Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome
-
Ariela Hoxha
,
Elena Mattia
Abstract
Background:
Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies have begun to be considered potentional biomarkers for antiphospholipid syndrome (APS). This cohort study investigate the role of aPS/PT antibodies as a risk factor for severe APS by evaluating the association between those antibodies and clinical/laboratory profiles of APS.
Methods:
Plasma/serum samples from 197 APS patients, 100 healthy subjects and 106 patients with autoimmune diseases were collected. IgG/IgM aPS/PT antibodies were assayed using commercial ELISA kit.
Results:
Prevalences of IgG and IgM aPS/PT (p<0.0001 and p=0.0009, respectively) and their titres (p<0.0001 and p=0.0002, respectively) were significantly higher in thrombosis/pregnancy group with respect to pregnancy morbidity alone. Prevalences of IgG and IgM aPS/PT (p<0.0001 and p=0.0004, respectively) and their mean levels (p=0.0001 for both) were significantly higher in the prematurity linked to life-threatening obstetric complications group with respect to miscarriage group. There was a significant relationship between IgG and IgM aPS/PT (p=0.001 and p=0.0002) and their mean levels were higher (p=0.0004 and p=0.0002, respectively) in the thrombotic microangiopathy group, considered a milestone manifestation of catastrophic APS. The relationship between IgG and IgM aPS/PT was significant and mean levels were higher in triple positive antiphospholipid antibody patients than in double and single positivity ones (p<0.0001 for all).
Conclusions:
APS/PT antibodies were associated to severe thrombosis, severe pregnancy complications inducing prematurity, and vascular microangiopathy, all generally associated to high risk APS forms requiring strong therapy.
Acknowledgments
The authors thank Mrs. Linda Inverso for editing the English version of the manuscript.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.10.1111/j.1538-7836.2006.01753.xSearch in Google Scholar
2. Bertolaccini ML, Amengual O, Atsumi T, Binder WL, de Laat B, Forastiero R, et al. ‘Non-criteria’ aPL tests: report of a task force and preconference workshop at the 13th International Congress on antiphospholipid Antibodies, Galveston, TX, USA, April 2010. Lupus, 2011;20:191–205.10.1177/0961203310397082Search in Google Scholar
3. Atsumi T, Ieko M, Bertolaccini ML, Ichikawa K, Tsutsumi A, Matsuura E, et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the antiphospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheum 2000;43:1982–93.10.1002/1529-0131(200009)43:9<1982::AID-ANR9>3.0.CO;2-2Search in Google Scholar
4. Peterson LK, Willis R, Harris EN, Branch WD, Tebo AE. Antibodies to phosphatidylserine/prothrombin complex in antiphospholipid syndrome: analytical and clinical perspectives. Adv Clin Chem 2016;73:1–28.10.1016/bs.acc.2015.10.003Search in Google Scholar
5. Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A systematic review. Thromb Haemost 2014;111:354–64.10.1160/TH13-06-0509Search in Google Scholar
6. Bertolaccini ML, Sciascia S, Murru V, Garcia-Fernandez C, Sanna G, Khamashta MA. Prevalence of antibodies to prothrombin in solid phase (aPT) and to phosphatidylserine-prothrombin complex (aPS/PT) in patients with and without lupus anticoagulant. Thromb Haemost 2013;109:207–13.10.1160/TH12-07-0527Search in Google Scholar
7. Matsuda J, Saitoh N, Gotoh M, Kawasugi K, Gohchi K, Tsukamoto M. Phosphatidylserine-dependent antiprothrombin antibody is exclusive to patients with lupus anticoagulant. Br J Rheumatol 1996;35:589–91.10.1093/rheumatology/35.6.589Search in Google Scholar
8. Pregnolato F, Chighizola CB, Encabo S, Shums Z, Norman GL, Tripodi A, et al. Anti-phosphatidylserine/prothrombin antibodies: an additional diagnostic marker for APS? Immunol Res 2013;56:432–8.10.1007/s12026-013-8421-zSearch in Google Scholar
9. Hoxha A, Ruffatti A, Tonello M, Bontadi A, Salvan E, Banzato A, et al. Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome. Lupus 2012;21:787–9.10.1177/0961203312441983Search in Google Scholar
10. Hoxha A, Ruffatti A, Mattia E, Meneghel L, Tonello M, Salvan E, et al. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome. Clin Chem Lab Med 2015;53:1265–70.10.1515/cclm-2014-1129Search in Google Scholar
11. Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. GAPSS: the global anti-phospholipid syndrome score. Rheumatology (Oxford) 2013;52:1397–403.10.1093/rheumatology/kes388Search in Google Scholar PubMed
12. Sciascia S, Sanna G, Murru V, Khamashta MA, Bertolaccini ML. Validation of a commercially available kit to detect anti-phosphatidylserine/prothrombin antibodies in a cohort of systemic lupus erythematosus patients. Thromb Res 2014;133:451–4.10.1016/j.thromres.2013.12.001Search in Google Scholar PubMed
13. Tincani A, Allegri F, Balestrieri G, Reber G, Sanmarco M, Meroni PL, et al. Minimal requirements for antiphospholipid antibodies ELISAs proposed by the European Forum on antiphospholipid antibodies. Thromb Res 2004;114:553–8.10.1016/j.thromres.2004.06.035Search in Google Scholar PubMed
14. Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC. Proposals for the measurement of anti-b2-glycoprotein I antibodies. Standardization group of the European forum on antiphospholipid antibodies. J Thromb Haemost 2004;2:1860–2.10.1111/j.1538-7836.2004.00910.xSearch in Google Scholar PubMed
15. Ruffatti A, Olivieri S, Tonello M, Bortolatti M, Bison E, Salvan E, et al. Influence of different IgG anticardiolipin antibody cut-off values on antiphospholipid syndrome classification. J Thromb Haemost 2008;6:1693–6.10.1111/j.1538-7836.2008.03121.xSearch in Google Scholar PubMed
16. Harris EN, Pierangeli SS. Revisiting the anticardiolipin test and its standardization. Lupus 2002;11:269–75.10.1191/0961203302lu202crSearch in Google Scholar PubMed
17. Forastiero R, Papalardo E, Watkins M, Nguyen H, Quirbach C, Jaskal K, et al. Evaluation of different immunoassays for the detection of antiphospholipid antibodies: report of a wet workshop during the 13th international congress on antiphospholipid antibodies. Clin Chim Acta 2014;428:99–105.10.1016/j.cca.2013.11.009Search in Google Scholar PubMed
18. Clinical and Laboratory Standards Institute. User verification of performance for precision and trueness; approved guidelines. 2nd ed. EP 15-A2. Wayne, PA: Clinical and Laboratory Standards Institute, 2005.Search in Google Scholar
19. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al; Subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardisation committee of the international society on thrombosis and haemostasis. Update of the guidelines for lupus anticoagulant detection. Subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardisation committee of the international society on thrombosis and haemostasis. J Thromb Haemost 2009;7:1737–40.10.1111/j.1538-7836.2009.03555.xSearch in Google Scholar PubMed
20. Bertolaccini ML, Atsumi T, Koike T, Hughes GR, Khamashta MA. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost 2005;93:289–97.10.1160/TH04-06-0382Search in Google Scholar PubMed
21. Vlagea A, Gil A, Cuesta MV, Arribas F, Diez J, Lavilla P, et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential markers of antiphospholipid syndrome. Clin Appl Thromb Hemost 2013;19:289–96.10.1177/1076029612437578Search in Google Scholar PubMed
22. Nojima J, Iwatani Y, Suehisa E, Kuratsune H, Kanakura Y. The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus. Haematologica 2006:91:699–702.Search in Google Scholar
23. Ruffatti A, Tonello M, Visentin MS, Bontadi A, Hoxha A, De Carolis S, et al. Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre,case-control study. Rheumatology (Oxford) 2011;50:1684–9.10.1093/rheumatology/ker139Search in Google Scholar
24. Asherson RA, Cervera R, Pierangeli SS. Microangiopathic antiphospholipid syndromes (MAPS) revisited—new concepts relating to antiphospholipid antibodies and syndromes. J Rheumatol 2007;34:1793–5.Search in Google Scholar
25. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Preeclampsia. Lancet 2010;376:631–44.10.1016/S0140-6736(10)60279-6Search in Google Scholar
26. Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005;93:147–52.Search in Google Scholar
27. Ruffatti A, Tonello M, Del Ross T, Cavazzana A, Grava C, Noventa F, et al. Antibody profile and clinical course in primary antiphospholipid syndrome and pregnancy morbidity. Thromb Haemost 2006;96:337–41.10.1160/TH06-05-0287Search in Google Scholar PubMed
28. Pengo V, Ruffatti A, Legnani C, Gresele P, Barcellona D, Erba N, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010;8:237–42.10.1111/j.1538-7836.2009.03674.xSearch in Google Scholar PubMed
29. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003;101:1827–32.10.1182/blood-2002-02-0441Search in Google Scholar PubMed
30. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res 2013;65:1869–73.10.1002/acr.22066Search in Google Scholar PubMed
31. Yelnik CM, Laskin CA, Porter TF, Branch DW, Buyon JP, Guerra MM, et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results.Lupus Sci Med 2016;3:e000131.10.1136/lupus-2015-000131Search in Google Scholar PubMed PubMed Central
32. Ruffatti A, Calligaro A, Hoxha A, Trevisanuto D, Ruffatti AT, Gervasi MT, et al. Laboratory and clinical features of pregnant women with antiphospholipid syndrome and neonatal outcome. Arthritis Care Res 2010;62:302–7.10.1002/acr.20098Search in Google Scholar PubMed
33. Ruffatti A, Del Ross T, Ciprian M, Bertero MT, Sciascia S, Scarpato S, et al. Antiphospholipid syndrome study group of Italian society of rheumatology. Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study. Ann Rheum Dis 2011;70:1083–6.10.1136/ard.2010.142042Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
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- False biochemical diagnosis of hyperthyroidism in streptavidin-biotin-based immunoassays: the problem of biotin intake and related interferences
- Vitamin K plasma levels determination in human health
- Mini Review
- Point-of-care testing INR: an overview
- Opinion Paper
- Could accreditation bodies facilitate the implementation of medical guidelines in laboratories?
- Genetics and Molecular Diagnostics
- QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions
- General Clinical Chemistry and Laboratory Medicine
- High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference
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- Retrospective evaluation of the clinical utility of serological biomarkers in Chinese patients with inflammatory bowel disease: 2-year clinical experience
- Infrared analysis of lipoproteins in the detection of alcohol biomarkers
- Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk
- Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome
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- The impact of admission neutrophil-to-platelet ratio on in-hospital and long-term mortality in patients with infective endocarditis
- Letters to the Editor
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- A simple method to detect biotin interference on immunoassays
- Proposed classification for a variant of Kounis syndrome
- Lyophilized hemoglobin E control material for the dichlorophenol-indophenol (DCIP) test
- Procalcitonin variation before and after 100-km ultramarathon
- Preliminary study in specific activity of molecular components in allergy: implications for diagnostics and relationship with disease severity
- A 2-min at 4500 g rather than a 15-min at 2200 g centrifugation does not impact the reliability of 10 critical coagulation assays
- Immunoassay interference caused by heterophilic antibodies interacting with biotin
- Red blood cell distribution width and mean platelet volume are potential prognostic indices for patients with primary biliary cirrhosis
- Neutrophil CD64 molecule expression can predict bloodstream infection in septic shock patients
Articles in the same Issue
- Frontmatter
- Editorial
- Biotin interference on immunoassay methods: sporadic cases or hidden epidemic?
- Reviews
- False biochemical diagnosis of hyperthyroidism in streptavidin-biotin-based immunoassays: the problem of biotin intake and related interferences
- Vitamin K plasma levels determination in human health
- Mini Review
- Point-of-care testing INR: an overview
- Opinion Paper
- Could accreditation bodies facilitate the implementation of medical guidelines in laboratories?
- Genetics and Molecular Diagnostics
- QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions
- General Clinical Chemistry and Laboratory Medicine
- High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference
- Multicenter performance evaluation of a second generation cortisol assay
- A rapid UPLC-MS/MS assay for the simultaneous measurement of fluconazole, voriconazole, posaconazole, itraconazole, and hydroxyitraconazole concentrations in serum
- A microplate assay to measure classical and alternative complement activity
- Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2
- Retrospective evaluation of the clinical utility of serological biomarkers in Chinese patients with inflammatory bowel disease: 2-year clinical experience
- Infrared analysis of lipoproteins in the detection of alcohol biomarkers
- Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk
- Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome
- Cardiovascular Diseases
- The impact of admission neutrophil-to-platelet ratio on in-hospital and long-term mortality in patients with infective endocarditis
- Letters to the Editor
- Biotin interference in immunoassays mimicking subclinical Graves’ disease and hyperestrogenism: a case series
- A simple method to detect biotin interference on immunoassays
- Proposed classification for a variant of Kounis syndrome
- Lyophilized hemoglobin E control material for the dichlorophenol-indophenol (DCIP) test
- Procalcitonin variation before and after 100-km ultramarathon
- Preliminary study in specific activity of molecular components in allergy: implications for diagnostics and relationship with disease severity
- A 2-min at 4500 g rather than a 15-min at 2200 g centrifugation does not impact the reliability of 10 critical coagulation assays
- Immunoassay interference caused by heterophilic antibodies interacting with biotin
- Red blood cell distribution width and mean platelet volume are potential prognostic indices for patients with primary biliary cirrhosis
- Neutrophil CD64 molecule expression can predict bloodstream infection in septic shock patients
