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Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini Lupus 2014 23: 1309 DOI: 10.1177/0961203314538332 The online version of this article can be found at: http://lup.sagepub.com/content/23/12/1309
Published by: http://www.sagepublications.com
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Lupus (2014) 23, 1309–1312 http://lup.sagepub.com
SPECIAL ARTICLE
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia1,2 and ML Bertolaccini1 1
Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London, UK; and 2Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID), Universita` di Torino, Italy
Antibodies to prothrombin can be detected by ELISA using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have been both related with the clinical manifestation of APS. Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient. This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of APS. Lupus (2014) 23, 1309–1312. Key words: Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; venous thrombosis; antiprothrombin; anti-phosphatidylserine; stroke
Introduction Antibodies to prothrombin can be detected by enzyme-linked immunosorbent assay (ELISA) using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have both been related with the clinical manifestation of APS.1,2 Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient.3 This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of antiphospholipid syndrome (APS).
Clinical utility of aPS/PT in the diagnosis of APS The association between APS and antibodies to prothrombin, detected either as aPT or aPS/PT,
Correspondence to: Maria Laura Bertolaccini, Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London, 4th Floor Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK. Email: [email protected]
has been evaluated with conflicting results.4–8 However, emerging evidence supports the clinical utility of aPS/PT in the diagnosis of APS.9 Early studies from Galli et al.3 showed aPS/PT in 95% of their patients with thrombosis, but no differences in prevalence were found between those patients with thrombosis and those without. Funke et al.10 reported that aPS/PT conferred an odds ratio (OR) of 2.8 for venous thrombosis and of 4.1 for arterial thrombosis in patients with systemic lupus erythematosus (SLE). In 2000, Atsumi et al.1 supported these data by showing that the presence of aPS/PT conferred a 3.6-fold increase in the risk of APS in 265 Japanese patients with systemic autoimmune diseases. Many subsequent reports have confirmed the association between aPS/PT and clinical manifestations of APS.2,9,11,12 Recent data from Zigon et al.13 reported that aPS/PT was the strongest independent risk factor for the presence of antiphospholipid antibodies (aPL)-related obstetric complications in a cohort of 156 patients with systemic autoimmune diseases. Sanfelippo et al.14 tested aPS/PT in a large cohort of 728 patients suspected of having APS, in the absence of anticardiolipin antibodies (aCL) or anti-b2 glycoprotein I (anti-b2GPI). Of the tested samples, 41 had elevated levels of aPS/PT, with thrombotic events occurring in 50% of the cases
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
10.1177/0961203314538332
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1310
with accessible medical histories. These results support the concept that testing for aPS/PT in patients negative for aCL, anti-b2GPI and lupus anticoagulant (LA) can contribute to the identification of APS in those who may go otherwise undiagnosed based on current testing recommendations. Data from our group also support the importance of aPS/PT as a diagnostic marker of APS.8 We evaluated several possible specificities combinations aiming to identify the aPL profile yielding the best diagnostic accuracy for APS. This study included 230 SLE patients, all tested for six aPL deriving 23 possible combinations of results. The profile including LA þ anti-b2GPI þ aPS/PT held the best diagnostic accuracy for APS as a whole (OR 3.73) and, individually, for each, thrombosis (OR 3.75) and pregnancy loss (OR 4.82) and the best specificity when compared with all the other attainable combinations of tests, including the current classification criteria profile. A recent systematic review suggested that routine measurement of aPS/PT (but not aPT) might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or SLE. Antibodies to prothrombin (both aPT and aPS/ PT) were shown to increase the risk of thrombosis (OR 2.3 (95% confidence interval (CI) 1.72–3.5)) but aPS/PT seemed to represent a stronger risk factor for thrombosis, for 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).15
aPS/PT as risk factors It is widely accepted that the risk of thrombosis progressively increases with the increase in number of positive aPL tests.23–26 A recent retrospective evaluation including 230 patients with SLE reported that the combination of LA, anti-b2GPI and aPS/PT had the best diagnostic accuracy for APS.8 Moreover, triple positivity for LA þ antib2GPI þ aPS/PT was more strongly associated with clinical events (thrombosis and/or pregnancy loss) when compared with double or single positivity for these antibodies. Risk prediction models have great potential to support clinical decision making and many, such as the Framingham risk score, SCORE, QRISK, and the Reynolds risk score, have been developed for cardiovascular disease.27,28 In APS, three score systems have been formulated to quantify the risk of thrombosis/obstetric events, aiming to help physicians to stratify patients.25,29,30 Two of these, the aPL score29 and the Global Anti-Phospholipid Syndrome Score (GAPSS),30 include antibodies to aPS/PT among the variables computed when assessing the risk for thrombosis or pregnancy morbidity. Positivity for aPS/PT was found to be an important variable when assessing the risk by using the GAPSS, suggesting that the addition of these antibodies can help in predicting APS-related clinical manifestations. Although promising, these tools need to be validated in independent larger cohorts.
aPS/PT and LA In 1988, Fleck et al.16 showed that aPT had LA activity. In addition, some antibodies responsible for LA activity bind to prothrombin in certain experimental conditions,17–19 and prothrombin has been shown to be required for expressing LA activity in aCL-depleted LA-positive plasma samples.17 Today it is widely accepted that antibodies to prothrombin, along with anti-b2GPI, are the major autoantibodies responsible for LA activity. Based on a strong association between aPS/PT and LA, some published studies suggest that aPS/ PT may be a surrogate test for LA and, therefore, a ‘LA-confirming property’ was asserted for these antibodies.7,20,21 Conversely, a recent paper from our group suggests that regardless of the high frequency of aPS/ PT, but not aPT, in patients with LA, their association with thrombosis seems to be independent from the presence of LA.22
Task force report on APS laboratory diagnostics and trends A task force of worldwide scientists in the field recently met, discussed and analysed critical questions related to ‘criteria’ and ‘non-criteria’ aPL tests in an evidence-based manner during the 14th International Congress on Antiphospholipid Antibodies (APLA, 18–21 September 2013, Rio De Janeiro, Brazil). Based on available evidence, the group concluded that a) testing for aPS/PT might contribute to assess the risk of thrombosis; b) testing for aPS/PT might contribute to a better identification of patients with APS; and c) results (confirmed after multivariate analysis) do not substantially differ between groups, suggesting that aPS/PT are truly relevant in APS,31 supporting the potential importance of testing for aPS/PT in routine practise. However, some methodological issues appertaining to all aPL are still under
Lupus Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1311
debate as subjects of major concern. Future studies focusing on harmonization and standardization of tests used to detect aPS/PT are urgently needed.
Conclusions Although some controversial data still exist, most of the available studies support the association between aPS/PT and the clinical manifestations of APS. Many groups are currently working towards further characterization of aPS/PT and their mechanisms of action; additional laboratory and clinical studies, however, are needed to conclusively define the relevance and prognosis impact of testing for these antibodies in daily routine clinical practise. The possibility of aPS/PT becoming an additional serological classification criterion for APS is under debate, especially when considering how to identify APS patients negative for classical aPL.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgements MLB is funded by the Louise Gergel Fellowship.
References 1 Atsumi T, Ieko M, Bertolaccini ML, 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: 1982–1993. 2 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: 289–297. 3 Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77: 486–491. 4 Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other antiphospholipid autoantibodies. Blood 1994; 84: 2854–2867.
5 Vaarala O, Puurunen M, Manttari M, Manninen V, Aho K, Palosuo T. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost 1996; 75: 456–459. 6 Bertolaccini ML, Atsumi T, Khamashta MA, Amengual O, Hughes GR. Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus. J Rheumatol 1998; 25: 1104–1108. 7 Pengo V, Denas G, Bison E, et al. Prevalence and significance of anti-prothrombin (aPT) antibodies in patients with lupus anticoagulant (LA). Thromb Res 2010; 126: 150–153. 8 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: 2512–2518. 9 Sciascia S, Khamashta MA, Bertolaccini ML. New tests to detect antiphospholipid antibodies: Antiprothrombin (aPT) and antiphosphatidylserine/prothrombin (aPS/PT) antibodies. Curr Rheumatol Rep 2014; 16: 415. 10 Funke A, Bertolaccini ML, Atsumi T, Amengual O, Khamashta MA, Hughes GRV. Autoantibodies to prothrombin-phosphatidylserine complex: Clinical significance in systemic lupus erythematosus. Arthritis Rheum 1998; 41: S240(abstract). 11 Bertolaccini ML, Gomez S, Pareja J, et al. Antiphospholipid antibody tests: Spreading the net. Ann Rheum Dis 2005; 64: 1639–1643. 12 Tselios K, Sarantopoulos A, Gkougkourellas I, Boura P. The role of antiphosphatidylserine/prothrombin antibodies in thrombotic manifestations of systemic lupus erythematosus patients. Front Neurol 2013; 4: 66. 13 Zigon P, Cucnik S, Ambrozic A, et al. Detection of antiphosphatidylserine/prothrombin antibodies and their potential diagnostic value. Clin Dev Immunol 2013; 2013: 724592. 14 Sanfelippo M, Joshi A, Schwartz S, Meister J, Goldberg J. Antibodies to phosphatidylserine/prothrombin complex in suspected antiphospholipid syndrome in the absence of antibodies to cardiolipin or beta-2-glycoprotein I. Lupus 2013; 22: 1349–1352. 15 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: 354–364. 16 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512–519. 17 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629–632. 18 Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83: 2878–2892. 19 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: An explanation for their pathogenic mechanism? Blood 1993; 81: 2618–2625. 20 Atsumi T, Amengual O, Yasuda S, Koike T. Antiprothrombin antibodies – are they worth assaying? Thromb Res 2004; 114: 533–538. 21 Pregnolato F, Chighizola CB, Encabo S, et al. Anti-phosphatidylserine/prothrombin antibodies: An additional diagnostic marker for APS? Immunol Res 2013; 56: 432–438. 22 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: 207–213. 23 Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8: 237–242. Lupus
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Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1312 24 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93: 1147–1152. 25 Sciascia S, Cosseddu D, Montaruli B, Kuzenko A, Bertero MT. Risk scale for the diagnosis of antiphospholipid syndrome. Ann Rheum Dis 2011; 70: 1517–1518. 26 Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: A multicenter prospective study. Blood 2011; 118: 4714–4718. 27 Tzoulaki I, Liberopoulos G, Ioannidis JP. Assessment of claims of improved prediction beyond the Framingham risk score. JAMA 2009; 302: 2345–2352. 28 Collins GS, Moons KG. Comparing risk prediction models. BMJ 2012; 344: e3186.
29 Otomo K, Atsumi T, Amengual O, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012; 64: 504–512. 30 Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. GAPSS: The Global Anti-Phospholipid Syndrome Score. Rheumatology (Oxford) 2013; 52: 1397–1403. 31 Bertolaccini ML, Amengual O, Andreoli L, et al. 14 th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. Epub 10 May 2014. pii: S1568-9972(14)00120-7. DOI: 10.1016/j.autrev. 2014.2014.05.001.
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Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini Lupus 2014 23: 1309 DOI: 10.1177/0961203314538332 The online version of this article can be found at: http://lup.sagepub.com/content/23/12/1309
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Sep 16, 2014 What is This?
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
Lupus (2014) 23, 1309–1312 http://lup.sagepub.com
SPECIAL ARTICLE
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia1,2 and ML Bertolaccini1 1
Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London, UK; and 2Centro di Ricerche di Immunologia Clinica ed Immunopatologia e Documentazione su Malattie Rare (CMID), Universita` di Torino, Italy
Antibodies to prothrombin can be detected by ELISA using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have been both related with the clinical manifestation of APS. Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient. This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of APS. Lupus (2014) 23, 1309–1312. Key words: Antiphospholipid antibodies; antiphospholipid syndrome; thrombosis; venous thrombosis; antiprothrombin; anti-phosphatidylserine; stroke
Introduction Antibodies to prothrombin can be detected by enzyme-linked immunosorbent assay (ELISA) using prothrombin coated onto irradiated plates (aPT) or the phosphatidylserine/prothrombin complex as antigen (aPS/PT) and they have both been related with the clinical manifestation of APS.1,2 Current evidence supports the concept that they belong to distinct populations of autoantibodies. Nevertheless, they can both be detected simultaneously in one patient.3 This mini-review will focus on data available on aPS/PT antibodies and their clinical utility in the diagnosis of antiphospholipid syndrome (APS).
Clinical utility of aPS/PT in the diagnosis of APS The association between APS and antibodies to prothrombin, detected either as aPT or aPS/PT,
Correspondence to: Maria Laura Bertolaccini, Graham Hughes Lupus Research Laboratory, Lupus Research Unit, The Rayne Institute, Division of Women’s Health, King’s College London, 4th Floor Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK. Email: [email protected]
has been evaluated with conflicting results.4–8 However, emerging evidence supports the clinical utility of aPS/PT in the diagnosis of APS.9 Early studies from Galli et al.3 showed aPS/PT in 95% of their patients with thrombosis, but no differences in prevalence were found between those patients with thrombosis and those without. Funke et al.10 reported that aPS/PT conferred an odds ratio (OR) of 2.8 for venous thrombosis and of 4.1 for arterial thrombosis in patients with systemic lupus erythematosus (SLE). In 2000, Atsumi et al.1 supported these data by showing that the presence of aPS/PT conferred a 3.6-fold increase in the risk of APS in 265 Japanese patients with systemic autoimmune diseases. Many subsequent reports have confirmed the association between aPS/PT and clinical manifestations of APS.2,9,11,12 Recent data from Zigon et al.13 reported that aPS/PT was the strongest independent risk factor for the presence of antiphospholipid antibodies (aPL)-related obstetric complications in a cohort of 156 patients with systemic autoimmune diseases. Sanfelippo et al.14 tested aPS/PT in a large cohort of 728 patients suspected of having APS, in the absence of anticardiolipin antibodies (aCL) or anti-b2 glycoprotein I (anti-b2GPI). Of the tested samples, 41 had elevated levels of aPS/PT, with thrombotic events occurring in 50% of the cases
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
10.1177/0961203314538332
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1310
with accessible medical histories. These results support the concept that testing for aPS/PT in patients negative for aCL, anti-b2GPI and lupus anticoagulant (LA) can contribute to the identification of APS in those who may go otherwise undiagnosed based on current testing recommendations. Data from our group also support the importance of aPS/PT as a diagnostic marker of APS.8 We evaluated several possible specificities combinations aiming to identify the aPL profile yielding the best diagnostic accuracy for APS. This study included 230 SLE patients, all tested for six aPL deriving 23 possible combinations of results. The profile including LA þ anti-b2GPI þ aPS/PT held the best diagnostic accuracy for APS as a whole (OR 3.73) and, individually, for each, thrombosis (OR 3.75) and pregnancy loss (OR 4.82) and the best specificity when compared with all the other attainable combinations of tests, including the current classification criteria profile. A recent systematic review suggested that routine measurement of aPS/PT (but not aPT) might be useful in establishing the thrombotic risk of patients with previous thrombosis and/or SLE. Antibodies to prothrombin (both aPT and aPS/ PT) were shown to increase the risk of thrombosis (OR 2.3 (95% confidence interval (CI) 1.72–3.5)) but aPS/PT seemed to represent a stronger risk factor for thrombosis, for 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).15
aPS/PT as risk factors It is widely accepted that the risk of thrombosis progressively increases with the increase in number of positive aPL tests.23–26 A recent retrospective evaluation including 230 patients with SLE reported that the combination of LA, anti-b2GPI and aPS/PT had the best diagnostic accuracy for APS.8 Moreover, triple positivity for LA þ antib2GPI þ aPS/PT was more strongly associated with clinical events (thrombosis and/or pregnancy loss) when compared with double or single positivity for these antibodies. Risk prediction models have great potential to support clinical decision making and many, such as the Framingham risk score, SCORE, QRISK, and the Reynolds risk score, have been developed for cardiovascular disease.27,28 In APS, three score systems have been formulated to quantify the risk of thrombosis/obstetric events, aiming to help physicians to stratify patients.25,29,30 Two of these, the aPL score29 and the Global Anti-Phospholipid Syndrome Score (GAPSS),30 include antibodies to aPS/PT among the variables computed when assessing the risk for thrombosis or pregnancy morbidity. Positivity for aPS/PT was found to be an important variable when assessing the risk by using the GAPSS, suggesting that the addition of these antibodies can help in predicting APS-related clinical manifestations. Although promising, these tools need to be validated in independent larger cohorts.
aPS/PT and LA In 1988, Fleck et al.16 showed that aPT had LA activity. In addition, some antibodies responsible for LA activity bind to prothrombin in certain experimental conditions,17–19 and prothrombin has been shown to be required for expressing LA activity in aCL-depleted LA-positive plasma samples.17 Today it is widely accepted that antibodies to prothrombin, along with anti-b2GPI, are the major autoantibodies responsible for LA activity. Based on a strong association between aPS/PT and LA, some published studies suggest that aPS/ PT may be a surrogate test for LA and, therefore, a ‘LA-confirming property’ was asserted for these antibodies.7,20,21 Conversely, a recent paper from our group suggests that regardless of the high frequency of aPS/ PT, but not aPT, in patients with LA, their association with thrombosis seems to be independent from the presence of LA.22
Task force report on APS laboratory diagnostics and trends A task force of worldwide scientists in the field recently met, discussed and analysed critical questions related to ‘criteria’ and ‘non-criteria’ aPL tests in an evidence-based manner during the 14th International Congress on Antiphospholipid Antibodies (APLA, 18–21 September 2013, Rio De Janeiro, Brazil). Based on available evidence, the group concluded that a) testing for aPS/PT might contribute to assess the risk of thrombosis; b) testing for aPS/PT might contribute to a better identification of patients with APS; and c) results (confirmed after multivariate analysis) do not substantially differ between groups, suggesting that aPS/PT are truly relevant in APS,31 supporting the potential importance of testing for aPS/PT in routine practise. However, some methodological issues appertaining to all aPL are still under
Lupus Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1311
debate as subjects of major concern. Future studies focusing on harmonization and standardization of tests used to detect aPS/PT are urgently needed.
Conclusions Although some controversial data still exist, most of the available studies support the association between aPS/PT and the clinical manifestations of APS. Many groups are currently working towards further characterization of aPS/PT and their mechanisms of action; additional laboratory and clinical studies, however, are needed to conclusively define the relevance and prognosis impact of testing for these antibodies in daily routine clinical practise. The possibility of aPS/PT becoming an additional serological classification criterion for APS is under debate, especially when considering how to identify APS patients negative for classical aPL.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgements MLB is funded by the Louise Gergel Fellowship.
References 1 Atsumi T, Ieko M, Bertolaccini ML, 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: 1982–1993. 2 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: 289–297. 3 Galli M, Beretta G, Daldossi M, Bevers EM, Barbui T. Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost 1997; 77: 486–491. 4 Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other antiphospholipid autoantibodies. Blood 1994; 84: 2854–2867.
5 Vaarala O, Puurunen M, Manttari M, Manninen V, Aho K, Palosuo T. Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men. Thromb Haemost 1996; 75: 456–459. 6 Bertolaccini ML, Atsumi T, Khamashta MA, Amengual O, Hughes GR. Autoantibodies to human prothrombin and clinical manifestations in 207 patients with systemic lupus erythematosus. J Rheumatol 1998; 25: 1104–1108. 7 Pengo V, Denas G, Bison E, et al. Prevalence and significance of anti-prothrombin (aPT) antibodies in patients with lupus anticoagulant (LA). Thromb Res 2010; 126: 150–153. 8 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: 2512–2518. 9 Sciascia S, Khamashta MA, Bertolaccini ML. New tests to detect antiphospholipid antibodies: Antiprothrombin (aPT) and antiphosphatidylserine/prothrombin (aPS/PT) antibodies. Curr Rheumatol Rep 2014; 16: 415. 10 Funke A, Bertolaccini ML, Atsumi T, Amengual O, Khamashta MA, Hughes GRV. Autoantibodies to prothrombin-phosphatidylserine complex: Clinical significance in systemic lupus erythematosus. Arthritis Rheum 1998; 41: S240(abstract). 11 Bertolaccini ML, Gomez S, Pareja J, et al. Antiphospholipid antibody tests: Spreading the net. Ann Rheum Dis 2005; 64: 1639–1643. 12 Tselios K, Sarantopoulos A, Gkougkourellas I, Boura P. The role of antiphosphatidylserine/prothrombin antibodies in thrombotic manifestations of systemic lupus erythematosus patients. Front Neurol 2013; 4: 66. 13 Zigon P, Cucnik S, Ambrozic A, et al. Detection of antiphosphatidylserine/prothrombin antibodies and their potential diagnostic value. Clin Dev Immunol 2013; 2013: 724592. 14 Sanfelippo M, Joshi A, Schwartz S, Meister J, Goldberg J. Antibodies to phosphatidylserine/prothrombin complex in suspected antiphospholipid syndrome in the absence of antibodies to cardiolipin or beta-2-glycoprotein I. Lupus 2013; 22: 1349–1352. 15 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: 354–364. 16 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512–519. 17 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629–632. 18 Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood 1994; 83: 2878–2892. 19 Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: An explanation for their pathogenic mechanism? Blood 1993; 81: 2618–2625. 20 Atsumi T, Amengual O, Yasuda S, Koike T. Antiprothrombin antibodies – are they worth assaying? Thromb Res 2004; 114: 533–538. 21 Pregnolato F, Chighizola CB, Encabo S, et al. Anti-phosphatidylserine/prothrombin antibodies: An additional diagnostic marker for APS? Immunol Res 2013; 56: 432–438. 22 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: 207–213. 23 Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8: 237–242. Lupus
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on September 30, 2014
Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome S Sciascia and ML Bertolaccini
1312 24 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93: 1147–1152. 25 Sciascia S, Cosseddu D, Montaruli B, Kuzenko A, Bertero MT. Risk scale for the diagnosis of antiphospholipid syndrome. Ann Rheum Dis 2011; 70: 1517–1518. 26 Pengo V, Ruffatti A, Legnani C, et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: A multicenter prospective study. Blood 2011; 118: 4714–4718. 27 Tzoulaki I, Liberopoulos G, Ioannidis JP. Assessment of claims of improved prediction beyond the Framingham risk score. JAMA 2009; 302: 2345–2352. 28 Collins GS, Moons KG. Comparing risk prediction models. BMJ 2012; 344: e3186.
29 Otomo K, Atsumi T, Amengual O, et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012; 64: 504–512. 30 Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. GAPSS: The Global Anti-Phospholipid Syndrome Score. Rheumatology (Oxford) 2013; 52: 1397–1403. 31 Bertolaccini ML, Amengual O, Andreoli L, et al. 14 th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. Epub 10 May 2014. pii: S1568-9972(14)00120-7. DOI: 10.1016/j.autrev. 2014.2014.05.001.
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