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
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 24. Juni 2013

Accepted after minor revision: 17. September 2013

Publikationsdatum:
27. November 2017 (online)

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.

 
  • References

  • 1 Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344.
  • 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.
  • 3 Loeliger L. Prothrombin as a co-factor of the circulating anticoagulant in systemic lupus erythematosus?. Thromb Diath Haemorrh 1959; 3: 237-256.
  • 4 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood 1999; 93: 2149-2157.
  • 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.
  • 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.
  • 7 Bertolaccini ML, Gomez S, Pareja JF. et al. Antiphospholipid antibody tests: spreading the net. Ann Rheum Dis 2005; 64: 1639-1643.
  • 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.
  • 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.
  • 10 Lowry R. Kappa as a Measure of Concordance in Categorical Sorting. Available at: http://facultyvassaredu/lowry/kappa.html. Accessed May 28, 2013.
  • 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.
  • 12 GRADE Working Group, GRADE profiler.. GRADEpro Version. Available at: http://www.gradeworkinggroup.org/. Accessed April 5, 2013.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 19 Vaarala O. Antiphospholipid antibodies and myocardial infarction. Lupus 1998; 7 (Suppl. 02) S132-134.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 30 Donohoe S. Detection and clinical associations of antiprothrombin antibodies. Am J Med 2001; 110: 229-230.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 45 Rask O, Hillarp A, Berntorp E. et al. Anti-prothrombin antibodies are associated with thrombosis in children. Thrombosis Res 2010; 125: 19-24.
  • 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.
  • 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.
  • 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.
  • 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.
  • 50 Miesbach W, Matthias T, Scharrer I. Identification of thrombin antibodies in patients with antiphospholipid syndrome. Ann NY Acad Sci 2005; 1050: 250-256.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 60 Hoxha A, Ruffatti A, Tonello M. et al. Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome. Lupus 2012; 21: 787-789.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.