoply of assays to investigate HIT which can be divided into two groups, antigen-based immunoassays that detect all antibodies against H/PF4 and are used as a first diagnostic step and functional assays that will identify only the antibodies capable of activating platelets and are mandatory to confirm a diagnosis of pathological HIT. The serotonin-release assay, known as SRA, has been the gold standard for decades, but in the last 10 years, other easier alternatives have been described. The current chapter will focus on whole blood multiple electrode aggregometry, a validated method for the functional diagnosis of HIT.
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Affiliation(s)
- Marie-Christine Morel-Kopp
- Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia.
- Northern Blood Research Centre, Kolling Institute, University of Sydney, Sydney, NSW, Australia.
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Chen LY, Schirmer U, Widder M, Gruel Y, Rollin J, Zipfel PF, Nguyen TH. Breast cancer cell-based ELISA: a potential material for better detection of heparin-induced thrombocytopenia antibodies. J Mater Chem B 2022; 10:7708-7716. [PMID: 36069407 DOI: 10.1039/d2tb01228f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Heparin-induced thrombocytopenia (HIT) is caused by newly formed platelet-activating antibodies against complexes formed between platelet factor 4 (PF4) and heparin (H). HIT can result in life-threatening complications; thus, early detection of HIT antibodies is crucial for the treatment of the disease. The enzyme-linked immune absorbance assay (ELISA) for the identification of HIT antibodies is widely used in many laboratories, but in general, this test provides only ∼50% accuracy while other methods show multiple limitations. Here, we developed a new cell-based ELISA to improve the detection of HIT antibodies. Instead of immobilizing PF4 or PF4/H complexes directly onto a plate as in the standard ELISA, we added the complexes on breast cancer cells, i.e., cell line MDA-MB-231, and applied the same protocol for antibody detection. Using confocal laser scanning microscopy and flow cytometry for the characterization of bound complexes, we identified two types of HIT-mimicked antibodies (KKO and 1E12), which were able to differentiate from the non-HIT antibody (RTO). PF4-treated MDA-MB-231 cells allowed binding of HIT-mimicked antibodies better than PF4/H complexes. With human sera, the cell-based ELISA allowed better differentiation of clinically relevant from non-clinically relevant HIT antibodies as compared with the standard ELISA. Our findings provide a potential approach that contributes to the development of better assays for the detection of HIT antibodies.
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Affiliation(s)
- Li-Yu Chen
- Institute for Bioprocessing and Analytical Measurement Techniques, Heiligenstadt, Germany.,Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
| | - Uwe Schirmer
- Institute for Bioprocessing and Analytical Measurement Techniques, Heiligenstadt, Germany
| | - Miriam Widder
- Institute for Bioprocessing and Analytical Measurement Techniques, Heiligenstadt, Germany
| | - Yves Gruel
- Université de Tours, EA7501 GICC, Tours, France.,Chu Tours, Laboratoire d'Hématologie-Hémostase, Tours, France
| | - Jérôme Rollin
- Université de Tours, EA7501 GICC, Tours, France.,Chu Tours, Laboratoire d'Hématologie-Hémostase, Tours, France
| | - Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
| | - Thi-Huong Nguyen
- Institute for Bioprocessing and Analytical Measurement Techniques, Heiligenstadt, Germany.,Institute for Chemistry and Biotechnology, Faculty of Mathematics and Natural Sciences, Technische Universität Ilmenau, 98694 Ilmenau, Germany.
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Farrar JE, Naik K, Van Matre ET, Martin KG, Magnotti LJ, Wood GC, Swanson JM. Characterization of platelet concentrations and evaluation of risk factors for thrombocytopenia following traumatic injury. TRAUMA-ENGLAND 2022. [DOI: 10.1177/14604086221076280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Introduction Thrombocytopenia is common in critically ill trauma patients and can lead to potentially broad differentials, including major bleeding, hemodilution, extracorporeal circuit losses, heparin-induced thrombocytopenia, and more. Understanding the normal time course of platelet decline and recovery may delineate thrombocytopenia(HIT) secondary to traumatic injury versus other inciting factors. Methods This retrospective study included trauma patients admitted over a 1-year period. The primary aim was characterizing the effect of trauma on platelet concentration and thrombocytopenia incidence in the first 30 days following injury. Thrombocytopenia was defined as platelet concentration <150 × 109/L. A secondary aim was evaluating significant factors contributing to thrombocytopenia. Results A total of 225 patients were included. Thrombocytopenia occurred in 67.3% of patients, and a platelet decline of 50% or greater occurred in 44%. Decrease in platelet concentration was significant from day 1 to day 4 (mean ± SD, 232 ± 86 vs 142 ± 76 × 109/L; p = .001). Platelets recovered to baseline on day 8 and peaked on day 16. Packed red blood cell or platelet transfusion, continuous renal replacement therapy, and acute liver injury independently predicted a ≥50% platelet decrease. HIT was not diagnosed in any patients. Conclusion Platelet nadir likely occurs approximately 4 days after injury and recovers relatively quickly thereafter. More studies are needed to evaluate the magnitude of effect on thrombocytopenia by factors beyond trauma.
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Affiliation(s)
- Julie E Farrar
- Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Mobile, AL, USA
| | - Kushal Naik
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Edward T Van Matre
- Department of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA
- Department of Pharmacy, Regional One Health, Memphis, TN, USA
| | | | - Louis J Magnotti
- Department of Surgery, University of Tennessee Health Science Center College of Medicine, Memphis, TN, USA
- Trauma Surgery Services, Regional One Health, Memphis, TN, USA
| | - G Christopher Wood
- Department of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA
- Department of Pharmacy, Regional One Health, Memphis, TN, USA
| | - Joseph M Swanson
- Department of Clinical Pharmacy and Translational Sciences, University of Tennessee Health Science Center College of Pharmacy, Memphis, TN, USA
- Department of Pharmacy, Regional One Health, Memphis, TN, USA
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Azzarone B, Veneziani I, Moretta L, Maggi E. Pathogenic Mechanisms of Vaccine-Induced Immune Thrombotic Thrombocytopenia in People Receiving Anti-COVID-19 Adenoviral-Based Vaccines: A Proposal. Front Immunol 2021; 12:728513. [PMID: 34484238 PMCID: PMC8415022 DOI: 10.3389/fimmu.2021.728513] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/02/2021] [Indexed: 11/25/2022] Open
Abstract
VITT is a rare, life-threatening syndrome characterized by thrombotic symptoms in combination with thrombocytopenia, which may occur in individuals receiving the first administration of adenoviral non replicating vectors (AVV) anti Covid19 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is characterized by high levels of serum IgG that bind PF4/polyanion complexes, thus triggering platelet activation. Therefore, identification of the fine pathophysiological mechanism by which vaccine components trigger platelet activation is mandatory. Herein, we propose a multistep mechanism involving both the AVV and the neo-synthetized Spike protein. The former can: i) spread rapidly into blood stream, ii), promote the early production of high levels of IL-6, iii) interact with erythrocytes, platelets, mast cells and endothelia, iv) favor the presence of extracellular DNA at the site of injection, v) activate platelets and mast cells to release PF4 and heparin. Moreover, AVV infection of mast cells may trigger aberrant inflammatory and immune responses in people affected by the mast cell activation syndrome (MCAS). The pre-existence of natural antibodies binding PF4/heparin complexes may amplify platelet activation and thrombotic events. Finally, neosynthesized Covid 19 Spike protein interacting with its ACE2 receptor on endothelia, platelets and leucocyte may trigger further thrombotic events unleashing the WITT syndrome.
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Affiliation(s)
- Bruno Azzarone
- Immunology Research Area, IRCCS Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Irene Veneziani
- Immunology Research Area, IRCCS Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Lorenzo Moretta
- Immunology Research Area, IRCCS Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Enrico Maggi
- Immunology Research Area, IRCCS Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Dykes KC, Johnson CA, Gong JZ, McKenzie SE, Husseinzadeh HD. Bleeding and Thrombotic Adverse Events in Hospitalized Patients Under Empiric Treatment for Suspected Heparin-Induced Thrombocytopenia While Awaiting Confirmatory Testing. Clin Appl Thromb Hemost 2021; 27:1076029621996473. [PMID: 33848189 PMCID: PMC8047835 DOI: 10.1177/1076029621996473] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Empiric management in suspected heparin-induced thrombocytopenia (HIT) is challenging due to imperfect prediction models, latency while awaiting test results and risks of empiric therapies. When there is high clinical suspicion for HIT, cessation of heparin and empiric non-heparin anticoagulation with FDA-approved argatroban is recommended. Alternatively off-label fondaparinux or watchful waiting have been utilized in clinical practice. Outcomes of patients empirically managed for HIT have not been compared directly in clinical trials and patients that ultimately do not have HIT are often overlooked. Clinicians need studies investigating empiric management to guide decision making in suspected HIT. In this study, adverse events (AE) were categorized and compared in patients being evaluated for HIT while undergoing empiric management by non-heparin anticoagulation with argatroban or fondaparinux, both at therapeutic or reduced doses, or watchful waiting with or without heparin. AE were defined as new thrombosis confirmed on imaging or new bleeding event after HIT was first suspected. A retrospective chart review of 312 patients tested for HIT at an academic hospital was conducted. 170 patients met inclusion criteria. Patients were excluded if the 4Ts score was < 4. The 4Ts score is a pretest probability for HIT based on thrombocytopenia degree, timing, alternative causes and presence of thrombosis. Included patients were divided according to management groups and compared with logistic regression analysis. Bleeding risk significantly differed between management groups (p = 0.002). Despite adjustment for bleeding risk, fondaparinux was associated with increased AE, (p = 0.03, OR = 5.81), while argatroban was not. There was no difference in AE based on time to initiation of empiric treatment and no advantage to reduced dosing with either anticoagulant. These findings challenge assumptions surrounding empiric HIT management.
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Affiliation(s)
- Kaitlyn C. Dykes
- Georgetown University Medical Center, Washington, DC, USA
- Kaitlyn C. Dykes, Georgetown University Medical Center, 3800 Reservoir Rd NW, Washington, DC 20007, USA. Emails: ;
| | | | - Jerald Z. Gong
- Hematopathology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Rubino JG, Arnold DM, Warkentin TE, Smith JW, Kelton JG, Nazy I. A comparative study of platelet factor 4-enhanced platelet activation assays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost 2021; 19:1096-1102. [PMID: 33387395 DOI: 10.1111/jth.15233] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/06/2020] [Accepted: 12/28/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Functional platelet activation assays, such as the serotonin release assay (SRA), are the gold standard for the diagnosis of heparin-induced thrombocytopenia (HIT). Recently, platelet activation assays using added platelet factor 4 (PF4) have been described and suggest improved sensitivity. Direct comparisons of these assays have not been performed. OBJECTIVE We compare the performance characteristics of three PF4-enhanced platelet activation assays, the PF4/heparin-SRA (PF4/hep-SRA), the PF4-SRA, and the P-selectin expression assay (PEA), at a single reference laboratory. METHODS Serum samples from two cohorts of patients were used. The referral cohort (n = 84) included samples that had previously undergone routine diagnostic testing for HIT and tested positive or negative using the SRA. The clinical cohort (n = 101) consisted of samples from patients with clinically confirmed HIT whose serum contained platelet-activating antibodies. We simultaneously tested all samples in PF4-enhanced SRA-based assays (PF4/hep-SRA, PF4-SRA) and the flow cytometry-based PEA. RESULTS In the referral cohort, the three PF4-enhanced assays identified all samples that were previously determined to be positive in the SRA. However, specificity of the PF4/hep-SRA was 96.6%, the PF4-SRA was 84.7%, and the PEA was 67.8%. In the clinical cohort of samples, all SRA-based assays displayed high performance characteristics (>92.1% sensitivity, >98.4% specificity). Sensitivity and specificity of the PEA was the lowest, 65.8% and 63.5%, respectively; but improved to 92.1% and 96.8% using preselected platelet donors. CONCLUSIONS All PF4-enhanced assays demonstrated good performance characteristics when platelet donors were preselected. Further comparisons across multiple laboratories should be conducted for consensus on optimal HIT diagnostic testing.
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Affiliation(s)
- Julian G Rubino
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
| | - Donald M Arnold
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- McMaster Centre for Transfusion Research, Hamilton, ON, Canada
| | - Theodore E Warkentin
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- McMaster Centre for Transfusion Research, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
| | - James W Smith
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
| | - John G Kelton
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- McMaster Centre for Transfusion Research, Hamilton, ON, Canada
| | - Ishac Nazy
- Department of Medicine, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada
- McMaster Centre for Transfusion Research, Hamilton, ON, Canada
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10
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Moreno-Duarte I, Cooter M, Onwuemene OA, Ghadimi K, Welsby IJ. Clinical outcomes of cardiac surgery patients undergoing therapeutic plasma exchange for heparin-induced thrombocytopenia. Vox Sang 2021; 116:217-224. [PMID: 32965049 PMCID: PMC10308265 DOI: 10.1111/vox.13008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 07/29/2020] [Accepted: 08/31/2020] [Indexed: 10/14/2023]
Abstract
BACKGROUND AND OBJECTIVES Heparin-induced thrombocytopenia (HIT) is an antibody-mediated condition that leads to thrombocytopenia and possible thrombosis. Patients with HIT who require cardiac surgery pose a challenge as high doses of heparin or heparin alternatives are required to permit cardiopulmonary bypass (CPB). Intraoperative therapeutic plasma exchange (TPE) is a valuable adjunct in the management of antibody-mediated syndromes including HIT. The clinical impact of TPE on thromboembolic events, bleeding and mortality after heparin re-exposure is not well established. We hypothesized that TPE with heparin re-exposure will not lead to HIT-related thromboembolic events, bleeding or increased mortality after cardiac surgery with CPB. MATERIALS AND METHODS We reviewed 330 patients who received perioperative TPE between September 2012 and September 2017. RESULTS Twenty four patients received TPE for HIT before anticipated heparin use for CPB. Most patients were males (79%) scheduled for advanced heart failure therapies. Three patients (12·5%) died within 30 days after surgery but none of the deaths were considered HIT-related. Thromboembolic events (TE) occurred in 3 patients within 7 days of surgery; of those, two were possibly HIT-related. CONCLUSION Therapeutic plasma exchange with heparin re-exposure was not strongly associated with HIT-related thrombosis/death after cardiac surgery with CPB.
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Affiliation(s)
| | - Mary Cooter
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Oluwatoyosi A Onwuemene
- Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Kamrouz Ghadimi
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
| | - Ian J Welsby
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
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11
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Arepally GM, Cines DB. Pathogenesis of heparin-induced thrombocytopenia. Transl Res 2020; 225:131-140. [PMID: 32417430 PMCID: PMC7487042 DOI: 10.1016/j.trsl.2020.04.014] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 01/19/2023]
Abstract
There are currently no effective substitutes for high intensity therapy with unfractionated heparin (UFH) for cardiovascular procedures based on its rapid onset of action, ease of monitoring and reversibility. The continued use of UFH in these and other settings requires vigilance for its most serious nonhemorrhagic complication, heparin induced thrombocytopenia (HIT). HIT is an immune prothrombotic disorder caused by antibodies that recognize complexes between platelet factor 4 (PF4) and polyanions such as heparin (H).The pathogenicity of anti-PF4/H antibodies is likely due to the formation of immune complexes that initiate intense procoagulant responses by vascular and hematopoietic cells that lead to the generation of platelet microparticles, monocyte and endothelial cell procoagulant activity, and neutrophil extracellular traps, among other outcomes. The development of anti-PF4/H antibodies after exposure to UFH greatly exceeds the incidence of clinical disease, but the biochemical features that distinguish pathogenic from nonpathogenic antibodies have not been identified. Diagnosis relies on pretest clinical probability, screening for anti-PF4/H antibodies and documentation of their platelet activating capacity. However, both clinical algorithms and test modalities have limited predictive values making diagnosis and management challenging. Given the unacceptable rates of recurrent thromboembolism and bleeding associated with current therapies, there is an unmet need for novel rational nonanticoagulant therapeutics based on the pathogenesis of HIT. We will review recent developments in our understanding of the pathogenesis of HIT and its implications for future approaches to diagnosis and management.
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Affiliation(s)
- Gowthami M Arepally
- Division of Hematology, Duke University Medical Center, Durham, North Carolina.
| | - Douglas B Cines
- Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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Abstract
Purpose of Review This review will illustrate the importance of heparin-induced thrombocytopenia in the intraoperative and critical care settings. Recent Findings Heparin-induced thrombocytopenia (HIT) occurs more frequently in surgical patients compared with medical patients due to the inflammatory release of platelet factor 4 and perioperative heparin exposure. Recognition of this disease requires a high index of suspicion. Diagnostic tools and therapeutic strategies have been expanded and refined in recent years. Summary HIT is a condition where antibodies against the heparin/platelet factor 4 complex interact with platelet receptors to promote platelet activation, aggregation, and thrombus formation. Our review will focus on intraoperative and postoperative considerations related to HIT to help the clinician better manage this rare but often devastating hypercoagulable disease process.
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13
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Lefler DS, Cuker A, Linkins LA, Warkentin TE, Pishko AM. Maximum 24-hour platelet count fall: Metric for improving the diagnosis of heparin-induced thrombocytopenia among patients with intermediate probability 4Ts scores. J Thromb Haemost 2020; 18:2018-2024. [PMID: 32430965 DOI: 10.1111/jth.14897] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/20/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Most patients with suspected heparin-induced thrombocytopenia (HIT) and an intermediate probability 4Ts score do not have HIT. We aimed to develop a metric based on the rate of platelet count fall to aid in discriminating HIT status among patients with an intermediate 4Ts score. METHODS We derived a measure of the maximum 24-hour percentage decrease in platelet count (Fallmax ) in a cohort of patients with suspected HIT and an intermediate 4Ts score at the University of Pennsylvania. We validated this metric in a prospectively collected cohort of patients with suspected HIT and an intermediate 4Ts score from four hospitals in Hamilton, Ontario. RESULTS One hundred fifty-eight and 139 patients were included in the analysis from the derivation and validation cohorts, respectively. Fallmax was significantly higher in HIT-positive patients in the derivation cohort (49.6% versus 38.6%, P = .009) and validation cohort (43.5% versus 29.3%, P = .027). The area under the receiver operating characteristic curve was 0.68 (95% confidence interval [CI] 0.57-0.78) and 0.71 (0.59-0.83) in the two cohorts, respectively. At Fallmax ≥ 30%, sensitivity and specificity were 95.5% and 29.4% in the derivation cohort and 80.0% and 52.7% in the validation cohort. CONCLUSIONS Among patients with suspected HIT and an intermediate 4Ts score, Fallmax aided in discriminating HIT-negative from HIT-positive patients. Using a measure that accounts for the rate of platelet count fall may help to avoid unnecessary suspension of heparin and treatment with an alternative anticoagulant in HIT-negative patients with an intermediate probability 4Ts score, though further evaluation is warranted.
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Affiliation(s)
- Daniel S Lefler
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Adam Cuker
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lori-Ann Linkins
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Theodore E Warkentin
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
- Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - Allyson M Pishko
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Prospective Evaluation of a Rapid Functional Assay for Heparin-Induced Thrombocytopenia Diagnosis in Critically Ill Patients. Crit Care Med 2020; 47:353-359. [PMID: 30507843 DOI: 10.1097/ccm.0000000000003574] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Overdiagnosis of heparin-induced thrombocytopenia remains an unresolved issue in the ICU leading to the unjustified switch from heparin to alternative anticoagulants or delays in anticoagulation. Platelet function assays significantly improve the specificity of heparin-induced thrombocytopenia diagnosis, but they are not readily available, involve technical difficulties and have a long turnaround time. We evaluated the performance of a rapid and easy to perform functional assay for heparin-induced thrombocytopenia diagnosis in ICU patients, known as "heparin-induced multiple electrode aggregometry." DESIGN In this observational prospective study patients were tested with the immunoglobulin G enzyme-linked immunosorbent assay, the serotonin release assay and heparin-induced multiple electrode aggregometry. Heparin-induced multiple electrode aggregometry was assessed against heparin-induced thrombocytopenia diagnosis (clinical picture in favor, serotonin release assay, and immunoglobulin G enzyme-linked immunosorbent assay positive) and serotonin release assay. SETTING Medical or surgical ICU of 35 medical centers. PATIENTS Patients suspected for heparin-induced thrombocytopenia hospitalized in medical or surgical ICU from January 2013 to May 2013. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Heparin-induced thrombocytopenia diagnosis was retained in 12 patients (14%). Using heparin-induced thrombocytopenia diagnosis as reference, heparin-induced multiple electrode aggregometry showed an excellent negative predictive value and sensitivity, at 98% and 92% respectively. Its positive predictive value and specificity were 100%. Receiver operating characteristic analysis with the serotonin release assay as reference showed an optimal heparin-induced multiple electrode aggregometry cut-off at 1,300 AU × minutes (specificity, 100%; sensitivity, 90%; area under the curve, 0.98; 95% CI, 0.95-1.0). The Kappa coefficient between heparin-induced multiple electrode aggregometry and the serotonin release assay was at 0.90%. CONCLUSIONS Heparin-induced multiple electrode aggregometry performed very well in heparin-induced thrombocytopenia diagnosis in ICU patients and agreed with the gold standard test for heparin-induced thrombocytopenia diagnosis, the serotonin release assay. Heparin-induced multiple electrode aggregometry is a reliable and rapid platelet functional assay that could decrease heparin-induced thrombocytopenia overdiagnosis in the ICU setting.
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15
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Warkentin TE, Nazy I, Sheppard JI, Smith JW, Kelton JG, Arnold DM. Serotonin-release assay-negative heparin-induced thrombocytopenia. Am J Hematol 2020; 95:38-47. [PMID: 31621093 DOI: 10.1002/ajh.25660] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/09/2019] [Accepted: 10/13/2019] [Indexed: 12/22/2022]
Abstract
Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Pathogenic HIT antibodies can be detected by the serotonin-release assay (SRA), a platelet activation test. We have regarded the SRA performed in our medical community ("McMaster" SRA) as having high sensitivity and specificity. Recently, the concept of "SRA-negative HIT" has been proposed for enzyme-immunoassay (EIA)-positive/SRA-negative patients with a HIT-compatible clinical picture, who test positive in a PF4-enhanced platelet activation assay. After identifying an index case of SRA-negative HIT, we estimated the frequency of this condition by performing the "PF4-SRA" (modified SRA using high concentrations of added PF4 rather than heparin) in EIA-positive patients from a cohort study evaluating clinical and laboratory diagnosis of HIT. We defined SRA-negative HIT as patients meeting three criteria: clinical picture compatible with HIT (4Ts ≥ 4 points); EIA-positive (≥1.00 units); and PF4-SRA-positive. Among 430 patients, 35 were EIA-positive/SRA-positive and 27 were EIA-positive/SRA-negative. Among these 27 SRA-negative patients, three were found to have subthreshold levels of platelet-activating antibodies by PF4-SRA, of whom one met clinical criteria for SRA-negative HIT. Thus, based on identifying one patient with SRA-negative HIT within a cohort study that found 35 SRA-positive HIT patients, we estimate the sensitivity of the McMaster SRA for diagnosis of HIT to be 35/36 (97.2%; 95% CI, 85.8-99.9%). Although the McMaster SRA is highly sensitive for HIT, occasional SRA-negative but EIA-positive patients strongly suspected of having HIT can have this diagnosis supported by a PF4-enhanced activation assay such as the PF4-SRA.
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Affiliation(s)
- Theodore E. Warkentin
- Department of Pathology and Molecular MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
- Department of MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
| | - Ishac Nazy
- Department of MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
| | - Jo‐Ann I. Sheppard
- Department of Pathology and Molecular MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
| | - James W. Smith
- Department of MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
| | - John G. Kelton
- Department of MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
| | - Donald M. Arnold
- Department of MedicineMichael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
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Voudris V, Georgiadou P, Kalogris P, Kostelidou T, Karabinis A, Gerotziafas G. Missed Heparin-Induced Thrombocytopenia (HIT) Diagnosis in a Patient with Acute Stent Thrombosis. AMERICAN JOURNAL OF CASE REPORTS 2019; 20:753-757. [PMID: 31133634 PMCID: PMC6558115 DOI: 10.12659/ajcr.914988] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Patient: Male, 74 Final Diagnosis: Heparin-induced thrombocytopenia (HIT) Symptoms: Chest discomfort Medication: Heparin Clinical Procedure: Angioplasty and bypass surgery Specialty: Cardiology
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Affiliation(s)
- Vassilis Voudris
- Division of Interventional Cardiology, Onassis Cardiac Surgery Center, Athens, Greece
| | - Panagiota Georgiadou
- Division of Interventional Cardiology, Onassis Cardiac Surgery Center, Athens, Greece
| | - Panagiotis Kalogris
- Division of Cardiothoracic Surgery, Onassis Cardiac Surgery Center, Athens, Greece
| | - Theodora Kostelidou
- Division of Thrombosis and Hemostasis, Onassis Cardiac Surgery Center, Athens, Greece
| | - Andreas Karabinis
- Department of Intensive Care, Onassis Cardiac Surgery Center, Athens, Greece
| | - Grigorios Gerotziafas
- Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, INSERM U938, Institut Universitaire de Cancérologie (IUC), Pierre and Marie Curie University (UPMC) Faculty of Medicine, Sorbonne Universités, Paris, France.,Biological Hematology Service Tenon Hospital, University Hospital Est Parisien, Assistance Publique Hôpitaux de Paris, Paris, France
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17
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Gallo T, Curry SC, Padilla-Jones A, Heise CW, Ramos KS, Woosley RL, Raschke RA. A computerized scoring system to improve assessment of heparin-induced thrombocytopenia risk. J Thromb Haemost 2019; 17:383-388. [PMID: 30552743 DOI: 10.1111/jth.14359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Indexed: 11/27/2022]
Abstract
Essentials Current risk scores for heparin-induced thrombocytopenia (HIT) are not computer-friendly. We compared a new computerized risk score with the 4Ts score in a large healthcare system. The computerized risk score agrees with the 4Ts score 85% of the time. The new score could potentially improve HIT diagnosis via incorporation into decision support. SUMMARY: Background (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The 4Ts score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation. Objectives Our main objective was to develop an HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified as being at risk for HIT. Methods We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system with that of a clinically calculated 4Ts score. We took a 4Ts score of ≥ 4 as the gold standard to determine whether HIT diagnostic testing should be performed. Results The best cutoff point of the HIT-CR score was a score of 3, which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% confidence interval 0.57-0.81). Ninety per cent of patients with 4Ts score of ≥ 4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT. Conclusion The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT.
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Affiliation(s)
- T Gallo
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Phoenix, AZ, USA
| | - S C Curry
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - A Padilla-Jones
- Banner Research Institute, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - C W Heise
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - K S Ramos
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - R L Woosley
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - R A Raschke
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
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18
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Huynh A, Arnold DM, Kelton JG, Smith JW, Horsewood P, Clare R, Guarné A, Nazy I. Characterization of platelet factor 4 amino acids that bind pathogenic antibodies in heparin-induced thrombocytopenia. J Thromb Haemost 2019; 17:389-399. [PMID: 30582672 DOI: 10.1111/jth.14369] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Indexed: 12/18/2022]
Abstract
Essentials Many patients produce antibodies but few lead to heparin-induced thrombocytopenia (HIT). Pathogenic epitopes are difficult to identify as HIT antibodies are polyclonal and polyspecific. KKO binding to platelet factor 4 (PF4) depends on 13 amino acids, three of which are newly observed. Five amino acids in PF4 can help distinguish pathogenic from non-pathogenic antibodies. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction that results in thrombocytopenia and, in some patients, thrombotic complications. HIT is mediated by antibodies that bind to complexes of platelet factor 4 (PF4) and heparin. The antigenic epitopes of these anti-PF4/heparin antibodies have not yet been precisely defined, because of the polyspecific immune response that characterizes HIT. Objectives To identify PF4 amino acids essential for binding pathogenic HIT antibodies. Methods Alanine scanning mutagenesis was utilized to produce 70 single point mutations of PF4. Each PF4 mutant was used in an enzyme immunoassay (EIA) to test their capacity to bind a platelet-activating murine monoclonal anti-PF4/heparin antibody (KKO) and HIT patient sera (n = 9). Results and Conclusions We identified 13 amino acids that were essential for binding KKO because they directly affected either the binding site or the antigenic conformation of PF4. We also identified 10 amino acids that were required for the binding of HIT patient sera and five of these amino acids were required for binding both KKO and the HIT patient sera. The 10 amino acids required for binding HIT sera were further tested to differentiate pathogenic HIT antibodies (platelet activating, n = 45) and non-pathogenic antibodies (EIA-positive but not platelet activating, n = 28). We identified five mutations of PF4 that were recognized to be essential for binding pathogenic HIT antibodies. Using alanine scanning mutagenesis, we characterized possible binding sites of pathogenic HIT antibodies on PF4.
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Affiliation(s)
- Angela Huynh
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Donald M Arnold
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada
- Canadian Blood Services, Hamilton, Ontario, Canada
| | - John G Kelton
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - James W Smith
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Peter Horsewood
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Rumi Clare
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Alba Guarné
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Ishac Nazy
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada
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19
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Schindewolf M. Fondaparinux in heparin-induced thrombocytopenia: A decade's worth of clinical experience. Res Pract Thromb Haemost 2019; 3:9-11. [PMID: 30656269 PMCID: PMC6332747 DOI: 10.1002/rth2.12169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/04/2018] [Indexed: 11/30/2022] Open
Affiliation(s)
- Marc Schindewolf
- Swiss Cardiovascular Center Division of Vascular Medicine University Hospital Bern Bern Switzerland
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20
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Heparin-Induced Thrombocytopenia. Platelets 2019. [DOI: 10.1016/b978-0-12-813456-6.00041-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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21
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Nguyen TH, Greinacher A. Distinct Binding Characteristics of Pathogenic Anti-Platelet Factor-4/Polyanion Antibodies to Antigens Coated on Different Substrates: A Perspective on Clinical Application. ACS NANO 2018; 12:12030-12041. [PMID: 30540167 DOI: 10.1021/acsnano.8b04487] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
The polyanion heparin, which is frequently used in patients, complexes with the platelet-derived cationic chemokine platelet factor (PF4, CXCL4). This results in the formation of anti-PF4/heparin antibodies (anti-PF4/H Abs). Anti-PF4/H Abs are classified into three groups: (i) nonpathogenic Abs (group 1) with no clinical relevance; (ii) pathogenic heparin-dependent Abs (group 2), which activate platelets and can cause the severe adverse drug effect heparin-induced thrombocytopenia (HIT); and (iii) pathogenic autoimmune-HIT Abs (group 3), in which group 3 anti-PF4/H Abs causes a HIT-like autoimmune disease in the absence of heparin. Enzyme immunoassays using PF4/H complexes coated on the solid phase for detection of anti-PF4/H Abs cannot differentiate between pathogenic and nonpathogenic anti-PF4/H Abs. By single-molecule force spectroscopy, we identify a specific feature of pathogenic group 2 and group 3 Abs antibodies that (in contrast to nonpathogenic group 1 Abs) their binding forces to PF4/H complexes coated on platelets were significantly higher compared with those of PF4/H complexes immobilized on a solid phase. Only group 3 Abs showed high binding forces to platelets without the addition of PF4. In the presence of 50 μg/mL PF4, group 2 Abs also showed high binding forces to platelets. In contrast, binding forces of group 1 Abs always remained low (<100 pN). Our findings may have major relevance for the development of clinically applicable solid-phase assays, which allow differentiation of pathogenic platelet-activating from nonpathogenic anti-PF4/H Abs. Membrane-based expression of antigens might also increase the specificity of other assays for the detection of pathogenic (auto)-antibodies in clinical medicine.
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Affiliation(s)
- Thi-Huong Nguyen
- Institute for Immunology and Transfusion Medicine , University Medicine Greifswald , 17475 Greifswald , Germany
- ZIK HIKE - Center for Innovation Competence, Humoral Immune Reactions in Cardiovascular Diseases , University of Greifswald , 17489 Greifswald , Germany
| | - Andreas Greinacher
- Institute for Immunology and Transfusion Medicine , University Medicine Greifswald , 17475 Greifswald , Germany
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22
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Amiral J, Seghatchian J. An update on evidence based diagnostic and confirmatory testing strategies for heparin induced thrombocytopenia using combined immunological and functional assays. Transfus Apher Sci 2018; 57:804-811. [PMID: 30401517 DOI: 10.1016/j.transci.2018.10.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
This manuscript aims to provide a concise review on current diagnostic/ confirmatory strategies of Heparin Induced Thrombocytopenia (HIT) with the combined use of immunological / functional assays in addition to the clinical probability. Laboratory diagnosis of HIT is of primordial importance as the related complications could become rapidly severe and life-threatening and can provoke limb amputation in some cases. The first action in the presence of HIT suspicion is to withdraw heparin and to initiate an alternative anticoagulant. Whilst vitamin K antagonists are not appropriate, anticoagulant options include Fondaparinux, Sodium Danaparoid, DOACs, Argatroban, and Bivalirudin. However, if HIT is excluded, patients can benefit again from the high therapeutic and antithrombotic efficacy of this drug, which remains superior to all the substitutive anticoagulant treatments. HIT is suspected in the presence of a platelet count drop > 50% on 2 successive counts, or a platelet count < 100 G/L, and of a significant clinical probability (4 Ts score). Testing patients' plasma is required for establishing the diagnosis. Laboratory investigation involves first the immunological measurement of heparin dependent IgG antibodies (mainly targeted to Heparin-Platelet Factor 4 complexes). When positive, a functional assay for platelet activation, performed at a low and high heparin concentration, allows confirming this disease. In any case, if the immuno-assay is negative, HIT can be excluded with a high probability, and heparin can be continued (if clinical examination favors this decision). Conversely, the higher the IgG antibody concentration is (and affinity), the higher is the probability of developing HIT. The functional assay has now become for confirming the platelet activation capacity of antibodies, and therefore confirming the presence of HIT. Up to now, the gold reference method for testing antibody-dependent platelet activation is the C14-Serotonin Release Assay, available only in very few laboratories working with radio-isotopes. A simple, sensitive, and accurate flow cytometry assay becomes now available to all clinical sites, and it can be easily used for testing the capacity of heparin dependent-antibodies to activate platelets, at low heparin concentration. This technique can be performed in any laboratory equipped with a flow cytometer and can make the HIT confirmation diagnosis rapidly available, which introduces a great improvement for management of patients with HIT. We believe that an evidence-based update on this topic is timely and well warranted.
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Affiliation(s)
- Jean Amiral
- SH-Consulting, Scientific Director and Consultant in Hemostasis, Andrésy France.
| | - Jerard Seghatchian
- International Consultancy in Blood Components Quality/Safety Improvement, Audit/ Inspection and DDR Strategies, London, UK.
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Zheng G, Streiff MB, Takemoto CM, Bynum J, Gelwan E, Jani J, Judge D, Kickler TS. The Clinical Utility of the Heparin Neutralization Assay in the Diagnosis of Heparin-Induced Thrombocytopenia. Clin Appl Thromb Hemost 2018; 24:749-754. [PMID: 28774196 PMCID: PMC6714880 DOI: 10.1177/1076029617721013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) remains diagnostically challenging. Immunoassays including PF4/heparin enzyme-linked immunosorbent assay (ELISA) have high sensitivity but low specificity. Whether the heparin neutralization assay (HNA) improves the diagnostic accuracy of the PF4/heparin ELISA for HIT is uncertain. In this study, to assess its clinical utility and evaluate whether it improves the diagnostic accuracy for HIT, we implemented HNA in conjunction with PF4/heparin ELISA over a 1-year period. A total of 1194 patient samples were submitted to the laboratory for testing from December 2015 to November 2016. Heparin neutralization assay alone is a poor predictor for HIT, but it has high negative predictive value (NPV): Cases with %inhibition <70% are always negative for serotonin release assay. It improves the diagnostic positive predictive value (PPV) of ELISA without compromising sensitivity: ELISA optical density (OD) ≥1.4 alone has a sensitivity of 88% (14/16) and a PPV of 61% (14/23); with HNA %inhibition ≥70%, the sensitivity remains 88% (14/16) and PPV is 82% (14/17). 4Ts score correlates with ELISA OD and predicts HIT; the predictive accuracy of 4Ts score is further improved by HNA. Interestingly, HNA %inhibition of <70% correlates with low 4Ts scores. Based on its high NPV, HNA has the potential to facilitate more timely and accurate HIT diagnosis.
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Affiliation(s)
- Gang Zheng
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael B. Streiff
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Clifford M. Takemoto
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jennifer Bynum
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elise Gelwan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jayesh Jani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Danielle Judge
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Thomas S. Kickler
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Platelet-Activating Antibodies Are Detectable at the Earliest Onset of Heparin-Induced Thrombocytopenia, With Implications for the Operating Characteristics of the Serotonin-Release Assay. Chest 2018; 153:1396-1404. [DOI: 10.1016/j.chest.2018.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/01/2017] [Accepted: 01/02/2018] [Indexed: 11/21/2022] Open
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25
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Boer C, Meesters MI, Milojevic M, Benedetto U, Bolliger D, von Heymann C, Jeppsson A, Koster A, Osnabrugge RL, Ranucci M, Ravn HB, Vonk AB, Wahba A, Pagano D. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. J Cardiothorac Vasc Anesth 2018; 32:88-120. [DOI: 10.1053/j.jvca.2017.06.026] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Indexed: 01/28/2023]
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26
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Maeda T, Nakagawa K, Murata K, Kanaumi Y, Seguchi S, Kawamura S, Kodama M, Kawai T, Kakutani I, Ohnishi Y, Kokame K, Okazaki H, Miyata S. Identifying patients at high risk of heparin-induced thrombocytopenia-associated thrombosis with a platelet activation assay using flow cytometry. Thromb Haemost 2017; 117:127-138. [DOI: 10.1160/th16-06-0482] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/17/2016] [Indexed: 01/21/2023]
Abstract
SummaryTo diagnose heparin-induced thrombocytopenia (HIT), detection of platelet-activating antibodies (HIT antibodies) is crucial. However, serum platelet activation profiles vary across patients and depend on test conditions. We evaluated the association between clinical outcomes and platelet-activating profiles assessed by a platelet microparticle assay (PMA), which detects activation of washed platelets induced by HIT antibodies, in 401 consecutive patients clinically suspected of having HIT. We made modifications to the assay, such as donor selection for washed platelets that increased sensitivity. Serum that activated platelets at a therapeutic (but not high) heparin concentration was defined as positive. Of these, serum that activated platelets within 30 minutes or in the absence of heparin was defined as strongly positive. The remaining samples were considered weakly positive. As a result, 97 % and 93 % of patients who tested strongly and weakly positive had clinical profiles consistent with HIT, respectively. The incidence of thromboembolic events (TEEs) after heparin exposure in patients who tested strongly positive, weakly positive, and negative was 61 %, 40 %, and 29 %, respectively. Among patients who did not experience a TEE on the day HIT was suspected, there was no significant difference in the cumulative incidence of subsequent TEEs between patients who tested strongly and weakly positive when argatroban was initiated on the same day (19.0 % vs 7.1 %, p=0.313), but there was a significant difference when argatroban therapy was delayed by one or more days (61.1 % vs 17.6 %, p=0.007). The modified PMA is effective in diagnosing HIT and identifying patients at high risk for HIT-associated TEEs.Supplementary Material to this article is available online at www.thrombosis-online.com.
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Lim MY, Foster J, Rourk A, Greenberg CS. Initial and long term impact of a multi-disciplinary task force in the diagnosis and management of heparin-induced thrombocytopenia. J Thromb Thrombolysis 2017; 45:130-134. [PMID: 29185142 DOI: 10.1007/s11239-017-1592-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Many medical centers are faced with a major challenge in making an accurate diagnosis of heparin-induced thrombocytopenia (HIT) and ensuring appropriate changes in management strategy in line with guideline recommendations. We report the initial and long-term impact and challenges of institution-wide changes in the diagnosis and management of HIT in the inpatient setting at an academic medical center. We established a HIT Task Force, consisting of a multidisciplinary team of non-malignant hematologists, nursing, pharmacist, pathology, blood bank and clinical lab informatics. Changes were implemented from 2011 to 2012. In 2013, testing for PF4 and SRA decreased by 37.5 and 85%, respectively. 100% of positive PF4 received an automatic hematology consult to guide management, leading to a 78% reduction in the use of direct thrombin inhibitors. Annual audits in the subsequent years demonstrated increasing testing for HIT due to changes in the electronic ordering system. Through continuous monitoring, these shortfalls were detected and intervene early on with continued success. The implementation of a centralized hospital-wide protocol via a multidisciplinary task force that coordinates testing and treatment of patients suspected of having HIT led to a substantial reduction in PF4 and SRA testing, as well as use of DTIs, resulting in a safe and cost-effective approach for the diagnosis and treatment of HIT. Our study highlights the important of continuous monitoring to maintain the improvements made. Despite our initial success, annual re-auditing allowed for early detection of challenges, which then allowed appropriate early intervention.
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Affiliation(s)
- Ming Y Lim
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, 39 Sabin Street, MSC 635, Charleston, SC, 29425, USA.
| | - Joyce Foster
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Angela Rourk
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Charles S Greenberg
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, 39 Sabin Street, MSC 635, Charleston, SC, 29425, USA
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Warkentin T. Scoring systems for heparin-induced thrombocytopenia (HIT): Whither now? Thromb Haemost 2017; 113:437-8. [DOI: 10.1160/th14-11-0974] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 11/24/2014] [Indexed: 11/05/2022]
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Joseph L, Gomes M, Al Solaiman F, Miro-Casas E, St John J, Ozaki A, Raju M, Dhariwal M, Kim E. External validation of the HIT Expert Probability (HEP) score. Thromb Haemost 2017; 113:633-40. [DOI: 10.1160/th14-05-0472] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 10/22/2014] [Indexed: 11/05/2022]
Abstract
SummaryThe diagnosis of heparin-induced thrombocytopenia (HIT) can be challenging. The HIT Expert Probability (HEP) Score has recently been proposed to aid in the diagnosis of HIT. We sought to externally and prospectively validate the HEP score. We prospectively assessed pretest probability of HIT for 51 consecutive patients referred to our Consultative Service for evaluation of possible HIT between August 1, 2012 and February 1, 2013. Two Vascular Medicine fellows independently applied the 4T and HEP scores for each patient. Two independent HIT expert adjudicators rendered a diagnosis of HIT likely or unlikely. The median (interquartile range) of 4T and HEP scores were 4.5 (3.0, 6.0) and 5 (3.0, 8.5), respectively. There were no significant differences between area under receiver-operating characteristic curves of 4T and HEP scores against the gold standard, confirmed HIT [defined as positive serotonin release assay and positive anti-PF4/heparin ELISA] (0.74 vs 0.73, p = 0.97). HEP score ≥ 2 was 100 % sensitive and 16 % specific for determining the presence of confirmed HIT while a 4T score > 3 was 93 % sensitive and 35 % specific. In conclusion, the HEP and 4T scores are excellent screening pretest probability models for HIT, however, in this prospective validation study, test characteristics for the diagnosis of HIT based on confirmatory laboratory testing and expert opinion are similar. Given the complexity of the HEP scoring model compared to that of the 4T score, further validation of the HEP score is warranted prior to widespread clinical acceptance.
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Koerber J, Mehta T, Forsyth L, Conger E, Corbets L, Mattson J, Smythe M. Assessing the impact of a heparin-induced thrombocytopenia protocol on patient management, outcomes and cost. Thromb Haemost 2017; 108:992-8. [DOI: 10.1160/th12-05-0289] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 08/09/2012] [Indexed: 11/05/2022]
Abstract
SummaryEstablishing the diagnosis of heparin induced thrombocytopenia (HIT) is challenging as laboratory tests for HIT vary in specificity and availability. As HIT suspicion far exceeds confirmation of diagnosis, overtreatment is an emerging concern. This pilot study evaluated the impact of a HIT Recognition and Management Protocol on direct thrombin inhibitor (DTI) prescribing, outcomes, and cost. The primary endpoint was DTI cessation within 12 hours of receipt of negative HIT serology. An observational cohort study using a pre-post design was performed. Sixty-one patients were in the pre-period (before implementation) and 46 in the post-period (after implementation). DTI therapy was discontinued within 12 hours of negative serology in 19.4% of pre-period patients compared to 40% of post-period patients, p=.058. DTI therapy was discontinued within 24 hours of receipt of a negative PF4/heparin ELISA more often in the post-period ; 7/23 (30.4%) pre-period patients versus 16/26 (61.5%) post-period patients, p <0.05. Protocol implementation resulted in a significant improvement in timely initiation of DTI therapy (within 12 hours of HIT antibody testing) in those with a moderate to high suspicion of HIT; 8/31 (25.8%) of pre-period patients versus 24/31 (77.4%) of post-period patients, p <0.0001. Thrombotic events occurred in significantly more patients in the pre-period as compared to the post-period; 21/61 (34.4%) versus 6/46 (13%), respectively, p = 0.01. Major bleeding was reduced by 6.6 % after protocol implementation. The projected annual cost savings from decreased inappropriate DTI use was over $450,000. Protocol implementation had a positive impact on DTI prescribing, outcomes and cost.
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Hesberg J, Santoso S, Bein G, Bakchoul T, Sachs U. Evaluation of a new nanoparticle-based lateral-flow immunoassay for the exclusion of heparin-induced thrombocytopenia (HIT). Thromb Haemost 2017. [DOI: 10.1160/th11-06-0390] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
SummaryHeparin-induced thrombocytopenia (HIT) is an adverse complication of heparin caused by HIT antibodies (abs) that recognise platelet factor 4-heparin (PF4/hep) complexes. Several laboratory tests are available for the confirmation and/or refutation of HIT. A reliable and rapid singlesample test is still pending. It was the objective of this study to evaluate a new lateral-flow immunoassay based on nanoparticle technology. A cohort of 452 surgical and medical patients suspected of having HIT was evaluated. All samples were tested in two IgG-specific ELISAs, in a particle gel immunoassay (PaGIA) and in a newly developed lateral-flow immunoassay (LFI-HIT) as well as in a functional test (HIPA). Clinical pre-test probability was determined using 4T's score. Platelet-activating antibodies were present in 34/452 patients, all of whom had intermediate to high clinical probability. PF4/hep abs were detected in 79, 87, 86, and 63 sera using the four different immunoassays. The negative predictive values (NPV) were 100% for both ELISA tests and LFI-HIT but only 99.2% for PaGIA. There were less false positives (n=29) in the LFI-HIT compared to any other test. Additionally, significantly less time was required to perform LFI-HIT than to perform the other immunoassays. In conclusion, a newly developed lateral-flow assay, LFI-HIT, was capable of identifying all HIT patients in a cohort in a short period of time. Beside an NPV of 100%, the rate of false-positive signals is significantly lower with LFI-HIT than with other immunoassay(s). These performance characteristics suggest a high potency in reducing the risk and costs in patients suspected of having HIT.
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Vanderbilt CM, McFarland C, Lind SE. Evaluation of a Reflex Testing Algorithm for Suspected Heparin-Induced Thrombocytopenia. Am J Clin Pathol 2017; 148:390-397. [PMID: 29059268 DOI: 10.1093/ajcp/aqx078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES We implemented a policy of reflex serotonin-release assay (SRA) testing for all patients with a positive heparin-induced thrombocytopenia (HIT) immunoassay. METHODS We identified all patients who had SRA testing sent as a consequence of a positive HIT immunoassay test. We reviewed charts of patients to calculate the 4Ts clinical score, determined the effect of testing on clinical management, and documented the change in utilization of direct thrombin inhibitors (DTIs). RESULTS The likelihood of a positive SRA varied with the optical density (OD) of the immunoassay. The performance of the immunoglobulin G (IgG)-specific and polytypic enzyme-linked immunosorbent assay was not statistically different. Both OD and 4Ts score correlated with the likelihood of a positive SRA but demonstrated poor specificity. Discontinuation of DTIs in patients with negative SRAs resulted in decreased drug utilization. CONCLUSIONS The IgG-specific HIT immunoassay OD correlates with the likelihood of a positive SRA but does not achieve high specificity. The reflex testing algorithm allows for definitive classification of patients, and the cost of such a reflex testing program may be offset by decreased utilization of DTIs.
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Affiliation(s)
| | - Craig McFarland
- Medicine, University of Colorado School of Medicine and the University of Colorado Hospital, Aurora
| | - Stuart E Lind
- Departments of Pathology
- Medicine, University of Colorado School of Medicine and the University of Colorado Hospital, Aurora
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Schindewolf M, Steindl J, Beyer-Westendorf J, Schellong S, Dohmen PM, Brachmann J, Madlener K, Pötzsch B, Klamroth R, Hankowitz J, Banik N, Eberle S, Müller MM, Kropff S, Lindhoff-Last E. Use of Fondaparinux Off-Label or Approved Anticoagulants for Management of Heparin-Induced Thrombocytopenia. J Am Coll Cardiol 2017; 70:2636-2648. [DOI: 10.1016/j.jacc.2017.09.1099] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 01/18/2023]
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Vayne C, Guery EA, Kizlik-Masson C, Rollin J, Bauters A, Gruel Y, Pouplard C. Beneficial effect of exogenous platelet factor 4 for detecting pathogenic heparin-induced thrombocytopenia antibodies. Br J Haematol 2017; 179:811-819. [DOI: 10.1111/bjh.14955] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 08/09/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Caroline Vayne
- Department of Haematology-Haemostasis; University Hospital of Tours; Tours France
- University François Rabelais; UMR CNRS 7292; Tours France
| | - Eve-Anne Guery
- Department of Haematology-Haemostasis; University Hospital of Tours; Tours France
- University François Rabelais; UMR CNRS 7292; Tours France
| | | | - Jérôme Rollin
- Department of Haematology-Haemostasis; University Hospital of Tours; Tours France
- University François Rabelais; UMR CNRS 7292; Tours France
| | - Anne Bauters
- Institute of Haematology-Transfusion; University Hospital of Lille; Lille France
| | - Yves Gruel
- Department of Haematology-Haemostasis; University Hospital of Tours; Tours France
- University François Rabelais; UMR CNRS 7292; Tours France
| | - Claire Pouplard
- Department of Haematology-Haemostasis; University Hospital of Tours; Tours France
- University François Rabelais; UMR CNRS 7292; Tours France
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Pagano D, Milojevic M, Meesters MI, Benedetto U, Bolliger D, von Heymann C, Jeppsson A, Koster A, Osnabrugge RL, Ranucci M, Ravn HB, Vonk ABA, Wahba A, Boer C. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Eur J Cardiothorac Surg 2017; 53:79-111. [DOI: 10.1093/ejcts/ezx325] [Citation(s) in RCA: 192] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Raschke RA, Gallo T, Curry SC, Whiting T, Padilla-Jones A, Warkentin TE, Puri A. Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia. J Thromb Haemost 2017; 15:1640-1645. [PMID: 28622439 DOI: 10.1111/jth.13758] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Indexed: 11/28/2022]
Abstract
Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. SUMMARY Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93-1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients.
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Affiliation(s)
- R A Raschke
- Division of Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Critical Care Medicine, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - T Gallo
- Division of Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - S C Curry
- Division of Clinical Data Analytics and Decision Support, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - T Whiting
- Department of Critical Care Medicine, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - A Padilla-Jones
- Banner Research Institute, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - T E Warkentin
- Department of Pathology and Molecular Medicine, and Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - A Puri
- Internal Medicine Residency, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA
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Abstract
Direct oral anticoagulants (DOACs) are attractive options for treatment of heparin-induced thrombocytopenia (HIT). We report our continuing experience in Hamilton, ON, Canada, since January 1, 2015 (when we completed our prospective study of rivaroxaban for HIT), using rivaroxaban for serologically confirmed HIT (4Ts score ≥4 points; positive platelet factor 4 [PF4]/heparin immunoassay, positive serotonin-release assay). We also performed a literature review of HIT treatment using DOACs (rivaroxaban, apixaban, dabigatran, edoxaban). We focused on patients who received DOAC therapy for acute HIT as either primary therapy (group A) or secondary therapy (group B; initial treatment using a non-DOAC/non-heparin anticoagulant with transition to a DOAC during HIT-associated thrombocytopenia). Our primary end point was occurrence of objectively documented thrombosis during DOAC therapy for acute HIT. We found that recovery without new, progressive, or recurrent thrombosis occurred in all 10 Hamilton patients with acute HIT treated with rivaroxaban. Data from the literature review plus these new data identified a thrombosis rate of 1 of 46 patients (2.2%; 95% CI, 0.4%-11.3%) in patients treated with rivaroxaban during acute HIT (group A, n = 25; group B, n = 21); major hemorrhage was seen in 0 of 46 patients. Similar outcomes in smaller numbers of patients were observed with apixaban (n = 12) and dabigatran (n = 11). DOACs offer simplified management of selected patients, as illustrated by a case of persisting (autoimmune) HIT (>2-month platelet recovery with inversely parallel waning of serum-induced heparin-independent serotonin release) with successful outpatient rivaroxaban management of HIT-associated thrombosis. Evidence supporting efficacy and safety of DOACs for acute HIT is increasing, with the most experience reported for rivaroxaban.
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Husseinzadeh HD, Gimotty PA, Pishko AM, Buckley M, Warkentin TE, Cuker A. Diagnostic accuracy of IgG-specific versus polyspecific enzyme-linked immunoassays in heparin-induced thrombocytopenia: a systematic review and meta-analysis. J Thromb Haemost 2017; 15:1203-1212. [PMID: 28374939 PMCID: PMC6039095 DOI: 10.1111/jth.13692] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Indexed: 12/17/2022]
Abstract
Essentials Immunoassay specificity varies in heparin-induced thrombocytopenia (HIT) testing. This meta-analysis examined 9 studies that tested samples by both IgG and polyspecific methods. IgG-specific assays confer superior diagnostic accuracy compared with polyspecific assays. These results further support recommendations in favor of IgG-specific testing. SUMMARY Background There are conflicting data on whether the IgG-specific or polyspecific antiplatelet factor 4/heparin (PF4/H) enzyme-linked immunosorbent assay (ELISA) is preferred for the laboratory diagnosis of heparin-induced thrombocytopenia (HIT). Objectives To directly compare diagnostic accuracy of IgG-specific versus polyspecific ELISA in HIT. Patients/Methods A systematic search yielded nine studies comprising 1948 patients with suspected HIT tested by both IgG-specific and polyspecific ELISAs and a reference standard against which the diagnostic accuracy of the ELISAs could be measured. Study quality was assessed by QUADAS-2 criteria. Results There was identical sensitivity for IgG-specific and polyspecific ELISAs (0.97; 95% confidence interval (CI), 0.95-0.99) and superior specificity of IgG-specific compared with polyspecific ELISA (0.87 [0.85-0.88] vs. 0.82 [0.80-0.84], respectively). Performance was similar in subgroups using the serotonin release assay and a single commercial ELISA manufacturer. The negative predictive values of IgG-specific and polyspecific ELISA were similarly high (0.99, [0.99-1.00], but the positive predictive value was superior with IgG-specific compared with polyspecific ELISA (0.56 [0.52-0.61] vs. 0.32 [0.28-0.35], respectively). The positive likelihood ratio (LR) was higher in IgG-specific than polyspecific ELISA, although negative LRs were similar. There was high risk of quality concerns in domains of index test and reference standard. Conclusions The superior diagnostic accuracy of IgG-specific ELISA reinforces the ISTH-SSC recommendation for standardization of laboratory testing for HIT. Likelihood ratios of individual assays may be used in combination with clinical scoring systems as part of an integrated diagnostic algorithm for HIT.
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Affiliation(s)
- H D Husseinzadeh
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - P A Gimotty
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - A M Pishko
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - M Buckley
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - T E Warkentin
- Departments of Pathology and Molecular Medicine, and Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
| | - A Cuker
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Abstract
OBJECTIVE Recent studies reveal a high occurrence of overdiagnosis of heparin-induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment. We reviewed patients who were admitted to surgical ICUs and were suspected of heparin-induced thrombocytopenia to identify how often patients were correctly treated. DESIGN In this clinical prospective study, data were collected including age, sex, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, serotonin release assay, and Warkentin 4Ts scores. Heparin-induced thrombocytopenia-positive patients were defined as those with both positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay (optical density, ≥ 0.40) and positive serotonin release assay results. SETTING Urban tertiary medical center. PATIENTS Patients admitted to the surgical and cardiac ICU who were presumed to have heparin-induced thrombocytopenia and underwent antiplatelet factor 4/heparin enzyme-linked immunosorbent assay and serotonin release assay testing between January 1, 2011, and August 1, 2014. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A total of 135 patients had 4Ts, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, and serotonin release assay scores. A total of 11 patients (8.1%) had positive serotonin release assay and 80 patients had positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay; 10 patients were identified as heparin-induced thrombocytopenia positive. Positive serotonin release assay was noted in nine of 11 patients (81.8%) with antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density greater than or equal to 2.0, compared with one of 22 patients (4.5%) with optical density values of 0.85-1.99, and one of 102 patients (1.0%) with optical density values of 0-0.84. Out of 135 patients, 29 patients (21.5%) received treatment with argatroban, lepirudin, or fondaparinux: 10 of 10 heparin-induced thrombocytopenia-positive patients (100%) compared with 19 of 125 heparin-induced thrombocytopenia-negative patients (15%). CONCLUSIONS Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold.
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Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nat Commun 2017; 8:14945. [PMID: 28530237 PMCID: PMC5458132 DOI: 10.1038/ncomms14945] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 02/15/2017] [Indexed: 01/07/2023] Open
Abstract
Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60–100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders. Antibodies against the platelet factor 4 (PF4) support bacterial host defence but in some cases may lead to heparin-induced thrombocytopenia (HIT). Nguyen et al. show that in autoimmune HIT a subset of antibodies binds strongly to PF4 causing its conformational change that leads to association of non-pathogenic PF4 antibodies and thrombotic platelet activation.
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Warkentin TE, Sheppard JAI, Linkins LA, Arnold DM, Nazy I. Performance characteristics of an automated latex immunoturbidimetric assay [HemosIL ® HIT-Ab (PF4-H) ] for the diagnosis of immune heparin-induced thrombocytopenia. Thromb Res 2017; 153:108-117. [DOI: 10.1016/j.thromres.2017.03.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/14/2017] [Accepted: 03/09/2017] [Indexed: 12/13/2022]
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Minet V, Dogné JM, Mullier F. Functional Assays in the Diagnosis of Heparin-Induced Thrombocytopenia: A Review. Molecules 2017; 22:molecules22040617. [PMID: 28398258 PMCID: PMC6153750 DOI: 10.3390/molecules22040617] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/05/2017] [Accepted: 04/08/2017] [Indexed: 01/09/2023] Open
Abstract
A rapid and accurate diagnosis in patients with suspected heparin-induced thrombocytopenia (HIT) is essential for patient management but remains challenging. Current HIT diagnosis ideally relies on a combination of clinical information, immunoassay and functional assay results. Platelet activation assays or functional assays detect HIT antibodies that are more clinically significant. Several functional assays have been developed and evaluated in the literature. They differ in the activation endpoint studied; the technique or technology used; the platelet donor selection; the platelet suspension (washed platelets, platelet rich plasma or whole blood); the patient sample (serum or plasma); and the heparin used (type and concentrations). Inconsistencies in controls performed and associated results interpretation are common. Thresholds and performances are determined differently among papers. Functional assays suffer from interlaboratory variability. This lack of standardization limits the evaluation and the accessibility of functional assays in laboratories. In the present article, we review all the current activation endpoints, techniques and methodologies of functional assays developed for HIT diagnosis.
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Affiliation(s)
- Valentine Minet
- Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur, Namur 5000, Belgium.
| | - Jean-Michel Dogné
- Department of Pharmacy, Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for LIfe Sciences (NARILIS), University of Namur, Namur 5000, Belgium.
| | - François Mullier
- CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), Hematology Laboratory, Université catholique de Louvain, Yvoir 5530, Belgium.
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Tran PN, Tran MH. Emerging Role of Direct Oral Anticoagulants in the Management of Heparin-Induced Thrombocytopenia. Clin Appl Thromb Hemost 2017; 24:201-209. [PMID: 28301915 DOI: 10.1177/1076029617696582] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) are rare but potentially limb- and life-threatening complications of heparin therapy. Continuation of heparin or low-molecular-weight heparin is contraindicated due to platelet activation in the presence of (heparin-dependent) HIT antibodies. Primary treatment options currently include argatroban, fondaparinux, or bivalirudin. However, the parenteral administration routes and interference of argatroban with traditional coagulation markers complicate management. The goal of this review is to assess the viability of direct oral anticoagulants as an alternative treatment option in patients with HIT/HITT. Their use in HIT/HITT is reasonable, given absent cross-reactivity preformed with HIT antibodies. Furthermore, their rapid onset of action and induction of effective anticoagulation provide a favorable basis for their use in this condition. Herein, we summarize 3 studies and 8 case reports comprising 56 patients in whom direct oral anticoagulants were used in the treatment of HIT/HITT.
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Affiliation(s)
- Phu Ngoc Tran
- 1 Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA, USA
| | - Minh-Ha Tran
- 2 Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, Irvine, CA, USA.,3 Department of Internal Medicine, University of California Irvine School of Medicine, Irvine, CA, USA
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Welsby IJ, Krakow EF, Heit JA, Williams EC, Arepally GM, Bar-Yosef S, Kong DF, Martinelli S, Dhakal I, Liu WW, Krischer J, Ortel TL. The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery. J Thromb Haemost 2017; 15:57-65. [PMID: 27714919 PMCID: PMC5280211 DOI: 10.1111/jth.13533] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Indexed: 12/18/2022]
Abstract
Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted. SUMMARY Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT. TRIAL REGISTRATION Duke IRB Protocol #00010736.
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Affiliation(s)
- I J Welsby
- Department of Anesthesiology and Critical Care, Durham, NC, USA
| | - E F Krakow
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - J A Heit
- Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Durham, NC, USA
| | - E C Williams
- Department of Medicine, Division of Hematology, University of Wisconsin, Durham, NC, USA
| | - G M Arepally
- Department of Medicine, Division of Hematology, Duke University Medical Center, Durham, NC, USA
| | - S Bar-Yosef
- Department of Anesthesiology, Durham VA Medical Center, Durham, NC, USA
| | - D F Kong
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - S Martinelli
- Department of Anesthesiology, University of North Carolina, Durham, NC, USA
| | - I Dhakal
- Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC, USA
| | - W W Liu
- Department of Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC, USA
| | - J Krischer
- Pediatric Epidemiology Center, University of South Florida Morsani College of Medicine, Durham, NC, USA
| | - T L Ortel
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
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Heparin-induced thrombocytopenia in pregnancy: an interdisciplinary challenge—a case report and literature review. Int J Obstet Anesth 2016; 26:79-82. [DOI: 10.1016/j.ijoa.2015.11.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 11/25/2015] [Accepted: 11/29/2015] [Indexed: 11/19/2022]
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Assfalg V, Hüser N. Heparin-induced thrombocytopenia in solid organ transplant recipients: The current scientific knowledge. World J Transplant 2016; 6:165-173. [PMID: 27011914 PMCID: PMC4801792 DOI: 10.5500/wjt.v6.i1.165] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 12/16/2015] [Accepted: 02/16/2016] [Indexed: 02/05/2023] Open
Abstract
Exposure to heparin is associated with a high incidence of immunization against platelet factor 4 (PF4)/heparin complexes. A subgroup of immunized patients is at risk of developing heparin-induced thrombocytopenia (HIT), an immune mediated prothrombotic adverse drug effect. Transplant recipients are frequently exposed to heparin either due to the underlying end-stage disease, which leads to listing and transplantation or during the transplant procedure and the perioperative period. To review the current scientific knowledge on anti-heparin/PF4 antibodies and HIT in transplant recipients a systematic PubMed literature search on articles in English language was performed. The definition of HIT is inconsistent amongst the publications. Overall, six studies and 15 case reports have been published on HIT before or after heart, liver, kidney, and lung transplantation, respectively. The frequency of seroconversion for anti-PF4/heparin antibodies ranged between 1.9% and 57.9%. However, different methods to detect anti-PF4/heparin antibodies were applied. In none of the studies HIT-associated thromboembolic events or fatalities were observed. More importantly, in patients with a history of HIT, reexposure to heparin during transplantation was not associated with thrombotic complications. Taken together, the overall incidence of HIT after solid organ transplantation seems to be very low. However, according to the current knowledge, cardiac transplant recipients may have the highest risk to develop HIT. Different alternative suggestions for heparin-free anticoagulation have been reported for recipients with suspected HIT albeit no official recommendations on management have been published for this special collective so far.
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Kerényi A, Beke Debreceni I, Oláh Z, Ilonczai P, Bereczky Z, Nagy B, Muszbek L, Kappelmayer J. Evaluation of flow cytometric HIT assays in relation to an IgG-Specific immunoassay and clinical outcome. CYTOMETRY PART B-CLINICAL CYTOMETRY 2016; 92:389-397. [PMID: 26860978 DOI: 10.1002/cyto.b.21362] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 01/06/2016] [Accepted: 02/01/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND Heparin-induced thrombocytopenia (HIT) is a severe side effect of heparin treatment caused by platelet activating IgG antibodies generated against the platelet factor 4 (PF4)-heparin complex. Thrombocytopenia and thrombosis are the leading clinical symptoms of HIT. METHODS The clinical pretest probability of HIT was evaluated by the 4T score system. Laboratory testing of HIT was performed by immunological detection of antibodies against PF4-heparin complex (EIA) and two functional assays. Heparin-dependent activation of donor platelets by patient plasma was detected by flow cytometry. Increased binding of Annexin-V to platelets and elevated number of platelet-derived microparticles (PMP) were the indicators of platelet activation. RESULTS EIA for IgG isotype HIT antibodies was performed in 405 suspected HIT patients. Based on negative EIA results, HIT was excluded in 365 (90%) of cases. In 40 patients with positive EIA test result functional tests were performed. Platelet activating antibodies were detected in 17 cases by Annexin V binding. PMP count analysis provided nearly identical results. The probability of a positive flow cytometric assay result was higher in patients with elevated antibody titer. 71% of patients with positive EIA and functional assay had thrombosis. CONCLUSIONS EIA is an important first line laboratory test in the diagnosis of HIT; however, HIT must be confirmed by a functional test. Annexin V binding and PMP assays using flow cytometry are functional HIT tests convenient in a clinical diagnostic laboratory. The positive results of functional assays may predict the onset of thrombosis. © 2016 International Clinical Cytometry Society.
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Affiliation(s)
- Adrienne Kerényi
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Hungary
| | - Ildikó Beke Debreceni
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Hungary
| | - Zsolt Oláh
- Department of Medicine, Faculty of Medicine, University of Debrecen, Hungary
| | - Péter Ilonczai
- Department of Medicine, Faculty of Medicine, University of Debrecen, Hungary
| | - Zsuzsanna Bereczky
- Division of Clinical Laboratory Science, Faculty of Medicine, University of Debrecen, Hungary
| | - Béla Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Hungary
| | - László Muszbek
- Division of Clinical Laboratory Science, Faculty of Medicine, University of Debrecen, Hungary
| | - János Kappelmayer
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Hungary
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Padmanabhan A, Jones CG, Curtis BR, Bougie DW, Sullivan MJ, Peswani N, McFarland JG, Eastwood D, Wang D, Aster RH. A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis. Chest 2016; 150:506-15. [PMID: 26905366 DOI: 10.1016/j.chest.2016.02.641] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 01/12/2016] [Accepted: 02/03/2016] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Almost without exception, patients with heparin-induced thrombocytopenia/thrombosis (HIT) have antibodies that recognize platelet factor 4 (PF4) in a complex with heparin; however, many heparin-treated patients without HIT are also antibody-positive. A platelet activation test, the serotonin release assay (SRA), is useful for identifying a subset of antibodies that are platelet-activating and most likely to cause HIT. However, this "gold standard" assay for HIT diagnosis is technically demanding and is routinely available only through referral laboratories, limiting its availability for timely diagnosis and management. METHODS We compared the diagnostic performance of the SRA with that of a technically simple platelet activation assay, the PF4-dependent P-selectin expression assay (PEA), which uses platelets pretreated with PF4 as targets for antibody detection. Archived serum samples from 91 patients for whom clinical information (HIT 4Ts [thrombocytopenia, timing of platelet count fall, thrombosis, and other causes of thrombocytopenia] score) was available were used. Patients with an intermediate 4Ts score and a PF4 ELISA (enzyme-linked immunosorbent assay) optical density ≥ 2.0, or a high 4Ts score and a PF4 ELISA optical density ≥ 1.0, were considered HIT positive; others were designated HIT negative. RESULTS The PEA had higher diagnostic accuracy (area under the curve, 0.92 vs 0.82; P = .02) than the SRA, using this definition of HIT. Eleven of 16 serum samples that were PEA positive and SRA negative were HIT positive. Studies done with identical target platelets and serially diluted samples from patients with HIT showed that the PEA is inherently more sensitive than the SRA for the detection of platelet-activating antibodies. CONCLUSIONS The PEA is technically less demanding than the SRA and may be more accurate for the diagnosis of HIT.
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Affiliation(s)
- Anand Padmanabhan
- Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.
| | - Curtis G Jones
- Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI
| | - Brian R Curtis
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI
| | - Daniel W Bougie
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI
| | - Mia J Sullivan
- Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI
| | - Namrata Peswani
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Janice G McFarland
- Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Daniel Eastwood
- Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI
| | - Demin Wang
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI
| | - Richard H Aster
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
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Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood 2016; 127:1954-9. [PMID: 26817956 DOI: 10.1182/blood-2015-07-660001] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 01/13/2016] [Indexed: 12/22/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction occurring in up to 5% of patients exposed to unfractionated heparin (UFH). We examined the impact of a hospital-wide strategy for avoiding heparin on the incidence of HIT, HIT with thrombosis (HITT), and HIT-related costs. The Avoid-Heparin Initiative, implemented at a tertiary care hospital in Toronto, Ontario, Canada, since 2006, involved replacing UFH with low-molecular-weight heparin (LMWH) for prophylactic and therapeutic indications. Consecutive cases with suspected HIT from 2003 through 2012 were reviewed. Rates of suspected HIT, adjudicated HIT, and HITT, along with HIT-related expenditures were compared in the pre-intervention (2003-2005) and the avoid-heparin (2007-2012) phases. The annual rate of suspected HIT decreased 42%, from 85.5 per 10 000 admissions in the pre-intervention phase to 49.0 per 10 000 admissions in the avoid-heparin phase ( ITALIC! P< .001). The annual rate of patients with a positive HIT assay decreased 63% from 16.5 to 6.1 per 10 000 admissions ( ITALIC! P< .001), adjudicated HIT decreased 79% from 10.7 to 2.2 per 10 000 admissions ( ITALIC! P< .001), and HITT decreased 91% from 4.6 to 0.4 per 10 000 admissions ( ITALIC! P< .001). Hospital HIT-related expenditures decreased by $266 938 per year in the avoid-heparin phase. To the best of our knowledge, this is the first study demonstrating the success and feasibility of a hospital-wide HIT prevention strategy.
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Lu BY, Kudlowitz D, Gardner LB. Clinical and laboratory characteristics associated with a high optical density anti-platelet factor 4 ELISA test. J Blood Med 2015; 6:277-83. [PMID: 26640392 PMCID: PMC4657791 DOI: 10.2147/jbm.s90179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Diagnosing heparin-induced thrombocytopenia, a potentially catastrophic immune-mediated disorder, continues to pose significant challenges for clinicians, as both clinical and laboratory tools lack specificity. There is mounting evidence supporting a positive correlation between definitive heparin-induced thrombocytopenia and optical density (OD) positivity from the widely available anti-platelet factor 4 enzyme-linked immunosorbent assays (PF4 ELISAs). However, the clinical features distinguishing these patients remain poorly understood. PATIENTS AND METHODS To better characterize this group, we conducted a case-controlled, retrospective chart review of patients from two large, urban academic institutions who underwent a PF4 ELISA at a central laboratory. Associations between OD and 18 clinical characteristics were calculated using the Fisher's exact test for categorical variables and Wilcoxon rank-sum test for continuous variables. RESULTS In total, 184 negative patients (OD <0.7), and 121 positive patients (OD >0.7), including 74 low-positive patients (0.7< OD <1.4) and 47 high-positive patients (OD >1.4) were identified. Several clinical variables were significantly different in the negative group compared with the positive group, including hospital day (P<0.001), previous admission within the past 3 months (P<0.001), and the presence of a new thrombus (P=0.003). However, many of these variables were not different between the negative and low-positive group, and were only distinct between the negative and high-positive group. When the low-positive and high-positive groups were compared, only the 4T score was significantly different (P=0.003). CONCLUSION These data indicate that those with OD >1.4 form a distinct clinical group and support the clinical utility of the 4T score.
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Affiliation(s)
- Benjamin Y Lu
- Department of Medicine, NYU School of Medicine, New York, NY, USA
| | - David Kudlowitz
- Department of Medicine, NYU School of Medicine, New York, NY, USA
| | - Lawrence B Gardner
- Department of Medicine, NYU School of Medicine, New York, NY, USA ; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA ; The Perlmutter Cancer Center, NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA
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