膜联蛋白A5影响系统性红斑狼疮血栓形成倾向的研究
|
摘要
研究背景和目的：
系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种典型的自身免疫性疾病。随着SLE近期生存率提高，心脑血管事件发病率显著增加，已形成第二个死亡高峰。研究生本人在从事硕士课题研究阶段，运用了比较蛋白质组学的方法，鉴定并验证了在SLE患者的外周血单个核细胞(peripheral blood mononuclear cells，PBMCs)中存在差异表达的16种蛋白质，并对这些蛋白质进行了相关的生物信息学分析。其中的膜联蛋白A5(annexin A5，AnxA5)在SLE患者中的高表达引起了我们的注意。AnxA5是膜联蛋白家族中少数具有抗凝活性的重要成员，但其在SLE发病中的确切机制目前尚无统一认识。如能明确它在SLE发病中的具体作用，对预防严重血管事件显然具有积极的意义。我们拟主要从SLE患者的临床表现及外周血中的AnxA5实际表达水平出发，明确AnxA5分子在SLE患者的外周血细胞中出现了表达差异，分析AnxA5的表达水平与SLE临床症候群的关联性。同时，筛查AnxA5及几种常见的抗磷脂抗体(anti-phospholipid antibody，aPL)在SLE患者血清中的表达水平，分析这些aPL分子相互之间以及与SLE不同临床表现的关联。最后我们通过外源性重组的AnxA5分子及anti-AnxA5单克隆抗体对SLE患者的数项临床凝血筛查实验进行干预，初步探讨AnxA5分子影响SLE患者血栓形成倾向的作用通路。
方法：
研究采集了200名女性SLE患者及174名健康对照者的血液标本。
1．通过二维电泳(2-DE)、聚丙烯酰胺凝胶电泳(SDS-PAGE)与免疫印迹(Western blot)，验证SLE患者外周血单个核细胞中AnxA5的表达情况，并分析在胞浆、胞膜亚细胞组分中的表达差异。对显影条带进行半定量处理后，分析统计意义及与临床指标的相关性。
2．运用酶联免疫吸附实验(ELISA)，测定患者及健康对照者的血清AnxA5浓度，同时测定相关分子anti-AnxA5抗体、β2糖蛋白I (β2GPI)、抗氧化性磷脂(anti-Ox-PLs)和抗心磷脂抗体(aCL IgG)的水平，分析这些分子相互之间及其与各种临床表现的相关性。
3．重组AnxA5蛋白和anti-AnxA5单克隆抗体对SLE患者及健康对照的贫血小板血浆进行体外干预，运用自动化凝血分析仪检测外源性物质干预后，凝血酶原时间(PT)、部分凝血活酶时间(APTT)、纤维蛋白原(Fib)和凝血酶时间(TT)等常规凝血筛查实验的结果变化。
主要结果：
1．Western blot验证了AnxA5在大多数SLE患者的PBMCs中存在高表达，半定量后的统计分析提示其变化有显著性意义(60.7%vs.6.4%，P=0.0004)。
2．SLE患者和健康对照者的PBMCs胞膜蛋白中，AnxA5无明显差异，而在胞浆蛋白中患者组的AnxA5高于健康对照组。
3．经环磷酰胺(CTX)治疗后的SLE患者，其PBMCs中的AnxA5明显低于未经CTX治疗的SLE患者(17.0%vs.97.4%，P=0.014)，但与CTX累计量不具有剂量依赖关系。
4．SLE患者血清中的AnxA5总体上明显低于健康对照者(26.8±3.0ng/mL vs.49.0±3.3ng/mL，P <0.0001)，但存在少数与对照者相近，甚至比对照者更高的SLE患者。
5．血清AnxA5升高的SLE患者与血栓形成性疾病的发生有明显相关性(Mann-Whitney Z=-2.084，P=0.037)。
6．SLE患者血清中的AnxA5与anti-AnxA5、β2GPI、anti-Ox-PLs、aCL IgG均无统计相关性。
7．Anti-AnxA5与血栓形成的相关性不完全明确，但受到血清anti-AnxA5极高值的影响较为明显(Pearson’s (r)=0.340，P <0.0005vs. Mann-Whitney=-1.272，P=0.203)。
8．外源性AnxA5及anti-AnxA5的干预都可以延长SLE患者的PT和APTT时间，以及缩短TT时间。
9．外源性anti-AnxA5的干预可以提高SLE患者血清中功能性Fib的含量。
10．外源性AnxA5干预健康对照的凝血筛查实验，结果的变化趋势与其干预SLE患者时相似，但后者的变化更为显著。
结论：
1．在SLE的发病过程中，外周血中的AnxA5具有在细胞内升高，在胞外血浆中降低的分布差异。这种分布特点可能发挥了某种保护作用，从而降低SLE患者出现血栓形成性疾病的机率。
2．AnxA5在SLE发病过程中，与其他几种主要的aPL没有相关性，而可能是较为独立地参与SLE的发病。
3．AnxA5及其抗体在SLE的发病过程中，可能主要通过凝血共同途径发挥作用，从而影响狼疮相关的血栓形成过程。
Background and Objective:
Systemic lupus erythematosus (SLE) is a classic autoimmune disease. As the short-termsurvival rate of SLE increased in these decades, chronic patients now suffer from increasingthrombosis-related symptoms, which had become a significant lethal factor for long-termprognosis. Our team used comparative proteomic strategies to identify16disregulatedproteins from peripheral blood monouclear cells (PBMCs) of SLE patients. Annexin A5(AnxA5) is one of the upregulated proteins, which we thought we should pay attention to.AnxA5is a distinctive annexin with anticoagulant activity that is rarely observed in theannexin family, but its detailed pathogenesis in SLE remains unclear. If the detailed functionof AnxA5in SLE could be elucidated, it should be very meaningful to help the SLE patientsto avoid the serious vascular events. To provide further insight about AnxA5into this disease,firstly we proposed to start our study about the AnxA5expression in peripheral blood and theclinical manifestation correlation. Secondly, we determined the sera concentrations of serveralanti-phospholipid antibodies, and analyzed their associations between AnxA5sera level ordifferent clinical parameters. At last we applied the recombination AnxA5and anti-AnxA5monoclonal IgG to intervene the progress of several blood coagulation screens, in order toprobe the possible mechanism pathway of the influence of AnxA5on lupus-relatedthrombophilia.
Methods:
The study involved200SLE patients and174healthy women.
1. A proteomic analysis was accomplished using two-dimensional electrophoresis (2-DE)and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) from PBMCslysate. Protein identification and expression were validated using Western blot.Semi-quantitation of bolt film bands were executed with Quantity One software and statisticalcorrelations between clinical manifestation were analyzed with SPSS software or manually, when necessary.
2. Sera AnxA5levels and four potentially related molecules, anti-AnxA antibodies, β2glycoprotein I (β2GPI), anti-oxidized phospholipids (anti-Ox-PLs) and anticardiolipin IgG(aCL IgG) were determined using enzyme-linked immunosorbent assays (ELISA). Statisticswere also analyzed with SPSS software.
3. Recombination AnxA5and anti-AnxA5monoclonal IgG were used as intervenors andbovine serum albumin (BSA) were use as unrelated control. Preliminary parallel coagulationassays of SLE patients and healthy controls were processed using an automatic analyzer.
Results:
1. Western blotting confirmed the over-expression of AnxA5, from the PBMCs of themost SLE patients including (SLE vs. control=60.7%vs.6.4%, P=0.0004).
2. No significant difference was observed in the results from the screening of thecytomembrane protein lysate. On the other hand, over-expression of AnxA5from theintracelluer protein lysate was observed from the SLE patients comparing to healthy control.
3. Reviewing the correlations indicated the cluster without cyclophosphamide (CTX)treatment exhibited much higher AnxA5than the CTX-treated cluster (treated vs. untreated=17.0%vs.97.4%, P=0.014, without dose-dependence).
4. ELISAs demonstrated the AnxA5concentrations of the patient sera (26.8±3.0ng/mL)were generally lower than the healthy donors (49.0±3.3ng/mL, P=0.0001), except forseveral patients, whose sera AnxA5were similar with, even higher than the most healthydonors.
5. A positive correlation was demonstrated between the manifestation of thrombosis andAnxA5(Mann-Whitney Z=-2.084，P=0.037).
6. No significance were found when searching for correlations between AnxA5and theother4molecular levels, anti-AnxA5, β2GPI, anti-Ox-PLs and aCL IgG.
7. The correlation between anti-AnxA5and lupus-related thrombophilia was notcompletely certain, but this disputed statistic was mostly contributed the anti-AnxA5extremum values (Pearson’s (r)=0.340，P <0.0005vs. Mann-Whitney=-1.272，P=0.203).
8. The coagulation assays using sera from SLE patients revealed that both elevatedAnxA5and anti-AnxA5shortened prothrombin time (PT), activated partial thromboplastintime (APTT) and prolonged thrombin time (TT)(P <0.01).
9. Anti-AnxA5raised functional fibrinogen levels of sera from SLE patients.
10. The intervention of AnxA5in healthy control group displayed a similar trend to theSLE groups on PT, APTT and TT, but the alterations were not as numerically significant orstatistically dramatic as these in SLE.
Conclusions:
1. The heterogeneous transcellular distribution, increased intracellular concentrations anddecreased serum levels of AnxA5represent a protective response to lupus-relatedthrombophilia.
2. AnxA5rarely correlated with several aPLs mentioned above, and could probably bean independent factor in the pathogenesis of SLE.
3. In the thrombogenesis of SLE, AnxA5and its antibodies, might mostly participate inthe common coagulation pathway, which promoted the hypercoagulation state of SLE.
系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种典型的自身免疫性疾病。随着SLE近期生存率提高，心脑血管事件发病率显著增加，已形成第二个死亡高峰。研究生本人在从事硕士课题研究阶段，运用了比较蛋白质组学的方法，鉴定并验证了在SLE患者的外周血单个核细胞(peripheral blood mononuclear cells，PBMCs)中存在差异表达的16种蛋白质，并对这些蛋白质进行了相关的生物信息学分析。其中的膜联蛋白A5(annexin A5，AnxA5)在SLE患者中的高表达引起了我们的注意。AnxA5是膜联蛋白家族中少数具有抗凝活性的重要成员，但其在SLE发病中的确切机制目前尚无统一认识。如能明确它在SLE发病中的具体作用，对预防严重血管事件显然具有积极的意义。我们拟主要从SLE患者的临床表现及外周血中的AnxA5实际表达水平出发，明确AnxA5分子在SLE患者的外周血细胞中出现了表达差异，分析AnxA5的表达水平与SLE临床症候群的关联性。同时，筛查AnxA5及几种常见的抗磷脂抗体(anti-phospholipid antibody，aPL)在SLE患者血清中的表达水平，分析这些aPL分子相互之间以及与SLE不同临床表现的关联。最后我们通过外源性重组的AnxA5分子及anti-AnxA5单克隆抗体对SLE患者的数项临床凝血筛查实验进行干预，初步探讨AnxA5分子影响SLE患者血栓形成倾向的作用通路。
方法：
研究采集了200名女性SLE患者及174名健康对照者的血液标本。
1．通过二维电泳(2-DE)、聚丙烯酰胺凝胶电泳(SDS-PAGE)与免疫印迹(Western blot)，验证SLE患者外周血单个核细胞中AnxA5的表达情况，并分析在胞浆、胞膜亚细胞组分中的表达差异。对显影条带进行半定量处理后，分析统计意义及与临床指标的相关性。
2．运用酶联免疫吸附实验(ELISA)，测定患者及健康对照者的血清AnxA5浓度，同时测定相关分子anti-AnxA5抗体、β2糖蛋白I (β2GPI)、抗氧化性磷脂(anti-Ox-PLs)和抗心磷脂抗体(aCL IgG)的水平，分析这些分子相互之间及其与各种临床表现的相关性。
3．重组AnxA5蛋白和anti-AnxA5单克隆抗体对SLE患者及健康对照的贫血小板血浆进行体外干预，运用自动化凝血分析仪检测外源性物质干预后，凝血酶原时间(PT)、部分凝血活酶时间(APTT)、纤维蛋白原(Fib)和凝血酶时间(TT)等常规凝血筛查实验的结果变化。
主要结果：
1．Western blot验证了AnxA5在大多数SLE患者的PBMCs中存在高表达，半定量后的统计分析提示其变化有显著性意义(60.7%vs.6.4%，P=0.0004)。
2．SLE患者和健康对照者的PBMCs胞膜蛋白中，AnxA5无明显差异，而在胞浆蛋白中患者组的AnxA5高于健康对照组。
3．经环磷酰胺(CTX)治疗后的SLE患者，其PBMCs中的AnxA5明显低于未经CTX治疗的SLE患者(17.0%vs.97.4%，P=0.014)，但与CTX累计量不具有剂量依赖关系。
4．SLE患者血清中的AnxA5总体上明显低于健康对照者(26.8±3.0ng/mL vs.49.0±3.3ng/mL，P <0.0001)，但存在少数与对照者相近，甚至比对照者更高的SLE患者。
5．血清AnxA5升高的SLE患者与血栓形成性疾病的发生有明显相关性(Mann-Whitney Z=-2.084，P=0.037)。
6．SLE患者血清中的AnxA5与anti-AnxA5、β2GPI、anti-Ox-PLs、aCL IgG均无统计相关性。
7．Anti-AnxA5与血栓形成的相关性不完全明确，但受到血清anti-AnxA5极高值的影响较为明显(Pearson’s (r)=0.340，P <0.0005vs. Mann-Whitney=-1.272，P=0.203)。
8．外源性AnxA5及anti-AnxA5的干预都可以延长SLE患者的PT和APTT时间，以及缩短TT时间。
9．外源性anti-AnxA5的干预可以提高SLE患者血清中功能性Fib的含量。
10．外源性AnxA5干预健康对照的凝血筛查实验，结果的变化趋势与其干预SLE患者时相似，但后者的变化更为显著。
结论：
1．在SLE的发病过程中，外周血中的AnxA5具有在细胞内升高，在胞外血浆中降低的分布差异。这种分布特点可能发挥了某种保护作用，从而降低SLE患者出现血栓形成性疾病的机率。
2．AnxA5在SLE发病过程中，与其他几种主要的aPL没有相关性，而可能是较为独立地参与SLE的发病。
3．AnxA5及其抗体在SLE的发病过程中，可能主要通过凝血共同途径发挥作用，从而影响狼疮相关的血栓形成过程。
Background and Objective:
Systemic lupus erythematosus (SLE) is a classic autoimmune disease. As the short-termsurvival rate of SLE increased in these decades, chronic patients now suffer from increasingthrombosis-related symptoms, which had become a significant lethal factor for long-termprognosis. Our team used comparative proteomic strategies to identify16disregulatedproteins from peripheral blood monouclear cells (PBMCs) of SLE patients. Annexin A5(AnxA5) is one of the upregulated proteins, which we thought we should pay attention to.AnxA5is a distinctive annexin with anticoagulant activity that is rarely observed in theannexin family, but its detailed pathogenesis in SLE remains unclear. If the detailed functionof AnxA5in SLE could be elucidated, it should be very meaningful to help the SLE patientsto avoid the serious vascular events. To provide further insight about AnxA5into this disease,firstly we proposed to start our study about the AnxA5expression in peripheral blood and theclinical manifestation correlation. Secondly, we determined the sera concentrations of serveralanti-phospholipid antibodies, and analyzed their associations between AnxA5sera level ordifferent clinical parameters. At last we applied the recombination AnxA5and anti-AnxA5monoclonal IgG to intervene the progress of several blood coagulation screens, in order toprobe the possible mechanism pathway of the influence of AnxA5on lupus-relatedthrombophilia.
Methods:
The study involved200SLE patients and174healthy women.
1. A proteomic analysis was accomplished using two-dimensional electrophoresis (2-DE)and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) from PBMCslysate. Protein identification and expression were validated using Western blot.Semi-quantitation of bolt film bands were executed with Quantity One software and statisticalcorrelations between clinical manifestation were analyzed with SPSS software or manually, when necessary.
2. Sera AnxA5levels and four potentially related molecules, anti-AnxA antibodies, β2glycoprotein I (β2GPI), anti-oxidized phospholipids (anti-Ox-PLs) and anticardiolipin IgG(aCL IgG) were determined using enzyme-linked immunosorbent assays (ELISA). Statisticswere also analyzed with SPSS software.
3. Recombination AnxA5and anti-AnxA5monoclonal IgG were used as intervenors andbovine serum albumin (BSA) were use as unrelated control. Preliminary parallel coagulationassays of SLE patients and healthy controls were processed using an automatic analyzer.
Results:
1. Western blotting confirmed the over-expression of AnxA5, from the PBMCs of themost SLE patients including (SLE vs. control=60.7%vs.6.4%, P=0.0004).
2. No significant difference was observed in the results from the screening of thecytomembrane protein lysate. On the other hand, over-expression of AnxA5from theintracelluer protein lysate was observed from the SLE patients comparing to healthy control.
3. Reviewing the correlations indicated the cluster without cyclophosphamide (CTX)treatment exhibited much higher AnxA5than the CTX-treated cluster (treated vs. untreated=17.0%vs.97.4%, P=0.014, without dose-dependence).
4. ELISAs demonstrated the AnxA5concentrations of the patient sera (26.8±3.0ng/mL)were generally lower than the healthy donors (49.0±3.3ng/mL, P=0.0001), except forseveral patients, whose sera AnxA5were similar with, even higher than the most healthydonors.
5. A positive correlation was demonstrated between the manifestation of thrombosis andAnxA5(Mann-Whitney Z=-2.084，P=0.037).
6. No significance were found when searching for correlations between AnxA5and theother4molecular levels, anti-AnxA5, β2GPI, anti-Ox-PLs and aCL IgG.
7. The correlation between anti-AnxA5and lupus-related thrombophilia was notcompletely certain, but this disputed statistic was mostly contributed the anti-AnxA5extremum values (Pearson’s (r)=0.340，P <0.0005vs. Mann-Whitney=-1.272，P=0.203).
8. The coagulation assays using sera from SLE patients revealed that both elevatedAnxA5and anti-AnxA5shortened prothrombin time (PT), activated partial thromboplastintime (APTT) and prolonged thrombin time (TT)(P <0.01).
9. Anti-AnxA5raised functional fibrinogen levels of sera from SLE patients.
10. The intervention of AnxA5in healthy control group displayed a similar trend to theSLE groups on PT, APTT and TT, but the alterations were not as numerically significant orstatistically dramatic as these in SLE.
Conclusions:
1. The heterogeneous transcellular distribution, increased intracellular concentrations anddecreased serum levels of AnxA5represent a protective response to lupus-relatedthrombophilia.
2. AnxA5rarely correlated with several aPLs mentioned above, and could probably bean independent factor in the pathogenesis of SLE.
3. In the thrombogenesis of SLE, AnxA5and its antibodies, might mostly participate inthe common coagulation pathway, which promoted the hypercoagulation state of SLE.
引文
1. Merrell M, Shulman LE. Determination of prognosis in chronic disease, illustrated bysystemic lupus erythematosus. J Chronic Dis.1955;1(1):12-32.
2. Decker JL, Klippel JH, Plotz PH, Steinberg AD. Cyclophosphamide or azathioprine inlupus glomerulonephritis. A controlled trial: results at28months. Ann Intern Med.1975;83(5):606-15.
3. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus.Medicine (Baltimore).2006;85(3):147-56.
4.谢尚葵，冯树芳，傅华.系统性红斑狼疮病人生存率的研究.中华医学杂志.1995(10):617-20.
5.陈盛,陈顺乐,顾越英,鲍春德.系统性红斑狼疮患者18年随访.中华风湿病学杂志.2000(01):27-30.
6.何伟,邓丹琪.影响系统性红斑狼疮生存率的相关因素.临床内科杂志.2008(12):807-10.
7. Rosner S, Ginzler EM, Diamond HS, Weiner M, Schlesinger M, Fries JF, et al. Amulticenter study of outcome in systemic lupus erythematosus. II. Causes of death.Arthritis Rheum.1982;25(6):612-7.
8. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity andmortality in systemic lupus erythematosus during a10-year period: a comparison of earlyand late manifestations in a cohort of1000patients. Medicine (Baltimore).2003;82(5):299-308.
9. Devreese K, Peerlinck K, Hoylaerts MF. Thrombotic risk assessment in theantiphospholipid syndrome requires more than the quantification of lupus anticoagulants.Blood.2010;115(4):870-8.
10. Tuthill JI, Khamashta MA. Management of antiphospholipid syndrome. J Autoimmun.2009;33(2):92-8.
11. de Laat B, Wu XX, van Lummel M, Derksen RH, de Groot PG, Rand JH. Correlationbetween antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I anda reduction in the anticoagulant activity of annexin A5. Blood.2007;109(4):1490-4.
12. Pengo V, Banzato A, Bison E, Bracco A, Denas G, Ruffatti A. What Have We Learnedabout Antiphospholipid Syndrome from Patients and Antiphospholipid Carrier Cohorts?Semin Thromb Hemost.2012;38(4):322-7.
13. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. Internationalconsensus statement on an update of the classification criteria for definiteantiphospholipid syndrome (APS). J Thromb Haemost.2006;4(2):295-306.
14. Reviakine I, Bergsma-Schutter W, Mazeres-Dubut C, Govorukhina N, Brisson A. Surfacetopography of the p3and p6annexin V crystal forms determined by atomic forcemicroscopy. J Struct Biol.2000;131(3):234-9.
15. Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev.2002;82(2):331-71.
16. Deng YJ, Huang ZX, Zhou CJ, Wang JW, You Y, Song ZQ, et al. Gene profiling involvedin immature CD4+T lymphocyte responsible for systemic lupus erythematosus. MolImmunol.2006;43(9):1497-507.
17. Kenis H, Hofstra L, Reutelingsperger CP. Annexin A5: shifting from a diagnostic towardsa therapeutic realm. Cell Mol Life Sci.2007;64(22):2859-62.
18. Cederholm A, Frostegard J. Annexin A5in cardiovascular disease and systemic lupuserythematosus. Immunobiology.2005;210(10):761-8.
19. Tomer A, Bar-Lev S, Fleisher S, Shenkman B, Friger M, Abu-Shakra M.Antiphospholipid antibody syndrome: the flow cytometric annexin A5competition assayas a diagnostic tool. Br J Haematol.2007;139(1):113-20.
20. de Laat B, Derksen RH, Mackie IJ, Roest M, Schoormans S, Woodhams BJ, et al.Annexin A5polymorphism (-1C-->T) and the presence of anti-annexin A5antibodies inthe antiphospholipid syndrome. Ann Rheum Dis.2006;65(11):1468-72.
21. Rand JH, Wu XX, Quinn AS, Taatjes DJ. Resistance to annexin A5anticoagulant activity:a thrombogenic mechanism for the antiphospholipid syndrome. Lupus.2008;17(10):922-30.
22. Kenis H, van Genderen H, Bennaghmouch A, Rinia HA, Frederik P, Narula J, et al. Cellsurface-expressed phosphatidylserine and annexin A5open a novel portal of cell entry. JBiol Chem.2004;279(50):52623-9.
23. Hochberg MC. Updating the American College of Rheumatology revised criteria for theclassification of systemic lupus erythematosus. Arthritis Rheum.1997;40(9):1725.
24. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activityindex2000. J Rheumatol.2002;29(2):288-91.
25. Peng J. Meeting report: Functional genomics and proteomics-applications, moleculardiagnostics&next generation sequencing. Biotechnology journal.2012;7(3):323-5.
26. Kaufmann H, Bailey JE, Fussenegger M. Use of antibodies for detection ofphosphorylated proteins separated by two-dimensional gel electrophoresis. Proteomics.2001;1(2):194-9.
27. Nagano K, Shinkawa T, Kato K, Inomata N, Yabuki N, Haramura M. Distinct cell surfaceproteome profiling by biotin labeling and glycoprotein capturing. J Proteomics.2011;74(10):1985-93.
28. Mann M. Can proteomics retire the western blot? J Proteome Res.2008;7(8):3065.
29. Raynal P, Hullin F, Ragab-Thomas JM, Fauvel J, Chap H. Annexin5as a potentialregulator of annexin1phosphorylation by protein kinase C. In vitro inhibition comparedwith quantitative data on annexin distribution in human endothelial cells. Biochem J.1993;292(3):759-65.
30. Giambanco I, Sorci G, Antonioli S, Rambotti MG, Spreca A, Bocchini V, et al.Immunocytochemical analyses of annexin V (CaBP33) in a human-derived glioma cellline. Expression of annexin V depends on cellular growth state. FEBS Lett.1993;323(1):45-50.
31. Peers SH, Smillie F, Elderfield AJ, Flower RJ. Glucocorticoid-and non-glucocorticoidinduction of lipocortins (annexins)1and2in rat peritoneal leucocytes in vivo. Br JPharmacol.1993;108(1):66-72.
32. Brachvogel B, Welzel H, Moch H, von der Mark K, Hofmann C, Poschl E. Sequentialexpression of annexin A5in the vasculature and skeletal elements during mousedevelopment. Mech Dev.2001;109(2):389-93.
33. Yeh HY, Klesius PH. Identification, phylogenetic relationships, characterization and geneexpression patterns of six different annexins of channel catfish. Vet ImmunolImmunopathol.2010;136(1):176-83.
34. McQuade P, Belanger MJ, Meng X, Guenther I, Krause S, Gonzalez TD, et al.Comparison of the in vivo distribution of four different annexin a5adducts in rhesusmonkeys. International journal of molecular imaging.2011;2(5):e405840.
35. Lahorte CM, van de Wiele C, Bacher K, van den Bossche B, Thierens H, van Belle S, etal. Biodistribution and dosimetry study of123I-rh-annexin V in mice and humans. NuclMed Commun.2003;24(8):871-80.
36. Wever KE, Wagener FA, Frielink C, Boerman OC, Scheffer GJ, Allison A, et al.Diannexin protects against renal ischemia reperfusion injury and targetsphosphatidylserines in ischemic tissue. PLoS One.2011;6(8):e24276.
37. Wang JG, Xu WD, Zhai WT, Li Y, Hu JW, Hu B, et al. Disorders in angiogenesis andredox pathways are main factors contributing to the progression of rheumatoid arthritis: Acomparative proteomics study. Arthritis Rheum.2012;64(4):993-1004.
38. Rovin BH, Birmingham DJ, Nagaraja HN, Yu CY, Hebert LA. Biomarker discovery inhuman SLE nephritis. Bull NYU Hosp Jt Dis.2007;65(3):187-93.
39. Korte EA, Gaffney PM, Powell DW. Contributions of mass spectrometry-basedproteomics to defining cellular mechanisms and diagnostic markers for systemic lupuserythematosus. Arthritis Res Ther.2012;14(1):204.
40. Doria A, Briani C. Lupus: improving long-term prognosis. Lupus.2008;17(3):166-70.
41. Jamoussi SK, Ben Dhaou B, Boussema F, Turki E, Kochbati S, Cherif O, et al. Unusualpresentation of Wegener's granulomatosis. Rev Med Interne.2010;31(8):e16-8.
42. Theodossiou C, Kroog G, Ettinghausen S, Tolcher A, Cowan K, O'Shaughnessy J. Acutearterial thrombosis in a patient with breast cancer after chemotherapy with5-fluorouracil,doxorubicin, leucovorin, cyclophosphamide, and interleukin-3. Cancer.1994;74(10):2808-10.
43. Chen YC, Cheng TT, Lai HM, Wu CH. Overwhelming septic cavernous sinus thrombosisin a woman after combination of high-dose steroid and intravenous cyclophosphamidetherapy for lupus nephritis. Lupus.2000;9(1):78-9.
44. Monceau V, Belikova Y, Kratassiouk G, Robidel E, Russo-Marie F, Charlemagne D.Myocyte apoptosis during acute myocardial infarction in rats is related to earlysarcolemmal translocation of annexin A5in border zone. Am J Physiol Heart CircPhysiol.2006;291(2):965-71.
45. Schmidt V, Giacomelli C, Gounou C, Lai-Kee-Him J, Brisson AR, Borsali R. Formationof annexin-a5protein/block copolymer micelle complexes: QCM-D and PAGEexperiments. Langmuir.2008;24(21):12189-95.
46. Turnay J, Guzman-Aranguez A, Lecona E, Barrasa JI, Olmo N, Lizarbe MA. Key role ofthe N-terminus of chicken annexin A5in vesicle aggregation. Protein Sci.2009;18(5):1095-106.
47. Dai Y, Hu C, Huang Y, Huang H, Liu J, Lv T. A proteomic study of peripheral bloodmononuclear cells in systemic lupus erythematosus. Lupus.2008;17(9):799-804.
48. Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, et al. Pregnancy loss inthe antiphospholipid-antibody syndrome--a possible thrombogenic mechanism. N Engl JMed.1997;337(3):154-60.
49. van Heerde WL, Reutelingsperger CP, Maassen C, Lux P, Derksen RH, de Groot PG. Thepresence of antiphospholipid antibodies is not related to increased levels of annexin A5inplasma. J Thromb Haemost.2003;1(3):532-6.
50. Ravassa S, Bennaghmouch A, Kenis H, Lindhout T, Hackeng T, Narula J, et al. AnnexinA5down-regulates surface expression of tissue factor: a novel mechanism of regulatingthe membrane receptor repertoir. J Biol Chem.2005;280(7):6028-35.
51. Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defectiveclearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol.2010;6(5):280-9.
52. van Bavel CC, Dieker JW, Kroeze Y, Tamboer WP, Voll R, Muller S, et al.Apoptosis-induced histone H3methylation is targeted by autoantibodies in systemiclupus erythematosus. Ann Rheum Dis.2011;70(1):201-7.
53. Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Anti-annexin V antibody insystemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipinantibody. Am J Hematol.1994;47(1):56-8.
54. Lakos G, Kiss E, Regeczy N, Tarjan P, Soltesz P, Zeher M, et al. Antiprothrombin andantiannexin V antibodies imply risk of thrombosis in patients with systemic autoimmunediseases. J Rheumatol.2000;27(4):924-9.
55. Hrycek A, Cieslik P. Annexin A5and anti-annexin antibodies in patients with systemiclupus erythematosus. Rheumatol Int.2012;32(5):1335-42.
56. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelinesfor lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/AntiphospholipidAntibody of the Scientific and Standardisation Committee of the International Society onThrombosis and Haemostasis. J Thromb Haemost.2009;7(10):1737-40.
57. Branch DW, Rote NS, Scott JR. The demonstration of lupus anticoagulant by anenzyme-linked immunoadsorbent assay. Clin Immunol Immunopathol.1986;39(2):298-307.
58. Rolla R, Vidali M, Serino R, Pergolini P, Albano E, Bellomo G. Antibodies againstoxidized phospholipids in laboratory tests exploring lupus anti-coagulant activity. ClinExp Immunol.2007;149(1):63-9.
59. Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, et al. Internationalconsensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report fromthe13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum.2012;64(1):1-10.
60. Erkan D, Barbhaiya M, George D, Sammaritano L, Lockshin M. Moderate versushigh-titer persistently anticardiolipin antibody positive patients: are they clinicallydifferent and does high-titer anti-beta2-glycoprotein-I antibody positivity offer additionalpredictive information? Lupus.2010;19(5):613-9.
61. Persijn L, Decavele AS, Schouwers S, Devreese K. Evaluation of a new set of automatedchemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies inthe laboratory diagnosis of the antiphospholipid syndrome. Thromb Res.2011;128(6):565-9.
62. Devreese KM, van Hoecke F. Anticardiolipin and anti-beta2glycoprotein-I antibodycut-off values in the diagnosis of antiphospholipid syndrome: more than calculating thein-house99th percentiles, even for new automated assays. Thromb Res.2011;128(6):598-600.
63. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis inantiphospholipid antibody syndrome. J Autoimmun.2010;35(3):248-55.
64. Doyle D. William Hewson (1739-74): the father of haematology. Br J Haematol.2006;133(4):375-81.
65. Griffin JH. Blood coagulation. The thrombin paradox. Nature.1995;378(6555):337-8.
66. Nakamura N, Kuragaki C, Shidara Y, Yamaji K, Wada Y. Antibody to annexin V hasanti-phospholipid and lupus anticoagulant properties. Am J Hematol.1995;49(4):347-8.
67. Vogler EA, Siedlecki CA. Contact activation of blood-plasma coagulation. Biomaterials.2009;30(10):1857-69.
68. Zhu D. Mathematical modeling of blood coagulation cascade: kinetics of intrinsic andextrinsic pathways in normal and deficient conditions. Blood Coagul Fibrinolysis.2007;18(7):637-46.
69. Tincani A, Morozzi G, Afeltra A, Alessandri C, Allegri F, Bistoni O, et al.Antiprothrombin antibodies: a comparative analysis of homemade and commercialmethods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelleMalattie Autoimmuni (FIRMA). Clin Exp Rheumatol.2007;25(2):268-74.
70. Dragoni F, Minotti C, Palumbo G, Faillace F, Redi R, Bongarzoni V, et al. As comparedto kaolin clotting time, silica clotting time is a specific and sensitive automated methodfor detecting lupus anticoagulant. Thromb Res.2001;101(2):45-51.
71. Mendelsohn EE, Solum NO, Brosstad F. Effects of platelets and platelet-derived materialon the activated partial thromboplastin time (Cephotest) coagulation test. Scand J ClinLab Invest.2005;65(4):321-32.
72. Vedeler C, Ulvestad E, Grundt I, Conti G, Nyland H, Matre R, et al. Fc receptor for IgG(FcR) on rat microglia. J Neuroimmunol.1994;49(1):19-24.
73. Kolev K, Lerant I, Skopal J, Kelemen A, Nagy Z, Machovich R. Impaired inactivation byantithrombin and hirudin and preserved fibrinogen-clotting activity of thrombin incomplex with anti-thrombin antibody from a patient with antiphospholipid syndrome.Thromb Haemost.2005;94(1):82-7.
74. Wang W, Xu J, Kirsch T. Annexin-mediated Ca2+influx regulates growth platechondrocyte maturation and apoptosis. J Biol Chem.2003;278(6):3762-9.
1. Azkargorta M, Arizmendi JM, Elortza F, Alkorta N, Zubiaga AM, Fullaondo A.Differential proteome profiles in E2F2-deficient T lymphocytes. Proteomics.2006;6(1):42-50.
2. Pavon EJ, Munoz P, Lario A, Longobardo V, Carrascal M, Abian J, et al. Proteomicanalysis of plasma from patients with systemic lupus erythematosus: increasedpresence of haptoglobin alpha2polypeptide chains over the alpha1isoforms.Proteomics.2006;6(1):282-92.
3. Deocharan B, Zhou Z, Antar K, Siconolfi-Baez L, Angeletti RH, Hardin J, et al.Alpha-actinin immunization elicits anti-chromatin autoimmunity in nonautoimmunemice. J Immunol.2007;179(2):1313-21.
4. Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al. Caspasesare activated in a branched protease cascade and control distinct downstreamprocesses in Fas-induced apoptosis. J Exp Med.1998;187(4):587-600.
5. Robinson WH, Steinman L, Utz PJ. Protein arrays for autoantibody profiling andfine-specificity mapping. Proteomics.2003;3(11):2077-84.
6. Thebault S, Gilbert D, Hubert M, Drouot L, Machour N, Lange C, et al. Orderlypattern of development of the autoantibody response in (New Zealand White xBXSB)F1lupus mice: characterization of target antigens and antigen spreading bytwo-dimensional gel electrophoresis and mass spectrometry. J Immunol.2002;169(7):4046-53.
7. Rovin BH, Birmingham DJ, Nagaraja HN, Yu CY, Hebert LA. Biomarker discovery inhuman SLE nephritis. Bull NYU Hosp Jt Dis.2007;65(3):187-93.
8. Mosley K, Tam FW, Edwards RJ, Crozier J, Pusey CD, Lightstone L. Urinaryproteomic profiles distinguish between active and inactive lupus nephritis.Rheumatology (Oxford).2006;45(12):1497-504.
9. Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, et al. Identification ofa urinary proteomic signature for lupus nephritis in children. Pediatr Nephrol.2007;22(12):2047-57.
10. Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, etal. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol.2007;18(3):913-22.
11. Lefranc D, Launay D, Dubucquoi S, de Seze J, Dussart P, Vermersch M, et al.Characterization of discriminant human brain antigenic targets in neuropsychiatricsystemic lupus erythematosus using an immunoproteomic approach. Arthritis Rheum.2007;56(10):3420-32.
12. Kimura A, Sakurai T, Tanaka Y, Hozumi I, Takahashi K, Takemura M, et al.Proteomic analysis of autoantibodies in neuropsychiatric systemic lupuserythematosus patient with white matter hyperintensities on brain MRI. Lupus.2008;17(1):16-20.
13. Li QZ, Xie C, Wu T, Mackay M, Aranow C, Putterman C, et al. Identification ofautoantibody clusters that best predict lupus disease activity using glomerularproteome arrays. J Clin Invest.2005;115(12):3428-39.
14. Li QZ, Zhou J, Wandstrat AE, Carr-Johnson F, Branch V, Karp DR, et al. Protein arrayautoantibody profiles for insights into systemic lupus erythematosus and incompletelupus syndromes. Clin Exp Immunol.2007;147(1):60-70.
15. Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, et al.Elevated serum levels of interferon-regulated chemokines are biomarkers for activehuman systemic lupus erythematosus. PLoS Med.2006;3(12):491.
16. Graves PR, Kwiek JJ, Fadden P, Ray R, Hardeman K, Coley AM, et al. Discovery ofnovel targets of quinoline drugs in the human purine binding proteome. MolPharmacol.2002;62(6):1364-72.
1. Shapiro SS. Lupus anticoagulants and anticardiolipin antibodies: personal reminiscences,a little history, and some random thoughts. J Thromb Haemost.2005;3(5):831-3.
2. Pengo V, Biasiolo A, Bison E, Chantarangkul V, Tripodi A. Antiphospholipid antibodyELISAs: survey on the performance of clinical laboratories assessed by using lyophilizedaffinity-purified IgG with anticardiolipin and anti-beta2-Glycoprotein I activity. ThrombRes.2007;120(1):127-33.
3. Sipek-Dolnicar A, Hojnik M, Bozic B, Vizjak A, Rozman B, Ferluga D. Clinicalpresentations and vascular histopathology in autopsied patients with systemic lupuserythematosus and anticardiolipin antibodies. Clin Exp Rheumatol.2002;20(3):335-42.
4. Mtiraoui N, Zammiti W, Fekih M, Hider S, Almawi WY, Mahjoub T. Lupus anticoagulantand antibodies to beta2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrentspontaneous abortion. Fertil Steril.2007;88(5):1458-61.
5. Frostegard AG, Su J, von Landenberg P, Frostegard J. Effects of anti-cardiolipinantibodies and IVIg on annexin A5binding to endothelial cells: implications forcardiovascular disease. Scand J Rheumatol.2010;39(1):77-83.
6. de Laat B, Wu X-X, van Lummel M, Derksen RHWM, de Groot PG, Rand JH.Correlation between antiphospholipid antibodies that recognize domain I ofbeta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood.2007;109(4):1490-4.
7. Ortona E, Capozzi A, Colasanti T, Conti F, Alessandri C, Longo A, et al.Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome.Blood.2010;116(16):2960-7.
8. Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, et al. Internationalconsensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report fromthe13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum.2012;64(1):1-10.
9. Rolla R, Vidali M, Serino R, Pergolini P, Albano E, Bellomo G. Antibodies againstoxidized phospholipids in laboratory tests exploring lupus anti-coagulant activity. ClinExp Immunol.2007;149(1):63-9.
10. Frank M, Sodin-Semrl S, Irman S, Bozic B, Rozman B. Beta2-glycoprotein I and annexinA5phospholipid interactions: artificial and cell membranes. Autoimmun Rev.2009;9(1):5-10.
11. Cucnik S, Kveder T, Rozman B, Bozic B. Binding of high-avidity anti-beta2-glycoproteinI antibodies. Rheumatology (Oxford).2004;43(11):1353-6.
12. Hanly JG, Smith SA. Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V bindingand the anti-phospholipid syndrome. Clin Exp Immunol.2000;120(3):537-43.
13. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. Internationalconsensus statement on an update of the classification criteria for definiteantiphospholipid syndrome (APS). J Thromb Haemost.2006;4(2):295-306.
14. Zoghlami-Rintelen C, Vormittag R, Sailer T, Lehr S, Quehenberger P, Rumpold H, et al.The presence of IgG antibodies against beta2-glycoprotein I predicts the risk ofthrombosis in patients with the lupus anticoagulant. J Thromb Haemost.2005;3(6):1160-5.
15. Bassi N, Ghirardello A, Iaccarino L, Zampieri S, Rampudda ME, Atzeni F, et al.OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients.Autoimmun Rev.2007;7(1):52-8.
16. de Laat B, Derksen RH, Reber G, Musial J, Swadzba J, Bozic B, et al. An internationalmulticentre-laboratory evaluation of a new assay to detect specifically lupusanticoagulants dependent on the presence of anti-beta2-glycoprotein autoantibodies. JThromb Haemost.2011;9(1):149-53.
17. Kraus M, Romisch J, Bastian B, Paques EP, Hartmann AA. Detection of humananti-annexin autoantibodies by enzyme immunoassays. J Immunoassay.1992;13(3):411-39.
18. Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Anti-annexin V antibody insystemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipinantibody. Am J Hematol.1994;47(1):56-8.
19. Bozic B, Irman S, Gaspersic N, Kveder T, Rozman B. Antibodies against annexin A5:detection pitfalls and clinical associations. Autoimmunity.2005;38(6):425-30.
20. Arnold J, Holmes Z, Pickering W, Farmer C, Regan L, Cohen H. Anti-beta2glycoprotein1and anti-annexin V antibodies in women with recurrent miscarriage. Br J Haematol.2001;113(4):911-4.
21. Siaka C, Lambert M, Caron C, Amiral J, Hachulla E, Hatron PY, et al. Low prevalence ofanti-annexin V antibodies in antiphospholipid syndrome with fetal loss. Rev Med Interne.1999;20(9):762-5.
22. Bizzaro N, Antico A, Musso M, Platzgummer S, Camogliano L, Tozzoli R, et al. Aprospective study of1038pregnancies on the predictive value of anti-annexin Vantibodies for fetal loss. Ann N Y Acad Sci.2005;1050:348-56.
23. Arai T, Matsubayashi H, Sugi T, Kondo A, Shida M, Suzuki T, et al. Anti-annexin A5antibodies in reproductive failures in relation to antiphospholipid antibodies andphosphatidylserine. Am J Reprod Immunol.2003;50(3):202-8.
24. Esposito G, Tamby MC, Chanseaud Y, Servettaz A, Guillevin L, Mouthon L.Anti-annexin V antibodies: are they prothrombotic? Autoimmun Rev.2005;4(1):55-60.
25. Gaspersic N, Ambrozic A, Bozic B, Majhenc J, Svetina S, Rozman B. Annexin A5binding to giant phospholipid vesicles is differentially affected by anti-beta2-glycoproteinI and anti-annexin A5antibodies. Rheumatology (Oxford).2007;46(1):81-6.
26. Irman S, Skarabot M, Musevic I, Rozman B, Bozic B. The use of atomic forcemicroscopy to study the pathologic effects of anti-annexin autoantibodies. J Autoimmun.2011;36(2):98-105.
27. de Laat B, Derksen RH, Mackie IJ, Roest M, Schoormans S, Woodhams BJ, et al.Annexin A5polymorphism (-1C-->T) and the presence of anti-annexin A5antibodies inthe antiphospholipid syndrome. Ann Rheum Dis.2006;65(11):1468-72.
28. Suzuki K, Satoh A, Hidaka T, Takayama E, Kataharada K, Matsumoto M, et al.Adsorption of anti-annexin V using dextran sulfate bound cellulose beads. J Clin Apher.2000;15(4):262-5.
29. Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant.Blood.1988;72(2):512-9.
30. Murakami F, Iijima K, Nakamura K, Ikawa S, Hayashibara H, Siraki K. Transitions ofeach inhibitor in a patient with lupus anticoagulant and anti-prothrombin antibody.Rinsho Byori.1996;44(7):692-6.
31. Akimoto T, Akama T, Kono I, Sumida T. Relationship between clinical features andbinding domains of anti-prothrombin autoantibodies in patients with systemic lupuserythematosus and antiphospholipid syndrome. Lupus.1999;8(9):761-6.
32. Simmelink MJ, Horbach DA, Derksen RH, Meijers JC, Bevers EM, Willems GM, et al.Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulantactivity by competing with the binding of clotting factors for catalytic phospholipidsurfaces. Br J Haematol.2001;113(3):621-9.
33. Nojima J, Kuratsune H, Suehisa E, Futsukaichi Y, Yamanishi H, Machii T, et al.Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essentialrisk factor for venous thromboembolism in patients with systemic lupus erythematosus.Br J Haematol.2001;114(3):647-54.
34. Horbach DA, van Oort E, Derksen RH, de Groot PG. The contribution ofanti-prothrombin-antibodies to lupus anticoagulant activity--discrimination betweenfunctional and non-functional anti-prothrombin-antibodies. Thromb Haemost.1998;79(4):790-5.
35. Bardin N, Alessi MC, Dignat-George F, Vague IJ, Sampol J, Harle JR, et al. Does theanti-prothrombin antibodies measurement provide additional information in patients withthrombosis? Immunobiology.2007;212(7):557-65.
36. Pengo V, Denas G, Bison E, Banzato A, Jose SP, Gresele P, et al. Prevalence andsignificance of anti-prothrombin (aPT) antibodies in patients with Lupus Anticoagulant(LAC). Thromb Res.2010;126(2):150-3.
37. Liestol S, Sandset PM, Mowinckel MC, Wisloff F. Activated protein C resistancedetermined with a thrombin generation-based test is associated with thrombotic events inpatients with lupus anticoagulants. J Thromb Haemost.2007;5(11):2204-10.
38. Le DT, Ho D, Olsen JO, Osterud B. Plasma and IgGs from patients with lupusanticoagulant induce tissue factor in monocytes: a possible risk factor for thrombosis. JThromb Haemost.2010;8(8):1861-3.
39. 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 the13thInternational Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April2010.Lupus.2011;20(2):191-205.
40. Simmelink MJ, Derksen RH, Arnout J, de Groot PG. A simple method to discriminatebetween beta2-glycoprotein I-and prothrombin-dependent lupus anticoagulants. JThromb Haemost.2003;1(4):740-7.
41. Parkpian V, Verasertniyom O, Vanichapuntu M, Totemchokchyakarn K, Nantiruj K,Pisitkul P, et al. Specificity and sensitivity of anti-beta2-glycoprotein I as compared withanticardiolipin antibody and lupus anticoagulant in Thai systemic lupus erythematosuspatients with clinical features of antiphospholipid syndrome. Clin Rheumatol.2007;26(10):1663-70.
42. Ieko M, Nakabayashi T, Tarumi T, Yoshida M, Naito S, Atsumi T, et al.Phosphatidylserine-dependent anti-prothrombin antibody as a new marker for thediagnosis of antiphospholipid syndrome. Rinsho Byori.2006;54(3):256-62.
2. Decker JL, Klippel JH, Plotz PH, Steinberg AD. Cyclophosphamide or azathioprine inlupus glomerulonephritis. A controlled trial: results at28months. Ann Intern Med.1975;83(5):606-15.
3. Kasitanon N, Magder LS, Petri M. Predictors of survival in systemic lupus erythematosus.Medicine (Baltimore).2006;85(3):147-56.
4.谢尚葵，冯树芳，傅华.系统性红斑狼疮病人生存率的研究.中华医学杂志.1995(10):617-20.
5.陈盛,陈顺乐,顾越英,鲍春德.系统性红斑狼疮患者18年随访.中华风湿病学杂志.2000(01):27-30.
6.何伟,邓丹琪.影响系统性红斑狼疮生存率的相关因素.临床内科杂志.2008(12):807-10.
7. Rosner S, Ginzler EM, Diamond HS, Weiner M, Schlesinger M, Fries JF, et al. Amulticenter study of outcome in systemic lupus erythematosus. II. Causes of death.Arthritis Rheum.1982;25(6):612-7.
8. Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, et al. Morbidity andmortality in systemic lupus erythematosus during a10-year period: a comparison of earlyand late manifestations in a cohort of1000patients. Medicine (Baltimore).2003;82(5):299-308.
9. Devreese K, Peerlinck K, Hoylaerts MF. Thrombotic risk assessment in theantiphospholipid syndrome requires more than the quantification of lupus anticoagulants.Blood.2010;115(4):870-8.
10. Tuthill JI, Khamashta MA. Management of antiphospholipid syndrome. J Autoimmun.2009;33(2):92-8.
11. de Laat B, Wu XX, van Lummel M, Derksen RH, de Groot PG, Rand JH. Correlationbetween antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I anda reduction in the anticoagulant activity of annexin A5. Blood.2007;109(4):1490-4.
12. Pengo V, Banzato A, Bison E, Bracco A, Denas G, Ruffatti A. What Have We Learnedabout Antiphospholipid Syndrome from Patients and Antiphospholipid Carrier Cohorts?Semin Thromb Hemost.2012;38(4):322-7.
13. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. Internationalconsensus statement on an update of the classification criteria for definiteantiphospholipid syndrome (APS). J Thromb Haemost.2006;4(2):295-306.
14. Reviakine I, Bergsma-Schutter W, Mazeres-Dubut C, Govorukhina N, Brisson A. Surfacetopography of the p3and p6annexin V crystal forms determined by atomic forcemicroscopy. J Struct Biol.2000;131(3):234-9.
15. Gerke V, Moss SE. Annexins: from structure to function. Physiol Rev.2002;82(2):331-71.
16. Deng YJ, Huang ZX, Zhou CJ, Wang JW, You Y, Song ZQ, et al. Gene profiling involvedin immature CD4+T lymphocyte responsible for systemic lupus erythematosus. MolImmunol.2006;43(9):1497-507.
17. Kenis H, Hofstra L, Reutelingsperger CP. Annexin A5: shifting from a diagnostic towardsa therapeutic realm. Cell Mol Life Sci.2007;64(22):2859-62.
18. Cederholm A, Frostegard J. Annexin A5in cardiovascular disease and systemic lupuserythematosus. Immunobiology.2005;210(10):761-8.
19. Tomer A, Bar-Lev S, Fleisher S, Shenkman B, Friger M, Abu-Shakra M.Antiphospholipid antibody syndrome: the flow cytometric annexin A5competition assayas a diagnostic tool. Br J Haematol.2007;139(1):113-20.
20. de Laat B, Derksen RH, Mackie IJ, Roest M, Schoormans S, Woodhams BJ, et al.Annexin A5polymorphism (-1C-->T) and the presence of anti-annexin A5antibodies inthe antiphospholipid syndrome. Ann Rheum Dis.2006;65(11):1468-72.
21. Rand JH, Wu XX, Quinn AS, Taatjes DJ. Resistance to annexin A5anticoagulant activity:a thrombogenic mechanism for the antiphospholipid syndrome. Lupus.2008;17(10):922-30.
22. Kenis H, van Genderen H, Bennaghmouch A, Rinia HA, Frederik P, Narula J, et al. Cellsurface-expressed phosphatidylserine and annexin A5open a novel portal of cell entry. JBiol Chem.2004;279(50):52623-9.
23. Hochberg MC. Updating the American College of Rheumatology revised criteria for theclassification of systemic lupus erythematosus. Arthritis Rheum.1997;40(9):1725.
24. Gladman DD, Ibanez D, Urowitz MB. Systemic lupus erythematosus disease activityindex2000. J Rheumatol.2002;29(2):288-91.
25. Peng J. Meeting report: Functional genomics and proteomics-applications, moleculardiagnostics&next generation sequencing. Biotechnology journal.2012;7(3):323-5.
26. Kaufmann H, Bailey JE, Fussenegger M. Use of antibodies for detection ofphosphorylated proteins separated by two-dimensional gel electrophoresis. Proteomics.2001;1(2):194-9.
27. Nagano K, Shinkawa T, Kato K, Inomata N, Yabuki N, Haramura M. Distinct cell surfaceproteome profiling by biotin labeling and glycoprotein capturing. J Proteomics.2011;74(10):1985-93.
28. Mann M. Can proteomics retire the western blot? J Proteome Res.2008;7(8):3065.
29. Raynal P, Hullin F, Ragab-Thomas JM, Fauvel J, Chap H. Annexin5as a potentialregulator of annexin1phosphorylation by protein kinase C. In vitro inhibition comparedwith quantitative data on annexin distribution in human endothelial cells. Biochem J.1993;292(3):759-65.
30. Giambanco I, Sorci G, Antonioli S, Rambotti MG, Spreca A, Bocchini V, et al.Immunocytochemical analyses of annexin V (CaBP33) in a human-derived glioma cellline. Expression of annexin V depends on cellular growth state. FEBS Lett.1993;323(1):45-50.
31. Peers SH, Smillie F, Elderfield AJ, Flower RJ. Glucocorticoid-and non-glucocorticoidinduction of lipocortins (annexins)1and2in rat peritoneal leucocytes in vivo. Br JPharmacol.1993;108(1):66-72.
32. Brachvogel B, Welzel H, Moch H, von der Mark K, Hofmann C, Poschl E. Sequentialexpression of annexin A5in the vasculature and skeletal elements during mousedevelopment. Mech Dev.2001;109(2):389-93.
33. Yeh HY, Klesius PH. Identification, phylogenetic relationships, characterization and geneexpression patterns of six different annexins of channel catfish. Vet ImmunolImmunopathol.2010;136(1):176-83.
34. McQuade P, Belanger MJ, Meng X, Guenther I, Krause S, Gonzalez TD, et al.Comparison of the in vivo distribution of four different annexin a5adducts in rhesusmonkeys. International journal of molecular imaging.2011;2(5):e405840.
35. Lahorte CM, van de Wiele C, Bacher K, van den Bossche B, Thierens H, van Belle S, etal. Biodistribution and dosimetry study of123I-rh-annexin V in mice and humans. NuclMed Commun.2003;24(8):871-80.
36. Wever KE, Wagener FA, Frielink C, Boerman OC, Scheffer GJ, Allison A, et al.Diannexin protects against renal ischemia reperfusion injury and targetsphosphatidylserines in ischemic tissue. PLoS One.2011;6(8):e24276.
37. Wang JG, Xu WD, Zhai WT, Li Y, Hu JW, Hu B, et al. Disorders in angiogenesis andredox pathways are main factors contributing to the progression of rheumatoid arthritis: Acomparative proteomics study. Arthritis Rheum.2012;64(4):993-1004.
38. Rovin BH, Birmingham DJ, Nagaraja HN, Yu CY, Hebert LA. Biomarker discovery inhuman SLE nephritis. Bull NYU Hosp Jt Dis.2007;65(3):187-93.
39. Korte EA, Gaffney PM, Powell DW. Contributions of mass spectrometry-basedproteomics to defining cellular mechanisms and diagnostic markers for systemic lupuserythematosus. Arthritis Res Ther.2012;14(1):204.
40. Doria A, Briani C. Lupus: improving long-term prognosis. Lupus.2008;17(3):166-70.
41. Jamoussi SK, Ben Dhaou B, Boussema F, Turki E, Kochbati S, Cherif O, et al. Unusualpresentation of Wegener's granulomatosis. Rev Med Interne.2010;31(8):e16-8.
42. Theodossiou C, Kroog G, Ettinghausen S, Tolcher A, Cowan K, O'Shaughnessy J. Acutearterial thrombosis in a patient with breast cancer after chemotherapy with5-fluorouracil,doxorubicin, leucovorin, cyclophosphamide, and interleukin-3. Cancer.1994;74(10):2808-10.
43. Chen YC, Cheng TT, Lai HM, Wu CH. Overwhelming septic cavernous sinus thrombosisin a woman after combination of high-dose steroid and intravenous cyclophosphamidetherapy for lupus nephritis. Lupus.2000;9(1):78-9.
44. Monceau V, Belikova Y, Kratassiouk G, Robidel E, Russo-Marie F, Charlemagne D.Myocyte apoptosis during acute myocardial infarction in rats is related to earlysarcolemmal translocation of annexin A5in border zone. Am J Physiol Heart CircPhysiol.2006;291(2):965-71.
45. Schmidt V, Giacomelli C, Gounou C, Lai-Kee-Him J, Brisson AR, Borsali R. Formationof annexin-a5protein/block copolymer micelle complexes: QCM-D and PAGEexperiments. Langmuir.2008;24(21):12189-95.
46. Turnay J, Guzman-Aranguez A, Lecona E, Barrasa JI, Olmo N, Lizarbe MA. Key role ofthe N-terminus of chicken annexin A5in vesicle aggregation. Protein Sci.2009;18(5):1095-106.
47. Dai Y, Hu C, Huang Y, Huang H, Liu J, Lv T. A proteomic study of peripheral bloodmononuclear cells in systemic lupus erythematosus. Lupus.2008;17(9):799-804.
48. Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, et al. Pregnancy loss inthe antiphospholipid-antibody syndrome--a possible thrombogenic mechanism. N Engl JMed.1997;337(3):154-60.
49. van Heerde WL, Reutelingsperger CP, Maassen C, Lux P, Derksen RH, de Groot PG. Thepresence of antiphospholipid antibodies is not related to increased levels of annexin A5inplasma. J Thromb Haemost.2003;1(3):532-6.
50. Ravassa S, Bennaghmouch A, Kenis H, Lindhout T, Hackeng T, Narula J, et al. AnnexinA5down-regulates surface expression of tissue factor: a novel mechanism of regulatingthe membrane receptor repertoir. J Biol Chem.2005;280(7):6028-35.
51. Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defectiveclearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol.2010;6(5):280-9.
52. van Bavel CC, Dieker JW, Kroeze Y, Tamboer WP, Voll R, Muller S, et al.Apoptosis-induced histone H3methylation is targeted by autoantibodies in systemiclupus erythematosus. Ann Rheum Dis.2011;70(1):201-7.
53. Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Anti-annexin V antibody insystemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipinantibody. Am J Hematol.1994;47(1):56-8.
54. Lakos G, Kiss E, Regeczy N, Tarjan P, Soltesz P, Zeher M, et al. Antiprothrombin andantiannexin V antibodies imply risk of thrombosis in patients with systemic autoimmunediseases. J Rheumatol.2000;27(4):924-9.
55. Hrycek A, Cieslik P. Annexin A5and anti-annexin antibodies in patients with systemiclupus erythematosus. Rheumatol Int.2012;32(5):1335-42.
56. Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, et al. Update of the guidelinesfor lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/AntiphospholipidAntibody of the Scientific and Standardisation Committee of the International Society onThrombosis and Haemostasis. J Thromb Haemost.2009;7(10):1737-40.
57. Branch DW, Rote NS, Scott JR. The demonstration of lupus anticoagulant by anenzyme-linked immunoadsorbent assay. Clin Immunol Immunopathol.1986;39(2):298-307.
58. Rolla R, Vidali M, Serino R, Pergolini P, Albano E, Bellomo G. Antibodies againstoxidized phospholipids in laboratory tests exploring lupus anti-coagulant activity. ClinExp Immunol.2007;149(1):63-9.
59. Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, et al. Internationalconsensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report fromthe13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum.2012;64(1):1-10.
60. Erkan D, Barbhaiya M, George D, Sammaritano L, Lockshin M. Moderate versushigh-titer persistently anticardiolipin antibody positive patients: are they clinicallydifferent and does high-titer anti-beta2-glycoprotein-I antibody positivity offer additionalpredictive information? Lupus.2010;19(5):613-9.
61. Persijn L, Decavele AS, Schouwers S, Devreese K. Evaluation of a new set of automatedchemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies inthe laboratory diagnosis of the antiphospholipid syndrome. Thromb Res.2011;128(6):565-9.
62. Devreese KM, van Hoecke F. Anticardiolipin and anti-beta2glycoprotein-I antibodycut-off values in the diagnosis of antiphospholipid syndrome: more than calculating thein-house99th percentiles, even for new automated assays. Thromb Res.2011;128(6):598-600.
63. Vlachoyiannopoulos PG, Routsias JG. A novel mechanism of thrombosis inantiphospholipid antibody syndrome. J Autoimmun.2010;35(3):248-55.
64. Doyle D. William Hewson (1739-74): the father of haematology. Br J Haematol.2006;133(4):375-81.
65. Griffin JH. Blood coagulation. The thrombin paradox. Nature.1995;378(6555):337-8.
66. Nakamura N, Kuragaki C, Shidara Y, Yamaji K, Wada Y. Antibody to annexin V hasanti-phospholipid and lupus anticoagulant properties. Am J Hematol.1995;49(4):347-8.
67. Vogler EA, Siedlecki CA. Contact activation of blood-plasma coagulation. Biomaterials.2009;30(10):1857-69.
68. Zhu D. Mathematical modeling of blood coagulation cascade: kinetics of intrinsic andextrinsic pathways in normal and deficient conditions. Blood Coagul Fibrinolysis.2007;18(7):637-46.
69. Tincani A, Morozzi G, Afeltra A, Alessandri C, Allegri F, Bistoni O, et al.Antiprothrombin antibodies: a comparative analysis of homemade and commercialmethods. A collaborative study by the Forum Interdisciplinare per la Ricerca nelleMalattie Autoimmuni (FIRMA). Clin Exp Rheumatol.2007;25(2):268-74.
70. Dragoni F, Minotti C, Palumbo G, Faillace F, Redi R, Bongarzoni V, et al. As comparedto kaolin clotting time, silica clotting time is a specific and sensitive automated methodfor detecting lupus anticoagulant. Thromb Res.2001;101(2):45-51.
71. Mendelsohn EE, Solum NO, Brosstad F. Effects of platelets and platelet-derived materialon the activated partial thromboplastin time (Cephotest) coagulation test. Scand J ClinLab Invest.2005;65(4):321-32.
72. Vedeler C, Ulvestad E, Grundt I, Conti G, Nyland H, Matre R, et al. Fc receptor for IgG(FcR) on rat microglia. J Neuroimmunol.1994;49(1):19-24.
73. Kolev K, Lerant I, Skopal J, Kelemen A, Nagy Z, Machovich R. Impaired inactivation byantithrombin and hirudin and preserved fibrinogen-clotting activity of thrombin incomplex with anti-thrombin antibody from a patient with antiphospholipid syndrome.Thromb Haemost.2005;94(1):82-7.
74. Wang W, Xu J, Kirsch T. Annexin-mediated Ca2+influx regulates growth platechondrocyte maturation and apoptosis. J Biol Chem.2003;278(6):3762-9.
1. Azkargorta M, Arizmendi JM, Elortza F, Alkorta N, Zubiaga AM, Fullaondo A.Differential proteome profiles in E2F2-deficient T lymphocytes. Proteomics.2006;6(1):42-50.
2. Pavon EJ, Munoz P, Lario A, Longobardo V, Carrascal M, Abian J, et al. Proteomicanalysis of plasma from patients with systemic lupus erythematosus: increasedpresence of haptoglobin alpha2polypeptide chains over the alpha1isoforms.Proteomics.2006;6(1):282-92.
3. Deocharan B, Zhou Z, Antar K, Siconolfi-Baez L, Angeletti RH, Hardin J, et al.Alpha-actinin immunization elicits anti-chromatin autoimmunity in nonautoimmunemice. J Immunol.2007;179(2):1313-21.
4. Hirata H, Takahashi A, Kobayashi S, Yonehara S, Sawai H, Okazaki T, et al. Caspasesare activated in a branched protease cascade and control distinct downstreamprocesses in Fas-induced apoptosis. J Exp Med.1998;187(4):587-600.
5. Robinson WH, Steinman L, Utz PJ. Protein arrays for autoantibody profiling andfine-specificity mapping. Proteomics.2003;3(11):2077-84.
6. Thebault S, Gilbert D, Hubert M, Drouot L, Machour N, Lange C, et al. Orderlypattern of development of the autoantibody response in (New Zealand White xBXSB)F1lupus mice: characterization of target antigens and antigen spreading bytwo-dimensional gel electrophoresis and mass spectrometry. J Immunol.2002;169(7):4046-53.
7. Rovin BH, Birmingham DJ, Nagaraja HN, Yu CY, Hebert LA. Biomarker discovery inhuman SLE nephritis. Bull NYU Hosp Jt Dis.2007;65(3):187-93.
8. Mosley K, Tam FW, Edwards RJ, Crozier J, Pusey CD, Lightstone L. Urinaryproteomic profiles distinguish between active and inactive lupus nephritis.Rheumatology (Oxford).2006;45(12):1497-504.
9. Suzuki M, Ross GF, Wiers K, Nelson S, Bennett M, Passo MH, et al. Identification ofa urinary proteomic signature for lupus nephritis in children. Pediatr Nephrol.2007;22(12):2047-57.
10. Varghese SA, Powell TB, Budisavljevic MN, Oates JC, Raymond JR, Almeida JS, etal. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol.2007;18(3):913-22.
11. Lefranc D, Launay D, Dubucquoi S, de Seze J, Dussart P, Vermersch M, et al.Characterization of discriminant human brain antigenic targets in neuropsychiatricsystemic lupus erythematosus using an immunoproteomic approach. Arthritis Rheum.2007;56(10):3420-32.
12. Kimura A, Sakurai T, Tanaka Y, Hozumi I, Takahashi K, Takemura M, et al.Proteomic analysis of autoantibodies in neuropsychiatric systemic lupuserythematosus patient with white matter hyperintensities on brain MRI. Lupus.2008;17(1):16-20.
13. Li QZ, Xie C, Wu T, Mackay M, Aranow C, Putterman C, et al. Identification ofautoantibody clusters that best predict lupus disease activity using glomerularproteome arrays. J Clin Invest.2005;115(12):3428-39.
14. Li QZ, Zhou J, Wandstrat AE, Carr-Johnson F, Branch V, Karp DR, et al. Protein arrayautoantibody profiles for insights into systemic lupus erythematosus and incompletelupus syndromes. Clin Exp Immunol.2007;147(1):60-70.
15. Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, et al.Elevated serum levels of interferon-regulated chemokines are biomarkers for activehuman systemic lupus erythematosus. PLoS Med.2006;3(12):491.
16. Graves PR, Kwiek JJ, Fadden P, Ray R, Hardeman K, Coley AM, et al. Discovery ofnovel targets of quinoline drugs in the human purine binding proteome. MolPharmacol.2002;62(6):1364-72.
1. Shapiro SS. Lupus anticoagulants and anticardiolipin antibodies: personal reminiscences,a little history, and some random thoughts. J Thromb Haemost.2005;3(5):831-3.
2. Pengo V, Biasiolo A, Bison E, Chantarangkul V, Tripodi A. Antiphospholipid antibodyELISAs: survey on the performance of clinical laboratories assessed by using lyophilizedaffinity-purified IgG with anticardiolipin and anti-beta2-Glycoprotein I activity. ThrombRes.2007;120(1):127-33.
3. Sipek-Dolnicar A, Hojnik M, Bozic B, Vizjak A, Rozman B, Ferluga D. Clinicalpresentations and vascular histopathology in autopsied patients with systemic lupuserythematosus and anticardiolipin antibodies. Clin Exp Rheumatol.2002;20(3):335-42.
4. Mtiraoui N, Zammiti W, Fekih M, Hider S, Almawi WY, Mahjoub T. Lupus anticoagulantand antibodies to beta2-glycoprotein I, annexin V, and cardiolipin as a cause of recurrentspontaneous abortion. Fertil Steril.2007;88(5):1458-61.
5. Frostegard AG, Su J, von Landenberg P, Frostegard J. Effects of anti-cardiolipinantibodies and IVIg on annexin A5binding to endothelial cells: implications forcardiovascular disease. Scand J Rheumatol.2010;39(1):77-83.
6. de Laat B, Wu X-X, van Lummel M, Derksen RHWM, de Groot PG, Rand JH.Correlation between antiphospholipid antibodies that recognize domain I ofbeta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood.2007;109(4):1490-4.
7. Ortona E, Capozzi A, Colasanti T, Conti F, Alessandri C, Longo A, et al.Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome.Blood.2010;116(16):2960-7.
8. Lakos G, Favaloro EJ, Harris EN, Meroni PL, Tincani A, Wong RC, et al. Internationalconsensus guidelines on anticardiolipin and anti-beta2-glycoprotein I testing: report fromthe13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum.2012;64(1):1-10.
9. Rolla R, Vidali M, Serino R, Pergolini P, Albano E, Bellomo G. Antibodies againstoxidized phospholipids in laboratory tests exploring lupus anti-coagulant activity. ClinExp Immunol.2007;149(1):63-9.
10. Frank M, Sodin-Semrl S, Irman S, Bozic B, Rozman B. Beta2-glycoprotein I and annexinA5phospholipid interactions: artificial and cell membranes. Autoimmun Rev.2009;9(1):5-10.
11. Cucnik S, Kveder T, Rozman B, Bozic B. Binding of high-avidity anti-beta2-glycoproteinI antibodies. Rheumatology (Oxford).2004;43(11):1353-6.
12. Hanly JG, Smith SA. Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V bindingand the anti-phospholipid syndrome. Clin Exp Immunol.2000;120(3):537-43.
13. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. Internationalconsensus statement on an update of the classification criteria for definiteantiphospholipid syndrome (APS). J Thromb Haemost.2006;4(2):295-306.
14. Zoghlami-Rintelen C, Vormittag R, Sailer T, Lehr S, Quehenberger P, Rumpold H, et al.The presence of IgG antibodies against beta2-glycoprotein I predicts the risk ofthrombosis in patients with the lupus anticoagulant. J Thromb Haemost.2005;3(6):1160-5.
15. Bassi N, Ghirardello A, Iaccarino L, Zampieri S, Rampudda ME, Atzeni F, et al.OxLDL/beta2GPI-anti-oxLDL/beta2GPI complex and atherosclerosis in SLE patients.Autoimmun Rev.2007;7(1):52-8.
16. de Laat B, Derksen RH, Reber G, Musial J, Swadzba J, Bozic B, et al. An internationalmulticentre-laboratory evaluation of a new assay to detect specifically lupusanticoagulants dependent on the presence of anti-beta2-glycoprotein autoantibodies. JThromb Haemost.2011;9(1):149-53.
17. Kraus M, Romisch J, Bastian B, Paques EP, Hartmann AA. Detection of humananti-annexin autoantibodies by enzyme immunoassays. J Immunoassay.1992;13(3):411-39.
18. Matsuda J, Saitoh N, Gohchi K, Gotoh M, Tsukamoto M. Anti-annexin V antibody insystemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipinantibody. Am J Hematol.1994;47(1):56-8.
19. Bozic B, Irman S, Gaspersic N, Kveder T, Rozman B. Antibodies against annexin A5:detection pitfalls and clinical associations. Autoimmunity.2005;38(6):425-30.
20. Arnold J, Holmes Z, Pickering W, Farmer C, Regan L, Cohen H. Anti-beta2glycoprotein1and anti-annexin V antibodies in women with recurrent miscarriage. Br J Haematol.2001;113(4):911-4.
21. Siaka C, Lambert M, Caron C, Amiral J, Hachulla E, Hatron PY, et al. Low prevalence ofanti-annexin V antibodies in antiphospholipid syndrome with fetal loss. Rev Med Interne.1999;20(9):762-5.
22. Bizzaro N, Antico A, Musso M, Platzgummer S, Camogliano L, Tozzoli R, et al. Aprospective study of1038pregnancies on the predictive value of anti-annexin Vantibodies for fetal loss. Ann N Y Acad Sci.2005;1050:348-56.
23. Arai T, Matsubayashi H, Sugi T, Kondo A, Shida M, Suzuki T, et al. Anti-annexin A5antibodies in reproductive failures in relation to antiphospholipid antibodies andphosphatidylserine. Am J Reprod Immunol.2003;50(3):202-8.
24. Esposito G, Tamby MC, Chanseaud Y, Servettaz A, Guillevin L, Mouthon L.Anti-annexin V antibodies: are they prothrombotic? Autoimmun Rev.2005;4(1):55-60.
25. Gaspersic N, Ambrozic A, Bozic B, Majhenc J, Svetina S, Rozman B. Annexin A5binding to giant phospholipid vesicles is differentially affected by anti-beta2-glycoproteinI and anti-annexin A5antibodies. Rheumatology (Oxford).2007;46(1):81-6.
26. Irman S, Skarabot M, Musevic I, Rozman B, Bozic B. The use of atomic forcemicroscopy to study the pathologic effects of anti-annexin autoantibodies. J Autoimmun.2011;36(2):98-105.
27. de Laat B, Derksen RH, Mackie IJ, Roest M, Schoormans S, Woodhams BJ, et al.Annexin A5polymorphism (-1C-->T) and the presence of anti-annexin A5antibodies inthe antiphospholipid syndrome. Ann Rheum Dis.2006;65(11):1468-72.
28. Suzuki K, Satoh A, Hidaka T, Takayama E, Kataharada K, Matsumoto M, et al.Adsorption of anti-annexin V using dextran sulfate bound cellulose beads. J Clin Apher.2000;15(4):262-5.
29. Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant.Blood.1988;72(2):512-9.
30. Murakami F, Iijima K, Nakamura K, Ikawa S, Hayashibara H, Siraki K. Transitions ofeach inhibitor in a patient with lupus anticoagulant and anti-prothrombin antibody.Rinsho Byori.1996;44(7):692-6.
31. Akimoto T, Akama T, Kono I, Sumida T. Relationship between clinical features andbinding domains of anti-prothrombin autoantibodies in patients with systemic lupuserythematosus and antiphospholipid syndrome. Lupus.1999;8(9):761-6.
32. Simmelink MJ, Horbach DA, Derksen RH, Meijers JC, Bevers EM, Willems GM, et al.Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulantactivity by competing with the binding of clotting factors for catalytic phospholipidsurfaces. Br J Haematol.2001;113(3):621-9.
33. Nojima J, Kuratsune H, Suehisa E, Futsukaichi Y, Yamanishi H, Machii T, et al.Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essentialrisk factor for venous thromboembolism in patients with systemic lupus erythematosus.Br J Haematol.2001;114(3):647-54.
34. Horbach DA, van Oort E, Derksen RH, de Groot PG. The contribution ofanti-prothrombin-antibodies to lupus anticoagulant activity--discrimination betweenfunctional and non-functional anti-prothrombin-antibodies. Thromb Haemost.1998;79(4):790-5.
35. Bardin N, Alessi MC, Dignat-George F, Vague IJ, Sampol J, Harle JR, et al. Does theanti-prothrombin antibodies measurement provide additional information in patients withthrombosis? Immunobiology.2007;212(7):557-65.
36. Pengo V, Denas G, Bison E, Banzato A, Jose SP, Gresele P, et al. Prevalence andsignificance of anti-prothrombin (aPT) antibodies in patients with Lupus Anticoagulant(LAC). Thromb Res.2010;126(2):150-3.
37. Liestol S, Sandset PM, Mowinckel MC, Wisloff F. Activated protein C resistancedetermined with a thrombin generation-based test is associated with thrombotic events inpatients with lupus anticoagulants. J Thromb Haemost.2007;5(11):2204-10.
38. Le DT, Ho D, Olsen JO, Osterud B. Plasma and IgGs from patients with lupusanticoagulant induce tissue factor in monocytes: a possible risk factor for thrombosis. JThromb Haemost.2010;8(8):1861-3.
39. 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 the13thInternational Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April2010.Lupus.2011;20(2):191-205.
40. Simmelink MJ, Derksen RH, Arnout J, de Groot PG. A simple method to discriminatebetween beta2-glycoprotein I-and prothrombin-dependent lupus anticoagulants. JThromb Haemost.2003;1(4):740-7.
41. Parkpian V, Verasertniyom O, Vanichapuntu M, Totemchokchyakarn K, Nantiruj K,Pisitkul P, et al. Specificity and sensitivity of anti-beta2-glycoprotein I as compared withanticardiolipin antibody and lupus anticoagulant in Thai systemic lupus erythematosuspatients with clinical features of antiphospholipid syndrome. Clin Rheumatol.2007;26(10):1663-70.
42. Ieko M, Nakabayashi T, Tarumi T, Yoshida M, Naito S, Atsumi T, et al.Phosphatidylserine-dependent anti-prothrombin antibody as a new marker for thediagnosis of antiphospholipid syndrome. Rinsho Byori.2006;54(3):256-62.