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Moore GW. Thrombophilia Screening: Not So Straightforward. Semin Thromb Hemost 2024; 50:1131-1152. [PMID: 38733983 DOI: 10.1055/s-0044-1786807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2024]
Abstract
Although inherited thrombophilias are lifelong risk factors for a first thrombotic episode, progression to thrombosis is multifactorial and not all individuals with inherited thrombophilia develop thrombosis in their lifetimes. Consequently, indiscriminate screening in patients with idiopathic thrombosis is not recommended, since presence of a thrombophilia does not necessarily predict recurrence or influence management, and testing should be selective. It follows that a decision to undertake laboratory detection of thrombophilia should be aligned with a concerted effort to identify any significant abnormalities, because it will inform patient management. Deficiencies of antithrombin and protein C are rare and usually determined using phenotypic assays assessing biological activities, whereas protein S deficiency (also rare) is commonly detected with antigenic assays for the free form of protein S since available activity assays are considered to lack specificity. In each case, no single phenotypic assay is capable of detecting every deficiency, because the various mutations express different molecular characteristics, rendering thrombophilia screening repertoires employing one assay per potential deficiency, of limited effectiveness. Activated protein C resistance (APCR) is more common than discrete deficiencies of antithrombin, protein C, and protein S and also often detected initially with phenotypic assays; however, some centres perform only genetic analysis for factor V Leiden, as this is responsible for most cases of hereditary APCR, accepting that acquired APCR and rare F5 mutations conferring APCR will go undetected if only factor V Leiden is evaluated. All phenotypic assays have interferences and limitations, which must be factored into decisions about if, and when, to test, and be given consideration in the laboratory during assay performance and interpretation. This review looks in detail at performance and limitations of routine phenotypic thrombophilia assays.
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Affiliation(s)
- Gary W Moore
- Specialist Haemostasis Laboratory, Cambridge Haemophilia and Thrombophilia Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
- Department of Natural Sciences, Middlesex University, London, United Kingdom
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2
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Foret T, Dufrost V, Lagrange J, Costa P, Mourey G, Lecompte T, Magy-Bertrand N, Regnault V, Zuily S, Wahl D. Thrombin Generation Assay in Antiphospholipid Antibodies Positive Subjects as a Personalized Thrombotic Risk Assessment: State of the Art and Perspectives. Curr Rheumatol Rep 2024; 26:178-187. [PMID: 38372872 DOI: 10.1007/s11926-024-01140-1] [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] [Accepted: 02/05/2024] [Indexed: 02/20/2024]
Abstract
PURPOSE OF THE REVIEW Thrombotic risk assessment in antiphospholipid positive (aPL +) subjects is a major challenge, and the study of in vitro thrombin generation (thrombin generation assays (TGA)) could provide useful information. Activated protein C (APC) sensitivity is involved in thrombotic events in antiphospholipid syndrome patients. We summarized methods used to assess APC sensitivity with TGA and evaluated the prognostic role of APC resistance through literature search. RECENT FINDINGS APC resistance induced by aPL is a complex pathway. Several cross-sectional studies assessed APC sensitivity to understand thrombotic event mechanisms in aPL + subjects. Only one prospective cohort had investigated the prognostic impact of APC resistance in aPL + subjects, with a positive and significant correlation between APC sensitivity and the risk of thrombosis during the follow up (hazard ratio, 6.07 [95% CI, 1.69-21.87]). APC resistance assessed with TGA could be associated with thrombotic events in aPL + subjects.
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Affiliation(s)
- Thomas Foret
- Vascular Medicine Unit, Vascular and Endovascular Surgery Department, CHU-Besancon, 3 BD Alexandre Fleming, F-25000, Besancon, France.
- Université de Franche-Comté, SINERGIES, F-25000, Besancon, France.
| | - Virginie Dufrost
- Université de Lorraine, INSERM, DCAC, F-54000, Nancy, France
- Vascular Medicine Division and National Referral Center for Rare Vascular and Systemic Autoimmune Diseases, CHRU-Nancy, F-54000, Nancy, France
| | - Jeremy Lagrange
- Université de Lorraine, INSERM, DCAC, F-54000, Nancy, France
- CHRU-Nancy, F-54000, Nancy, France
| | - Patricia Costa
- Vascular Medicine Unit, Vascular and Endovascular Surgery Department, CHU-Besancon, 3 BD Alexandre Fleming, F-25000, Besancon, France
| | - Guillaume Mourey
- Université de Franche-Comté, SINERGIES, F-25000, Besancon, France
- Medical Biology Laboratory, Biological Haemostasis Department, CHU Besançon, F-25000, Besançon, France
| | - Thomas Lecompte
- Vascular Medicine Division and National Referral Center for Rare Vascular and Systemic Autoimmune Diseases, CHRU-Nancy, F-54000, Nancy, France
- Université de Lorraine, Nancy, France
| | | | - Veronique Regnault
- Université de Lorraine, INSERM, DCAC, F-54000, Nancy, France
- CHRU-Nancy, F-54000, Nancy, France
| | - Stéphane Zuily
- Université de Lorraine, INSERM, DCAC, F-54000, Nancy, France
- Vascular Medicine Division and National Referral Center for Rare Vascular and Systemic Autoimmune Diseases, CHRU-Nancy, F-54000, Nancy, France
| | - Denis Wahl
- Université de Lorraine, INSERM, DCAC, F-54000, Nancy, France
- Vascular Medicine Division and National Referral Center for Rare Vascular and Systemic Autoimmune Diseases, CHRU-Nancy, F-54000, Nancy, France
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3
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Dicks AB, Moussallem E, Stanbro M, Walls J, Gandhi S, Gray BH. A Comprehensive Review of Risk Factors and Thrombophilia Evaluation in Venous Thromboembolism. J Clin Med 2024; 13:362. [PMID: 38256496 PMCID: PMC10816375 DOI: 10.3390/jcm13020362] [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: 12/15/2023] [Revised: 12/29/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant cause of morbidity and mortality worldwide. There are many factors, both acquired and inherited, known to increase the risk of VTE. Most of these result in increased risk via several common mechanisms including circulatory stasis, endothelial damage, or increased hypercoagulability. Overall, a risk factor can be identified in the majority of patients with VTE; however, not all risk factors carry the same predictive value. It is important for clinicians to understand the potency of each individual risk factor when managing patients who have a VTE or are at risk of developing VTE. With this, many providers consider performing a thrombophilia evaluation to further define a patient's risk. However, guidance on who to test and when to test is controversial and not always clear. This comprehensive review attempts to address these aspects/concerns by providing an overview of the multifaceted risk factors associated with VTE as well as examining the role of performing a thrombophilia evaluation, including the indications and timing of performing such an evaluation.
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Affiliation(s)
- Andrew B. Dicks
- Department of Vascular Surgery, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA; (E.M.); (M.S.); (S.G.); (B.H.G.)
| | - Elie Moussallem
- Department of Vascular Surgery, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA; (E.M.); (M.S.); (S.G.); (B.H.G.)
| | - Marcus Stanbro
- Department of Vascular Surgery, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA; (E.M.); (M.S.); (S.G.); (B.H.G.)
| | - Jay Walls
- Department of Hematology, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA;
| | - Sagar Gandhi
- Department of Vascular Surgery, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA; (E.M.); (M.S.); (S.G.); (B.H.G.)
| | - Bruce H. Gray
- Department of Vascular Surgery, Prisma Health, University of South Carolina School of Medicine—Greenville, Greenville, SC 29601, USA; (E.M.); (M.S.); (S.G.); (B.H.G.)
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4
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Hisada R, Atsumi T. An Antiphospholipid Antibody Profile as a Biomarker for Thrombophilia in Systemic Lupus Erythematosus. Biomolecules 2023; 13:biom13040617. [PMID: 37189365 DOI: 10.3390/biom13040617] [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: 01/31/2023] [Revised: 02/27/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Despite recent advances in treatment and significant improvements in prognosis, thrombosis remains the major cause of death in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are the main triggers of thrombosis in patients with SLE, with a frequency of approximately 30-40%. Lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies, which are included in the criteria for antiphospholipid syndrome, and 'non-criteria' aPL such as anti-phosphatidylserine/prothrombin complex antibodies, are risk factors for thrombosis in patients with SLE. Multiple positivity for aPL is also associated with an increased risk of thrombosis, and scores calculated from aPL profiles can predict the risk of developing thrombosis. Although there is insufficient evidence for treatment, aPL-positive SLE patients should/may be treated with anticoagulants and/or low-dose aspirin as appropriate. This review summarises the evidence on the clinical significance of the aPL profile as a biomarker of thrombophilia in patients with SLE.
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Affiliation(s)
- Ryo Hisada
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Kita-Ku, Sapporo 060-8638, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Kita-Ku, Sapporo 060-8638, Japan
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5
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Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol 2022; 44:347-362. [PMID: 35122116 PMCID: PMC8816310 DOI: 10.1007/s00281-022-00916-w] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.
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Affiliation(s)
- Jason S Knight
- Division of Rheumatology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
| | - Yogendra Kanthi
- Division of Intramural Research National Heart, Lung, and Blood Institute, Bethesda, MD, USA
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6
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A Novel Mutation in the VPS13B Gene in a Cohen Syndrome Patient with Positive Antiphospholipid Antibodies. Case Reports Immunol 2021; 2021:3143609. [PMID: 34484844 PMCID: PMC8413065 DOI: 10.1155/2021/3143609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/16/2021] [Indexed: 11/17/2022] Open
Abstract
Cohen syndrome is an autosomal recessive disorder with the primary symptoms of mental deficiency, progressive retinopathy, hypotonia, microcephaly, obesity of midchildhood onset, intermittent neutropenia, and dysmorphic facial features. The syndrome has high phenotypic heterogeneity and is caused by loss-of-function mutations in the VPS13B gene. Here, we introduce a novel homozygous nonsense mutation (c.8698G > T, p.E2900X) in the VPS13B gene in an 11-year-old Iranian boy with major symptoms of Cohen syndrome. He also had mild anemia accompanied by positive antiphospholipid antibodies, the latter has never been previously reported in Cohen syndrome.
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7
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Liao YX, Guo YF, Wang YX, Liu AH, Zhang CL. Systemic lupus erythematosus combined with primary hyperfibrinolysis and protein C and protein S deficiency: A case report. World J Clin Cases 2021; 9:2008-2014. [PMID: 33748254 PMCID: PMC7953391 DOI: 10.12998/wjcc.v9.i8.2008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by systemic involvement and multiple autoantibodies in the serum. Patients with protein C (PC) and protein S (PS) deficiency are prone to thrombosis. In contrast, patients with primary hyperfibrino-lysis tend to bleed.
CASE SUMMARY A 52-year-old female patient with bilateral pleural effusion was diagnosed with "tuberculous pleurisy" and treated with anti-tuberculosis drugs and prednisone. The coagulation-related laboratory results showed decreased fibrinogen, PC activity, PS activity, and antithrombin Ш activity. The immune-related laboratory results showed positive antinuclear antibody, anti-Smith antibody, anticardiolipin antibody (ACL), anti-β2-glycoprotein I antibody (aβ2GPI) and direct Coomb’s test and decreased complement 3 and complement 4. Thoracoscopy was performed and bloody pleural fluid was drained. Pathology of the pleural biopsy showed lymphocytes, plasma cells, and a few eosinophils in adipose and fibrous connective tissue. Results of whole exome sequencing of blood showed no genetic mutations suggesting the presence of hereditary hematological diseases. The patient was finally diagnosed with SLE and primary hyperfibrinolysis, and was treated with prednisolone, hydroxychloroquine, and compound cyclophosphamide.
CONCLUSION PC and PS deficiency in SLE might be related to ACL and aβ2GPI. SLE and primary hyperfibrinolysis can coexist in one patient, with both a risk of thrombosis and a risk of bleeding.
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Affiliation(s)
- Yi-Xuan Liao
- Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yan-Fei Guo
- Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yu-Xia Wang
- Department of Pulmonary and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Ai-Hua Liu
- Department of Rheumatology and Immunology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Chun-Li Zhang
- Department of Hematology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
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8
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Velasco-Rodríguez D, Laso RV, García-Raso A, Mahíllo-Fernández I, Guzmán-López K, Martín-Herrero S, Barral EJ, Vegas-Sánchez MDC, Martínez-Becerra MJ, de la Plaza R, Romero LFL, Mínguez D, Alonso-Domínguez JM, López CB, López AG, Fernández MSS, Llamas-Sillero P. Thrombin generation in subjects with lupus anticoagulant without prior thrombosis or gestational morbidities. Thromb Res 2020; 196:425-431. [PMID: 33038586 DOI: 10.1016/j.thromres.2020.09.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/27/2020] [Accepted: 09/17/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Lupus anticoagulant (LA) can be a cause of thrombosis and/or pregnancy morbidities, producing antiphospholipid syndrome (APS). An increase in thrombin generation (TG) is correlated with prothrombotic status. Several changes in TG-derived parameters have been reported in APS patients. OBJECTIVES Evaluate whether the TG phenotype of APS can also be described in LA subjects without clinical manifestations of APS, and to investigate the possible influence of both LA potency and antiphospholipid (aPL) profile on it. RESULTS TG was analyzed in 153 cases of LA and 41 healthy controls. We have observed prolongation of both lag time (3.7 min vs 2.32 min, p < 0.001) and time to peak (6.48 min vs 5.27 min, p < 0.001), increased peak height (221.7 nM vs 182.7 nM, p < 0.001), slightly higher ETP (221.7 nM·min vs 182.7 nM·min, p = 0.041), and higher velocity index (100.7 nM/min vs 74.53 nM/min, p = 0.001) in LA subjects compared to controls. After adding thrombomodulin (TM), ETP%inh was significantly lower in LA group (37.90% vs 59.90%, p < 0.001) showing resistance to TM/activated protein C (APC). Significant differences were found in lag time, time to peak and ETP%inh according to the potency and aPL profile. CONCLUSIONS Previously described differences in TG-derived parameters in APS patients have been confirmed in incidental LA subjects: prolonged lag time and time to peak, slightly higher ETP, higher peak height, and less sensitivity to TM/APC. High LA potency and triple-positive aPL profile enhance differences in lag time, time to peak and, especially, increase APC resistance, but no effect in ETP was observed.
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Affiliation(s)
- Diego Velasco-Rodríguez
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain.
| | - Rosa Vidal Laso
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | - Aránzazu García-Raso
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | | | - Karina Guzmán-López
- Department of Immunology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - Sara Martín-Herrero
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | - Elena Jiménez Barral
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | | | | | - Reyes de la Plaza
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | | | - Dolores Mínguez
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | | | - Carlos Blas López
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | - Amanda García López
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain
| | | | - Pilar Llamas-Sillero
- Department of Hematology, Hospital Universitario Fundación Jiménez Díaz, IIS-FJD, Madrid, Spain; Department of Hematology, Hospitales Quirón públicos, IIS-FJD, Universidad Autónoma de Madrid, Madrid, Spain
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9
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Zuily S, de Laat B, Guillemin F, Kelchtermans H, Magy-Bertrand N, Desmurs-Clavel H, Lambert M, Poindron V, de Maistre E, Dufrost V, Risse J, Shums Z, Norman GL, de Groot PG, Lacolley P, Lecompte T, Regnault V, Wahl D. Anti–Domain I β2-Glycoprotein I Antibodies and Activated Protein C Resistance Predict Thrombosis in Antiphospholipid Syndrome: TAC(I)T Study. J Appl Lab Med 2020; 5:1242-1252. [DOI: 10.1093/jalm/jfaa072] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 04/24/2020] [Indexed: 11/13/2022]
Abstract
Abstract
Background
Antibodies binding to domain I of β2-glycoprotein I (aDI) and activated protein C (APC) resistance are associated with an increased risk of thrombosis in cross-sectional studies. The objective of this study was to assess their predictive value for future thromboembolic events in patients with antiphospholipid antibodies (aPL) or antiphospholipid syndrome.
Methods
This prospective multicenter cohort study included consecutive patients with aPL or systemic lupus erythematosus. We followed 137 patients (43.5 ± 15.4 year old; 107 women) for a mean duration of 43.1 ± 20.7 months.
Results
We detected aDI IgG antibodies by ELISA in 21 patients. An APC sensitivity ratio (APCsr) was determined using a thrombin generation–based test. The APCsr was higher in patients with anti–domain I antibodies demonstrating APC resistance (0.75 ± 0.13 vs 0.48 ± 0.20, P < 0.0001). In univariate analysis, the hazard ratio (HR) for thrombosis over time was higher in patients with aDI IgG (3.31 [95% CI, 1.15–9.52]; P = 0.03) and patients with higher APC resistance (APCsr >95th percentile; HR, 6.07 [95% CI, 1.69–21.87]; P = 0.006). A sensitivity analysis showed an increased risk of higher aDI IgG levels up to HR 5.61 (95% CI, 1.93–16.31; P = 0.01). In multivariate analysis, aDI IgG (HR, 3.90 [95% CI, 1.33–11.46]; P = 0.01) and APC resistance (HR, 4.98 [95% CI, 1.36–18.28]; P = 0.02) remained significant predictors of thrombosis over time.
Conclusions
Our study shows that novel tests for antibodies recognizing domain I of β2-glycoprotein I and functional tests identifying APC resistance are significant predictors of thrombosis over time and may be useful for risk stratification.
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Affiliation(s)
- Stephane Zuily
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
| | - Bas de Laat
- Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Francis Guillemin
- University of Lorraine, Nancy, France
- Inserm, CIC-EC CIE1433, Nancy, France
| | - Hilde Kelchtermans
- Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | | | - Marc Lambert
- CHRU de Lille, Department of Internal Medicine, Lille, France
| | - Vincent Poindron
- CHU de Strasbourg, Internal Medicine and Clinical Immunology Department, Strasbourg, France
| | | | - Virginie Dufrost
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
| | - Jessie Risse
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
| | - Zakera Shums
- CHU de Dijon, Hematology Department, Dijon, France
| | | | - Philip G de Groot
- Synapse Research Institute, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands
- Clinical Chemistry and Haematology, University Medical Centre (UMC) Utrecht, Utrecht, The Netherlands
| | - Patrick Lacolley
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
| | - Thomas Lecompte
- Nancy University Hospital, Hematology Laboratory, Nancy, France
| | - Véronique Regnault
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
| | - Denis Wahl
- Nancy University Hospital, Vascular Medicine Division and Regional Competence Center for Rare Vascular and Systemic Autoimmune Diseases, Nancy, France
- Inserm, U1116, Nancy, France
- Nancy University, Nancy, France
- University of Lorraine, Nancy, France
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10
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Chaturvedi S, McCrae KR. Clinical Risk Assessment in the Antiphospholipid Syndrome: Current Landscape and Emerging Biomarkers. Curr Rheumatol Rep 2018; 19:43. [PMID: 28711993 DOI: 10.1007/s11926-017-0668-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Laboratory criteria for the classification of antiphospholipid syndrome include the detection of a lupus anticoagulant and/or anticardiolipin and anti-β2-glycoprotein I antibodies. However, the majority of patients who test positive in these assays do not have thrombosis. Current risk-stratification tools are largely limited to the antiphospholipid antibody profile and traditional thrombotic risk factors. RECENT FINDINGS Novel biomarkers that correlate with disease activity and potentially provide insight into future clinical events include domain 1 specific anti-β2GPI antibodies, antibodies to other phospholipids or phospholipid/protein antigens (such as anti-PS/PT), and functional/biological assays such as thrombin generation, complement activation, levels of circulating microparticles, and annexin A5 resistance. Clinical risk scores may also have value in predicting clinical events. Biomarkers that predict thrombosis risk in patients with antiphospholipid antibodies have been long sought, and several biomarkers have been proposed. Ultimately, integration of biomarkers with established assays and clinical characteristics may offer the best chance of identifying patients at highest risk of APS-related complications.
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Affiliation(s)
- Shruti Chaturvedi
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37235, USA
| | - Keith R McCrae
- Department of Cellular and Molecular Medicine, Taussig Cancer Institute, Cleveland Clinic, CA6-154, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
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Abstract
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein 1 antibodies. APS can present with a variety of clinical phenotypes, including thrombosis in the veins, arteries and microvasculature as well as obstetrical complications. The pathophysiological hallmark is thrombosis, but other factors such as complement activation might be important. Prevention of thrombotic manifestations associated with APS includes lifestyle changes and, in individuals at high risk, low-dose aspirin. Prevention and treatment of thrombotic events are dependent mainly on the use of vitamin K antagonists. Immunosuppression and anticomplement therapy have been used anecdotally but have not been adequately tested. Pregnancy morbidity includes unexplained recurrent early miscarriage, fetal death and late obstetrical manifestation such as pre-eclampsia, premature birth or fetal growth restriction associated with placental insufficiency. Current treatment to prevent obstetrical morbidity is based on low-dose aspirin and/or low-molecular-weight heparin and has improved pregnancy outcomes to achieve successful live birth in >70% of pregnancies. Although hydroxychloroquine and pravastatin might further improve pregnancy outcomes, prospective clinical trials are required to confirm these findings.
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INFLUENCE OF L-ARGININ AND AMINOGUANIDINE ON RENAL FREE-RADICAL OXIDATION RATES IN CASES OF EXPERIMENTAL ANTIPHOSPOLIPID SYNDROME. WORLD OF MEDICINE AND BIOLOGY 2018. [DOI: 10.26724/2079-8334-2018-3-65-210-214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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de Groot PG, de Laat B. Mechanisms of thrombosis in systemic lupus erythematosus and antiphospholipid syndrome. Best Pract Res Clin Rheumatol 2017; 31:334-341. [PMID: 29224675 DOI: 10.1016/j.berh.2017.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 08/27/2017] [Indexed: 12/16/2022]
Abstract
The presence of antiphospholipid antibodies is one of the most common acquired risk factors for thrombosis. Antiphospholipid antibodies is a collective term for a set of autoantibodies with closely related but different specificity. Experiments in which isolated patient antibodies were injected into mice have shown that a specific subset of autoantibodies, those directed against the first domain of plasma protein β2-glycoprotein I, can explain the increased risk of thrombosis. Experiments performed with these mice have shown that autoantibodies against β2-glycoprotein I bind to and activate cells such as endothelial cells, monocytes, and platelets. Activation of these cells, all involved in the regulation of hemostasis, results in a shift towards a prothrombotic state. How this process is regulated, whether this is the only mechanism involved, and whether this is the only subpopulation responsible for the increased thrombotic risk is unknown. In this review, we will critically discuss what is known and what is debatable on the pathophysiology of antiphospholipid syndrome.
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Affiliation(s)
| | - Bas de Laat
- Synapse Research Institute, Maastricht, The Netherlands
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Chaturvedi S, McCrae KR. Diagnosis and management of the antiphospholipid syndrome. Blood Rev 2017; 31:406-417. [PMID: 28784423 DOI: 10.1016/j.blre.2017.07.006] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 06/22/2017] [Accepted: 07/28/2017] [Indexed: 12/14/2022]
Abstract
Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy complications in the presence of persistent antiphospholipid antibodies (APLA). Laboratory diagnosis of APLA depends upon the detection of a lupus anticoagulant, which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin (aCL) and anti-β2-glycoprotein-1 (β2GPI) antibodies. APLA are primarily directed toward phospholipid binding proteins. Pathophysiologic mechanisms underlying thrombosis and pregnancy loss in APS include APLA induced cellular activation, inhibition of natural anticoagulant and fibrinolytic systems, and complement activation, among others. There is a high rate of recurrent thrombosis in APS, especially in triple positive patients (patients with lupus anticoagulant, aCL and anti-β2GPI antibodies), and indefinite anticoagulation with a vitamin K antagonist is the standard of care for thrombotic APS. There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOAC) in thrombotic APS. Aspirin with low molecular weight or unfractionated heparin may reduce the incidence of pregnancy loss in obstetric APS. Recent insights into the pathogenesis of APS have led to the identification of new potential therapeutic interventions, including anti-inflammatory and immunomodulatory therapies. Additional research is needed to better understand the effects of APLA on activation of signaling pathways in vascular cells, to identify more predictive biomarkers that define patients at greatest risk for a first or recurrent APLA-related clinical event, and to determine the safety and efficacy of DOACs and novel anti-inflammatory and immune-modulatory therapies for refractory APS.
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Affiliation(s)
- Shruti Chaturvedi
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Keith R McCrae
- Department of Hematology and Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
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Brandt KJ, Kruithof EKO, de Moerloose P. Receptors involved in cell activation by antiphospholipid antibodies. Thromb Res 2013; 132:408-13. [PMID: 24054056 DOI: 10.1016/j.thromres.2013.08.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 08/16/2013] [Accepted: 08/18/2013] [Indexed: 02/08/2023]
Abstract
The antiphospholipid syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). The plasma protein β2-glycoprotein 1 (β2GP1) has been identified as a major target of aPLA associated with APS. Cell activation by aPLA appears to be a major pathogenic cause in the pathogenesis of APS. Receptors, co-receptors and accessory molecules are known to assist the pathogenic effects of aPLA. Members of the TLR family and the platelet receptor apolipoprotein E receptor 2' (apoER2'), a receptor belonging to the low-density lipoprotein receptor (LDL-R) family, as well as GPIbα, were identified as putative candidates for aPLA recognition. CD14, a co-receptor for TLR2 and TLR4, and annexin A2, a ubiquitous Ca2+ -binding protein that is essential for actin-dependent vesicle transport, could serve as important accessory molecules in mediating the pathogenic effects of aPLA. Finally, complement activation has been reported in association with the pathogenicity of APS. The relative contribution of these different mechanisms in the pathogenesis of APS is controversial. Here, we review the various in vivo and in vitro models that have been used to investigate the pathogenic mechanisms of aPLA in APS.
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Affiliation(s)
- Karim J Brandt
- Division of Angiology and Hemostasis, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
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Zuily S, Aissa KA, Membre A, Regnault V, Lecompte T, Wahl D. Thrombin generation in antiphospholipid syndrome. Lupus 2012; 21:758-60. [DOI: 10.1177/0961203312440059] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Our objective was to study acquired Activated Protein C (APC) resistance in patients with antiphospholipid antibodies (aPL) using a thrombin generation based assay. We compared patients with and without lupus (systemic lupus erythematosus, SLE). A parameter summarizing APC inhibition of thrombin generation with increasing APC concentrations (IC50-APC) was increased in all patient groups compared to controls: median values were 15.3 (interquartile range, IQR, 9.7 to 34.0) in patients with primary antiphospholipid syndrome (APS), 27.3 (IQR 23.5 to 43.5) in patients with SLE without APS, 64.1 (IQR 25.9 to 65.0) in patients with SLE/APS compared to 10.4 [IQR 8.5 to 15.8] in controls, respectively p = 0.003, p = 0.0001 and p = 0.0001. In conclusion, patients with SLE and primary APS displayed a hypercoagulable state characterized by APC resistance.
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Affiliation(s)
- S Zuily
- Inserm, U961, Vandoeuvre-lès-Nancy, France
- Université de Lorraine, France
- CHU Nancy, Competence Center for Systemic Autoimmune Diseases and Division of Vascular Medicine, Vandoeuvre-lès-Nancy, France
| | | | | | - V Regnault
- Inserm, U961, Vandoeuvre-lès-Nancy, France
| | - T Lecompte
- Inserm, U961, Vandoeuvre-lès-Nancy, France
- Université de Lorraine, France
- CHU Nancy, Competence Center for Systemic Autoimmune Diseases and Division of Vascular Medicine, Vandoeuvre-lès-Nancy, France
- Hematology Geneva, Switzerland
| | - D Wahl
- Inserm, U961, Vandoeuvre-lès-Nancy, France
- Université de Lorraine, France
- CHU Nancy, Competence Center for Systemic Autoimmune Diseases and Division of Vascular Medicine, Vandoeuvre-lès-Nancy, France
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Alessandri C, Conti F, Pendolino M, Mancini R, Valesini G. New autoantigens in the antiphospholipid syndrome. Autoimmun Rev 2011; 10:609-16. [DOI: 10.1016/j.autrev.2011.04.011] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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de Groot PG, Derksen RHWM, Urbanus RT. The role of LRP8 (ApoER2') in the pathophysiology of the antiphospholipid syndrome. Lupus 2010; 19:389-93. [PMID: 20353975 DOI: 10.1177/0961203309360542] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
One of the greatest enigmas in thrombosis research is the observation that one can diagnose a person with a thrombotic risk with a prolongation of the clotting time. Our textbooks have taught us that prolongation of clotting correlates with a tendency to bleed. To confuse our textbook knowledge further, the same patients often have a prolonged bleeding time, a diagnostic test to detect a dysfunction in primary haemostasis. In this paper we critically review the literature that tries to explain the contradiction that exists between in-vitro diagnostic tests and the observed clinical manifestations and discuss our current opinion on how antiphospholipid antibodies can disturb the haemostatic balance.
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Affiliation(s)
- P G de Groot
- Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands.
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Abstract
Haemostasis is a delicate balance between procoagulant and anticoagulant processes. In the human body usually anticoagulant mechanisms prevail over procoagulant mechanisms, thereby preventing a prothrombotic state. The antiphospholipid syndrome is an example in which this balance is shifted to a more prothrombotic state due to the presence of antiphospholipid antibodies. One of the most extensively proposed pathogenic mechanisms within the antiphospholipid syndrome is the inhibition of protein C by antiphospholipid antibodies. Antiphospholipid antibodies have been described to have different actions on the protein C pathway, for example decreasing protein C and/or S plasma levels, inducing increased resistance against activated protein C and lowering thrombin levels (resulting in an impaired protein C activation). This review briefly discusses the actions of protein C in human body but mainly focuses on the effects of antiphospholipid antibodies on the protein C pathway that have been described in literature.
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Affiliation(s)
- R T Urbanus
- Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, The Netherlands
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Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci 2009; 7:15-8. [PMID: 20046230 PMCID: PMC2792733 DOI: 10.7150/ijms.7.15] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2009] [Accepted: 11/30/2009] [Indexed: 11/19/2022] Open
Abstract
Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS.The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4+/-0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9+/-2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.
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Affiliation(s)
- Hirohisa Okuma
- Department of Neurology, Tokai University Tokyo Hospital, Tokyo, Japan.
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