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Myoung SS, Francis SJ, Chen J, Lee G, Rauova L, Poncz M, Cines DB, Kuchibhatla M, Khandelwal S, Arepally GM. Complement activation as a biomarker for platelet-activating antibodies in heparin-induced thrombocytopenia. J Thromb Haemost 2025; 23:1066-1076. [PMID: 39725085 PMCID: PMC11890944 DOI: 10.1016/j.jtha.2024.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Immunoglobulin G antibodies (Abs) to platelet factor 4 (PF4) complexed to heparin (PF4/H) commonly occur after H exposure but cause life-threatening complications of H-induced thrombocytopenia (HIT) in only a few patients. Presently, only platelet activation assays reliably distinguish anti-PF4/H Abs that cause disease (HIT Abs) from those likely to be asymptomatic (AAbs). OBJECTIVES Recent studies indicate that complement activation is an important serologic property of HIT Abs and is essential for IgG Fc receptor IIA-mediated cellular activation. As platelet activation by HIT Abs also relies on IgG Fc receptor IIA activation, we correlated the complement- and platelet-activating properties of anti-PF4/H Abs in a clinically annotated patient cohort. METHODS Clinical and laboratory features of patients with HIT (n = 8) and AAbs+ (n = 14) were correlated with properties of complement, platelet, and monocyte/neutrophil activation. RESULTS Expected clinical and laboratory differences were seen between HIT and AAb+ patients, with HIT patients having lower mean platelet counts, greater percentage drop in platelet counts, higher 4T and HIT expert probability scores, higher anti-PF4 polyclonal and immunoglobulin G Ab levels, and serotonin release assay positivity. Ex vivo assays revealed significant differences in complement activation by HIT vs AAb+ patients, with the extent of complement activation closely correlated with percent serotonin release by anti-PF4/H Abs and matrix metalloproteinase-9 and interleukin-8 release in whole blood. CONCLUSION These findings suggest that complement activation strongly correlates with cellular activation endpoints, including platelet and monocyte/neutrophil activation, and if confirmed in a larger prospective study, may serve as a "functional" biomarker for pathogenic HIT Abs.
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Affiliation(s)
- Sooho S Myoung
- Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Samuel J Francis
- Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA
| | - Jonah Chen
- Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA
| | - Grace Lee
- Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA
| | - Lubica Rauova
- Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Mortimer Poncz
- Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Douglas B Cines
- Department of Pathology and Laboratory Medicine, Perelman-University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | | | - Sanjay Khandelwal
- Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA.
| | - Gowthami M Arepally
- Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA.
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2
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Moghaddam OM, Ramsheh ZH, Sedighi M, Amanollahi A, Lahiji MN. Association between time of heparin exposure and platelets decline in patients with heparin induced thrombocytopenia. Hematol Transfus Cell Ther 2024; 46:572-574. [PMID: 38307828 PMCID: PMC11451345 DOI: 10.1016/j.htct.2023.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 10/29/2023] [Accepted: 11/13/2023] [Indexed: 02/04/2024] Open
Affiliation(s)
- Omid Moradi Moghaddam
- Trauma and Injury Research Center, Iran University of Medical Sciences, Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Sedighi
- Trauma and Injury Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Amanollahi
- Trauma and Injury Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Niakan Lahiji
- Trauma and Injury Research Center, Iran University of Medical Sciences, Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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3
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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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Zlamal J, Aliotta A, Alberio L, Chen V, Bakchoul T. Diagnostic value of antibody-induced procoagulant platelets in heparin-induced thrombocytopenia: communication from the ISTH SSC Subcommittee on Platelet Immunology. J Thromb Haemost 2024; 22:860-868. [PMID: 38065529 DOI: 10.1016/j.jtha.2023.11.019] [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: 07/27/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/30/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic disorder characterized by a drop in platelet count and an increased risk of thromboembolic events. The accurate diagnosis of HIT involves clinical assessment and laboratory testing with well-characterized functional tests. Recent research has shown the potential of investigating procoagulant platelet formation induced by HIT antibodies. To successfully implement these assays in clinical laboratories, careful consideration of technical and preanalytical factors is crucial. In this communication from the SSC Platelet Immunology, we provide a consensus from experts on the use of flow cytometry in HIT diagnosis, highlighting the importance of standardized protocols.
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Affiliation(s)
- Jan Zlamal
- Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany
| | - Alessandro Aliotta
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Lorenzo Alberio
- Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Vivien Chen
- ANZAC Research Institute, Sydney Local Health District, Sydney, New South Wales, Australia; Department of Haematology, Concord Repatriation General Hospital and NSW Health Pathology, Sydney, New South Wales, Australia; Concord Clinical School, University of Sydney, Sydney, New South Wales, Australia
| | - Tamam Bakchoul
- Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen, Tübingen, Germany; Centre for Clinical Transfusion Medicine, Tübingen, Germany.
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5
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Bissola AL, Daka M, Ivetic N, Clare R, Pai M, Kelton JG, Arnold DM, Nazy I. Evaluation of laboratory testing parameters for vaccine-induced immune thrombotic thrombocytopenia and their implications for diagnosis. J Thromb Haemost 2024; 22:304-306. [PMID: 37866513 DOI: 10.1016/j.jtha.2023.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023]
Affiliation(s)
- Anna-Lise Bissola
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Mercy Daka
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Nikola Ivetic
- 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
| | - Menaka Pai
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John G Kelton
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - Donald M Arnold
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - Ishac Nazy
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Michael G. DeGroote Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University Hamilton, Hamilton, Ontario, Canada.
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6
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Warkentin TE. Immunologic Effects of Heparin Associated With Hemodialysis: Focus on Heparin-Induced Thrombocytopenia. Semin Nephrol 2023; 43:151479. [PMID: 38195304 DOI: 10.1016/j.semnephrol.2023.151479] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Intermittent hemodialysis (HD) is almost invariably performed with heparin, and thus HD patients are at risk of developing the immune-mediated adverse effect heparin-induced thrombocytopenia (HIT), caused by anti-platelet factor 4/heparin IgG, which strongly activates platelets. HIT patients develop hypercoagulability with greatly increased risk of thrombosis, both venous and arterial. Certain HIT-associated complications are more likely to develop among HD patients, including hemofilter thrombosis despite heparin, intravascular catheter and/or arteriovenous fistula-associated thrombosis, post-heparin bolus anaphylactoid/anaphylactic reactions, and thrombotic stroke and acute limb artery thrombosis (reflecting the high frequency of underlying arteriopathy in many patients with renal failure). Management of HIT in HD usually requires use of an alternative (non-heparin) anticoagulant; for example, danaparoid sodium (outside the USA) or argatroban (USA and elsewhere). Whether heparin-grafted hemodialyzers (without systemic heparin) can be used safely in acute HIT is unknown. The HIT immune response is remarkably transient and usually not retriggered by subsequent heparin administration. Accordingly, since renal failure patients often require long-term HD, there may be the opportunity-following seroreversion (loss of platelet-activating HIT antibodies)-to restart heparin for HD, a practice that appears to have a low likelihood of retriggering HIT.
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Affiliation(s)
- Theodore E Warkentin
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada; Department of Medicine, McMaster University, Hamilton, Canada; Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton Health Sciences, Hamilton, Canada; Service of Benign Hematology, Hamilton General Hospital, Hamilton Health Sciences, Hamilton, Canada.
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7
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Batool A, Chaudhry S, Javaid A, Kenney A. Autoimmune Heparin-Induced Thrombocytopenia: A Diagnostic and Management Challenge After Transcatheter Aortic Valve Replacement. Cureus 2023; 15:e45453. [PMID: 37859883 PMCID: PMC10583616 DOI: 10.7759/cureus.45453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2023] [Indexed: 10/21/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a commonly encountered condition, especially in inpatient settings, and is often attributed to high mortality and prolonged hospital stays. A rare entity, autoimmune heparin-induced thrombocytopenia (aHIT) refers to a condition in which antiplatelet factor-4 (PF4) antibodies activate platelets even in the absence of heparin. Our patient presented 12 days after transcatheter aortic valve replacement (TAVR) with altered mental status and severe thrombocytopenia. Further work-up revealed acute thromboembolic cerebrovascular accident (CVA), and the HIT antibody was positive. He was started on intravenous argatroban infusion with poor response. Platelet factor-4 antibodies were positive as well, and he was started on intravenous immunoglobulins (IVIG) therapy resulting in platelet recovery. This case is a reminder to consider autoimmune HIT, especially when platelet count fails to improve with conventional therapy.
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Affiliation(s)
- Aisha Batool
- Internal Medicine, Columbia St. Mary Hospital, Milwaukee, USA
| | | | | | - Ashley Kenney
- Hospital Medicine, Health Partners, Minneapolis, USA
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8
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Alhanshani AA. Heparin Induced Thrombocytopenia - Pathophysiology, Diagnosis and Treatment: A Narrative Review. Int J Gen Med 2023; 16:3947-3953. [PMID: 37667778 PMCID: PMC10475297 DOI: 10.2147/ijgm.s420327] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/02/2023] [Indexed: 09/06/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated complication following heparin exposure and is considered to be the most severe adverse reaction to heparin treatment that is not associated with bleeding. Development of autoantibodies against platelet factor 4 (PF4) - heparin complex constitutes the basis of the pathophysiological changes in patients suffering from HIT, which then binds to the surface of platelets and monocytes, thus provoking their activation and subsequent aggregation, ultimately leading to the formation of thrombosis. Formation of arterial and venous thrombosis is aggravated by the simultaneous activation of platelets and monocytes with a substantial mortality rate. The incidence of HIT is reported to be significantly lower in pediatric patients compared with adults. Diagnosis of HIT in pediatric population remains a clinical entity supplemented by laboratory evaluation. The positive predictive value of laboratory evaluation is further elevated by the use of scoring systems and predictive models used for hastening the diagnosis of HIT. Use of alternative anticoagulants like direct thrombin inhibitors and factor Xa inhibitors form the mainstay of treatment in cases of HIT, however, more prospective studies would be required in the pediatric population to delineate definitive guidelines for proper management of patients in this age-group. This article delivers diagnostic and treatment approach in case of patients with HIT, wherein the pathophysiology, clinical manifestations, diagnostic approach and the management of patients with HIT has been described.
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Affiliation(s)
- Ahmad A Alhanshani
- Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia
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9
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Erich BJ, Knutson J, Barnes BJ. Analysis of heparin-induced thrombocytopenia diagnostic and management strategies in individuals with inconclusive antibody optical densities. Blood Coagul Fibrinolysis 2023; 34:272-280. [PMID: 37115961 DOI: 10.1097/mbc.0000000000001220] [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: 04/30/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) is an uncommon but serious complication of exposure to heparin. Antibody optical densities (ODs) used to diagnose HIT exceeding 2 are highly suggestive of disease, whereas ODs less than 0.5 often 'rule out' HIT. Variation in the clinical care of patients with inconclusive ODs between 0.5 and 2 is likely. This single-centre, retrospective analysis evaluates the diagnosis, management and outcomes of those with antibody ODs between 0.5 and 2. We queried our institution's Healthcare Enterprise Repository for Ontological Narration (HERON) database to identify individuals with antibody ODs between 0.5 and 2. Chart review was completed to calculate 4T scores, corroborate diagnosis codes with documented information in our electronic health record (EHR) and evaluate the diagnosis, management and outcomes of these individuals. These data were evaluated using descriptive and univariate statistics. Among individuals evaluated for HIT between November 2007 and July 2020, we identified 302 individuals with ODs between 0.5 and 2. Serotonin release assays (SRAs) were assessed in 55% (165/302) and were positive in 12% (20/165). In those with available data, 96% with low 4T scores had negative SRAs and 4% had positive SRAs. As 4T scores and antibody ODs proportionally increased, SRA positivity also increased. Clinical management varied widely; however, 4T scoring remains a valuable assessment in this cohort. In those with HIT antibody ODs between 0.5 and 2, true positives were uncommon, and their clinical management varied widely. Fortunately, 4T scoring is a useful prognostic tool that improves the diagnosis and management among those with inconclusive HIT.
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Affiliation(s)
| | - Jace Knutson
- Inpatient Pharmacy, The University of Kansas Health System
| | - Brian J Barnes
- School of Pharmacy, The University of Kansas Medical Center, Kansas City, Kansas, USA
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10
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Muacevic A, Adler JR, Ma MQ, Rojas Hernandez CM, Elsayem A. Heparin-Induced Thrombocytopenia at the Emergency Department Due to Intermittent Heparin Flush in a Patient Undergoing Stem Cell Transplant. Cureus 2022; 14:e31798. [PMID: 36569714 PMCID: PMC9780017 DOI: 10.7759/cureus.31798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2022] [Indexed: 11/23/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin products, but not warfarin. HIT usually occurs 5‒10 days after exposure to heparin. Here, we report a case of HIT with multiple thrombotic events and severe thrombocytopenia resulting from intermittent intravenous heparin flushes for maintenance of a newly placed subclavian central venous catheter (CVC) for stem cell transplant. The patient is a woman in her forties with multiple myeloma who presented to the emergency department (ED) with dyspnea, pleuritic-type chest pain, hemoptysis, and worsening left-leg swelling. Heparin had been used to flush the CVC. Her platelet count began dropping approximately one week after insertion. The patient was receiving other medications known to cause thrombocytopenia. She had undergone multiple platelet transfusions. In the ED, her lab results showed thrombocytopenia), anemia; renal insufficiency; and elevated troponin, prothrombin time, and D-dimer levels. Because of the hemoptysis and thrombocytopenia, she initially received platelet transfusion and oxygen. She was found to have deep vein thrombosis of the lower extremity and started a referral to interventional radiology for inferior vena cava (IVC) filter placement. However, further review and consultation of the Benign Hematology service, discussion about the timing of decreased platelet count shortly after CVC placement and heparin administration, and the presence of thrombosis, suggested a high pre-test probability of HIT. Anticoagulation with argatroban was initiated, and IVC filter insertion was canceled. Further workup confirmed HIT diagnosis and saddle pulmonary embolism. During the patient's hospitalization, her platelets continued to improve and reached baseline upon discharge. She was transitioned to fondaparinux at the time of discharge. A few weeks later, she had successful stem cell transplantation. Emergency physicians treating patients with thrombocytopenia receiving heparin, even in small amounts, should consider the possibility of HIT and be familiar with its management.
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Jimenez DC, Warner ED, Ahmad D, Rosen JL, Al-Rawas N, Morris RJ, Alvarez R, Rame JE, Entwistle JW, Massey HT, Tchantchaleishvili V. Cardiac transplantation after heparin induced thrombocytopenia: A systematic review. Clin Transplant 2021; 36:e14567. [PMID: 34927287 DOI: 10.1111/ctr.14567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/10/2021] [Accepted: 12/14/2021] [Indexed: 11/29/2022]
Abstract
PURPOSE Heparin induced thrombocytopenia (HIT) presents a unique challenge in patients requiring orthotopic heart transplantation (OHT). We sought to pool the existing evidence in a systematic review. METHODS Electronic search was performed to identify all relevant studies on OHT in patients with HIT. Patient-level data for 33 patients from 21 studies were extracted for statistical analysis. RESULTS Median patient age was 51 [41, 55] years, with 75.8% (25/33) males. All patients had a clinical diagnosis of HIT, and anti PF4/Heparin antibodies were positive in 87.9% (29/33). Median lowest reported platelet count was 46 × 109 /L [27.2, 73.5]. Intraoperatively, 61% (20/33) of patients were given unfractionated heparin (UFH), while 39% (13/33) were given alternative anticoagulants. The alternative agent subgroup required more antifibrinolytics [54% (7/13) vs. 10% (2/20), p = 0.02] and clotting factors [69.2% (9/13) vs. 15.0% (3/20) p<0.01]. Peri-operative thrombosis occurred more in [53.8% (7/13) vs 0% (0/20, p<0.01) alternate agent subgroup. More patients in the alternate agent subgroup required post-operative transfusions [54% (7/13) vs. 0% (0/20), p<0.01]. Thirty-day mortality of 15.2% (5/33) was comparable between the subgroups. CONCLUSION Heparin use during OHT may be associated with less adverse effects compared to use of other anticoagulants with no difference in 30-day mortality. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Diana C Jimenez
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Eric D Warner
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Danial Ahmad
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Jake L Rosen
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Nawar Al-Rawas
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Rohinton J Morris
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Rene Alvarez
- Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - J Eduardo Rame
- Division of Cardiology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - John W Entwistle
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - H Todd Massey
- Division of Cardiac Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, 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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13
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Warkentin TE, Smythe MA, Ali MA, Aslam N, Sheppard JI, Smith JW, Moore JC, Arnold DM, Nazy I. Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT? Am J Hematol 2021; 96:320-329. [PMID: 33326124 DOI: 10.1002/ajh.26075] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/07/2020] [Accepted: 12/14/2020] [Indexed: 12/28/2022]
Abstract
IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.
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Affiliation(s)
- Theodore E. Warkentin
- Department of Pathology and Molecular Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
- Department of Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
| | - Maureen A. Smythe
- Department of Pharmaceutical Services Beaumont Hospital Royal Oak Michigan USA
- Department of Pharmacy Practice Wayne State University Detroit Michigan USA
- Oakland University William Beaumont School of Medicine Rochester Michigan USA
| | - Mona A. Ali
- Department of Pharmaceutical Services Beaumont Hospital Royal Oak Michigan USA
| | - Naveed Aslam
- Oakland University William Beaumont School of Medicine Rochester Michigan USA
| | - Jo‐Ann I. Sheppard
- Department of Pathology and Molecular Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
| | - James W. Smith
- Department of Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
| | - Jane C. Moore
- Department of Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
| | - Donald M. Arnold
- Department of Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
| | - Ishac Nazy
- Department of Medicine Michael G. DeGroote School of Medicine Hamilton Ontario Canada
- McMaster Centre for Transfusion Research Hamilton Ontario Canada
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Arepally GM, Padmanabhan A. Heparin-Induced Thrombocytopenia: A Focus on Thrombosis. Arterioscler Thromb Vasc Biol 2021; 41:141-152. [PMID: 33267665 PMCID: PMC7769912 DOI: 10.1161/atvbaha.120.315445] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 11/13/2020] [Indexed: 01/19/2023]
Abstract
Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.
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Affiliation(s)
| | - Anand Padmanabhan
- Divisions of Hematopathology, Transfusion Medicine, and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (A.P.)
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15
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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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Warkentin TE. Challenges in Detecting Clinically Relevant Heparin-Induced Thrombocytopenia Antibodies. Hamostaseologie 2020; 40:472-484. [PMID: 33091948 PMCID: PMC7581458 DOI: 10.1055/a-1223-3329] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is an antibody-mediated hypercoagulable state featuring high thrombosis risk and distinct pathogenesis involving immunoglobulin G-mediated platelet activation. The target of the immune response is a cationic “self” protein, platelet factor 4 (PF4), rendered antigenic by heparin. A key problem is that only a minority of anti-PF4/polyanion antibodies induced by heparin are pathogenic, i.e., capable of causing platelet activation and thereby clinical HIT. Since thrombocytopenia occurs frequently in hospitalized, heparin-treated patients, testing for “HIT antibodies” is common; thus, the problem of distinguishing between pathogenic and nonpathogenic antibodies is important. The central concept is that those antibodies that have platelet-activating properties demonstrable in vitro correlate well with pathogenicity, as shown by platelet activation tests such as the serotonin-release assay (SRA) and heparin-induced platelet activation assay. However, in most circumstances, immunoassays are used for first-line testing, and so it is important for clinicians to appreciate which immunoassay result profiles—in the appropriate clinical context—predict the presence of platelet-activating antibodies (Bayesian analysis). Clinicians with access to rapid, on-demand HIT immunoassays (e.g., particle gel immunoassay, latex immunoturbidimetric assay, chemiluminescent immunoassay) can look beyond simple dichotomous result interpretation (“negative”/“positive”) and incorporate semiquantitative interpretation, where, for example, a strong-positive immunoassay result (or even combination of two immunoassays) points to a greater probability of detecting platelet-activating antibodies, and hence supporting a diagnosis of HIT. Recent recognition of “SRA-negative HIT” has increased the importance of semiquantitative interpretation of immunoassays, given that strong immunoassay reactivity is a potential clue indicating possible HIT despite a (false) negative platelet activation assay.
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Affiliation(s)
- Theodore E Warkentin
- Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.,Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.,Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, Hamilton, Ontario, Canada.,Service of Clinical Hematology, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario, Canada.,McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada
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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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Singh N, Singh Lubana S, Tsai HM. Myocardial Infarction with Limb Arterial and Venous Thrombosis in a Patient with Enoxaparin-Induced Thrombocytopenia. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e922498. [PMID: 32469847 PMCID: PMC7286187 DOI: 10.12659/ajcr.922498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Patient: Female, 67-year-old Final Diagnosis: Enoxaparin induced thrombocytopenia with life threatening thrombosis Symptoms: Chest discomfort Medication:— Clinical Procedure: — Specialty: Hematology
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Affiliation(s)
- Navdeep Singh
- Department of Medicine, Division of Hospice and Palliative Care, North Shore University Hospital, Manhasset, NY, USA
| | - Sandeep Singh Lubana
- Department of Medicine, Division of Hematology and Oncology, State University New York (SUNY) Downstate Medical Center, Brooklyn, NY, USA
| | - Han-Mou Tsai
- Department of Medicine, Division of Hematology and Oncology, State University New York (SUNY) Downstate Medical Center, Brooklyn, NY, USA
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Patriarcheas V, Pikoulas A, Kostis M, Charpidou A, Dimakakos E. Heparin-induced Thrombocytopenia: Pathophysiology, Diagnosis and Management. Cureus 2020; 12:e7385. [PMID: 32337112 PMCID: PMC7179984 DOI: 10.7759/cureus.7385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 03/24/2020] [Indexed: 01/16/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT), even rare, is a life-threatening, immune-mediated complication of heparin exposure. It is considered the most severe non-bleeding adverse reaction of heparin treatment and one of the most important adverse drug reactions. The pathophysiological basis of HIT results from the formation of an immunocomplex consisting of an auto-antibody against platelet factor 4 (PF4) - heparin complex, which binds to the surface of platelets and monocytes, provoking their activation by cross-linking FcgIIA receptors. Platelets and monocyte activation, leads to the generation of catastrophic arterial and venous thrombosis, with a mortality rate of 20%, without early recognition. The definitive diagnosis of HIT i.e., clinical and laboratory evidence, can not be done at the onset of symptoms because laboratory results may not be available for several days. Thus, the initial approach is to predict the likelihood of HIT, because in highly suspected patients immediate heparin cessation and initiation of alternative anticoagulation treatment are crucial for the prevention of the devastating thrombotic sequelae. Herein, we describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the management of patients with HIT.
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Affiliation(s)
| | | | - Minas Kostis
- Internal Medicine, University Hospital of Patras, Patras, GRC
| | - Andriani Charpidou
- Internal Medicine, Thoracic Diseases General Hospital Sotiria, Athens, GRC
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20
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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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21
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Liederman Z, Van Cott EM, Smock K, Meijer P, Selby R. Heparin-induced thrombocytopenia: An international assessment of the quality of laboratory testing. J Thromb Haemost 2019; 17:2123-2130. [PMID: 31420903 DOI: 10.1111/jth.14611] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 08/12/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Accurate diagnosis of heparin-induced thrombocytopenia (HIT) is essential to ensure timely treatment and prevent complications. Current diagnostic assays include enzyme-linked immunosorbent assays (ELISAs) and rapid immunoassays (RIs). RIs offer fast turnaround times but were not significantly represented in previous external proficiency testing challenges. OBJECTIVES To use external proficiency testing to assess qualitative concordance for heparin/PF4 antibody detection. METHODS From 2013 to 2017, the External Quality Control for Assays and Tests (ECAT) Foundation distributed 10 samples internationally. RESULTS In total, 437 laboratories submitted 3149 results. ELISAs accounted for 1484 (47%) responses with RIs accounting for 1665 (53%) responses. RI use increased over the 5-year period. ELISAs classified 96% of both consensus positive and consensus negative samples concordantly. The coefficient of variation (CV) for positive sample optical densities (ODs) ranged from 35% to 50% when combining ELISA assay methods together. Quantitative RIs classified 97% of consensus-positive and 98% of consensus-negative samples concordantly. Qualitative RIs had a higher proportion of discordant responses and classified 88% of consensus-positive samples and 73% of consensus-negative samples concordantly. Of RIs only latex immunoassays and IgG specific chemiluminescent assays identified > 95% of samples concordantly with consensus. CONCLUSION Quantitative RIs and ELISAs classify > 95% of samples concordantly. The ODs from different ELISA methods vary considerably and are not interchangeable. Qualitative RI use is increasing despite a greater proportion of discordant classifications. This includes a higher than expected number of negative classifications for consensus-positive samples among many RIs, challenging their use as "rule out" tests.
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Affiliation(s)
| | - Elizabeth M Van Cott
- Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
| | - Kristi Smock
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
- ARUP Laboratories, Hemostasis/Thrombosis Laboratory, Salt Lake City, UT, USA
| | - Piet Meijer
- ECAT Foundation, External Quality Control for Assays and Tests, Voorschoten, the Netherlands
| | - Rita Selby
- Department of Laboratory Medicine and Medicine, University of Toronto, Toronto, ON, Canada
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22
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Pollak U. Heparin-induced thrombocytopenia complicating extracorporeal membrane oxygenation support: Review of the literature and alternative anticoagulants. J Thromb Haemost 2019; 17:1608-1622. [PMID: 31313454 DOI: 10.1111/jth.14575] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/25/2019] [Accepted: 07/11/2019] [Indexed: 01/19/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) is a life-threatening prothrombotic, immune-mediated complication of unfractionated heparin and low molecular weight heparin therapy. HIT is characterized by moderate thrombocytopenia 5-10 days after initial heparin exposure, detection of platelet-activating anti-platelet factor 4/heparin antibodies and an increased risk of venous and arterial thrombosis. Extracorporeal membrane oxygenation (ECMO) is a form of mechanical circulatory support used in critically ill patients with respiratory or cardiac failure. Systemic anticoagulation is used to alleviate the thrombotic complications that may occur when blood is exposed to artificial surfaces within the ECMO circuit. Therefore, when HIT complicates patients on ECMO support, it is associated with a high thrombotic morbidity and mortality. The risk for HIT correlates with the accumulative dosage of heparin exposure. In ECMO patients receiving continuous infusion of heparin for circuit patency, the risk for HIT is not neglected and must be thought of in the differential diagnosis of the appropriate clinical and laboratory circumstances. The following article reviews the current knowledge in HIT complicating ECMO patients and the alternative anticoagulation options in the presence of HIT.
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Affiliation(s)
- Uri Pollak
- Pediatric Cardiac Critical Care Unit, Hadassah University Medical Center, Jerusalem, Israel
- Pediatric Cardiology, Hadassah University Medical Center, Jerusalem, Israel
- Pediatric Extracorporeal Support Program, Hadassah University Medical Center, Jerusalem, Israel
- The Hebrew University Hadassah Medical School, Jerusalem, Israel
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23
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Cipok M, Tomer A, Elalamy I, Kirgner I, Dror N, Kay S, Deutsch VR. Pathogenic heparin-induced thrombocytopenia and thrombosis (HIT) antibodies determined by rapid functional flow cytometry. Eur J Haematol 2019; 103:225-233. [PMID: 31206215 DOI: 10.1111/ejh.13277] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/05/2019] [Accepted: 06/06/2019] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Reliable diagnosis of heparin-induced thrombocytopenia and thrombosis (HIT) is mandatory for patient management, yet prompt determination of pathogenic antibodies remains an unmet clinical challenge. Common immunoassays carry inherent limitations and functional assays which detect antibody-mediated platelet activation are not usually readily available to routine laboratories, especially the serotonin release assay (SRA), being technically demanding, time consuming, and requires high level expertise. To overcome some of these limitations, we have developed a practical functional flow cytometric assay (FCA) for routine clinical use. METHODS A simple FCA is described which avoids platelet manipulation, is highly specific and sensitive compared with SRA, and provides rapid results. RESULTS Of the 650 consecutive samples, from HIT-suspected patients, 99 (15.3%) were positive by the PaGIA Heparin/PF4 immunoassay and 31 (4.8%) by FCA. Average platelet activation was 11-fold higher in PaGIA+/FCA+ vs PaGIA-/FCA- samples. Of 21 SRA-positive samples, 19 were FCA-positive (relative sensitivity 90.5%), and of 42 SRA-negative samples, 40 were FCA-negative (relative specificity 95.2%). The FCA showed significantly higher correlation with the clinical presentation of HIT (4Ts score) performed on 182 patients, compared with PaGIA Heparin/PF4 (ROC-plot analysis, AUC 0.93 vs 0.63, P < 0.001). At a 92% sensitivity, the assay specificity was 96%. CONCLUSIONS The present FCA is practical for routine testing, providing prompt reliable results for initial diagnosis and confirmation, to effectively assist in HIT patient management.
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Affiliation(s)
- Michal Cipok
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aaron Tomer
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ismail Elalamy
- Hematology and Thrombosis Center, Tenon University Hospital, INSERM UMRS 938, Sorbonne University, Paris, France.,Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ilya Kirgner
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Naama Dror
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sigi Kay
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Varda R Deutsch
- The Hematology Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Warkentin TE. Laboratory diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol 2019; 41 Suppl 1:15-25. [PMID: 31069988 DOI: 10.1111/ijlh.12993] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/25/2019] [Accepted: 02/01/2019] [Indexed: 12/18/2022]
Abstract
Heparin-induced thrombocytopenia (HIT) is a clinical-pathological disorder; thus, laboratory testing for the pathogenic platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies is central for diagnosis. The "iceberg" model summarizes the inter-relationship between platelet activation assays and PF4-dependent immunoassays, with platelet-activating antibodies comprising a subset of anti-PF4/heparin antibodies. The platelet serotonin-release assay (SRA), performed by reference laboratories, has high sensitivity and specificity for HIT (~95% each), and is especially suited for detecting highly pathogenic HIT sera containing both heparin-dependent and heparin-independent platelet-activating antibodies; this latter subgroup of antibodies explains "autoimmune HIT" disorders (delayed-onset, persisting, spontaneous, heparin "flush," fondaparinux-associated). Recently, SRA-negative HIT has become recognized, in which serum from some HIT patients contains subthreshold levels of platelet-activating antibodies (by SRA) that become detectable using a PF4-enhanced platelet activation assay. Unusual immunologic features of HIT include early antibody detectability (at onset of platelet count fall) and antibody transience (seroreversion). Widely available PF4-dependent enzyme immunoassays (EIAs) have high sensitivity but poor specificity for HIT, although specificity is enhanced with IgG-specific EIAs and strong positive results; unfortunately, EIA results are usually not available in real time. Automated rapid immunoassays, such as the chemiluminescence immunoassay (CLIA) and latex immunoturbidimetric assay (LIA), facilitate real-time laboratory diagnosis. Recently available likelihood ratio (LR) data for positive (LR+) and negative (LR-) test results allow clinicians to adjust their pretest probabilities for HIT, using Bayesian analysis, into real-time posttest probabilities that are dramatically increased (test positive) or decreased (test negative). Moreover, (semi-)quantitative CLIA- and LIA-positive results (weak, moderate, strong positive) can further refine the posttest probability of HIT.
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Affiliation(s)
- Theodore E Warkentin
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.,Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario, Canada.,McMaster Centre for Transfusion Research, Hamilton, Ontario, Canada
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25
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Prospective evaluation of heparin-induced thrombocytopenia expert probability and 4T scores in Chinese patients with suspected heparin-induced thrombocytopenia. Chin Med J (Engl) 2019; 132:1441-1447. [PMID: 31205102 PMCID: PMC6629329 DOI: 10.1097/cm9.0000000000000261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Supplemental Digital Content is available in the text Background Diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. This study aimed to compare the diagnostic performance of HIT expert probability (HEP) and 4T scores, and to evaluate the inter-observer reliability for the 4T score in a clinical setting. Methods This prospective study included HIT-suspected patients between 2016 and 2018. Three hematologists assessed the HEP and 4T scores. Correlations between scores and anti-platelet factor 4 (anti-PF4)/heparin antibodies were evaluated. Receiver operating characteristic curves and area under the curve (AUC) were used to assess the predictive accuracy of these two scoring models. The intraclass correlation coefficient (ICC) was used to assess the inter-observer agreement of 4T scores between residents and hematologists. Results Of the 89 subjects included, 22 (24.7%) were positive for anti-PF4/heparin antibody. The correlations between antibody titer and either HEP or 4T scores were similar (r = 0.392, P < 0.01 for the HEP score; r = 0.444, P < 0.01 for the 4T score). No significant difference in the diagnostic performance was displayed between these two scores (AUC for the HEP score: 0.778 vs. AUC for the 4T score: 0.741, P = 0.357). Only 72 4T scores were collected from the residents, with a surprisingly low percentage of observers (43.1%) presenting the four individual item scores which made up their 4T score. The AUC of 4T score assessed by residents and hematologists was 0.657 (95% confidence interval [CI]: 536–0.765) and 0.780 (95% CI: 0.667–0.869, P < 0.05), respectively. The ICC of 4T score between residents and hematologists was 0.49 (95% CI: 0.29–0.65, P < 0.01), demonstrating a fair inter-observer agreement. Conclusions The HEP score does not display a better performance for predicting HIT than the 4T score. With the unsatisfactory completion rate, the inter-observer agreement of 4T score in a tertiary hospital is fair, underscoring the necessity for continuing education for physicians.
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Joseph J, Rabbolini D, Enjeti AK, Favaloro E, Kopp M, McRae S, Pasalic L, Tan CW, Ward CM, Chong BH. Diagnosis and management of heparin‐induced thrombocytopenia: a consensus statement from the Thrombosis and Haemostasis Society of Australia and New ZealandHITWriting Group. Med J Aust 2019; 210:509-516. [DOI: 10.5694/mja2.50213] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Joanne Joseph
- St Vincent's Hospital Sydney NSW
- St Vincent's Clinical SchoolUniversity of New South Wales Sydney NSW
| | - David Rabbolini
- Royal North Shore Hospital Sydney NSW
- Northern Blood Research CentreKolling Institute of Medical Research Sydney NSW
| | | | - Emmanuel Favaloro
- Institute of Clinical Pathology and Medical Research Sydney NSW
- Westmead Hospital Sydney NSW
| | | | | | - Leonardo Pasalic
- Institute of Clinical Pathology and Medical Research Sydney NSW
- Westmead Hospital Sydney NSW
| | | | - Christopher M Ward
- Royal North Shore Hospital Sydney NSW
- Northern Blood Research CentreKolling Institute of Medical Research Sydney NSW
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27
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Pabst D, Boone JB, Soleimani B, Brehm CE. Heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation and the role of a heparin-bonded circuit. Perfusion 2019; 34:584-589. [DOI: 10.1177/0267659119842056] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: In patients supported with extracorporeal membrane oxygenation, and who develop heparin-induced thrombocytopenia, there is no clear evidence to support changing to a non-heparin-coated extracorporeal membrane oxygenation circuit. Our goal was to evaluate clinical outcomes of patients who were continued on heparin-bonded circuits despite diagnosed heparin-induced thrombocytopenia. Methods: We completed a single-center retrospective study of all patients who underwent extracorporeal membrane oxygenation support from July 2008 to July 2017 and were tested heparin-induced thrombocytopenia positive while on extracorporeal membrane oxygenation support. After diagnosis of heparin-induced thrombocytopenia, mean platelet count (k/µL) was measured on consecutive days for 14 days. Results: Out of 455 patients, 14 (3.1%) had a diagnosis of heparin-induced thrombocytopenia by serotonin release assay and systemic heparin treatment was discontinued in every case. In total, 11 of the heparin-induced thrombocytopenia patients (78.6%) survived to discharge. The overall survival of all 455 extracorporeal membrane oxygenation patients was 54.1%. Platelets counts after discontinuation of systemic heparin in the heparin-induced thrombocytopenia patients increased from a mean of 59.8 k/µL at time of heparin-induced thrombocytopenia diagnosis to a mean of 280.2 k/µL at 14 days after discontinuation of heparin despite continuation of the heparin-bonded circuit. Platelet count increased in heparin-induced thrombocytopenia patients on extracorporeal membrane oxygenation support after discontinuation of systemic heparin even if maintained on the heparin-bonded circuit. Conclusion: Discontinuation of systemic heparin but continuation of heparin-coated extracorporeal membrane oxygenation circuits appeared to be an appropriate response for our extracorporeal membrane oxygenation–supported patients who developed heparin-induced thrombocytopenia. Survival in this group was not significantly different to those patients on extracorporeal membrane oxygenation without heparin-induced thrombocytopenia. Larger studies should evaluate the safety of heparin-bonded extracorporeal membrane oxygenation systems in heparin-induced thrombocytopenia patients.
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Affiliation(s)
- Dirk Pabst
- Heart and Vascular Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Center for Emergency Medicine, University Hospital Essen, Essen, Germany
| | | | - Behzad Soleimani
- Heart and Vascular Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Christoph E Brehm
- Heart and Vascular Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
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Ivetic N, Arnold DM, Smith JW, Huynh A, Kelton JG, Nazy I. A platelet viability assay (PVA) for the diagnosis of heparin-induced thrombocytopenia. Platelets 2019; 30:1017-1021. [DOI: 10.1080/09537104.2018.1562169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Nikola Ivetic
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Donald M. Arnold
- 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
| | - Angela Huynh
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - John G. Kelton
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Ishac Nazy
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
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Solanki J, Shenoy S, Downs E, Palkimas S, Goldman S, Sharma AM. Heparin-Induced Thrombocytopenia and Cardiac Surgery. Semin Thorac Cardiovasc Surg 2019; 31:335-344. [DOI: 10.1053/j.semtcvs.2018.10.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 12/16/2022]
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Fibronectin modulates formation of PF4/heparin complexes and is a potential factor for reducing risk of developing HIT. Blood 2018; 133:978-989. [PMID: 30573633 DOI: 10.1182/blood-2018-05-850370] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 12/10/2018] [Indexed: 11/20/2022] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Platelet activation assays that use "washed" platelets are more sensitive for detecting HIT antibodies than platelet-rich plasma (PRP)-based assays. Moreover, heparin-exposed patients vary considerably with respect to the risk of PF4/heparin immunization and, among antibody-positive patients, the risk of subsequent "breakthrough" of clinical HIT with manifestation of thrombocytopenia. We used washed platelets and PRP, standard laboratory HIT tests, and physicochemical methods to identify a plasma factor interfering with PF4/heparin complexes and anti-PF4/heparin antibody-platelet interaction, thus explaining differences in functional assays. To investigate a modulating risk for PF4/heparin immunization and breakthrough of HIT, we also tested 89 plasmas from 2 serosurveillance trials. Fibronectin levels were measured in 4 patient groups exhibiting different degrees of heparin-dependent immunization and expression of HIT. The heat-labile plasma protein, fibronectin, inhibited PF4 binding to platelets in a dose-dependent fashion, particularly in washed (vs PRP) systems. Fibronectin also inhibited PF4/heparin binding to platelets, anti-PF4/heparin antibody binding to PF4/heparin complexes, and anti-PF4/heparin antibody-induced platelet activation as a result of PF4/heparin complex disruption. In addition, plasma fibronectin levels increased progressively among the following 4 patient groups: enzyme-linked immunosorbent assay (ELISA)+/serotonin-release assay (SRA)+/HIT+ < ELISA+/SRA+/HIT- ∼ ELISA+/SRA-/HIT- < ELISA-/SRA-/HIT-. Altogether, these findings suggest that fibronectin interferes with PF4/heparin complex formation and anti-PF4/heparin antibody-induced platelet activation. Reduced fibronectin levels in washed platelet assays help to explain the greater sensitivity of washed platelet (vs PRP) assays for HIT. More importantly, lower plasma fibronectin levels could represent a risk factor for PF4/heparin immunization and clinical breakthrough of HIT.
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31
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Rauova L, Arepally G, Poncz M, Cines DB. Molecular and cellular pathogenesis of heparin-induced thrombocytopenia (HIT). Autoimmun Rev 2018; 17:1046-1052. [PMID: 30103043 DOI: 10.1016/j.autrev.2018.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 05/09/2018] [Indexed: 01/19/2023]
Affiliation(s)
- Lubica Rauova
- Division of Hematology, Department of Pediatrics, Childrens Hospital of Philadelphia, USA; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, USA
| | - Gowthami Arepally
- Division of Hematology, Department of Medicine, Duke University School of Medicine, USA
| | - Mortimer Poncz
- Division of Hematology, Department of Pediatrics, Childrens Hospital of Philadelphia, USA; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, USA
| | - Douglas B Cines
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, USA; Department of Medicine, University of Pennsylvania, Perelman School of Medicine, USA.
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32
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Warkentin TE. Platelet Activation Testing for Heparin-Induced Thrombocytopenia Antibodies: A Problem That Needs Fixing? Chest 2018; 150:478-80. [PMID: 27613972 DOI: 10.1016/j.chest.2016.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 04/03/2016] [Accepted: 04/04/2016] [Indexed: 11/25/2022] Open
Affiliation(s)
- Theodore E Warkentin
- Department of Pathology and Molecular Medicine, and the Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.
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33
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Sain M, Burilovic V, Tomicic M, Jelicic I. High ANTI-PF4/Heparin Antibodies Titer and Thromboses Due to Infection 9 Months After Cessation of Heparin in Hemodialyzed Patient With Heparin-Induced Thrombocytopenia. Ther Apher Dial 2018; 22:558-559. [PMID: 29856115 DOI: 10.1111/1744-9987.12699] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 03/05/2018] [Accepted: 04/02/2018] [Indexed: 11/29/2022]
Affiliation(s)
- Milenka Sain
- Department of Nephrology and Dialysis, University Hospital Center Split, Split, Croatia
| | - Vedrana Burilovic
- Department of Transfusion Medicine, University Hospital Center Split, Split, Croatia
| | - Maja Tomicic
- Department of Transfusion Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ivo Jelicic
- Department of Nephrology and Dialysis, University Hospital Center Split, Split, Croatia
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35
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Nagler M, Bakchoul T. Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost 2017; 116:823-834. [DOI: 10.1160/th16-03-0240] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 08/16/2016] [Indexed: 12/27/2022]
Abstract
SummaryA rapid diagnostic work-up is required in patients with suspected heparin-induced thrombocytopenia (HIT). However, diagnosis of HIT is challenging due to a number of practical issues and methodological limitations. Many laboratory tests and a few clinical scoring systems are available but the individual characteristics and the diagnostic accuracy of these are hard to appraise. The 4Ts score is a well evaluated clinical assessment tool with the potential to rule out HIT in many patients. Still, it requires experience and is subject to a relevant inter-observer variability. Immunoassays such as enzyme-linked immunosorbent assays or recently developed rapid assays are able to exclude HIT in a number of patients. But, accuracy of immunoassays differs depending on type of assay, threshold, antibody specificity and even manufacturer. Due to a comparatively low positive predictive value, HIT cannot be confirmed by immunoassays alone. In addition, only some of them are immediately accessible, particularly in small laboratories. While functional assays such as the serotonin release assay (SRA) and the heparin-induced platelet activation assay (HIPA) are considered as gold standard for diagnosis of HIT, they require a highly specialised laboratory. In addition, some of them are not adequately evaluated. In clinical practice, we recommend an integrated diagnostic approach combining not only clinical assessment (the 4Ts score) but immunoassays and functional assays as well. We propose a clear diagnostic algorithm supporting clinical decision-making. Furthermore, we provide an overview of all current laboratory techniques for HIT and discuss diagnostic pathways and strategies to reduce diagnostic errors, and future perspectives.
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36
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Selleng S, Selleng K. Heparin-induced thrombocytopenia in cardiac surgery and critically ill patients. Thromb Haemost 2017; 116:843-851. [DOI: 10.1160/th16-03-0230] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/16/2016] [Indexed: 11/05/2022]
Abstract
SummaryThrombocytopenia as well as anti-platelet factor 4/heparin (PF4/H) antibodies are common in cardiac surgery patients and those treated in the intensive care unit. In contrast, heparin-induced thrombocytopenia (HIT) is uncommon in these populations (∼1 % and ∼0.5 %, respectively). A stepwise approach where testing for anti-PF4/H antibodies is performed only in patients with typical clinical symptoms of HIT improves diagnostic specificity of the laboratory assays without losing sensitivity, thereby helping to avoid overdiagnosis and resulting HIT overtreatment. Short-term re-exposure to heparin, especially given intraoperatively for cardiovascular surgery, is a reasonable therapeutic option in patients with a history of HIT who subsequently test negative for HIT antibodies. Organ failure(s), enhanced bleeding risks, and other characteristics require special considerations regarding non-heparin anticoagulation: Argatroban is the alternative anticoagulant with pharmacokinetics independent of renal function, but it has a prolonged half-life in case of impaired liver function. For bivalirudin, protocols during cardiopulmonary bypass surgery are established, and it is suitable for patients with liver insufficiency. A major issue of direct thrombin inhibitors are false high activated partial thromboplastin time values in patients with comorbidities affecting prothrombin, which can result in systematic underdosing of the drugs. This is not the case for danaparoid and fondaparinux, which can be monitored by anti-factor Xa assays, but have long half-lives and no suitable antidote. This review includes also information on management of on- and off-pump cardiac surgery, ventricular assist devices, percutaneous interventions, continuous renal replacement therapy, and extracorporeal membrane oxygenation in patients with HIT.
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37
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Pollak U, Mishaly D, Kenet G, Vardi A. Heparin-induced thrombocytopenia complicating children after the Fontan procedure: Single-center experience and review of the literature. CONGENIT HEART DIS 2017; 13:16-25. [DOI: 10.1111/chd.12557] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/27/2017] [Accepted: 11/06/2017] [Indexed: 01/19/2023]
Affiliation(s)
- Uri Pollak
- Department of Pediatric Cardiac Intensive Care; The Edmond J. Safra International Congenital Heart Center, The Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center; Tel Aviv Israel
- Department of Pediatric Cardiology; The Edmond J. Safra International Congenital Heart Center, The Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center; Tel Hashomer Israel
- The Sackler Faculty of Medicine; Tel Aviv University; Tel Aviv Israel
| | - David Mishaly
- The Sackler Faculty of Medicine; Tel Aviv University; Tel Aviv Israel
- Department of Pediatric and Congenital Cardiac Surgery; The Edmond J. Safra International Congenital Heart Center, The Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center; Tel Hashomer Israel
| | - Gili Kenet
- The Sackler Faculty of Medicine; Tel Aviv University; Tel Aviv Israel
- National Hemophilia Center and Institute of Thrombosis and Hemostasis, The Chaim Sheba Medical Center; Tel Hashomer Israel
| | - Amir Vardi
- Department of Pediatric Cardiac Intensive Care; The Edmond J. Safra International Congenital Heart Center, The Edmond and Lily Safra Children's Hospital, The Chaim Sheba Medical Center; Tel Aviv Israel
- The Sackler Faculty of Medicine; Tel Aviv University; Tel Aviv Israel
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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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39
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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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Maličev E, Maček Kvanka M, Klemenc P, Rožman P. The level of heparin-induced antibodies in correlation with the result of the flow cytometric functional assay in the patients with suspected HIT. J Clin Pathol 2017; 70:1084-1087. [DOI: 10.1136/jclinpath-2017-204498] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Indexed: 02/03/2023]
Abstract
Heparin can induce the formation of antibodies against a heparin complex with a platelet factor 4 (PF4), leading to platelet activation and the development of heparin-induced thrombocytopaenia (HIT). Because screening ELISA does not discriminate between platelet activating and non-activating anti-heparin/PF4 antibodies, each positive result is confirmed by an additional functional assay. We analysed 1004 sera of patients with suspected HIT. Optical density (OD) values of ELISA-positive results were correlated with the risk for a positive result with our functional flow cytometric assay. Only 10.7% were ELISA positive and 59.8% of those were positive with the functional assay. The positive functional assay was found in 23.4% of patients with OD<1.0, in 57.7% with 1.0<OD<2.0 and in 94.1% with OD>2.0. Although our results showed that higher ELISA OD values increasethe possibility of the presence of platelet-activating anti-heparin/PF4 antibodies , there is no need for improving ELISA cut-off value for positive result.
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Salter BS, Weiner MM, Trinh MA, Heller J, Evans AS, Adams DH, Fischer GW. Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review. J Am Coll Cardiol 2017; 67:2519-32. [PMID: 27230048 DOI: 10.1016/j.jacc.2016.02.073] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/03/2016] [Accepted: 02/08/2016] [Indexed: 12/13/2022]
Abstract
Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse drug reaction to unfractionated heparin or, less commonly, to low-molecular weight heparin. In this comprehensive review, the authors highlight heparin-induced thrombocytopenia's risk factors, clinical presentation, pathophysiology, diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality.
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Affiliation(s)
- Benjamin S Salter
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York.
| | - Menachem M Weiner
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Muoi A Trinh
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Joshua Heller
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - Adam S Evans
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
| | - David H Adams
- Department of Cardiac Surgery, Mount Sinai Medical Center, New York, New York
| | - Gregory W Fischer
- Department of Anesthesiology, Mount Sinai Medical Center, New York, New York
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42
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Favaloro EJ, McCaughan G, Pasalic L. Clinical and laboratory diagnosis of heparin induced thrombocytopenia: an update. Pathology 2017; 49:346-355. [DOI: 10.1016/j.pathol.2017.02.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/17/2017] [Accepted: 02/26/2017] [Indexed: 10/19/2022]
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Platelet Count Trends and Prevalence of Heparin-Induced Thrombocytopenia in a Cohort of Extracorporeal Membrane Oxygenator Patients. Crit Care Med 2017; 44:e1031-e1037. [PMID: 27441904 DOI: 10.1097/ccm.0000000000001869] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To assess the prevalence of heparin-induced thrombocytopenia and to study platelet count trends potentially suggestive of heparin-induced thrombocytopenia in a population of extracorporeal membrane oxygenator patients. DESIGN Retrospective cohort study. SETTING A total of 926-bed teaching hospital. PATIENTS Extracorporeal membrane oxygenator patients who survived longer than 48 hours from extracorporeal membrane oxygenator initiation between January 1, 2009, and December 31, 2013. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Demographic and clinical data were collected prospectively on all extracorporeal membrane oxygenator patients. Heparin-induced thrombocytopenia testing results and platelet count variables were obtained from the electronic medical record. We used our institutional algorithm to interpret the results of heparin-induced thrombocytopenia testing. Ninety-six extracorporeal membrane oxygenator patients met the inclusion criteria. Eight patients met the algorithm criteria for heparin-induced thrombocytopenia diagnosis and seven of those had documented thromboembolic event while on extracorporeal membrane oxygenator (prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia related thrombosis, 8.3 and 7.3, respectively). Heparin-induced thrombocytopenia positive patients were younger; all underwent venoarterial extracorporeal membrane oxygenator; spent more hours on extracorporeal membrane oxygenator; had significantly higher heparin-induced thrombocytopenia enzyme-linked immunosorbent assays optical density; had a higher prevalence of thromboembolic events and reached platelet count nadir later. There was no difference in mortality between heparin-induced thrombocytopenia positive and negative patients. Comparison of platelet count trends revealed that there was no statistically significant difference between the predefined study groups. CONCLUSIONS Prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia-related thrombosis among extracorporeal membrane oxygenator patients at our institution is relatively high. Using platelet count trends to guide decision to test for heparin-induced thrombocytopenia is not an optimal strategy in extracorporeal membrane oxygenator patients. Without a validated pretest probability clinical score, serosurveillance in a defined high-risk group of extracorporeal membrane oxygenator patients may be needed.
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Abstract
Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate cellular FcγRIIA on platelets and monocytes to propagate a hypercoagulable state culminating in life-threatening thrombosis. It is now recognized that anti-PF4/heparin antibodies develop commonly after heparin exposure, but only a subset of sensitized patients progress to life-threatening complications of thrombocytopenia and thrombosis. Recent scientific developments have clarified mechanisms underlying PF4/heparin immunogenicity, disease susceptibility, and clinical manifestations of disease. Insights from clinical and laboratory findings have also been recently harnessed for disease prevention. This review will summarize our current understanding of HIT by reviewing pathogenesis, essential clinical and laboratory features, and management.
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45
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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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Nagler M, Cuker A. Profile of Instrumentation Laboratory's HemosIL® AcuStar HIT-Ab(PF4-H) assay for diagnosis of heparin-induced thrombocytopenia. Expert Rev Mol Diagn 2017; 17:419-426. [PMID: 28271738 DOI: 10.1080/14737159.2017.1304213] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Immunoassays play an essential role in the diagnosis of heparin-induced thrombocytopenia (HIT). The objective of this article is to review HemosIL® AcuStar HIT-Ab(PF4-H) (Instrumentation Laboratory, Bedford, MA, USA), a new chemiluminescent immunoassay for HIT. Areas covered: The authors searched the published literature for evaluation studies of HemosIL® AcuStar HIT-Ab(PF4-H) and sought information from the manufacturer. In this paper, the authors discuss the analytical principle and technical aspects of the assay; describe its diagnostic performance in validation studies; report on its reproducibility, cost-effectiveness, and regulatory status; and discuss the implications of the assay on clinical practice and means of integrating it in diagnostic pathways. HemosIL® AcuStar HIT-Ab(PF4-H) is compared with other rapid assays and widely used enzyme-linked immunoassays for the diagnosis of HIT. Expert commentary: HemosIL® AcuStar HIT-Ab(PF4-H) is automatable, can be performed 24 h per day, offers a rapid turnaround time, and appears to have favorable diagnostic accuracy, particularly at thresholds above that listed in the label. These advantages could lead to improved patient outcomes through rapid provision of results at the point of care, enhancing the accuracy of initial diagnosis.
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Affiliation(s)
- Michael Nagler
- a Department of Haematology and Central Haematology Laboratory , University of Bern , Bern , Switzerland
| | - Adam Cuker
- b Departments of Medicine and Pathology & Laboratory Medicine , University of Pennsylvania , Philadelphia , PA , USA
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Farm M, Bakchoul T, Frisk T, Althaus K, Odenrick A, Norberg EM, Berndtsson M, Antovic JP. Evaluation of a diagnostic algorithm for Heparin-Induced Thrombocytopenia. Thromb Res 2017; 152:77-81. [PMID: 28262567 DOI: 10.1016/j.thromres.2017.02.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/12/2017] [Accepted: 02/16/2017] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Heparin-Induced Thrombocytopenia (HIT) is a rare but serious immune-mediated complication of heparin treatment. HIT is characterized by an acute, transient prothrombotic state combined with thrombocytopenia and is caused by platelet-activating IgG antibodies that bind to complexes of heparin and platelet factor 4. The diagnosis of HIT relies on clinical presentation and the demonstration of HIT antibodies. One approach to improve the efficacy of laboratory analysis is to use a diagnostic algorithm. AIM To evaluate one diagnostic algorithm for HIT where the 4 T's clinical risk score is combined with immunochemical and/or functional assays. MATERIALS AND METHODS The quality of the diagnostic algorithm was retrospectively evaluated in 101 patients with suspected HIT. Laboratory results obtained from the diagnostic algorithm were compared to Heparin-Induced Platelet Aggregation (HIPA) and clinico-pathological evaluation of patients' medical records. RESULTS We found that the algorithm had a diagnostic efficacy of 94%, with specificity of 94% and sensitivity 94%. Positive likelihood ratio (LR+) was 16.0, and the negative likelihood ratio (LR-) 15.5. The efficacy of PaGIA (n=95) was 0.46, and IgG-specific HPF4-abELISA (n=54) was 0.87. CONCLUSIONS The diagnostic algorithm for HIT is sufficiently accurate and leads to in overall faster results and decreased cost of analysis. The weakest link of the algorithm is the risk of miscalculated 4T's scores, which is inevitably exacerbated by the insufficient experience most clinicians have with HIT. This highlights the importance of clear instructions from the laboratory and coagulation clinic.
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Affiliation(s)
- Maria Farm
- Clinical Chemistry, Karolinska University Hospital, Molecular Medicine & Surgery, Karolinska Institutet L7:00, 171 76 Stockholm, Sweden.
| | - Tamam Bakchoul
- Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald Ernst-Moritz-Arndt University Greifswald, Klinikum Sauerbruckstrasse, 17487 Greifswald, Germany.
| | - Tony Frisk
- Coagulation Medicine, Karolinska University Hospital D1:02, 171 76 Stockholm, Sweden.
| | - Karina Althaus
- Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald Ernst-Moritz-Arndt University Greifswald, Klinikum Sauerbruckstrasse, 17487 Greifswald, Germany.
| | - Alice Odenrick
- Clinical Chemistry, Karolinska University Hospital, Molecular Medicine & Surgery, Karolinska Institutet L7:00, 171 76 Stockholm, Sweden.
| | - Eva-Marie Norberg
- Clinical Chemistry, Karolinska University Hospital, Molecular Medicine & Surgery, Karolinska Institutet L7:00, 171 76 Stockholm, Sweden.
| | - Maria Berndtsson
- Clinical Chemistry, Karolinska University Hospital, Molecular Medicine & Surgery, Karolinska Institutet L7:00, 171 76 Stockholm, Sweden.
| | - Jovan P Antovic
- Clinical Chemistry, Karolinska University Hospital, Molecular Medicine & Surgery, Karolinska Institutet L7:00, 171 76 Stockholm, Sweden.
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Abstract
Due to familiarity, short half-life, ease of monitoring, and the availability of a reversal agent, heparin remains the anticoagulant of choice for cardiac operations requiring cardiopulmonary bypass (CPB). However, occasionally patients require CPB but should not receive heparin, most often because of acute or subacute heparin-induced thrombocytopenia (HIT). In these cases, if it is not feasible to wait for the disappearance of HIT antibodies, an alternative anticoagulant must be selected. A number of non-heparin anticoagulant options have been explored. However, current recommendations suggest the use of a direct thrombin inhibitor such as bivalirudin. This review describes the use of heparin alternatives for the conduct of CPB with a focus on the direct thrombin inhibitors.
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Onwuemene O, Arepally GM. Heparin-induced thrombocytopenia: research and clinical updates. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2016; 2016:262-268. [PMID: 27913490 PMCID: PMC6142447 DOI: 10.1182/asheducation-2016.1.262] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Heparin-induced thrombocytopenia (HIT) remains an important diagnosis to consider in hospitalized patients developing thrombocytopenia. HIT is an immune-mediated prothrombotic disorder caused by antibodies to platelet factor 4 (PF4) and heparin. Recent basic scientific studies have advanced our understanding of disease pathogenesis through studies of the PF4/heparin structure, immune mechanisms, and cellular basis of thrombosis. Clinical advances have also occurred in areas of HIT prevention, description of disease variants, and diagnostic strategies. Emerging anticoagulants with the potential to change HIT treatment are evolving, although with limited data. This review will provide a current perspective on HIT pathogenesis, disease features, diagnostic strategies, and role of emerging therapies for the management of HIT.
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Affiliation(s)
- Oluwatoyosi Onwuemene
- Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Gowthami M Arepally
- Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC
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Mya HT, Tay HM, Gan SW, Surendran S, Yeang SH, Lim CC, Choong H, Lee LH, Ng HJ. Screening frequency, incidence and pattern of heparin-induced thrombocytopenia syndrome at a large tertiary institution. Int J Hematol 2016; 104:92-8. [DOI: 10.1007/s12185-016-2013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/08/2016] [Accepted: 03/08/2016] [Indexed: 01/04/2023]
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