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Hacialioglu RA, Kielkopf M, Branca M, Clenin L, Boronylo A, Silimon N, Göldlin MB, Scutelnic A, Kaesmacher J, Mujanovic A, Meinel TR, Seiffge DJ, Heldner MR, Liberman AL, Navi BB, Fischer U, Arnold M, Jung S, Bücke P, Beyeler M. Factors impacting D-dimer levels in patients with acute ischemic cerebrovascular events. J Stroke Cerebrovasc Dis 2024; 33:107834. [PMID: 38936311 DOI: 10.1016/j.jstrokecerebrovasdis.2024.107834] [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: 04/12/2024] [Revised: 06/12/2024] [Accepted: 06/23/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND AND OBJECTIVES A better understanding of the factors influencing D-dimer levels in code stroke patients is needed to guide further investigations of concomitant thrombotic conditions. This study aimed to investigate the impact of time from symptom onset and other factors on D-dimer levels in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). METHODS Data on consecutive AIS and TIA patients treated at our tertiary-care stroke center between January 2015 and December 2020 were retrospectively assessed. Patients with available D-dimer levels were evaluated for eligibility. Multivariable non-linear regression analyses were performed. RESULTS In total, 2467 AIS patients and 708 TIA patients were included. The median D-dimer levels differed between the AIS and TIA groups (746 µg/L [interquartile range 381-1468] versus 442 µg/L [interquartile range 244-800], p<0.001). In AIS patients, an early increase in D-dimer levels was demonstrated within the first 6 h (standardized beta coefficient [β] 0.728; 95% confidence interval [CI] 0.324-1.121). This was followed by an immediate decrease (β -13.022; 95% CI -20.401 to -5.643) and then by a second, late increase after 35 h (β 11.750; 95% CI 4.71-18.791). No time-dependent fluctuation in D-dimer levels was observed in TIA patients. CONCLUSION The time from symptom onset may affect D-dimer levels in patients with AIS but not those with TIA. Further studies confirming these findings and validating time-specific variations are needed to enable D-dimer levels to be used efficiently as an acute stroke and thrombotic risk biomarker.
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Affiliation(s)
- Recep-Ali Hacialioglu
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Moritz Kielkopf
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Mattia Branca
- CTU Bern, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - Leander Clenin
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Anna Boronylo
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Norbert Silimon
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Martina B Göldlin
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Adrian Scutelnic
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Johannes Kaesmacher
- Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Adnan Mujanovic
- Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Thomas R Meinel
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - David J Seiffge
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Mirjam R Heldner
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Ava L Liberman
- Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Babak B Navi
- Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Urs Fischer
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Marcel Arnold
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Simon Jung
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Philipp Bücke
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland
| | - Morin Beyeler
- Department of Neurology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland; Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine, New York, NY, USA; Graduate School for Health Sciences, University of Bern, Switzerland.
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MacNeill M, Mansory EM, Lazo-Langner A, Phua CW. Acquired Hemophilia A Masquerading as Bleeding on Anticoagulation: A Case Report Including Key Laboratory Considerations. Cureus 2023; 15:e41029. [PMID: 37519483 PMCID: PMC10373513 DOI: 10.7759/cureus.41029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 08/01/2023] Open
Abstract
We report a case of a patient with recurrent hematomas while on anticoagulation for a pulmonary embolism and a prolonged hospital stay due to a delayed diagnosis for acquired hemophilia A. Acquired hemophilia A is a rare autoimmune bleeding disorder with autoantibodies directed against coagulation factor VIII (FVIII), leading to an acquired FVIII deficiency. A prolonged isolated activated partial thromboplastin time (aPTT) in a bleeding patient warrants workup for acquired hemophilia A. This is specifically challenging in patients with thrombosis on anticoagulation and can lead to significant delays in diagnosis and associated morbidities. The case highlights the need for further awareness of this disease, potential laboratory pitfalls when conducting and interpreting coagulation assays, and the management considerations in a patient with a simultaneous thrombotic and hemorrhagic condition.
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Affiliation(s)
- Michael MacNeill
- Medicine, Schulich School of Medicine & Dentistry, Western University, London, CAN
| | | | | | - Chai W Phua
- Hematology, Schulich School of Medicine & Dentistry, Western University, London, CAN
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Guy S, Shepherd MF, Bowyer AE, Kitchen S. How to assess parallelism in factor assays: coefficient of variation of results with different dilutions or slope ratio? Int J Lab Hematol 2023; 45:229-240. [PMID: 36484119 DOI: 10.1111/ijlh.14002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Non-parallelism in factor assays can lead to incorrect factor activities. Parallelism can be assessed by calculating the coefficient of variation (CV) of results obtained on 3 dilutions of the same sample. Some authors have proposed that if there is <15% then the average activity is reportable. Some analysers use a slope ratio (SR) to calculate parallelism, with an acceptance range of approximately 0.9-1.1. METHODS We evaluated CV and SR in one stage FII-FXII assays on Sysmex CS5100i using Innovin or Actin FS. Frozen normal and pathological plasmas, plasmas containing Direct Oral Anticoagulants, Direct Thrombin Inhibitors or Lupus Anticoagulant were analysed to assess possible non-parallelism. RESULTS In plasmas with factor levels >25 IU/dl (plus no interfering substances) all CVs were < 15%. One sample (low factor activities 10-15 IU/dl), had CVs > 15% in FII, FVII and FXII assays only. SR outside of 0.9-1.1 were seen in FII and FXII assays at different levels of clotting factor including some within the normal range. Non-parallelism was detected more frequently with SR than CV for those with interfering substances. CONCLUSIONS SR outside of 0.9-1.1 were seen in different levels of clotting factors, including samples which did not contain interfering substances. The target of 15% CV was a better discriminator than a SR for acceptance. When factor levels were reduced to around 10-15 IU/dl, a target 20 %CV was more appropriate than 15%. It might be appropriate for laboratories to assess locally whether their acceptance criteria need to be wider at low levels of clotting factors.
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Affiliation(s)
- Susan Guy
- Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
| | - M Fiona Shepherd
- Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
| | - Annette E Bowyer
- Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
| | - Steve Kitchen
- Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK
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Schiffer S, Schwers S, Heitmeier S. The effect of rivaroxaban on biomarkers in blood and plasma: a review of preclinical and clinical evidence. J Thromb Thrombolysis 2023; 55:449-463. [PMID: 36746885 PMCID: PMC10110699 DOI: 10.1007/s11239-023-02776-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2023] [Indexed: 02/08/2023]
Abstract
Rivaroxaban is a direct, oral factor Xa inhibitor that is used for the prevention and treatment of various thromboembolic disorders. Several preclinical and clinical studies have utilized specific molecules as biomarkers to investigate the potential role of rivaroxaban beyond its anticoagulant activity and across a range of biological processes. The aim of this review is to summarize the existing evidence regarding the use of blood-based biomarkers to characterize the effects of rivaroxaban on coagulation and other pathways, including platelet activation, inflammation and endothelial effects. After a literature search using PubMed, almost 100 preclinical and clinical studies were identified that investigated the effects of rivaroxaban using molecular biomarkers. In agreement with the preclinical data, clinical studies reported a trend for reduction in the blood concentrations of D-dimers, thrombin-antithrombin complex and prothrombin fragment 1 + 2 following treatment with rivaroxaban in both healthy individuals and those with various chronic conditions. Preclinical and also some clinical studies have also reported a potential impact of rivaroxaban on the concentrations of platelet activation biomarkers (von Willebrand factor, P-selectin and thrombomodulin), endothelial activation biomarkers (matrix metalloproteinase-9, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and inflammation biomarkers (interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1). Based on the results of biomarker studies, molecular biomarkers can be used in addition to traditional coagulation assays to increase the understanding of the anticoagulation effects of rivaroxaban. Moreover, there is preliminary evidence to suggest that rivaroxaban may have an impact on the biological pathways of platelet activation, endothelial activation and inflammation; however, owing to paucity of clinical data to investigate the trends reported in preclinical studies, further investigation is required to clarify these observations.
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Affiliation(s)
- Sonja Schiffer
- Bayer AG, Pharmaceuticals, R&D, 42113 Wuppertal, Germany
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022. [DOI: 10.12998/wjcc.v10.i9.2698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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Meng Y, Li Y, Ye YJ, Ma Q, Zhang JB, Qin H, Deng YY, Tian HY. Associations between coagulation factor XII, coagulation factor XI, and stability of venous thromboembolism: A case-control study. World J Clin Cases 2022; 10:2700-2709. [PMID: 35434115 PMCID: PMC8968801 DOI: 10.12998/wjcc.v10.i9.2700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/29/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pulmonary embolism (PE) is a fatal clinical syndrome that is generally caused by an embolus from unstable deep venous thrombosis (DVT). However, clinical and biochemical factors that are related to the stability of DVT are not fully understood.
AIM To evaluate the relationships between plasma antigen levels of factor XII (FXII:Ag) and factor XI (FXI:Ag) with the stability of DVT.
METHODS Patients with DVT and no PE, DVT and PE, and controls with no DVT or PE that matched for age, gender, and comorbidities were included in this study. FXII:Ag and FXI:Ag in peripheral venous blood were measured using enzyme-linked immunosorbent assays.
RESULTS Using the 95th percentile of FXI:Ag in patients with DVT and PE as the cut-off, a higher FXI:Ag was associated with a higher risk of unstable DVT (odds ratio: 3.15, 95% confidence interval: 1.18-8.43, P = 0.019). Stratified analyses showed consistent results in patients ≤ 60 years (P = 0.020), but not in those > 60 years (P = 0.346).
CONCLUSION Higher plasma FXI:Ag might be a marker for unstable DVT, which might be associated with PE in these patients.
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Affiliation(s)
- Yan Meng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - You Li
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yan-Jun Ye
- Department of Breast and Thyroid Surgery, Baoji People’s Hospital, Baoji 721000, Shannxi Province, China
| | - Qiang Ma
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Jun-Bo Zhang
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hao Qin
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Yang-Yang Deng
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
| | - Hong-Yan Tian
- Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shannxi Province, China
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Perifanis V, Neokleous N, Tsakiris DA. Update on laboratory testing and hemostasis assessment in patients receiving direct oral anticoagulants (DOACs). THROMBOSIS UPDATE 2021. [DOI: 10.1016/j.tru.2021.100084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Hanna F, Hyppa A, Prakash A, Vithanarachchi U, Dawar HU, Sanga Z, Olabode G, Crisp H, Khalafallah AA. Real-World Data on Characteristics and Management of Community Patients Receiving Anticoagulation Therapy Who Presented with Acute Bleeding to the Emergency Department at a Regional Australian Hospital: A Prospective Observational Study. Mediterr J Hematol Infect Dis 2021; 13:e2021017. [PMID: 33747398 PMCID: PMC7938926 DOI: 10.4084/mjhid.2021.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/05/2021] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVE To study patients receiving anticoagulants with or without antiplatelet therapy presenting at a regional Australian hospital with bleeding. The main aims are to explore: (1) patients' characteristics and management provided; (2) association between the type of anticoagulant and antiplatelet agent used and the requirement of reversal; (3) and the length of hospital stay (LoS) in conjunction with bleeding episode and management. METHODS A prospective cross-sectional review of medical records of all patients who presented at a tertiary referral centre with bleeding while receiving anticoagulation therapy between January 2016 and June 2018. Data included: patients, demographics, investigations (kidney and liver function tests, coagulation profile, FBC), LoS, bleeding site, type of and reason for anticoagulation therapy, and management provided. Data analysis included descriptive statistics, χ2 association, and regression models. RESULTS Among the 144 eligible patients, 75 (52.1%) were male, and the mean age was 76 years (SD=11.1). Gastrointestinal tract bleeding was the most common (n=48, 33.3%), followed by epistaxis (n=32, 22.2%). Atrial fibrillation was the commonest reason for anticoagulation therapy (n=65, 45.1%). Warfarin was commonly used (n=74, 51.4%), followed by aspirin (n=29, 20.1%), rivaroxaban (n=26, 18.1%), and apixaban (n=12, 8.3%). The majority had increased blood urea nitrogen (n=67, 46.5%), while 58 (40.3%) had an elevated serum creatinine level, and 59 (41.0%) had a mild reduction in eGFR. Thirty-five of the warfarinised patients (47.3%) had an INR above their condition's target range despite normal liver function. Severe anaemia (Hb<80g/L) was reported in 88 patients (61.1%). DOACs were associated with a reduced likelihood of receiving reversal (B= -1.7, P=<.001), and with a shorter LoS (B= -4.1, P=.046) when compared with warfarin, LMWH, and antiplatelet therapy. CONCLUSION Warfarin use was common among patients who presented with acute bleeding, and the INR in many warfarinised patients exceeded the target for their condition. DOACs were associated with a reduced likelihood of receiving reversal and a shorter LoS than warfarin, LMWH, which might support a broader application of DOACs into community practice.
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Affiliation(s)
- Fayez Hanna
- Faculty of Health Sciences, Launceston, University of Tasmania, Tasmania, 7249, Australia
- Department of Haematology, Specialist Care Australia, Launceston, Tasmania, 7250 Australia
| | - Annemarie Hyppa
- Department of Haematology, Specialist Care Australia, Launceston, Tasmania, 7250 Australia
- Medical School, University of Saarland, Homburg, Germany
| | - Ajay Prakash
- Faculty of Health Sciences, Launceston, University of Tasmania, Tasmania, 7249, Australia
- Department of Haematology, Specialist Care Australia, Launceston, Tasmania, 7250 Australia
| | - Usira Vithanarachchi
- Faculty of Health Sciences, Launceston, University of Tasmania, Tasmania, 7249, Australia
- Department of Haematology, Specialist Care Australia, Launceston, Tasmania, 7250 Australia
| | - Hizb U Dawar
- Augusta Medical Centre, Lenah Valley 7008, Tasmania, Australia
| | - Zar Sanga
- Augusta Medical Centre, Lenah Valley 7008, Tasmania, Australia
| | - George Olabode
- Launceston General Hospital, Launceston, Tasmania, 7250 Australia
| | - Hamish Crisp
- Launceston General Hospital, Launceston, Tasmania, 7250 Australia
| | - Alhossain A. Khalafallah
- Faculty of Health Sciences, Launceston, University of Tasmania, Tasmania, 7249, Australia
- Department of Haematology, Specialist Care Australia, Launceston, Tasmania, 7250 Australia
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Begic E, Hadzidedic S, Obradovic S, Begic Z, Causevic M. Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer's Disease Diagnosis. J Alzheimers Dis 2020; 77:375-386. [PMID: 32804133 DOI: 10.3233/jad-200358] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Alzheimer's disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer's disease. OBJECTIVE To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer's disease. METHODS SOMAscan assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer's disease. RESULTS Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer's disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer's-type diagnosis are factors IX and XI-an increase in both factors is associated with a reduction in cognitive function. CONCLUSION Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer's-type neurodegeneration.
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Affiliation(s)
- Edin Begic
- Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina.,Department of Cardiology, General Hospital "Prim.Dr. Abdulah Nakas", Sarajevo, Bosnia and Herzegovina
| | - Suncica Hadzidedic
- Computer Science and Information Systems Department, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina.,Department of Computer Science, Durham University, Durham, UK
| | - Slobodan Obradovic
- Clinic for Emergency and Internal Medicine, Military Medical Academy, University of Defense, Belgrade, Serbia
| | - Zijo Begic
- Department of Pediatric Cardiology, Pediatric Clinic, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Mirsada Causevic
- Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
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Favaloro EJ, Gilmore G, Bonar R, Dean E, Arunachalam S, Mohammed S, Baker R. Reducing the effect of DOAC interference in laboratory testing for factor VIII and factor IX: A comparative study using DOAC Stop and andexanet alfa to neutralize rivaroxaban effects. Haemophilia 2020; 26:354-362. [PMID: 31962376 DOI: 10.1111/hae.13930] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/20/2019] [Accepted: 01/01/2020] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Investigation of factors (F) VIII and IX is common, with testing important for diagnosis or exclusion of haemophilia A or B, associated acquired conditions and factor inhibitors. Rivaroxaban, a common direct anti-Xa agent, causes significant interference in clotting assays, including substantial false reduction of factor levels. AIM To assess whether rivaroxaban-induced interference of FVIII and FIX testing could be neutralized. MATERIALS AND METHODS An international, cross-laboratory exercise for FVIII (n = 84) and FIX (n = 74), using four samples: (A) pool of normal plasma; (B) pool spiked with rivaroxaban (200 ng/mL); (C) rivaroxaban sample subsequently treated with 'DOAC Stop' and; (D) rivaroxaban sample treated with andexanet alfa (200 μg/mL). Testing performed blind to sample type. RESULTS All laboratories reported normal FIX and 94% reported normal FVIII in the pool sample. Instead, 55% and 95%, respectively, reported abnormal FIX and FVIII levels for the rivaroxaban sample. DOAC Stop treatment evidenced a correction in most laboratories (100% reported normal FIX and 86% normal FVIII). Andexanet alfa provided intermediate results, with many laboratories still reporting abnormal results (59% for FVIII, 18% for FIX). We also identified reagent-specific issues. CONCLUSIONS As expected, rivaroxaban caused false low values of FVIII and FIX. This might lead to increased testing to identify the cause of low factor levels and potentially lead to false identification of (mild) haemophilia A or B if unrecognized by clinicians/laboratories. DOAC Stop effectively neutralized the rivaroxaban effect, but andexanet alfa less so, with reagent-related effects evident, and thus, false low values sometimes persisted.
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Affiliation(s)
- Emmanuel J Favaloro
- Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia.,Sydney Centres for Thrombosis and Haemostasis, Westmead, NSW, Australia
| | - Grace Gilmore
- Western Australian Centre for Thrombosis and Haemostasis (WACTH), Murdoch University, Perth, WA, Australia
| | - Roslyn Bonar
- Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP), St Leonards, NSW, Australia
| | - Elysse Dean
- Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP), St Leonards, NSW, Australia
| | - Sandya Arunachalam
- Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP), St Leonards, NSW, Australia
| | - Soma Mohammed
- Department of Laboratory Haematology, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, NSW, Australia
| | - Ross Baker
- Western Australian Centre for Thrombosis and Haemostasis (WACTH), Murdoch University, Perth, WA, Australia
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Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M, Caughey T, Bauer KA, Kuemmerle N, Wong E, Wun T, McLaughlin M, Hidalgo M, Neuberg D, Furie B, Flaumenhaft R. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight 2019; 4:125851. [PMID: 30652973 PMCID: PMC6478409 DOI: 10.1172/jci.insight.125851] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 01/14/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Protein disulfide isomerase (PDI) is a thiol isomerase secreted by vascular cells that is required for thrombus formation. Quercetin flavonoids inhibit PDI activity and block platelet accumulation and fibrin generation at the site of a vascular injury in mouse models, but the clinical effect of targeting extracellular PDI in humans has not been studied. METHODS We conducted a multicenter phase II trial of sequential dosing cohorts to evaluate the efficacy of targeting PDI with isoquercetin to reduce hypercoagulability in cancer patients at high risk for thrombosis. Patients received isoquercetin at 500 mg (cohort A, n = 28) or 1000 mg (cohort B, n = 29) daily for 56 days, with laboratory assays performed at baseline and the end of the study, along with bilateral lower extremity compression ultrasound. The primary efficacy endpoint was a reduction in D-dimer, and the primary clinical endpoint included pulmonary embolism or proximal deep vein thrombosis. RESULTS The administration of 1000 mg isoquercetin decreased D-dimer plasma concentrations by a median of -21.9% (P = 0.0002). There were no primary VTE events or major hemorrhages observed in either cohort. Isoquercetin increased PDI inhibitory activity in plasma (37.0% in cohort A, n = 25, P < 0.001; 73.3% in cohort B, n = 22, P < 0.001, respectively). Corroborating the antithrombotic efficacy, we also observed a significant decrease in platelet-dependent thrombin generation (cohort A median decrease -31.1%, P = 0.007; cohort B median decrease -57.2%, P = 0.004) and circulating soluble P selectin at the 1000 mg isoquercetin dose (median decrease -57.9%, P < 0.0001). CONCLUSIONS Isoquercetin targets extracellular PDI and improves markers of coagulation in advanced cancer patients. TRIAL REGISTRATION Clinicaltrials.gov NCT02195232. FUNDING Quercegen Pharmaceuticals; National Heart, Lung, and Blood Institute (NHLBI; U54HL112302, R35HL135775, and T32HL007917); and NHLBI Consortium Linking Oncology and Thrombosis (U01HL143365).
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Affiliation(s)
- Jeffrey I. Zwicker
- Division of Hemostasis and Thrombosis and
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Benjamin L. Schlechter
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Howard A. Liebman
- Jane Anne Nohl Division of Hematology, University of Southern California, Los Angeles, California, USA
| | | | - Maneka Puligandla
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | - Kenneth A. Bauer
- Division of Hemostasis and Thrombosis and
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Nancy Kuemmerle
- White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, USA
| | - Ellice Wong
- Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA
| | - Ted Wun
- Division of Hematology Oncology, University of California Davis School of Medicine, VA Northern California Health Care System, Sacramento, California, USA
| | | | - Manuel Hidalgo
- Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Donna Neuberg
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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