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DOI: 10.1055/s-0039-1692701
Validity of Coagulation Activation Markers in Antiphospholipid Syndrome: A Systematic Review and Meta-analysis with a Short Data Report
Publication History
Publication Date:
24 June 2019 (online)
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Abstract
Prothrombin fragment F1 + 2 (F1 + 2) and thrombin–antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case–control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-β2-glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL −ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL −ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL −ve SLE patients and between aPL −ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS (p < 0.0001), inversely correlated with IgG aCL, IgM aPT, and LA (p = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted F1 + 2 (p = 0.01). IgG aCL inversely predicts F1 + 2. IgG aCL positivity introduces heterogeneity in the F1 + 2 ES, whereas the lack of heterogeneity in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements may be unfounded as already demonstrated for TAT in the 1990s.
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References
- 1 Bauer KA. Activation markers of coagulation. Best Pract Res Clin Haematol 1999; 12 (03) 387-406
- 2 Miyakis S, Lockshin MD, Atsumi T. , et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
- 3 Ames PRJ, Tommasino C, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies--a crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76 (02) 190-194
- 4 Shibata S, Harpel PC, Gharavi A, Rand J, Fillit H. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. Blood 1994; 83 (09) 2532-2540
- 5 Liberati A, Altman DG, Tetzlaff J. , et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151 (04) W65-W94
- 6 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 + 2 fragment and thrombin--antithrombin complex. Blood 1982; 59 (05) 1086-1097
- 7 Wells GA, Shea B, O'Connell D. , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm . Accessed May 24, 2019
- 8 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): 557-560
- 9 Tang JL, Liu JL. Misleading funnel plot for detection of bias in meta-analysis. J Clin Epidemiol 2000; 53 (05) 477-484
- 10 Lau J, Ioannidis JPA, Terrin N, Schmid CH, Olkin I. The case of the misleading funnel plot. BMJ 2006; 333 (7568): 597-600
- 11 Devreese KM, Pierangeli SS, de Laat B, Tripodi A, Atsumi T, Ortel TL. ; Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12 (05) 792-795
- 12 Gschwandtner ME, Eichinger S, Hütter D. , et al. Lupus anticoagulant and thromboembolism: evaluation of fibrinogen, natural inhibitors and molecular markers of thrombosis. Blood Coagul Fibrinolysis 1996; 7 (03) 325-330
- 13 Yamazaki M, Asakura H, Saito M. , et al. Prothrombin fragment 1 + 2 measures treatment effect in patients with antiphospholipid syndrome. Thromb Res 1998; 91 (03) 121-128
- 14 Reverter JC, Tàssies D, Font J. , et al. Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein s. Arterioscler Thromb Vasc Biol 1996; 16 (11) 1319-1326
- 15 Matsuda J, Gohchi K, Kawasugi K. Increased factor VIIa levels in systemic lupus erythematosus patients with lupus anticoagulant. Int J Hematol 1997; 65 (02) 143-149
- 16 Martinuzzo ME, Forastiero RR, Kordich L, Carreras LO. Increased lipid peroxidation correlates with platelet activation but not with markers of endothelial cell and blood coagulation activation in patients with antiphospholipid antibodies. Br J Haematol 2001; 114 (04) 845-851
- 17 Ginsberg JS, Demers C, Brill-Edwards P. , et al. Increased thrombin generation and activity in patients with systemic lupus erythematosus and anticardiolipin antibodies: evidence for a prothrombotic state. Blood 1993; 81 (11) 2958-2963
- 18 Ferro D, Quintarelli C, Valesini G, Violi F. Lupus anticoagulant and increased thrombin generation in patients with systemic lupus erythematosus. Blood 1994; 83 (01) 304
- 19 Martini F, Farsi A, Gori AM. , et al. Antiphospholipid antibodies (aPL) increase the potential monocyte procoagulant activity in patients with systemic lupus erythematosus. Lupus 1996; 5 (03) 206-211
- 20 Ferro D, Pittoni V, Quintarelli C. , et al. Coexistence of anti-phospholipid antibodies and endothelial perturbation in systemic lupus erythematosus patients with ongoing prothrombotic state. Circulation 1997; 95 (06) 1425-1432
- 21 Praticò D, Ferro D, Iuliano L. , et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999; 93 (10) 3401-3407
- 22 Ferro D, Basili S, Roccaforte S. , et al. Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus. Arthritis Rheum 1999; 42 (12) 2689-2697
- 23 Ellis MH, Kesler A, Friedman Z, Drucker I, Radnai Y, Kott E. Value of prothrombin fragment 1.2 (F 1.2) in the diagnosis of stroke in young patients with antiphospholipid antibodies. Clin Appl Thromb Hemost 2000; 6 (02) 61-64
- 24 Vogel JJ, Reber G, de Moerloose P. Laboratory and clinical features in systemic lupus erythematosus patients with or without anticardiolipin antibodies. Thromb Res 1991; 62 (05) 545-556
- 25 Nakase T, Wada H, Minamikawa K. , et al. Increased activated protein C-protein C inhibitor complex level in patients positive for lupus anticoagulant. Blood Coagul Fibrinolysis 1994; 5 (02) 173-177
- 26 Pereira J, Alfaro G, Goycoolea M. , et al. Circulating platelet-derived microparticles in systemic lupus erythematosus. Association with increased thrombin generation and procoagulant state. Thromb Haemost 2006; 95 (01) 94-99
- 27 Bugała K, Mazurek A, Gryga K. , et al. Influence of autoimmunity and inflammation on endothelial function and thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 2018; 37 (08) 2087-2093
- 28 Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135-148
- 29 Pozzi N, Chen Z, Pelc LA, Shropshire DB, Di Cera E. The linker connecting the two kringles plays a key role in prothrombin activation. Proc Natl Acad Sci U S A 2014; 111 (21) 7630-7635
- 30 Malia RG, Brroksfield G, Bulman I, Greaves M. Prothrombin fragment F1 + 2: the epitope for antiphospholipid antibody expression. Presented at the XVI Congress of the International Society for Thrombosis & Haemostasis, Florence, Italy, June 6–12 (Abstract 689), 1997
- 31 Matsuda J, Matsuyama A, Atsumi G, Ohkura N. Sole existence of antithrombin antibody in patients with systemic lupus erythematosus showing tendency of its antigenic determinants directing against exosite II (antithrombin/heparin binding site) of thrombin. Blood Coagul Fibrinolysis 2008; 19 (01) 66-69
- 32 Merashli M, Alves J, Ames PRJ. Clinical relevance of antiphospholipid antibodies in systemic sclerosis: a systematic review and meta-analysis. Semin Arthritis Rheum 2017; 46 (05) 615-624
- 33 Merashli M, Alves JD, Gentile F, Ames PRJ. Relevance of antiphospholipid antibodies in multiple sclerosis: a systematic review and meta analysis. Semin Arthritis Rheum 2017; 46 (06) 810-818
- 34 Douketis JD, Crowther MA, Julian JA. , et al. The effects of low-intensity warfarin on coagulation activation in patients with antiphospholipid antibodies and systemic lupus erythematosus. Thromb Haemost 1999; 82 (03) 1028-1032
- 35 Cohen H, Hunt BJ, Efthymiou M. , et al; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016; 3 (09) e426-e436