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1
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Parks AL, Stevens SM, Woller SC. Anticoagulant therapy in renal insufficiency theme: Anticoagulation in complex situations. Thromb Res 2024; 241:109097. [PMID: 39094333 PMCID: PMC11418398 DOI: 10.1016/j.thromres.2024.109097] [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: 12/08/2023] [Revised: 04/12/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024]
Abstract
Many patients with impaired renal function have concurrent indications for anticoagulant therapy, including atrial fibrillation and venous thromboembolism. For mild chronic kidney disease, data from clinical trials and existing guidelines can be applied to clinical management. The benefits and harms of anticoagulation therapy in patients with more advanced renal impairment are nuanced, as both thrombotic and bleeding risk are increased. Until recently, data regarding anticoagulants in severe renal impairment were primarily observational, but emerging evidence includes a few small clinical trials and the emergence of novel agents hypothesized to have improved efficacy and safety in this population. In this review, we summarize existing data on anticoagulation in patients with chronic kidney disease. We suggest a framework for anticoagulation decision-making in the burgeoning worldwide population of patients with chronic kidney disease.
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Affiliation(s)
- Anna L Parks
- Division of Hematology & Hematologic Malignancies, Department of Internal Medicine, University of Utah, United States of America.
| | - Scott M Stevens
- Department of Medicine, Intermountain Medical Center, Intermountain Health, United States of America; Division of General Internal Medicine, Department of Internal Medicine, University of Utah, United States of America
| | - Scott C Woller
- Department of Medicine, Intermountain Medical Center, Intermountain Health, United States of America; Division of General Internal Medicine, Department of Internal Medicine, University of Utah, United States of America
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2
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Sukumaran M, Cantrell DR, D'Agostino C, Jahromi BS, Ansari SA, Potts MB. Bivalirudin as a substitute for heparin in neurointervention for patients with heparin-induced thrombocytopenia. J Stroke Cerebrovasc Dis 2024; 33:107310. [PMID: 38636321 DOI: 10.1016/j.jstrokecerebrovasdis.2023.107310] [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: 03/20/2023] [Revised: 07/20/2023] [Accepted: 08/15/2023] [Indexed: 04/20/2024] Open
Abstract
OBJECTIVES Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients. RESULTS Bivalirudin was safely and effectively used in the case reported, with no thrombotic or hemorrhagic complications. Our literature review revealed a paucity of studies on the use of heparin alternatives, including bivalirudin, in neuroendovascular procedures in patients with heparin-induced thrombocytopenia. CONCLUSIONS Heparin-induced thrombocytopenia is an important iatrogenic disease process in patients undergoing neuroendovascular procedures, and developing protocols to diagnose and manage heparin-induced thrombocytopenia is important for healthcare systems. While further research needs to be done to establish the full range of anticoagulation options to substitute for heparin, our case indicates bivalirudin as a potential candidate.
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Affiliation(s)
- Madhav Sukumaran
- Clinical Fellow, Cerebrovascular and Endovascular Neurosurgery, Department of Neurosurgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02215, United States.
| | - Donald R Cantrell
- Departments of Radiology and Neurology, Northwestern Medicine, United States
| | | | - Babak S Jahromi
- Departments of Neurological Surgery, Neurology, and Radiology, Northwestern Medicine, United States
| | - Sameer A Ansari
- Departments of Neurological Surgery, Neurology, and Radiology, Northwestern Medicine, United States
| | - Matthew B Potts
- Departments of Neurological Surgery, Neurology, and Radiology, Northwestern Medicine, United States
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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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Abidi E, El Nekidy WS, Atallah B, Al Zaman K, Ghisulal P, El Lababidi R, Manla Y, Ahmed I, Sadik Z, Taha A, Askalany M, Cherfan A, Helal M, Sultan S, Khan U, Kakar V, Mallat J. Sustaining Life versus Altering Life-Saving Drugs: Insights to Explain the Paradoxical Effect of Extracorporeal Membrane Oxygenation on Drugs. J Clin Med 2023; 12:3748. [PMID: 37297946 PMCID: PMC10253730 DOI: 10.3390/jcm12113748] [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: 04/22/2023] [Revised: 05/17/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
There has been a substantial increase in the use of extracorporeal membrane oxygenation (ECMO) support in critically ill adults. Understanding the complex changes that could affect drugs' pharmacokinetics (PK) and pharmacodynamics (PD) is of suitable need. Therefore, critically ill patients on ECMO represent a challenging clinical situation to manage pharmacotherapy. Thus, clinicians' ability to predict PK and PD alterations within this complex clinical context is fundamental to ensure further optimal and, sometimes, individualized therapeutic plans that balance clinical outcomes with the minimum drug adverse events. Although ECMO remains an irreplaceable extracorporeal technology, and despite the resurgence in its use for respiratory and cardiac failures, especially in the era of the COVID-19 pandemic, scarce data exist on both its effect on the most commonly used drugs and their relative management to achieve the best therapeutic outcomes. The goal of this review is to provide key information about some evidence-based PK alterations of the drugs used in an ECMO setting and their monitoring.
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Affiliation(s)
- Emna Abidi
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Wasim S. El Nekidy
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
| | - Bassam Atallah
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
| | - Khaled Al Zaman
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Praveen Ghisulal
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Rania El Lababidi
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Yosef Manla
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Ihab Ahmed
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Ziad Sadik
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Ahmed Taha
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Mohamed Askalany
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Antoine Cherfan
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Mohamed Helal
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Saad Sultan
- Department of Pharmacy, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates; (E.A.)
| | - Umar Khan
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Vivek Kakar
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
| | - Jihad Mallat
- Cleveland Clinic Lerner, College of Medicine, Cleveland, OH 44195, USA
- Critical Care Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi P.O. Box 112412, United Arab Emirates
- Faculty of Medicine, Normandy University, UNICAEN, ED 497 Caen, France
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Kashir J, Ambia AR, Shafqat A, Sajid MR, AlKattan K, Yaqinuddin A. Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT). J Leukoc Biol 2022; 111:725-734. [PMID: 34467562 PMCID: PMC8667645 DOI: 10.1002/jlb.5covr0621-320rr] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/17/2022] Open
Abstract
Following on from the devastating spread of COVID-19, a major global priority has been the production, procurement, and distribution of effective vaccines to ensure that the global pandemic reaches an end. However, concerns were raised about worrying side effects, particularly the occurrence of thrombosis and thrombocytopenia after administration of the Oxford/AstraZeneca and Johnson & Johnson's Janssen COVID-19 vaccine, in a phenomenon being termed vaccine-induced thrombotic thrombocytopenia (VITT). Similar to heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, purportedly leading to neutrophil-platelet aggregate formation. Although thrombosis has also been a common association with COVID-19, the precise molecular mechanisms governing its occurrence are yet to be established. Recently, increasing evidence highlights the NLRP3 (NOD-like, leucine-rich repeat domains, and pyrin domain-containing protein) inflammasome complex along with IL-1β and effete neutrophils producing neutrophil extracellular traps (NETs) through NETosis. Herein, we propose and discuss that perhaps the incidence of VITT may be due to inflammatory reactions mediated via IL-1β/NLRP3 inflammasome activation and consequent overproduction of NETs, where similar autoimmune mechanisms are observed in HIT. We also discuss avenues by which such modalities could be treated to prevent the occurrence of adverse events and ensure vaccine rollouts remain safe and on target to end the current pandemic.
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Affiliation(s)
- Junaid Kashir
- Alfaisal UniversityRiyadhKingdom of Saudi Arabia
- Department of Comparative MedicineKing Faisal Specialist Hospital and Research CenterRiyadhKingdom of Saudi Arabia
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Laner-Plamberger S, Oeller M, Rohde E, Schallmoser K, Strunk D. Heparin and Derivatives for Advanced Cell Therapies. Int J Mol Sci 2021; 22:12041. [PMID: 34769471 PMCID: PMC8584295 DOI: 10.3390/ijms222112041] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 12/27/2022] Open
Abstract
Heparin and its derivatives are saving thousands of human lives annually, by successfully preventing and treating thromboembolic events. Although the mode of action during anticoagulation is well studied, their influence on cell behavior is not fully understood as is the risk of bleeding and other side effects. New applications in regenerative medicine have evolved supporting production of cell-based therapeutics or as a substrate for creating functionalized matrices in biotechnology. The currently resurgent interest in heparins is related to the expected combined anti-inflammatory, anti-thrombotic and anti-viral action against COVID-19. Based on a concise summary of key biochemical and clinical data, this review summarizes the impact for manufacturing and application of cell therapeutics and highlights the need for discriminating the different heparins.
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Affiliation(s)
- Sandra Laner-Plamberger
- Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria; (S.L.-P.); (M.O.); (E.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria;
| | - Michaela Oeller
- Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria; (S.L.-P.); (M.O.); (E.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria;
| | - Eva Rohde
- Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria; (S.L.-P.); (M.O.); (E.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria;
| | - Katharina Schallmoser
- Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria; (S.L.-P.); (M.O.); (E.R.)
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria;
| | - Dirk Strunk
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria;
- Cell Therapy Institute, Paracelsus Medical University of Salzburg, 5020 Salzburg, Austria
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7
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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: 38] [Impact Index Per Article: 9.5] [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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8
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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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9
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Kato C, Oakes M, Kim M, Desai A, Olson SR, Raghunathan V, Shatzel JJ. Anticoagulation strategies in extracorporeal circulatory devices in adult populations. Eur J Haematol 2020; 106:19-31. [PMID: 32946632 DOI: 10.1111/ejh.13520] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/27/2020] [Accepted: 08/31/2020] [Indexed: 12/16/2022]
Abstract
Extracorporeal circulatory devices such as hemodialysis and extracorporeal membrane oxygenation can be lifesaving; however, they are also prone to pathologic events including device failure, venous and arterial thrombosis, hemorrhage, and an accelerated risk for atherosclerotic disease due to interactions between blood components and device surfaces of varying biocompatibility. While extracorporeal devices may be used acutely for limited periods of time (eg, extracorporeal membrane oxygenation, continuous venovenous hemofiltration, therapeutic apheresis), some patients require chronic use of these technologies (eg, intermittent hemodialysis and left ventricular assist devices). Given the substantial thrombotic risks associated with extracorporeal devices, multiple antiplatelet and anticoagulation strategies-including unfractionated heparin, low-molecular-weight heparin, citrate, direct thrombin inhibitors, and direct oral anticoagulants, have been used to mitigate the thrombotic milieu within the patient and device. In the following manuscript, we outline the current data on anticoagulation strategies for commonly used extracorporeal circulatory devices, highlighting the potential benefits and complications involved with each.
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Affiliation(s)
- Catherine Kato
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Michael Oakes
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Morris Kim
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Anish Desai
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Sven R Olson
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Vikram Raghunathan
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - Joseph J Shatzel
- Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
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10
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Riker RR, May TL, Fraser GL, Gagnon DJ, Bandara M, Zemrak WR, Seder DB. Heparin-induced thrombocytopenia with thrombosis in COVID-19 adult respiratory distress syndrome. Res Pract Thromb Haemost 2020; 4:936-941. [PMID: 32685905 PMCID: PMC7276726 DOI: 10.1002/rth2.12390] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/08/2020] [Accepted: 05/13/2020] [Indexed: 01/08/2023] Open
Abstract
Early reports of coronavirus disease 2019 (COVID-19) clinical features describe a hypercoagulable state, and recent guidelines recommend prophylactic anticoagulation for patients with COVID-19 with low-molecular-weight heparin, but this would be contraindicated in the presence of heparin-induced thrombocytopenia (HIT). We address the key clinical question whether HIT is also present during COVID-19. We report 3 cases of thrombocytopenia with antiplatelet factor 4 antibodies among 16 intubated patients with COVID-19 with adult respiratory distress syndrome, a higher-than-expected incidence of 19%. Each patient had evidence of thrombosis (pulmonary embolism, upper extremity venous thromboses, and skin necrosis, respectively). The serotonin release assay confirmed HIT in 1 case, and 2 cases were negative. We believe this is the first reported case of HIT during the COVID-19 pandemic. Recognition that the thrombocytopenia represented HIT in the confirmed case was delayed. We recommend clinicians monitor platelet counts closely during heparin therapy, with a low threshold to evaluate for HIT.
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A "Catastrophic" Heparin-Induced Thrombocytopenia. Case Rep Med 2020; 2020:6985020. [PMID: 32328108 PMCID: PMC7174963 DOI: 10.1155/2020/6985020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/31/2020] [Indexed: 12/31/2022] Open
Abstract
Background Heparin-induced thrombocytopenia (HIT) is a transient, antibody-mediated thrombocytopenia syndrome that usually follows exposure to unfractioned heparin (UFH) or low-molecular-weight heparin (LMWH). In contrast to other pathological conditions which lead to thrombocytopenia and bleeding complications, HIT results in a paradoxical prothrombotic state. It is caused by antibodies directed to complexes containing UFH or LMWH and a self-platelet protein: the platelet factor 4 (PF4). The heparin-PF4 immune complex leads to activation of platelets, monocytes, and endothelial cells which release procoagulant proteins and tissue factor with subsequent blood coagulation activation. Case Report. We describe the case of a woman undergone to knee replacement and affected by urosepsis who developed a HIT after exposure to enoxaparin. The thrombotic burden was very impressive involving the arterial and venous cerebral vessel and the venous pulmonary, hepatic, and inferior legs vascular beds. The patient was successfully treated with fondaparinux without recurrent thrombosis or bleeding. The clinical scenario could be named “catastrophic HIT” like the catastrophic antiphospholipid syndrome since they have a similar pathogenetic mechanism involving both platelets and monocytes procoagulant activities and a similar clinical manifestation with a life-threatening multiple arterial and/or venous thromboses. Conclusion Patients presenting with HIT could show a very impressive thrombotic burden resembling to that of the catastrophic antiphospholipid syndrome. A careful differential diagnosis should be made towards other pathological conditions which lead to thrombocytopenia to avoid an unnecessary and potentially harmful platelet transfusion. Although fondaparinux is off-label, its use in patients with HIT is simple and seems to be effective.
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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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13
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Prospective Evaluation of a Rapid Functional Assay for Heparin-Induced Thrombocytopenia Diagnosis in Critically Ill Patients. Crit Care Med 2020; 47:353-359. [PMID: 30507843 DOI: 10.1097/ccm.0000000000003574] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Overdiagnosis of heparin-induced thrombocytopenia remains an unresolved issue in the ICU leading to the unjustified switch from heparin to alternative anticoagulants or delays in anticoagulation. Platelet function assays significantly improve the specificity of heparin-induced thrombocytopenia diagnosis, but they are not readily available, involve technical difficulties and have a long turnaround time. We evaluated the performance of a rapid and easy to perform functional assay for heparin-induced thrombocytopenia diagnosis in ICU patients, known as "heparin-induced multiple electrode aggregometry." DESIGN In this observational prospective study patients were tested with the immunoglobulin G enzyme-linked immunosorbent assay, the serotonin release assay and heparin-induced multiple electrode aggregometry. Heparin-induced multiple electrode aggregometry was assessed against heparin-induced thrombocytopenia diagnosis (clinical picture in favor, serotonin release assay, and immunoglobulin G enzyme-linked immunosorbent assay positive) and serotonin release assay. SETTING Medical or surgical ICU of 35 medical centers. PATIENTS Patients suspected for heparin-induced thrombocytopenia hospitalized in medical or surgical ICU from January 2013 to May 2013. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Heparin-induced thrombocytopenia diagnosis was retained in 12 patients (14%). Using heparin-induced thrombocytopenia diagnosis as reference, heparin-induced multiple electrode aggregometry showed an excellent negative predictive value and sensitivity, at 98% and 92% respectively. Its positive predictive value and specificity were 100%. Receiver operating characteristic analysis with the serotonin release assay as reference showed an optimal heparin-induced multiple electrode aggregometry cut-off at 1,300 AU × minutes (specificity, 100%; sensitivity, 90%; area under the curve, 0.98; 95% CI, 0.95-1.0). The Kappa coefficient between heparin-induced multiple electrode aggregometry and the serotonin release assay was at 0.90%. CONCLUSIONS Heparin-induced multiple electrode aggregometry performed very well in heparin-induced thrombocytopenia diagnosis in ICU patients and agreed with the gold standard test for heparin-induced thrombocytopenia diagnosis, the serotonin release assay. Heparin-induced multiple electrode aggregometry is a reliable and rapid platelet functional assay that could decrease heparin-induced thrombocytopenia overdiagnosis in the ICU setting.
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Abstract
Evaluating, diagnosing, and managing patients with consumptive thrombocytopenia is challenging because of the overlapping nature of many of the diseases that reduce platelet counts. Immune thrombocytopenia (and its variations), drug-induced immune thrombocytopenia, and heparin-induced thrombocytopenia result from autoimmune antibody-mediated destruction of platelets. Thrombotic thrombocytopenia (both congenital and acquired) and the hemolytic uremic syndromes (both typical and atypical) are thrombotic microangiopathies associated with platelet aggregation and consumption along with anemia and renal dysfunction. Rapid history taking, physical assessment, and laboratory evaluation are crucial to accurately managing patients with these disorders. Platelet-associated coagulopathies are infrequently encountered by most providers, and limited exposure to these types of patients, combined with the wide variety of treatment options for reversing bleeding or thrombotic sequelae, makes management difficult. This article reviews the pathophysiology, patient presentation, diagnostic testing, and specific management strategies and challenges of these thrombocytopenias.
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Affiliation(s)
- Thomas A VanDruff
- Thomas A. VanDruff is Critical Care Nurse Practitioner, PMA Health at the Virginia Hospital Center, 1625 North George Mason Drive, Arlington, VA 22205
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15
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Zheng Y, Zhu W, Haribhai D, Williams CB, Aster RH, Wen R, Wang D. Regulatory T Cells Control PF4/Heparin Antibody Production in Mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2019; 203:1786-1792. [PMID: 31471526 PMCID: PMC6944762 DOI: 10.4049/jimmunol.1900196] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 07/31/2019] [Indexed: 11/19/2022]
Abstract
Heparin-induced thrombocytopenia is a relatively common drug-induced immune disorder that can have life-threatening consequences for affected patients. Immune complexes consisting of heparin, platelet factor 4 (PF4), and PF4/heparin-reactive Abs are central to the pathogenesis of heparin-induced thrombocytopenia. Regulatory T (Treg) cells are a subpopulation of CD4 T cells that play a key role in regulating immune responses, but their role in controlling PF4/heparin-specific Ab production is unknown. In the studies described in this article, we found that Foxp3-deficient mice lacking functional Treg cells spontaneously produced PF4/heparin-specific Abs. Following transplantation with bone marrow cells from Foxp3-deficient but not wild-type mice, Rag1-deficient recipients also produced PF4/heparin-specific Abs spontaneously. Adoptively transferred Treg cells prevented spontaneous production of PF4/heparin-specific Abs in Foxp3-deficient mice and inhibited PF4/heparin complex-induced production of PF4/heparin-specific IgGs in wild-type mice. Treg cells suppress immune responses mainly through releasing anti-inflammatory cytokines, such as IL-10. IL-10-deficient mice spontaneously produced PF4/heparin-specific Abs. Moreover, bone marrow chimeric mice with CD4 T cell-specific deletion of IL-10 increased PF4/heparin-specific IgG production upon PF4/heparin complex challenge. Short-term IL-10 administration suppresses PF4/heparin-specific IgG production in wild-type mice. Taken together, these findings demonstrate that Treg cells play an important role in suppressing PF4/heparin-specific Ab production.
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Affiliation(s)
- Yongwei Zheng
- Blood Research Institute, Versiti, Milwaukee, WI 53226
| | - Wen Zhu
- Blood Research Institute, Versiti, Milwaukee, WI 53226
| | - Dipica Haribhai
- Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and
| | - Calvin B Williams
- Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and
| | | | - Renren Wen
- Blood Research Institute, Versiti, Milwaukee, WI 53226
| | - Demin Wang
- Blood Research Institute, Versiti, Milwaukee, WI 53226;
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226
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16
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Laliberte B, Reed BN. Use of an argatroban-based purge solution in a percutaneous ventricular assist device. Am J Health Syst Pharm 2019; 74:e163-e169. [PMID: 28438820 DOI: 10.2146/ajhp160212] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The use of an argatroban-based percutaneous ventricular assist device (pVAD) purge solution in a patient with suspected heparin-induced thrombocytopenia (HIT) is described. SUMMARY A 70-year-old woman in cardiogenic shock was admitted to a coronary care unit after being discovered unresponsive at home. A transthoracic echocardiogram revealed a low ejection fraction and findings consistent with takotsubo cardiomyopathy. Administration of multiple inotropes and vasopressors was initially required for hemodynamic support. The patient was implanted with an Impella pVAD (Abiomed, Inc., Danvers, MA) using a heparin-based purge solution; an i.v. heparin infusion was initiated for supplemental systemic anticoagulation. Over the next 24 hours, the patient's platelet count decreased from 168,000 to 37,000 cells/μL. Given a differential diagnosis that included HIT, the patient was transitioned to an argatroban-based purge solution. Due to prolonged activated partial thromboplastin times, a systemic argatroban infusion was not initiated, and the patient remained fully anticoagulated throughout pVAD support with only the argatroban-based purge solution. An HIT antibody test was negative. On hospitalization day 9 (day 6 of pVAD support with argatroban use), the patient became hemodynamically stable and was weaned off pVAD support. Three days later, the platelet count had recovered to 117,000 cells/μL (from a nadir of 21,000 cells/μL). During pVAD support, the patient developed hemolytic anemia with minimal bleeding complications. CONCLUSION Argatroban was used as a purge solution anticoagulant in a patient with an Impella pVAD and found to be a safe and effective alternative to heparin.
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Affiliation(s)
| | - Brent N Reed
- Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD.
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17
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Laner-Plamberger S, Oeller M, Poupardin R, Krisch L, Hochmann S, Kalathur R, Pachler K, Kreutzer C, Erdmann G, Rohde E, Strunk D, Schallmoser K. Heparin Differentially Impacts Gene Expression of Stromal Cells from Various Tissues. Sci Rep 2019; 9:7258. [PMID: 31076619 PMCID: PMC6510770 DOI: 10.1038/s41598-019-43700-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 04/29/2019] [Indexed: 12/11/2022] Open
Abstract
Pooled human platelet lysate (pHPL) is increasingly used as replacement of animal serum for manufacturing of stromal cell therapeutics. Porcine heparin is commonly applied to avoid clotting of pHPL-supplemented medium but the influence of heparin on cell behavior is still unclear. Aim of this study was to investigate cellular uptake of heparin by fluoresceinamine-labeling and its impact on expression of genes, proteins and function of human stromal cells derived from bone marrow (BM), umbilical cord (UC) and white adipose tissue (WAT). Cells were isolated and propagated using various pHPL-supplemented media with or without heparin. Flow cytometry and immunocytochemistry showed differential cellular internalization and lysosomal accumulation of heparin. Transcriptome profiling revealed regulation of distinct gene sets by heparin including signaling cascades involved in proliferation, cell adhesion, apoptosis, inflammation and angiogenesis, depending on stromal cell origin. The influence of heparin on the WNT, PDGF, NOTCH and TGFbeta signaling pathways was further analyzed by a bead-based western blot revealing most alterations in BM-derived stromal cells. Despite these observations heparin had no substantial effect on long-term proliferation and in vitro tri-lineage differentiation of stromal cells, indicating compatibility for clinically applied cell products.
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Affiliation(s)
- Sandra Laner-Plamberger
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Michaela Oeller
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Rodolphe Poupardin
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Cell Therapy Institute, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Linda Krisch
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Sarah Hochmann
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Cell Therapy Institute, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Ravi Kalathur
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Cell Therapy Institute, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Department for Biomedicine, University of Basel, Basel, Switzerland
| | - Karin Pachler
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,GMP Unit, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Christina Kreutzer
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Institute for Experimental Neuroregeneration, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | | | - Eva Rohde
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Dirk Strunk
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria.,Cell Therapy Institute, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Katharina Schallmoser
- Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University of Salzburg, Salzburg, Austria. .,Department of Transfusion Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria.
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18
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Perdomo J, Leung HHL, Ahmadi Z, Yan F, Chong JJH, Passam FH, Chong BH. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun 2019; 10:1322. [PMID: 30899022 PMCID: PMC6428879 DOI: 10.1038/s41467-019-09160-7] [Citation(s) in RCA: 291] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/21/2019] [Indexed: 01/15/2023] Open
Abstract
Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies. The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
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Affiliation(s)
- José Perdomo
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Halina H L Leung
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Zohra Ahmadi
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Feng Yan
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - James J H Chong
- Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.,Centre for Heart Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia.,Department of Cardiology, Westmead Hospital, Sydney, NSW, Australia.,Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia
| | - Freda H Passam
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Beng H Chong
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. .,New South Wales Health Pathology, St George and Sutherland Hospitals, Sydney, NSW, Australia.
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19
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Gallo T, Curry SC, Padilla-Jones A, Heise CW, Ramos KS, Woosley RL, Raschke RA. A computerized scoring system to improve assessment of heparin-induced thrombocytopenia risk. J Thromb Haemost 2019; 17:383-388. [PMID: 30552743 DOI: 10.1111/jth.14359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Indexed: 11/27/2022]
Abstract
Essentials Current risk scores for heparin-induced thrombocytopenia (HIT) are not computer-friendly. We compared a new computerized risk score with the 4Ts score in a large healthcare system. The computerized risk score agrees with the 4Ts score 85% of the time. The new score could potentially improve HIT diagnosis via incorporation into decision support. SUMMARY: Background (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The 4Ts score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation. Objectives Our main objective was to develop an HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified as being at risk for HIT. Methods We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system with that of a clinically calculated 4Ts score. We took a 4Ts score of ≥ 4 as the gold standard to determine whether HIT diagnostic testing should be performed. Results The best cutoff point of the HIT-CR score was a score of 3, which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% confidence interval 0.57-0.81). Ninety per cent of patients with 4Ts score of ≥ 4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT. Conclusion The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT.
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Affiliation(s)
- T Gallo
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Phoenix, AZ, USA
| | - S C Curry
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - A Padilla-Jones
- Banner Research Institute, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - C W Heise
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
- Department of Medical Toxicology, Banner - University Medical Center Phoenix, Phoenix, AZ, USA
| | - K S Ramos
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - R L Woosley
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - R A Raschke
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
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20
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Kelton JG, Vrbensky JR, Arnold DM. How do we diagnose immune thrombocytopenia in 2018? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2018; 2018:561-567. [PMID: 30504358 PMCID: PMC6245958 DOI: 10.1182/asheducation-2018.1.561] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
In this report, we will review the various clinical and laboratory approaches to diagnosing immune thrombocytopenia (ITP), with a focus on its laboratory diagnosis. We will also summarize the results from a number of laboratories that have applied techniques to detect anti-platelet autoantibodies as diagnostic tests for ITP. Although there is considerable variability in methods among laboratories, there is general agreement that platelet autoantibody testing has a high specificity but low sensitivity. This suggests several possibilities: (1) the ideal test for ITP has yet to be developed, (2) current test methods need to be improved, or (3) ITP is the clinical expression of a variety of thrombocytopenic disorders with different underlying mechanisms. Even the clinical diagnosis of ITP is complex, and experienced clinicians do not always agree on whether a particular patient has ITP. Improvements in the diagnostic approach to ITP are necessary to improve the management of this disorder.
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Affiliation(s)
- John G. Kelton
- Michael G. DeGroote School of Medicine, Department of Medicine and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- Michael G. DeGroote Initiative for Innovation in Healthcare, McMaster University, Hamilton, ON, Canada
| | - John R. Vrbensky
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Donald M. Arnold
- Michael G. DeGroote School of Medicine, Department of Medicine and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
- McMaster Centre for Transfusion Research, Hamilton, ON, Canada; and
- Canadian Blood Services, Hamilton, ON, Canada
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21
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He Y, He H, Liu D, Long Y, Su L, Cheng W. Fondaparinux in a critically Ill patient with heparin-induced thrombocytopenia: A case report. Medicine (Baltimore) 2018; 97:e12236. [PMID: 30212955 PMCID: PMC6156017 DOI: 10.1097/md.0000000000012236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/14/2018] [Indexed: 11/25/2022] Open
Abstract
RATIONALE Fondaparinux, as a factor Xa-inhibitor, is used off label to manage heparin-induced thrombocytopenia (HIT), but little experience with HIT patients has been reported in the literature. Moreover, the use of fondaparinux for full anticoagulation in critically ill patients with HIT and renal insufficiency is limited. PATIENT CONCERNS A trauma patient, who had received low molecular weight heparin (LMWH) and heparin to treat venous thromboembolism, developed thrombocytopenia and multiple organ dysfunction in the intensive care unit (ICU). Also, her deep venous thromboembolism (DVT) continued to progress. DIAGNOSIS The final diagnosis was HIT. INTERVENTIONS Fondaparinux was temporarily used for anticoagulation treatment of DVT for 7 days when another anticoagulant (argatroban) was unavailable. Although the patient had kidney dysfunction, a full therapeutic dose of 7.5 mg fondaparinux was administered every morning through subcutaneous injection for consecutive 7 days. OUTCOMES The patient's thrombocytopenia and thrombosis were successfully treated without bleeding complications during therapeutic fondaparinux administration. LESSONS This is the first case reporting the successful use of fondaparinux for full anticoagulation for DVT in a critically ill patient with HIT and renal insufficiency. Our experience suggests that fondaparinux might be an alternative for anticoagulation treatment in patients with HIT and kidney dysfunction if another anticoagulant (argatroban) is unavailable.
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22
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Stimac G, Walters ET, Elmarsafi T, Attinger C, Evans KK. Incidence of heparin-induced thrombocytopenia in lower-extremity free flap reconstruction correlates with the overall surgical population. J Plast Reconstr Aesthet Surg 2018; 71:1252-1259. [PMID: 29980457 DOI: 10.1016/j.bjps.2018.05.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 04/09/2018] [Accepted: 05/26/2018] [Indexed: 11/30/2022]
Abstract
BACKGROUND Lower-extremity free flap reconstruction is a growing trend in the management of lower extremity wounds. Heparin-induced thrombocytopenia (HIT) is a significant risk to free flap reconstruction. The purpose of this study was to investigate the incidence of HIT in patients receiving lower-extremity free flap surgery. METHODS We conducted a retrospective, single center, IRB approved cohort study in which we reviewed all patients who received lower-extremity free flap surgeries between 2011 and 2016. The 4T and HIT Expert Probability (HEP) scores were calculated to assess the likelihood of HIT. RESULTS One hundred patient charts revealed three patients with HIT. One patient was excluded due to a prior diagnosis of HIT. HIT incidence in patients receiving lower-extremity free flaps was between 1% and 3%, which is consistent with the national average. 4T scores indicated that two of three HIT-positive patients had a high probability of HIT (approximately 64%), and one of three HIT-positive patients had an intermediate probability (approximately 14%). HEP scoring indicated that all the three (100%) patients had HIT. CONCLUSIONS These data suggest that the incidence of HIT in patients receiving lower-extremity free flaps correlates with the incidence of HIT nationally. The use of available scoring methods and other algorithms, combined with patient history helps to assess the immediate perioperative risks of HIT in the absence of rapid immunologic confirmatory tests. This knowledge can allow for successful free flap salvage or for performance of free flaps in patients with a history of HIT.
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Affiliation(s)
- Gregory Stimac
- School of Medicine, Georgetown University, 3900 Reservoir Rd NW, Washington DC 20007, United States
| | - Elliot T Walters
- Diabetic Limb Salvage, Department of Plastic Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Rd NW, Washington DC 20007, United States
| | - Tammer Elmarsafi
- Diabetic Limb Salvage, Department of Plastic Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Rd NW, Washington DC 20007, United States
| | - Christopher Attinger
- Department of Plastic Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Rd NW, Washington DC 20007, United States
| | - Karen K Evans
- Department of Plastic Surgery, MedStar Georgetown University Hospital, 3800 Reservoir Rd NW, Washington DC 20007, United States.
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23
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Wahby KA, Riley LK, Tennenberg SD. Assessment of an Extended Interval Fondaparinux Dosing Regimen for Venous Thromboembolism Prophylaxis in Critically Ill Patients with Severe Renal Dysfunction Using Antifactor Xa Levels. Pharmacotherapy 2018; 37:1241-1248. [PMID: 28833353 DOI: 10.1002/phar.2014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Pharmacologic options for venous thromboembolism (VTE) prophylaxis are often limited in critically ill patients due to thrombocytopenia and multisystem organ dysfunction. Fondaparinux offers potential advantages in the critically ill; however, it is currently contraindicated in severe renal dysfunction (SRD). We evaluated anti-factor Xa levels in critically ill patients with SRD who were receiving an extended interval dosing regimen of fondaparinux for VTE prophylaxis. METHODS A prospective, single-arm, interventional study was conducted at two academic hospitals of the Detroit Medical Center. Eligible patients were in the intensive care unit, had an estimated creatinine clearance of less than 30 ml/minute, and had either acute kidney injury or end-stage renal disease; several patients were taking renal replacement therapy. Fondaparinux was administered at an extended interval dosing regimen of 2.5 mg subcutaneously every 48 hours. Fondaparinux peak and trough anti-factor Xa levels were obtained. Lower extremity venous duplex studies were performed at baseline and study completion to assess for deep vein thrombosis (DVT), and patients were monitored for bleeding complications. RESULTS Thirty-two patients were enrolled. Patients received a median of four doses (interquartile range two to five) of fondaparinux. Fondaparinux peak (n=98) and trough (n=86) anti-factor Xa levels were 0.36 ± 0.18 mg/L and 0.17 ± 0.11 mg/L (mean ± SD), respectively, and were similar to levels reported in patients with normal renal function receiving conventional once-daily dosing. No lower extremity DVTs or suspected VTE events occurred. Two (6%) patients had significant bleeding events. CONCLUSIONS In critically ill patients with SRD, an extended interval fondaparinux dosing regimen of 2.5 mg every 48 hours for VTE prophylaxis achieved peak and trough anti-factor Xa levels similar to those reported in noncritically ill patients with normal renal function receiving once-daily fondaparinux. This regimen offers an alternative for patients with SRD when heparinoids must be avoided.
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Affiliation(s)
- Krista A Wahby
- Department of Pharmacy, Harper University Hospital, Detroit, Michigan
| | - Lauren K Riley
- Department of Pharmacy, Detroit Receiving Hospital, Detroit, Michigan
| | - Steven D Tennenberg
- Department of Surgery, Wayne State University School of Medicine, Detroit, Michigan
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24
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Schindewolf M, Paulik M, Kroll H, Kaufmann R, Wolter M, Boehncke W, Lindhoff‐Last E, Recke A, Ludwig RJ. Low incidence of heparin‐induced skin lesions in orthopedic surgery patients with low‐molecular‐weight heparins. Clin Exp Allergy 2018; 48:1016-1024. [DOI: 10.1111/cea.13159] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 01/29/2018] [Accepted: 02/22/2018] [Indexed: 12/24/2022]
Affiliation(s)
- M. Schindewolf
- Department of Internal Medicine Division of Hemostaseology Goethe University Hospital Frankfurt Frankfurt am Main Germany
- Division of Vascular Medicine Swiss Cardiovascular Center Inselspital Bern University Hospital Bern Switzerland
| | - M. Paulik
- Department of Internal Medicine Division of Hemostaseology Goethe University Hospital Frankfurt Frankfurt am Main Germany
| | - H. Kroll
- Institute for Transfusion Medicine Dessau Red Cross Blood Transfusion Service NSTOB Dessau Germany
| | - R. Kaufmann
- Department of Dermatology Goethe University Hospital Frankfurt Frankfurt am Main Germany
| | - M. Wolter
- Department of Dermatology Goethe University Hospital Frankfurt Frankfurt am Main Germany
| | - W.‐H. Boehncke
- Division of Dermatology and Venereology Geneva University Hospitals Geneva Switzerland
- Department of Pathology and Immunology University of Geneva Geneva Switzerland
| | - E. Lindhoff‐Last
- Department of Internal Medicine Division of Hemostaseology Goethe University Hospital Frankfurt Frankfurt am Main Germany
- Agaplesion Bethanien Hospital Cardiovascular Centre Bethanien (CCB) Frankfurt am Main Germany
| | - A. Recke
- Department of Dermatology and Lübeck Institute of Experimental Dermatology University of Lübeck Lübeck Germany
| | - R. J. Ludwig
- Department of Dermatology and Lübeck Institute of Experimental Dermatology University of Lübeck Lübeck Germany
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25
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Gameiro J, Jorge S, Lopes JA. Haemodialysis-related-heparin-induced thrombocytopenia: Case series and literature review. Nefrologia 2018; 38:551-557. [PMID: 29871769 DOI: 10.1016/j.nefro.2018.02.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 02/12/2018] [Accepted: 02/27/2018] [Indexed: 01/18/2023] Open
Abstract
Heparin-induced thrombocytopenia (HIT) is a serious and life-threatening complication that occurs in five per cent of patients exposed to heparin. It should be considered in patients with a platelet count <100×109cells/l or a >50% decrease from baseline count in association with heparin therapy. Thromboembolic complications develop in 50% of patients. Bleeding is rare as the platelet count nadir typically does not drop below 20×109cells/l. Up to 12% of dialysis patients develop HIT, named haemodialysis-related-heparin-induced thrombocytopenia (HD-HIT), as they are a risk group with continuous exposure to heparin. The definition of HD-HIT is less strict, in the range of a platelet count decrease of 30% and below 150×109cells/l due to the intermittent use of heparin. Heparin cessation and alternative anticoagulation are the key interventions in patients with HIT. In dialysis patients, citrate anticoagulation, heparin-free dialysis or peritoneal dialysis are options that must be considered. The authors describe the presentation, diagnosis, treatment and outcomes of five cases of HD-HIT, and emphasize the importance of an accurate diagnosis and early intervention in order to reduce the mortality risk, which can be as high as 20 per cent.
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Affiliation(s)
- Joana Gameiro
- Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal.
| | - Sofia Jorge
- Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal
| | - José António Lopes
- Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Lisboa Norte, EPE, Av. Prof. Egas Moniz, 1649-035 Lisboa, Portugal
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Abstract
: Heparin-induced thrombocytopenia (HIT) occurs in patients receiving heparin-containing products due to the formation of platelet-activating antibodies to heparin and platelet factor 4. Diagnosis includes utilization of a scoring system known as the 4-T score, and HIT laboratory assays. Recently, obesity was identified as a potential factor associated with the development of HIT. The objective of this study was to evaluate the association of HIT with obesity in ICU and general medicine patients. We performed a chart review of adult patients within the Methodist Healthcare System, and included patients who had an ELISA and serotonin release assay laboratory tests reported within same hospital admission in which they also had documented receipt of heparin. Obese patients were compared with nonobese patients (BMI < 30) for the primary outcome of HIT occurrence, and secondary outcomes including rate of thrombosis, 4-T scores, and ELISA optical density values. We also generated a 5-T score by including one additional point for those with a BMI of 30 or more to determine the predictive value of this score in identifying HIT. Obesity was confirmed to be a risk factor for HIT, and the 5-T score model was also predictive of the development of HIT. However, the 5-T score was not statistically more predictive of HIT than the 4-T score. Predicting HIT remains challenging and novel markers of HIT are needed to improve HIT recognition. Although obesity did not improve the 4-T score, it may improve the predictability of other scoring systems, and further investigation is warranted.
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27
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Krauel K, Medvedev N, Palankar R, Greinacher A, Delcea M. Micropatterned array to assess the interaction of single platelets with platelet factor 4-heparin-IgG complexes. Thromb Haemost 2017; 111:862-72. [DOI: 10.1160/th13-09-0752] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 12/13/2013] [Indexed: 12/17/2022]
Abstract
SummaryWe report a strategy to generate by electron beam lithography high fidelity micropatterned arrays to assess the interaction of single platelets with immobilised ligands. As a proof-of-principle we functionalised the microarrays with platelet factor 4 (PF4)-heparin-IgG complexes. We embedded biotinylated water-soluble quantum dots into polyethylene glycol (PEG)-coated micropatterned arrays and functionalised them via streptavidin to bind biotinylated ligands, here biotinylated-PF4/heparin complexes. The integrity of the PF4/heparin-complexes was shown by binding of anti-PF4/heparin antibodies. Ligand density was quantified by immunofluorescence and immunogold antibody labelling. Real-time calcium imaging was employed for read-out of single platelets activated on micropatterned surfaces functionalised with PF4/heparin-IgG complexes. With the smallest micropatterns (0.5x0.5 µm) we show that single platelets become strongly activated by binding to surface-immobilised PF4/heparin-IgG, while on larger micropatterns (10x10 µm), platelet aggregates formed. These findings that HIT antibodies can cause platelet activation on microarrays illustrate how this novel method opens new avenues to study platelet function at single cell level. Generating functionalized microarray surfaces to which highly complex ligands can be bound and quantified has the potential for platelet and other cell function assays integrated into high-throughput microfluidic microdevices.
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Lim MY, Foster J, Rourk A, Greenberg CS. Initial and long term impact of a multi-disciplinary task force in the diagnosis and management of heparin-induced thrombocytopenia. J Thromb Thrombolysis 2017; 45:130-134. [PMID: 29185142 DOI: 10.1007/s11239-017-1592-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Many medical centers are faced with a major challenge in making an accurate diagnosis of heparin-induced thrombocytopenia (HIT) and ensuring appropriate changes in management strategy in line with guideline recommendations. We report the initial and long-term impact and challenges of institution-wide changes in the diagnosis and management of HIT in the inpatient setting at an academic medical center. We established a HIT Task Force, consisting of a multidisciplinary team of non-malignant hematologists, nursing, pharmacist, pathology, blood bank and clinical lab informatics. Changes were implemented from 2011 to 2012. In 2013, testing for PF4 and SRA decreased by 37.5 and 85%, respectively. 100% of positive PF4 received an automatic hematology consult to guide management, leading to a 78% reduction in the use of direct thrombin inhibitors. Annual audits in the subsequent years demonstrated increasing testing for HIT due to changes in the electronic ordering system. Through continuous monitoring, these shortfalls were detected and intervene early on with continued success. The implementation of a centralized hospital-wide protocol via a multidisciplinary task force that coordinates testing and treatment of patients suspected of having HIT led to a substantial reduction in PF4 and SRA testing, as well as use of DTIs, resulting in a safe and cost-effective approach for the diagnosis and treatment of HIT. Our study highlights the important of continuous monitoring to maintain the improvements made. Despite our initial success, annual re-auditing allowed for early detection of challenges, which then allowed appropriate early intervention.
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Affiliation(s)
- Ming Y Lim
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, 39 Sabin Street, MSC 635, Charleston, SC, 29425, USA.
| | - Joyce Foster
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Angela Rourk
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Charles S Greenberg
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, 39 Sabin Street, MSC 635, Charleston, SC, 29425, USA
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29
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Schindewolf M, Steindl J, Beyer-Westendorf J, Schellong S, Dohmen PM, Brachmann J, Madlener K, Pötzsch B, Klamroth R, Hankowitz J, Banik N, Eberle S, Müller MM, Kropff S, Lindhoff-Last E. Use of Fondaparinux Off-Label or Approved Anticoagulants for Management of Heparin-Induced Thrombocytopenia. J Am Coll Cardiol 2017; 70:2636-2648. [DOI: 10.1016/j.jacc.2017.09.1099] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 09/15/2017] [Accepted: 09/18/2017] [Indexed: 01/18/2023]
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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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Abstract
Alopecia has been observed with many anticoagulants although the mechanism is unclear. A 20 year old female with recurrent DVTs developed alopecia with multiple anticoagulants, including heparin derivatives and the new oral anticoagulants. This resolved with discontinuation of the agents. The patient was ultimately able to be anticoagulated with fondaparinux long term without any alopecia. This case addresses the Key Clinical Question of management and recognition of anticoagulant induced alopecia. This side effect can result from almost any of the available agents and is quickly reversible, underlining the importance of tailoring treatment to the individual and their experiences.
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Affiliation(s)
- Angela C Weyand
- University of Michigan Medical School, Department of Pediatrics and Communicable Diseases, Division of Pediatric Hematology and Oncology, 8200 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, (ph) 734-615-8232
| | - Jordan A Shavit
- University of Michigan Medical School, Department of Pediatrics and Communicable Diseases, Division of Pediatric Hematology and Oncology, 8200 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, (ph) 734-615-8232, @clot1
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32
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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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Wadowski PP, Felli A, Schiferer A, Panzer S, Opfermann P, Dworschak M, Holaubek C, Aliabadi-Zuckermann A, Steinlechner B. Argatroban in Thrombocytopenic Patients Sensitized to Circulating Protamine-Heparin Complexes. J Cardiothorac Vasc Anesth 2017; 31:1779-1783. [PMID: 28764988 DOI: 10.1053/j.jvca.2017.03.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Indexed: 11/11/2022]
Affiliation(s)
- Patricia Pia Wadowski
- Department of Internal Medicine II, Division of Angiology, Medical University of Vienna, Vienna, Austria
| | - Alessia Felli
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Arno Schiferer
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Simon Panzer
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
| | - Philipp Opfermann
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Martin Dworschak
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Caroline Holaubek
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | | | - Barbara Steinlechner
- Department of Anesthesia, Critical Care and Pain Medicine, Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria.
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Is low serum albumin level a significant predictor for the development of heparin-induced thrombocytopenia-thrombosis? Ann Hematol 2017; 96:1033-1036. [PMID: 28289828 DOI: 10.1007/s00277-017-2971-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 03/04/2017] [Indexed: 10/20/2022]
Abstract
The present study investigates the effect of albumin levels in patients who have developed heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosis (HITT). A retrospective observational cohort study was conducted at King Abudlaziz Medical City (KAMC), a university teaching hospital, on patients diagnosed with HIT between June 2013 and December 2014. Clinical and laboratory findings were used to confirm HIT. Albumin levels were reported on admission as baseline and during HIT occurrence. Twenty-eight patients were identified as HIT positive by enzyme-linked immunosorbent assay (ELISA), with a cutoff value of ≥1 optical density units and pretest probability "4Ts" score of ≥4. Of the 28 patients, nine (32%) developed HITT. Demographic characteristics of the patients who developed HIT and HITT were similar. The mean albumin level for patients who developed HITT was significantly lower than that for patients who developed HIT (p < 0.001). Our findings suggest that patients with low serum albumin levels are at greater risk of developing HITT. This finding awaits confirmation in larger prospective clinical trials.
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35
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Spontaneous Heparin-Induced Thrombocytopenia and Venous Thromboembolism following Total Knee Arthroplasty. Case Rep Hematol 2017; 2017:4918623. [PMID: 28261509 PMCID: PMC5316441 DOI: 10.1155/2017/4918623] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/18/2017] [Indexed: 11/17/2022] Open
Abstract
A 72-year-old Caucasian woman was admitted for an elective left total knee arthroplasty. Her surgery was uncomplicated and she was discharged to a rehabilitation facility. Twelve days later, she developed acute shortness of breath followed by a syncopal episode. She was hypoxic and cyanotic, requiring hospitalization and intubation, and was subsequently diagnosed with bilateral submassive pulmonary emboli and bilateral lower extremity deep vein thrombosis. She was started on unfractionated heparin infusion. Within 24 hours of exposure, she had an acute decrease in platelet count to 48,000. Heparin was discontinued and argatroban was initiated due to concern for heparin-induced thrombocytopenia (HIT). Both quantitative enzyme immunoassay and functional assay confirmed the diagnosis of HIT. The patient had no prior lifetime heparin exposure. Given the absence of preceding heparin therapy, this case is consistent with the diagnosis of spontaneous HIT.
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36
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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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37
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Heparin-induced Thrombocytopenia Presenting With Deep Venous Thrombosis and Pulmonary Embolism Successfully Treated With Rivaroxaban: Clinical Case Report and Review of Current Experiences. J Cardiovasc Pharmacol 2016; 68:391-394. [DOI: 10.1097/fjc.0000000000000421] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Cost-effectiveness of anticoagulants for suspected heparin-induced thrombocytopenia in the United States. Blood 2016; 128:3043-3051. [PMID: 27793877 PMCID: PMC6863170 DOI: 10.1182/blood-2016-07-728030] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 10/11/2016] [Indexed: 12/19/2022] Open
Abstract
Despite the availability of multiple nonheparin anticoagulants for the treatment of heparin-induced thrombocytopenia (HIT), few data are available comparing the cost-effectiveness of these agents. This analysis is particularly important when considering differences in the risk of adverse effects, routes of administration, requirements for phlebotomy and laboratory monitoring, and overall drug costs. We conducted a cost-effectiveness analysis of argatroban, bivalirudin, and fondaparinux for the treatment of suspected HIT from the institutional perspective. A 3-arm decision-tree model was developed that employs standard practices for anticoagulation monitoring. We incorporated published data on drug efficacy and probability of HIT-related thromboembolism and major bleeding. We considered both institutional costs and average wholesale price (AWP) and performed probabilistic sensitivity analyses (PSA) to address any uncertainty in model parameters. Using institutional costs, fondaparinux prevailed over both argatroban and bivalirudin in terms of cost ($151 vs $1250 and $1466, respectively) and adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). Results were consistent when AWP was used, with fondaparinux being less expensive ($555 vs $3081 and $2187, respectively) and more effective in terms of adverse events averted (0.9989 vs 0.9957 and 0.9947, respectively). The PSA confirmed our findings using both institutional costs and AWP. In conclusion, fondaparinux subcutaneous injection afforded significant advantages in terms of cost savings and adverse events averted compared with IV argatroban or bivalirudin infusions. Our data strongly suggest potential cost savings with fondaparinux and underscore the critical need for larger clinical studies of fondaparinux in the treatment of suspected HIT.
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39
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Kunk PR, Brown J, McShane M, Palkimas S, Gail Macik B. Direct oral anticoagulants in hypercoagulable states. J Thromb Thrombolysis 2016; 43:79-85. [DOI: 10.1007/s11239-016-1420-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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40
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Heparin-induced thrombocytopenia in pregnancy: an interdisciplinary challenge—a case report and literature review. Int J Obstet Anesth 2016; 26:79-82. [DOI: 10.1016/j.ijoa.2015.11.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 11/25/2015] [Accepted: 11/29/2015] [Indexed: 11/19/2022]
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41
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Pimenta REF, Yoshida WB, Rollo HA, Sobreira ML, Bertanha M, Mariúba JVDO, Jaldin RG, de Camargo PAB. Trombocitopenia induzida por heparina em paciente com oclusão arterial aguda. J Vasc Bras 2016; 15:138-141. [PMID: 29930579 PMCID: PMC5829708 DOI: 10.1590/1677-5449.004215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Resumo A trombocitopenia induzida por heparina é uma complicação grave da terapêutica anticoagulante com heparina e está associada à formação de anticorpos antifator IV plaquetário. Costuma surgir a partir do quinto dia do tratamento, com queda de pelo menos 50% da contagem plaquetária. Em decorrência da ativação plaquetária concomitante, pode ocorrer quadro de trombose, venosa ou arterial, com repercussões clínicas graves. Apresentamos um caso de paciente portador de síndrome do anticorpo antifosfolípide, com quadro de oclusão arterial aguda, que foi tratado cirurgicamente e recebeu heparina não fracionada no intra e pós-operatório. No quinto dia de tratamento anticoagulante, apresentou queda maior de 50% da contagem de plaquetas em relação à contagem pré-heparina. A suspeita de trombocitopenia induzida por heparina e seus aspectos diagnósticos e terapêuticos serão abordados neste desafio terapêutico.
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Affiliation(s)
| | - Winston Bonetti Yoshida
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Botucatu, SP, Brasil
| | - Hamilton Almeida Rollo
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Botucatu, SP, Brasil
| | - Marcone Lima Sobreira
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Botucatu, SP, Brasil
| | - Matheus Bertanha
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Botucatu, SP, Brasil
| | | | - Rodrigo Gibin Jaldin
- Universidade Estadual Paulista - UNESP, Faculdade de Medicina de Botucatu, Botucatu, SP, Brasil
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Furie K, Khan M. Secondary Prevention of Cardioembolic Stroke. Stroke 2016. [DOI: 10.1016/b978-0-323-29544-4.00062-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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43
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Abstract
Abstract
The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin-induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and safety of DOACs in these high-risk populations are underway.
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44
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Jolissaint JS, Mulloy DP, Swanson JC, Albon DP, Lau CL. Bilateral Lung Transplantation From a Donor With Heparin-Induced Thrombocytopenia. Ann Thorac Surg 2015; 100:e1-3. [PMID: 26140799 DOI: 10.1016/j.athoracsur.2015.02.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/03/2015] [Accepted: 02/06/2015] [Indexed: 11/24/2022]
Abstract
We report the case of a 46-year-old male patient with a history of cystic fibrosis who received bilateral lung transplantation from a donor who died secondary to complications of heparin-induced thrombocytopenia. Postoperatively, he exhibited transient focal neurologic deficits and radiographic evidence of multiple cortical and subcortical infarctions. He was treated with a combination of fondaparinux and standard immunosuppressive therapy, made a full recovery, and experienced significantly improved lung function compared to pretransplantation capacity.
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Affiliation(s)
| | - Daniel P Mulloy
- Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Julia C Swanson
- Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Dana P Albon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Christine L Lau
- Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.
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46
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Spontaneous heparin-induced thrombocytopenia presenting as bilateral adrenal hemorrhages and pulmonary embolism after total knee arthroplasty. Arthroplast Today 2015; 1:69-71. [PMID: 28326374 PMCID: PMC4956682 DOI: 10.1016/j.artd.2015.07.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/30/2015] [Accepted: 07/22/2015] [Indexed: 11/21/2022] Open
Abstract
Heparin-induced thrombocytopenia syndrome is an acquired potentially life-threatening prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 bound to heparin or heparin-like molecules. It typically occurs after exposure to unfractionated heparin, to a lesser extent after exposure to low-molecular-weight heparins, and rarely after exposure to fondaparinux. Herein, we report the case of a 48-year-old woman who developed severe thrombocytopenia, bilateral pulmonary embolism, and bilateral adrenal hemorrhages after total knee arthroplasty without evidence of heparin exposure. Antibodies to the heparin-platelet factor 4 complex and serotonin-release assay were positive. Spontaneous heparin-induced thrombocytopenia syndrome should be considered in patients with unexplained thrombocytopenia after knee replacement surgery even without heparin exposure, and a high index of suspicion for adrenal hemorrhage is needed in patients with fever, abdominal pain, and shock.
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Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2015; 37:267-315. [PMID: 26320110 DOI: 10.1093/eurheartj/ehv320] [Citation(s) in RCA: 4373] [Impact Index Per Article: 437.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Gupta S, Tiruvoipati R, Green C, Botha J, Tran H. Heparin induced thrombocytopenia in critically ill: Diagnostic dilemmas and management conundrums. World J Crit Care Med 2015; 4:202-212. [PMID: 26261772 PMCID: PMC4524817 DOI: 10.5492/wjccm.v4.i3.202] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 02/25/2015] [Accepted: 07/14/2015] [Indexed: 02/06/2023] Open
Abstract
Thrombocytopenia is often noted in critically ill patients. While there are many reasons for thrombocytopenia, the use of heparin and its derivatives is increasingly noted to be associated with thrombocytopenia. Heparin induced thrombocytopenia syndrome (HITS) is a distinct entity that is characterised by the occurrence of thrombocytopenia in conjunction with thrombotic manifestations after exposure to unfractionated heparin or low molecular weight heparin. HITS is an immunologic disorder mediated by antibodies to heparin-platelet factor 4 (PF4) complex. HITS is an uncommon cause of thrombocytopenia. Reported incidence of HITS in patients exposed to heparin varies from 0.2% to up to 5%. HITS is rare in ICU populations, with estimates varying from 0.39%-0.48%. It is a complex problem which may cause diagnostic dilemmas and management conundrum. The diagnosis of HITS centers around detection of antibodies against PF4-heparin complexes. Immunoassays performed by most pathology laboratories detect the presence of antibodies, but do not reveal whether the antibodies are pathological. Platelet activation assays demonstrate the presence of clinically relevant antibodies, but only a minority of laboratories conduct them. Several anticoagulants are used in management of HITS. In this review we discuss the incidence, pathogenesis, diagnosis and management of HITS.
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Nazi I, Arnold DM, Moore JC, Smith JW, Ivetic N, Horsewood P, Warkentin TE, Kelton JG. Pitfalls in the diagnosis of heparin-Induced thrombocytopenia: A 6-year experience from a reference laboratory. Am J Hematol 2015; 90:629-33. [PMID: 25809312 DOI: 10.1002/ajh.24025] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 03/03/2015] [Accepted: 03/21/2015] [Indexed: 12/11/2022]
Abstract
Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies against complexes of platelet factor 4 (PF4) and heparin. The diagnosis of HIT is contingent on accurate and timely laboratory testing. Recently, alternative anticoagulants for the treatment of HIT have been introduced along with algorithms for better HIT diagnosis. However, the increased reliance on immunoassays for the diagnosis of HIT may have harmful consequences due to the high rate of false positive results. To compare trends and implications of current HIT testing approaches, we analyzed results over a six-year period from the McMaster University Platelet Immunology Reference Laboratory. From 2008 to 2013, 8,546 samples were investigated for HIT using both an in-house IgG-specific anti-PF4/heparin enzyme immunoassay (EIA) and the serotonin-release assay (SRA). Of 8,546 samples tested, 13.4% were true-positives (positive in both assays); 65.6% were true-negatives (negative in both assays); 20.9% were presumed false positive for HIT (EIA-positive/SRA-negative); and 0.2% were EIA-negative/SRA-positive. The frequency of EIA-positive/SRA-negative results increased over time (from 12.9% in 2008 to 22.9% in 2013). We found that the number of SRA-negative samples was reduced from referring centers that used an immunoassay as an initial screen; however, 41% of those samples tested negative in the immunoassay and in the SRA at the reference laboratory. The suspicion of HIT continues at a high rate and the agreement between the EIA and SRA test results remains problematic.
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Affiliation(s)
- Ishac Nazi
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
| | - Donald M. Arnold
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
- Canadian Blood Services; Hamilton Ontario Canada
| | - Jane C. Moore
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
- Department of Pathology and Molecular Medicine; McMaster University; Hamilton Ontario Canada
| | - James W. Smith
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
| | - Nikola Ivetic
- Department of Biochemistry and Biomedical Sciences; McMaster University; Hamilton Ontario Canada
| | - Peter Horsewood
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
| | - Theodore E. Warkentin
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
- Department of Pathology and Molecular Medicine; McMaster University; Hamilton Ontario Canada
| | - John G. Kelton
- Department of Medicine. Michael G. DeGroote School of Medicine; McMaster University; Hamilton Ontario Canada
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