Download PDF
Thromb Haemost 2014; 111(02): 354-364
DOI: 10.1160/TH13-06-0509
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome

A systematic review
Savino Sciascia
1   Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London
2   Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID), Università di Torino, Italy
,
Giovanni Sanna
3   Louise Coote Lupus Unit, Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK
,
Veronica Murru
1   Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London
,
Dario Roccatello
2   Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID), Università di Torino, Italy
,
Munther A. Khamashta
1   Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London
3   Louise Coote Lupus Unit, Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, UK
,
Maria Laura Bertolaccini
1   Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London
› Author Affiliations
Further Information

Publication History

Received: 24 June 2013

Accepted after minor revision: 17 September 2013

Publication Date:
27 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Antibodies to prothrombin are detected by directly coating prothrombin on irradiated ELISA plates (aPT) or by using the phosphatidylserine/ prothrombin complex as antigen (aPS/PT). Although these antibodies have both been associated with antiphospholipid syndrome (APS) and a correlation between the two assays have been reported, it seems that aPT and aPS/PT belong to different populations of autoantibodies. It was our objective to systematically review the available evidence on aPT and aPS/PT antibodies and the risk of thrombosis in APS. Medline-reports published between 1988 and 2013 investigating aPT and aPS/PT as a risk factor for thrombosis were included. Whenever possible, antibody isotype(s) and site of thrombosis were analysed. This systematic review is based on available data from more than 7,000 patients and controls from 38 studies analysing aPT and 10 aPS/PT. Antibodies to prothrombin (both aPT and aPS/PT) increased the risk of thrombosis (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.72–3.5). aPS/PT seemed to represent a stronger risk factor for thrombosis, both arterial and/or venous than aPT (OR 5.11; 95%CI 4.2–6.3 and OR 1.82; 95%CI 1.44–2.75, respectively). In conclusion, routine measurement of aPS/PT (but not aPT) might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or systemic lupus erythematosus. Their inclusion as laboratory criteria for the APS should be indisputably further explored.

Keywords

Antiphospholipid antibodies - antiphospholipid syndrome - venous thrombosis - stroke

 

  • References

  • 1 Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344.
    CrossrefPubMedGoogle Scholar
  • 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: 295-306.
    CrossrefPubMedGoogle Scholar
  • 3 Loeliger L. Prothrombin as a co-factor of the circulating anticoagulant in systemic lupus erythematosus?. Thromb Diath Haemorrh 1959; 3: 237-256.
    PubMedGoogle Scholar
  • 4 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-2157.
    CrossrefPubMedGoogle Scholar
  • 5 Haj-Yahia S, Sherer Y, Blank M. et al. Anti-prothrombin antibodies cause thrombosis in a novel qualitative ex-vivo animal model. Lupus 2003; 12: 364-369.
    CrossrefPubMedGoogle Scholar
  • 6 Bertolaccini ML, Atsumi T, Koike T. et al. Antiprothrombin antibodies detected in two different assay systems. Prevalence and clinical significance in systemic lupus erythematosus. Thromb Haemost 2005; 93: 289-297.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Bertolaccini ML, Gomez S, Pareja JF. et al. Antiphospholipid antibody tests: spreading the net. Ann Rheum Dis 2005; 64: 1639-1643.
    CrossrefPubMedGoogle Scholar
  • 8 Galli M, Luciani D, Bertolini G. et al. Anti-beta 2-glycoprotein I, antiprothrom-bin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003; 102: 2717-2723.
    CrossrefPubMedGoogle Scholar
  • 9 Galli M, Luciani D, Bertolini G. et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101: 1827-1832.
    CrossrefPubMedGoogle Scholar
  • 10 Lowry R. Kappa as a Measure of Concordance in Categorical Sorting. Available at: http://facultyvassaredu/lowry/kappa.html. Accessed May 28, 2013.
    PubMedGoogle Scholar
  • 11 Wells GA, Shea B, O’Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed May 28, 2013.
    PubMedGoogle Scholar
  • 12 GRADE Working Group, GRADE profiler.. GRADEpro Version. Available at: http://www.gradeworkinggroup.org/. Accessed April 5, 2013.
    PubMed
  • 13 Horbach DA, Derksen RH, de Groot PG. The presence of anti-beta 2-glycopro-tein I and anti-prothrombin antibodies and their correlations with venous and arterial thrombosis. Ann Med Int 1996; 147 (Suppl. 01) 42-43.
    PubMedGoogle Scholar
  • 14 Pengo V, Biasiolo A, Brocco T. et al. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75: 721-724.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Puurunen M, Vaarala O, Julkunen H. et al. Antibodies to phospholipid-binding plasma proteins and occurrence of thrombosis in patients with systemic lupus erythematosus. Clin Immunol Immunopathol 1996; 80: 16-22.
    CrossrefPubMedGoogle Scholar
  • 16 Forastiero RR, Martinuzzo ME, Cerrato GS. et al. Relationship of anti beta2-gly-coprotein I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 1997; 78: 1008-1014.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Palosuo T, Virtamo J, Haukka J. et al. High antibody levels to prothrombin imply a risk of deep venous thrombosis and pulmonary embolism in middle-aged men-- a nested case-control study. Thromb Haemost 1997; 78: 1178-1182.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Bertolaccini ML, Atsumi T, Khamashta MA. et al. Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus. J Rheumatol 1998; 25: 1104-1108.
    PubMedGoogle Scholar
  • 19 Vaarala O. Antiphospholipid antibodies and myocardial infarction. Lupus 1998; 7 (Suppl. 02) S132-134.
    CrossrefPubMedGoogle Scholar
  • 20 Martinuzzo ME, Pombo G, Forastiero RR. et al. Lupus anticoagulant, high levels of anticardiolipin, and anti-beta2-glycoprotein I antibodies are associated with chronic thromboembolic pulmonary hypertension. J Rheumatol 1998; 25: 1313-1319.
    PubMedGoogle Scholar
  • 21 Akimoto T, Akama T, Kono I. et al. Relationship between clinical features and binding domains of anti-prothrombin autoantibodies in patients with systemic lupus erythematosus and antiphospholipid syndrome. Lupus 1999; 8: 761-766.
    CrossrefPubMedGoogle Scholar
  • 22 Galli M, Dlott J, Norbis F. et al. Lupus anticoagulants and thrombosis: clinical association of different coagulation and immunologic tests. Thromb Haemost 2000; 84: 1012-1016.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Lakos G, Kiss E, Regeczy N. et al. Antiprothrombin and antiannexin V antibodies imply risk of thrombosis in patients with systemic autoimmune diseases. J Rheumatol 2000; 27: 924-929.
    PubMedGoogle Scholar
  • 24 Atsumi T, Ieko M, Bertolaccini ML. et al. Association of autoantibodies against the phosphatidylserine-prothrombin complex with manifestations of the anti-phospholipid syndrome and with the presence of lupus anticoagulant. Arthritis Rheuma 2000; 43: 1982-1993.
    CrossrefPubMedGoogle Scholar
  • 25 Donohoe S, MacKie IJ, Isenberg D. et al. Anti-prothrombin antibodies: assay conditions and clinical associations in the anti-phospholipid syndrome. Br J Haematol 2001; 113: 544-549.
    CrossrefPubMedGoogle Scholar
  • 26 Nojima J, Kuratsune H, Suehisa E. et al. Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essential risk factor for venous throm-boembolism in patients with systemic lupus erythematosus. Br J Haematol 2001; 114: 647-654.
    CrossrefPubMedGoogle Scholar
  • 27 Nojima J, Kuratsune H, Suehisa E. et al. Association between the prevalence of antibodies to beta(2)-glycoprotein I, prothrombin, protein C, protein S, and annexin V in patients with systemic lupus erythematosus and thrombotic and thrombocytopenic complications. Clinical Chem 2001; 47: 1008-1015.
    CrossrefPubMedGoogle Scholar
  • 28 Pasquier E, Amiral J, de Saint Martin L. et al. A cross sectional study of anti-phospholipid-protein antibodies in patients with venous thromboembolism. Thromb Haemost 2001; 86: 538-542.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Sands JJ, Nudo SA, Moore KD. et al. Antibodies to prothrombin, factor V, and beta2-glycoprotein I and vascular access thrombosis. ASAIO J 2001; 47: 507-510.
    CrossrefPubMedGoogle Scholar
  • 30 Donohoe S. Detection and clinical associations of antiprothrombin antibodies. Am J Med 2001; 110: 229-230.
    CrossrefPubMedGoogle Scholar
  • 31 Salcido-Ochoa F, Cabiedes J, Alarcon-Segovia D. et al. Antiprothrombin antibodies in patients with systemic lupus erythematosus or with primary anti-phospholipid syndrome. J Clin Rheumatol 2002; 8: 251-255.
    CrossrefPubMedGoogle Scholar
  • 32 Simmelink MJ, De Groot PG, Derksen RH. A study on associations between antiprothrombin antibodies, antiplasminogen antibodies and thrombosis. J Thromb Haemost 2003; 1: 735-739.
    CrossrefPubMedGoogle Scholar
  • 33 Previtali S, Barbui T, Galli M. Anti-beta2-glycoprotein I and anti-prothrombin antibodies in antiphospholipid-negative patients with thrombosis: a case control study. Thromb Haemost 2002; 88: 729-732.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Musial J, Swadzba J, Motyl A. et al. Clinical significance of antiphospholipid protein antibodies. Receiver operating characteristics plot analysis. J Rheumatol 2003; 30: 723-730.
    PubMedGoogle Scholar
  • 35 Ishikura K, Wada H, Kamikura Y. et al. High prevalence of anti-prothrombin antibody in patients with deep vein thrombosis. Am J Hematol 2004; 76: 338-342.
    CrossrefPubMedGoogle Scholar
  • 36 Koskenmies S, Vaarala O, Widen E. et al. The association of antibodies to car-diolipin, beta 2-glycoprotein I, prothrombin, and oxidized low-density lipopro-tein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus. Scand J Rheumatol 2004; 33: 246-252.
    CrossrefPubMedGoogle Scholar
  • 37 Zanon E, Saggiorato G, Ramon R. et al. Anti-prothrombin antibodies as a potential risk factor of recurrent venous thromboembolism. Thromb Haemost 2004; 91: 255-258.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Forastiero R, Martinuzzo M, Pombo G. et al. A prospective study of antibodies to beta2-glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost 2005; 3: 1231-1238.
    CrossrefPubMedGoogle Scholar
  • 39 Tsutsumi A, Hayashi T, Chino Y. et al. Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays. Modern Rheumatol 2006; 16: 158-164.
    CrossrefPubMedGoogle Scholar
  • 40 Gould T, Tikly M, Asherson R. et al. Prevalence and clinical correlates of anti-phospholipid antibodies in South Africans with systemic lupus erythematosus. Scand J Rheumatol 2006; 35: 29-34.
    CrossrefPubMedGoogle Scholar
  • 41 Bizzaro N, Ghirardello A, Zampieri S. et al. Anti-prothrombin antibodies predict thrombosis in patients with systemic lupus erythematosus: a 15-year longitudinal study. J Thromb Haemost 2007; 5: 1158-1164.
    CrossrefPubMedGoogle Scholar
  • 42 Sailer T, Vormittag R, Zoghlami C. et al. The clinical significance of anti-pro-thrombin antibodies for risk assessment of thromboembolism in patients with lupus anticoagulant. Thrombosis Res 2007; 120: 295-302.
    CrossrefPubMedGoogle Scholar
  • 43 Bardin N, Alessi MC, Dignat-George F. et al. Does the anti-prothrombin antibodies measurement provide additional information in patients with thrombosis?. Immunobiology 2007; 212: 557-565.
    CrossrefPubMedGoogle Scholar
  • 44 Szodoray P, Tarr T, Tumpek J. et al. Identification of rare anti-phospholipid/pro-tein co-factor autoantibodies in patients with systemic lupus erythematosus. Autoimmunity 2009; 42: 497-506.
    CrossrefPubMedGoogle Scholar
  • 45 Rask O, Hillarp A, Berntorp E. et al. Anti-prothrombin antibodies are associated with thrombosis in children. Thrombosis Res 2010; 125: 19-24.
    CrossrefPubMedGoogle Scholar
  • 46 Hoxha A, Ruffatti A, Pittoni M. et al. The clinical significance of autoantibodies directed against prothrombin in primary antiphospholipid syndrome. Clin Chim Acta 2012; 413: 911-913.
    CrossrefPubMedGoogle Scholar
  • 47 Horita T, Ichikawa K, Kataoka H. et al. Human monoclonal antibodies against the complex of phosphatidylserine and prothrombin from patients with the antiphospholipid antibodies. Lupus 2007; 16: 509-516.
    CrossrefPubMedGoogle Scholar
  • 48 Jaskowski TD, Wilson AR, Hill HR. et al. Autoantibodies against phosphati-dylserine, prothrombin and phosphatidylserine-prothrombin complex: identical or distinct diagnostic tools for antiphospholipid syndrome?. Clin Chim Acta 2009; 410: 19-24.
    CrossrefPubMedGoogle Scholar
  • 49 Locht H, Wiik A. Prevalence of antibodies against oxidised LDL in a cohort of 163 patients with positive anti-phospholipid antibodies and recent thrombosis. Rheumatol Intern 2006; 26: 416-421.
    CrossrefPubMedGoogle Scholar
  • 50 Miesbach W, Matthias T, Scharrer I. Identification of thrombin antibodies in patients with antiphospholipid syndrome. Ann NY Acad Sci 2005; 1050: 250-256.
    CrossrefPubMedGoogle Scholar
  • 51 Horbach DA, van Oort E, Tempelman MJ. et al. The prevalence of a non-phos-pholipid-binding form of beta2-glycoprotein I in human plasma--consequences for the development of anti-beta2-glycoprotein I antibodies. Thromb Haemost 1998; 80: 791-797.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Nojima J, Iwatani Y, Suehisa E. et al. The presence of anti-phosphatidylserine/pro-thrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus. Haematologica 2006; 91: 699-702.
    PubMedGoogle Scholar
  • 53 Adams MJ, Palatinus AA, Harvey AM. et al. Impaired control of the tissue factor pathway of blood coagulation in systemic lupus erythematosus. Lupus 2011; 20: 1474-1483.
    CrossrefPubMedGoogle Scholar
  • 54 Lee KO, Kim WJ, Na SJ. et al. Clinical significance of anti-annexin V antibody in acute cerebral ischemia. J Neurol Sci 2011; 305: 53-56.
    CrossrefPubMedGoogle Scholar
  • 55 Cojocaru IM, Cojocaru M, Popescu AN. et al. Study of antiphospholipid antibodies in type 2 diabetes mellitus with and without diabetic retinopathy. Roman J Internal Med 2009; 47: 267-271.
    PubMedGoogle Scholar
  • 56 Robertson B, Urquhart C, Ford I. et al. Platelet and coagulation activation markers in myeloproliferative diseases: relationships with JAK2 V6I7 F status, clonality, and antiphospholipid antibodies. J Thromb Haemost 2007; 5: 1679-1685.
    CrossrefPubMedGoogle Scholar
  • 57 Santamaria A, Oliver A, Borrell M. et al. Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels. Stroke 2003; 34: 2387-2391.
    CrossrefPubMedGoogle Scholar
  • 58 Chen WH, Kao YF, Lan MY. et al. A perturbation of antithrombin-III and protein C coupling associates with an increase of anti-beta2-glycoprotein I antibody in non-antiphospholipid antibody syndrome cerebral ischemia. Blood Coagul Fibrinolysis 2002; 13: 703-709.
    CrossrefPubMedGoogle Scholar
  • 59 Adams MJ, Donohoe S, Mackie IJ. et al. Anti-tissue factor pathway inhibitor activity in patients with primary antiphospholipid syndrome. Br J Haematol 2001; 114: 375-379.
    CrossrefPubMedGoogle Scholar
  • 60 Hoxha A, Ruffatti A, Tonello M. et al. Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome. Lupus 2012; 21: 787-789.
    CrossrefPubMedGoogle Scholar
  • 61 Okuma H, Kitagawa Y, Ishikawa T. et al. Study of phosphatidylserine-dependent anti-prothrombin antibody in cerebral infarction. Intern Med 2009; 48: 1351-1355.
    CrossrefPubMedGoogle Scholar
  • 62 Bertolaccini ML, Atsumi T, Escudero Contreras A. et al. The value of IgA anti-phospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus. J Rheumatol 2001; 28: 2637-2643.
    PubMedGoogle Scholar
  • 63 Hasegawa M, Sato S, Yanaba K. et al. Autoantibodies against phosphatidylser-ine-prothrombin complex in patients with systemic sclerosis. Ann Rheum Dis 2004; 63: 1514-1517.
    CrossrefPubMedGoogle Scholar
  • 64 Hasegawa M, Fujimoto M, Hayakawa I. et al. Anti-phosphatidylserine-pro-thrombin complex antibodies in patients with localized scleroderma. Clin Exp Rheumatol 2006; 24: 19-24.
    PubMedGoogle Scholar
  • 65 Nojima J, Kuratsune H, Suehisa E. et al. Acquired activated protein C resistance associated with IgG antibodies against beta2-glycoprotein I and prothrombin as a strong risk factor for venous thromboembolism. Clin Chem 2005; 51: 545-552.
    CrossrefPubMedGoogle Scholar
  • 66 Nojima J, Kuratsune H, Suehisa E. et al. Strong correlation between the prevalence of cerebral infarction and the presence of anti-cardiolipin/beta2-glycopro-tein I and anti-phosphatidylserine/prothrombin antibodies--Co-existence of these antibodies enhances ADP-induced platelet activation in vitro. Thromb Haemost 2004; 91: 967-976.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Vlagea AD, Gil A, Cuesta MV. et al. Antiphosphatidylserine/Prothrombin Antibodies (aPS/PT) as Potential Markers of Antiphospholipid Syndrome. Clin Appl Thromb Hemost 2013; 19: 289-296.
    CrossrefPubMedGoogle Scholar
  • 68 Inanc M, Donohoe S, Ravirajan CT. et al. Anti-beta2-glycoprotein I, anti-pro-thrombin and anticardiolipin antibodies in a longitudinal study of patients with systemic lupus erythematosus and the antiphospholipid syndrome. Br J Rheu-matol 1998; 37: 1089-1094.
    CrossrefPubMedGoogle Scholar
  • 69 Zigon P, Ambrozic A, Cucnik S. et al. Modified phosphatidylserine-dependent antiprothrombin [corrected] ELISA enables identification of patients negative for other antiphospholipid antibodies and also detects low avidity antibodies. Clin Chem Lab Med 2011; 49: 1011-1018.
    CrossrefPubMedGoogle Scholar
  • 70 Zigon P, Cucnik S, Ambrozic A. et al. Antibodies to phosphatidylserine/pro-thrombin complex as an additional diagnostic marker of APS?. Lupus 2012; 21: 790-792.
    CrossrefPubMedGoogle Scholar
  • 71 Pengo V, Denas G, Bison E. et al. Prevalence and significance of anti-prothrom-bin (aPT) antibodies in patients with Lupus Anticoagulant (LA). Thrombosis Res 2010; 126: 150-153.
    CrossrefPubMedGoogle Scholar
  • 72 Wahl DG, Guillemin F, de Maistre E. et al. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus-- a meta-analysis. Lupus 1997; 6: 467-473.
    CrossrefPubMedGoogle Scholar
  • 73 Wahl DG, Guillemin F, de Maistre E. et al. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15-22.
    CrossrefPubMedGoogle Scholar
  • 74 Martinelli I, Mannucci PM, De Stefano V. et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353-2358.
    CrossrefPubMedGoogle Scholar