Download PDF
Thromb Haemost 2020; 120(04): 592-598
DOI: 10.1055/s-0040-1705115
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Antiphosphatidylserine/Prothrombin Antibodies: An Update on Their Association with Clinical Manifestations of Antiphospholipid Syndrome

Massimo Radin
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
,
Silvia G. Foddai
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
,
Irene Cecchi
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
,
Elena Rubini
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
,
Karen Schreiber
3   Department of Thrombosis and Haemophilia, Guy's and St Thomas' Hospital, London, United Kingdom
4   Department of Rheumatology, Copenhagen University Hospital, Copenhagen, Denmark
,
Dario Roccatello
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
,
Maria Laura Bertolaccini
2   Academic Department of Vascular Surgery, School of Cardiovascular Sciences and Medicine, King's College London, United Kingdom
,
Savino Sciascia
1   Center of Research of Immunopathology and Rare Diseases-Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, and SCDU Nephrology and Dialysis, S. Giovanni Bosco Hospital, Turin, Italy
› Author Affiliations Funding M.L.B. is funded by the King’s BHF Centre for Award Excellence RE/18/2/34213; M.R. is funded by a grant from the Italian Ministry of Health SG-2018-12368028.
Further Information

Publication History

30 October 2019

15 January 2020

Publication Date:
17 March 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Objective The aim of the study is to perform a systematic review on the recent available evidence on antiphosphatidylserine/prothrombin (aPS/PT) antibodies and their association with clinical manifestations of the antiphospholipid syndrome (APS).

Methods A detailed literature search was applied a priori to Ovid MEDLINE, In-Process and Other Non-Indexed Citation 2012 to present and to abstract from EULAR and ACR/ARHP Annual Meetings (2012–2019).

Results Data from 2,901 patients, 587 diseases controls and 559 healthy controls included in 15 retrieved studies was analyzed. The patient population included 1,219 patients classified as APS according to the Sidney criteria, 285 patients with isolated persistently positive antiphospholipid antibodies (aPL) and 1,397 patients with a clinical suspicion of APS. Twelve studies, including 1,888 patients, analyzed the association between aPS/PT antibodies and thrombosis. We observed a statistically significant association between aPS/PT IgG/IgM positivity and thrombotic events (mean odds ratio [OR]: 6.8 [95% CI: 3.18–16.4], p < 0.05), confirmed when analyzing aPS/PT IgG (mean OR: 6.7 [95% CI: 3.04–21.6], p < 0.05) and aPS/PT IgM (mean OR: 4.35 [95% CI: 1.54–17.77], p < 0.05) separately. Seven studies, including 1,388 patients, evaluated the association between aPS/PT antibodies and PM. When pooled together, we found a statistically significant association between any PM and aPS/PT IgG/IgM positivity (mean OR: 10.6 [95% CI: 3.54–35.38], p < 0.05), particularly aPS/PT IgG positivity (mean OR: 6.7 [95% CI: 3.04–21.6], p < 0.05).

Conclusion Our results highlight the strong association between aPS/PT and the clinical manifestations of APS. With the available level of evidence, aPS/PT testing can be considered as a robust test applicable in the investigation of patients suspected for APS, also beyond the research settings.

Keywords

antiphospholipid syndrome - antiphospholipid antibodies - antiphosphatidylserine - antiphosphatidylserine/prothrombin - non criteria aPL - thrombosis - autoimmunity

Authors' Contributions

R.M., S.G.F., C.I., R.E., and S.K. searched the literature, assisted with the organization of the manuscript, interpreted and collected data, and wrote and edited the systematic review. R.M., S.S., R.D., and M.L.B. interpreted and collected data, helped to design the figures and panel, and wrote and edited the systematic review.


 

  • References

  • 1 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
    CrossrefPubMedSearch in Google Scholar
  • 2 Vikerfors A, Johansson A-B, Gustafsson JT. , et al. Clinical manifestations and anti-phospholipid antibodies in 712 patients with systemic lupus erythematosus: evaluation of two diagnostic assays. Rheumatology (Oxford) 2013; 52 (03) 501-509
    CrossrefPubMedSearch in Google Scholar
  • 3 Pengo V, Biasiolo A, Bison E, Chantarangkul V, Tripodi A. ; Italian Federation of Anticoagulation Clinics (FCSA). Antiphospholipid antibody ELISAs: survey on the performance of clinical laboratories assessed by using lyophilized affinity-purified IgG with anticardiolipin and anti-beta2-Glycoprotein I activity. Thromb Res 2007; 120 (01) 127-133
    CrossrefPubMedSearch in Google Scholar
  • 4 Parkpian V, Verasertniyom O, Vanichapuntu M. , et al. Specificity and sensitivity of anti-beta2-glycoprotein I as compared with anticardiolipin antibody and lupus anticoagulant in Thai systemic lupus erythematosus patients with clinical features of antiphospholipid syndrome. Clin Rheumatol 2007; 26 (10) 1663-1670
    CrossrefPubMedSearch in Google Scholar
  • 5 Radin M, Cecchi I, Pérez-Sánchez C. Antiphospholipid antibodies negativization: time for testing for non-criteria aPL?. Lupus 2017; 26 (13) 1457-1458
    CrossrefPubMedSearch in Google Scholar
  • 6 Sciascia S, Radin M, Bazzan M, Roccatello D. Novel diagnostic and therapeutic frontiers in thrombotic anti-phospholipid syndrome. Intern Emerg Med 2017; 12 (01) 1-7
    CrossrefPubMedSearch in Google Scholar
  • 7 Rodríguez-García V, Ioannou Y, Fernández-Nebro A, Isenberg DA, Giles IP. Examining the prevalence of non-criteria anti-phospholipid antibodies in patients with anti-phospholipid syndrome: a systematic review. Rheumatology (Oxford) 2015; 54 (11) 2042-2050
    CrossrefPubMedSearch in Google Scholar
  • 8 Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M, Khamashta MA. Seronegative antiphospholipid syndrome. Rheumatology (Oxford) 2013; 52 (08) 1358-1367
    CrossrefPubMedSearch in Google Scholar
  • 9 Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. GAPSS: the Global Anti-Phospholipid Syndrome Score. Rheumatology (Oxford) 2013; 52 (08) 1397-1403
    CrossrefPubMedSearch in Google Scholar
  • 10 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 (02) 354-364
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Ramagopalan SV, Wotton CJ, Handel AE, Yeates D, Goldacre MJ. Risk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study. BMC Med 2011; 9: 1
    CrossrefPubMedSearch in Google Scholar
  • 12 PRISMA 2009 Checklist. Available at: http://prisma-statement.org/documents/PRISMA%202009%20checklist.pdf . Accessed February 11, 2020
    PubMed
  • 13 Mullen MT, Messé SR, Kasner SE. , et al. Anti-phosphatidylserine-prothrombin antibodies are associated with outcome in aTIA cohort. Front Neurol 2012; 3: 1–6
    PubMedSearch in Google Scholar
  • 14 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 (03) 451-454
    CrossrefPubMedSearch in Google Scholar
  • 15 Kim H, Kim JE, Hwang SM, Lee HR, Han KS, Kim HK. Synergistic thrombotic risk of antibodies against phosphatidylserine and prothrombin and β-2-glycoprotein I. Clin Appl Thromb Hemost 2014; 20 (04) 442-447
    CrossrefPubMedSearch in Google Scholar
  • 16 Hoxha A, Ruffatti A, Mattia E. , et al. Relationship between antiphosphatidylserine/prothrombin and conventional antiphospholipid antibodies in primary antiphospholipid syndrome. Clin Chem Lab Med 2015; 53 (08) 1265-1270
    PubMedSearch in Google Scholar
  • 17 Žigon P, Perdan Pirkmajer K, Tomšič M. , et al. Anti-Phosphatidylserine/Prothrombin Antibodies Are Associated with Adverse Pregnancy Outcomes. J Immunol Res 2015 Doi: 10.1155/2015/975704
    PubMedSearch in Google Scholar
  • 18 Zuily S, de Laat B, Mohamed S. , et al; TAC(I)T investigators. Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study. Rheumatology (Oxford) 2015; 54 (11) 2071-2075
    CrossrefPubMedSearch in Google Scholar
  • 19 Amengual O, Forastiero R, Sugiura-Ogasawara M. , et al. Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. Lupus 2017; 26 (03) 266-276
    CrossrefPubMedSearch in Google Scholar
  • 20 Marchetti T, de Moerloose P, Gris JC. Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study. J Thromb Haemost 2016; 14 (04) 675-684
    CrossrefPubMedSearch in Google Scholar
  • 21 Hoxha A, Mattia E, Tonello M, Grava C, Pengo V, Ruffatti A. Antiphosphatidylserine/prothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome. Clin Chem Lab Med 2017; 55 (06) 890-898
    CrossrefPubMedSearch in Google Scholar
  • 22 Lee JS, Gu J, Park HS, Yoo HJ, Kim HK. Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk. Clin Chem Lab Med 2017; 55 (06) 882-889
    CrossrefPubMedSearch in Google Scholar
  • 23 Zhu L, Li C, Liu N. , et al. Diagnostic value of antibodies to phosphatidylserine/prothrombin complex for antiphospholipid syndrome in Chinese patients. Clin Rheumatol 2017; 36 (02) 401-406
    CrossrefPubMedSearch in Google Scholar
  • 24 Zhang S, Wu Z, Zhang W. , et al. Antibodies to phosphatidylserine/prothrombin (aPS/PT) enhanced the diagnostic performance in Chinese patients with antiphospholipid syndrome. Clin Chem Lab Med 2018; 56 (06) 939-946
    CrossrefPubMedSearch in Google Scholar
  • 25 Shi H, Zheng H, Yin Y-F. , et al. Antiphosphatidylserine/prothrombin antibodies (aPS/PT) as potential diagnostic markers and risk predictors of venous thrombosis and obstetric complications in antiphospholipid syndrome. Clin Chem Lab Med 2018; 56 (04) 614-624
    CrossrefPubMedSearch in Google Scholar
  • 26 Ganapati A, Goel R, Kabeerdoss J, Gowri M, Mathew J, Danda D. Study of clinical utility of antibodies to phosphatidylserine/prothrombin complex in Asian-Indian patients with suspected APS. Clin Rheumatol 2019; 38 (02) 545-553
    CrossrefPubMedSearch in Google Scholar
  • 27 Núñez-Álvarez CA, Hernández-Molina G, Bermúdez-Bermejo P. , et al. Prevalence and associations of anti-phosphatidylserine/prothrombin antibodies with clinical phenotypes in patients with primary antiphospholipid syndrome: aPS/PT antibodies in primary antiphospholipid syndrome. Thromb Res 2019; 174: 141-147
    CrossrefPubMedSearch in Google Scholar
  • 28 Bertolaccini ML. Antibodies to prothrombin. Lupus 2012; 21 (07) 729-731
    CrossrefPubMedSearch in Google Scholar
  • 29 Pozzi N, Di Cera E. Prothrombin structure: unanticipated features and opportunities. Expert Rev Proteomics 2014; 11 (06) 653-655
    CrossrefPubMedSearch in Google Scholar
  • 30 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 (02) 289-297
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Bertolaccini ML, Gomez S, Pareja JFP. , et al. Antiphospholipid antibody tests: spreading the net. Ann Rheum Dis 2005; 64 (11) 1639-1643
    CrossrefPubMedSearch in Google Scholar
  • 32 Chinnaraj M, Planer W, Pengo V, Pozzi N. Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis. Blood Adv 2019; 3 (11) 1738-1749
    CrossrefPubMedSearch in Google Scholar
  • 33 Sciascia S, Murru V, Sanna G, Roccatello D, Khamashta MA, Bertolaccini ML. Clinical accuracy for diagnosis of antiphospholipid syndrome in systemic lupus erythematosus: evaluation of 23 possible combinations of antiphospholipid antibody specificities. J Thromb Haemost 2012; 10 (12) 2512-2518
    CrossrefPubMedSearch in Google Scholar
  • 34 Pengo V, Del Ross T, Ruffatti A. , et al. Lupus anticoagulant identifies two distinct groups of patients with different antibody patterns. Thromb Res 2018; 172: 172-178
    CrossrefPubMedSearch in Google Scholar
  • 35 Tonello M, Mattia E, Favaro M. , et al. IgG phosphatidylserine/prothrombin antibodies as a risk factor of thrombosis in antiphospholipid antibody carriers. Thromb Res 2019; 177: 157-160
    CrossrefPubMedSearch in Google Scholar