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New targeted therapies for treatment of thrombosis in antiphospholipid syndrome

Published online by Cambridge University Press:  13 November 2007

Silvia S. Pierangeli ,
Mariano E. Vega-Ostertag  and
Emilio B. González
Silvia S. Pierangeli*
Affiliation:
Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
Mariano E. Vega-Ostertag
Affiliation:
Instituto Fares Taie, Mar del Plata, Buenos Aires, Argentina.
Emilio B. González
Affiliation:
Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
*
*Corresponding author: Silvia S. Pierangeli, Division of Rheumatology, Department of Internal Medicine, 301University Boulevard, Galveston, TX 77555-1165, USA. Tel: +1 409 772 0222; Fax: +1 409 772 0223; E-mail: [email protected]
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Abstract

Antiphospholipid (aPL) antibodies (Abs) are associated with thrombosis and pregnancy loss in antiphospholipid syndrome (APS), a disorder initially characterised in patients with systemic lupus erythematosus (SLE) but now known to occur in the absence of other autoimmune disease. There is strong evidence that aPL Abs are pathogenic in vivo, from studies of animal models of thrombosis, endothelial cell activation and pregnancy loss. In recent years, progress has been made in characterising the molecular basis of this pathogenicity, which includes direct effects on platelets, endothelial cells and monocytes as well as activation of complement. This review summarises the clinical manifestations of APS and current modalities of treatment, and explains recent advances in understanding the molecular events triggered by aPL Abs on target cells in coagulation pathways as well as effects of aPL Abs on complement activation. Based on this information and on additional scientific evidence using in vitro and in vivo models, new potential targeted therapies for treatment and/or prevention of thrombosis in APS are proposed and discussed.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 9 , Issue 30 , November 2007 , pp. 1 - 15
Copyright
Copyright © Cambridge University Press 2007

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References

References

1Harris, E.N. (1987) Syndrome of the black swan. Br J Rheumatol 26, 324-326Google Scholar
2Wilson, W.A. et al. (1999) International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 42, 1309-1311Google Scholar
3McNeil, H.P. et al. (1990) Antiphospholipid antibodies are directed against a complex antigen that includes lipid binding inhibitor of coagulation: β2 glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 87, 4120-4124CrossRefGoogle ScholarPubMed
4Atsumi, T. and Koike, T. (2002) Clinical relevance of antiprothrombin antibodies. Autoimmun Rev 1, 49-53CrossRefGoogle ScholarPubMed
5Lin, X.S. et al. (2007) Some Antiphospholipid antibodies recognize conformational epitopes shared by β2glycoprotein I and the homologous catalytic domains of several serine proteases. Arthritis Rheum 56, 1638-1647CrossRefGoogle ScholarPubMed
6Chen, X.X. et al. (2007) Some plasmin-induced antibodies bind to cardiolipin, display lupus anticoagulant activity and induce fetal loss in mice J Immunol 178, 5351-5356Google Scholar
7Cesarman-Maus, G. et al. (2006) Autoantibodies against the fibrinolytic receptor, annexin A2, in antiphospholipid syndrome. Blood 107, 4375-7382Google Scholar
8Boey, M.L. et al. (1983) Thrombosis in SLE: striking associations with the presence of circulating lupus anticoagulant. Br Med J 287, 101-102CrossRefGoogle Scholar
9Ginsburg, K.S. et al. (1992) Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis, Ann Intern Med 117, 997-1002CrossRefGoogle ScholarPubMed
10McClain, M.T. et al. (2004) The prevalence, onset and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum 50, 1226-1232CrossRefGoogle ScholarPubMed
11Moroni, G. et al. (2004) Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am J Kidney Dis 43, 28-36CrossRefGoogle ScholarPubMed
12Moroni, G. et al. (2005) The long-term prognosis of renal transplantation in patients with lupus nephritis. Am J Kidney Dis 45, 903-911CrossRefGoogle ScholarPubMed
13Miyakis, S. et al. (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4, 295-306CrossRefGoogle Scholar
14Gleason, C.B. et al. (1993) A comparison of cardiac valvular involvement in the primary antiphospholipid syndrome versus anticardiolipin negative systemic lupus erythematosus. Am Heart J 125, 1123-1129CrossRefGoogle ScholarPubMed
15Toubi, E. et al. (2005) Livedo reticularis is a marker for predicting multi-system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol 23, 499-504Google ScholarPubMed
16Atsumi, T. et al. (2005) Antiphospholipid antibody associated thrombocytopenia and the paradoxical risk of thrombosis. Lupus 14, 499-504CrossRefGoogle ScholarPubMed
17Levine, S.R. et al. (2000) Cerebrovascular disease and antiphospholipid antibodies in systemic lupus erythematosus, lupus-like disease, and the primary antiphospholipid syndrome. Am J Med 51, 169-185Google Scholar
18Sherer, Y. et al. (2002) Transverse myelitis in patients with antiphospholipid antibodies – the importance of early diagnosis and treatment. Clin Rheumatol 21, 207-210CrossRefGoogle ScholarPubMed
19Al-Matar, M., Jaimes, J. and Malleson, P. (2000) Chorea as the presenting clinical feature of primary antiphospholipid syndrome in childhood. Neuropediatrics 2, 107-108CrossRefGoogle Scholar
20Hughes, G.R. (2003) Migraine, memory loss, and “multiple sclerosis”. Neurological features of the antiphospholipid (Hughes') syndrome. Postgrad Med J 79, 81-83CrossRefGoogle ScholarPubMed
21Mesa, H.A. et al. (1993) Sneddon's syndrome and phospholipid antibodies. Clin Rheumatol 12, 253-256CrossRefGoogle ScholarPubMed
22Shoenfeld, Y. et al. (2004) Features associated with epilepsy in the antiphospholipid syndrome. J Rheumatol 31, 1344-1348Google Scholar
23Asherson, R.A. (2005) Multiorgan failure and antiphospholipid antibodies: the catastrophic antiphospholipid (Asherson's) syndrome. Immunobiology 210, 727-733CrossRefGoogle ScholarPubMed
24Wiedermann, F.J. (2006) Alveolar and serum antiphospholipid antibodies in acute respiratory distress syndrome associated with catastrophic antiphospholipid syndrome. Ann Rheum Dis 65, 413CrossRefGoogle ScholarPubMed
25Asherson, R.A. and Cervera, R. (2003) Unusual manifestations of the antiphospholipid syndrome. Clin Rev Allergy Immunol 1, 61-78Google Scholar
26Nzerue, C.M. et al. (2002) “Black swan in the kidney”: renal involvement in the antiphospholipid antibody syndrome. Kidney 62, 733-744Google ScholarPubMed
27Tektonidou, M.G. et al. (2003) Asyptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis Rheum 48, 732-736CrossRefGoogle Scholar
28Khamashta, M.A. et al. (1995) The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 332, 993-997CrossRefGoogle ScholarPubMed
29Krnic-Barrie, S. et al. (1997) A retrospective review of 61 patients with antiphospholipid syndrome. Arch Intern Med 157, 2101-2108CrossRefGoogle ScholarPubMed
30Crowther, M.A. et al. (2003) A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349, 1133-1138CrossRefGoogle ScholarPubMed
31Finazzi, G. et al. (2005) A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3, 848-853Google Scholar
32Garcia, D.A., Khamashta, M.A. and Crowther, M.A. (2007) How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review. Blood [Epub ahead of print]CrossRefGoogle ScholarPubMed
33Erkan, D. et al. (2002) A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 41, 924-929CrossRefGoogle ScholarPubMed
34Erkan, D. et al. (2007) Aspirin for primary thrombosis prevention in the antiphospholipid syndrome. Arthritis Rheum 56, 2382-2391Google Scholar
35Rubenstein, E. et al. (2006) Rituximab treatment for resistant antiphospholipid syndrome. J Rheumatol 33, 355-357Google ScholarPubMed
36Branch, D.W. et al. (1990) Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol 163, 210-216Google Scholar
37Blank, M. et al. (1991) Induction of anti-phospholipid syndrome in naïve mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A 88, 3069-3073Google Scholar
38Pierangeli, S.S. et al. (1999) Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 99, 1997-2000Google Scholar
39Jankowski, M. et al. (2003) Thrombogenicity of β2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically induced thrombosis model in the hamster. Blood 101, 157-162CrossRefGoogle Scholar
40Roubey, R.A.S. (1998) Mechanisms of autoantibody-mediated thrombosis. Lupus 7, S114-119CrossRefGoogle ScholarPubMed
41Holers, V.M. et al. (2002) C3 activation is required for anti-phospholipid antibody-induced fetal loss. J Exp Med 195, 211-220CrossRefGoogle Scholar
42Salmon, J.E., Girardi, G. and Holers, V.M. (2002) Complement activation as a mediator of antiphospholipid antibody induced pregnancy loss and thrombosis. Ann Rheum Dis 61, 46-50Google Scholar
43Pierangeli, S.S. et al. (2005) Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 52, 2120-2124Google Scholar
44Fischetti, F. et al. (2005) Thrombus formation induced by antibodies to β2 glycoprotein I is complement-dependent and requires a priming factor. Blood 106, 2340-2346CrossRefGoogle ScholarPubMed
45Khamashta, M.A. et al. (1988) Immune mediated mechanism for thrombosis: antiphospholipid antibody binding to platelet membranes. Ann Rheum Dis 47, 849-854CrossRefGoogle ScholarPubMed
46Campbell, A.L. et al. (1995) Comparison of the effect of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. Thromb Haemost 73, 529-534Google Scholar
47Espinola, R.G. et al. (2002) Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies. Thromb Haemost 87, 518-522CrossRefGoogle ScholarPubMed
48Edwards, M.H. et al. (1997) Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 96, 4380-4384CrossRefGoogle ScholarPubMed
49Martinuzzo, M.E. et al. (1993) Antiphospholipid Antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 70, 667-671Google ScholarPubMed
50Forastiero, R. et al. (1998) Anti − β2glycoprotein I antibodies and platelet activation in patients with antiphospholipid antibodies: association with increased excretion of platelet-derived thromboxane urinary metabolites. Thromb Haemost 79, 42-45Google Scholar
51Robbins, D.L. (1998) Effect of anticardiolipin/˙β2glycoprotein I complexes on production of thromboxane A2 by platelets from patients with the Antiphospholipid syndrome. J Rheumatol 25, 51-56Google ScholarPubMed
52Opara, E., Robbins, D.L. and Ziboh, V.A. (2003) Cyclic-AMP agonists inhibit antiphospholipid/β2glycoprotein I induced synthesis of human platelet thromboxane A2 in vitro. J Rheumatol 30, 55-59Google Scholar
53Vega-Ostertag, M., Harris, E.N. and Pierangeli, S.S. (2004) Intracellular events in platelet activation induced by antiphospholipid antibodies in the presence of low doses of thrombin. Arthritis Rheum 50, 2911-2919Google Scholar
54Lutters, B.C. et al. (2003) Dimers of β2glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′. J Biol Chem 278, 33831-33838Google Scholar
55Shi, T. et al. (2006) Anti−β2glycoprotein I antibodies in complex with β2 glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib/IX-V. Arthritis Rheum 54, 2558-2567CrossRefGoogle Scholar
56Simantov, E. et al. (1995) Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 96, 2211-2219Google Scholar
57Pierangeli, S.S. et al. (2001) Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Circ Res 88, 245-250CrossRefGoogle ScholarPubMed
58Espinola, R.G. et al. (2002) E-selectin mediated pathogenic effects of antiphospholipid antibodies. J Thromb Haemost 1, 843-848Google Scholar
59Kaplanski, G. et al. (2000) Increased soluble vascular cell adhesion molecule 1 concentrations in patients with primary or systemic lupus erythematosus-related antiphospholipid syndrome: correlations with the severity of thrombosis. Arthritis Rheum 43, 55-643.0.CO;2-M>CrossRefGoogle ScholarPubMed
60Nemerson, Y. (1988) Tissue factor and hemostasis. Blood 71, 1-8Google Scholar
61Semerato, N. and Colucci, M. (1997) Tissue factor in health and disease. Thromb Haemost 78, 759-764Google Scholar
62Kornberg, A. et al. (1994) Induction of tissue factor-like activity in monocyes by anti-cardiolipin antibodies. J Immunol 153, 1328-1332Google Scholar
63Cuadrado, M.J. et al. (1997) Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum 40, 834-841Google Scholar
64Amengual, O. et al. (1998) The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 79, 276-281Google Scholar
65Dobado-Barrios, M. (1999) Increased levels of TF mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb Haemost 82, 1578-1582Google Scholar
66Martini, F. et al. (1996) Antiphospholipid antibodies (aPL) increase the potential monocyte procoagulant activity in patients with systemic lupus erythematosus. Lupus 5, 206-211CrossRefGoogle ScholarPubMed
67Reverter, J.C. (1998) Effects of human monoclonal anticardiolipin antibodies on platelet function and on tissue factor expression on monocytes. Arthritis Rheum 41, 1420-1427Google Scholar
68Forastiero, R.R., Martinuzzo, M.E. and De Larranaga, G. (2005) Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprous related antiphospholipid antibodies. Lupus 14, 129-136Google Scholar
69Zhou, H., Wolberg, A.S. and Roubey, R.A. (2004) Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep. Blood 104, 2353-2358Google Scholar
70Cuadrado, M.J. et al. (2006) Vascular endotelial growth factor expresión in monocytes from patients with primary antiphospholipid síndrome. J Thromb Haemost 4, 2461-2469Google Scholar
71Williams, F.M. et al. (2000) Systemic endothelial cell markers in primary antiphospholipid syndrome. J Thromb Haemost 84, 742-746Google Scholar
72Xie, H., Ray, P.E. and Short, B.L. (2005) NF-kappa B activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation. Stroke 36, 1047-1052Google Scholar
73Morgan, E.N. et al. (2003) Nuclear factor kappa B mediates a procoagulant response in monocytes during extracorporeal circulation. J Thorac Cardiovasc Surg 125, 165-171Google Scholar
74Chen, F. et al. (1999) New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45, 7-17CrossRefGoogle ScholarPubMed
75Saccani, S., Pantano, S. and Natoli, G. (2002) p38-dependent marking of inflammatory genes for increasing NF-kappa B recruitment. Nat Immunol 3, 69-75Google Scholar
76Firestein, G.S. (2004) NF-κB: holy grail for rheumatoid arthritis. Arthritis Rheum 50, 2381-2386CrossRefGoogle ScholarPubMed
77Cohen, P. (1997) The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol 7, 353-358CrossRefGoogle ScholarPubMed
78McGilvray, I.D. et al. (2002) Monocyte adhesion and transmigration induce tissue-factor expression: role of the mitogen-activated protein kinases. Shock 18, 51-57CrossRefGoogle ScholarPubMed
79Dunoyer-Geindre, S. (2002) NF-κB is an essential intermediate in the activation of endothelial cells by anti-β2glycoprotein I antibodies. Thromb Haemost 88, 851-857CrossRefGoogle Scholar
80Bohgaki, M. et al. (2004) The p38 mitogen-activated protein kinase (MAPK) pathway mediates induction of the tissue factor gene in monocytes stimulated with human monoclonal anti-β2glycoprotein I antibodies. Int Immunol 16, 1632-1641Google Scholar
81Vega-Ostertag, M. et al. (2005) Involvement of p38 MAPK in the up-regulation of tissue factor on endothelial cells by antiphospholipid antibodies. Arthritis Rheum 52, 1545-1554CrossRefGoogle ScholarPubMed
82López-Pedrera, C. et al. (2006) Antiphopholipid antibodies from patients with the antiphospholipid syndrome induce tissue factor expression through the simultaneous activation of NF-KappaB/Rel proteins via p38 mitogen-activated protein kinase pathway, and of the MEK-1/ERK pathway. Arthritis Rheum 54, 301-311Google Scholar
83Simoncini, S. et al. (2004) Role of reactive oxygen species and p38 MAPK in the induction of the pro-adhesive endothelial state mediated by IgG from patients with anti-phospholipid syndrome. Int Immunol 17, 489-500CrossRefGoogle Scholar
84Vega-Ostertag, M.E. et al. (2007) Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation. J Thromb Haemost 5, 1828-1834CrossRefGoogle ScholarPubMed
85Montiel-Manzano, G. et al. (2007) In vivo effects of an inhibitor of nuclear factor-kappa (κ) B on thrombogenic properties of Antiphospholipid antibodies. Ann NY Acad Sci 1108, 540-553CrossRefGoogle ScholarPubMed
86Meroni, P.L. et al. (2001) Statins prevent endothelial cell activation induced by antiphospholipid (anti-β2glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype. Arthritis Rheum 44, 2870-2878Google Scholar
87Ferrara, D.E. et al. (2003) Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum 48, 3272-3279CrossRefGoogle Scholar
88Ferrara, D.E. et al. (2004) Fluvastatin inhibits upregulation of tissue factor expression by antiphospholipid antibodies on endothelial cells. J Thromb Haemost 2, 1558-1563Google Scholar
89Bouma, B. et al. (1999) Adhesion mechanism of human β2glycoprotein I to phospholipids based on its crystal structure. EMBO J 18, 5166-5174Google Scholar
90Ioannou, J. et al. (2006) Domain I of β2glycoprotein I ameliorates thrombosis induced by antiphospholipid antibodies in mice. Arthritis Rheum 54 (suppl), S559 (Abstract)Google Scholar
91Del Papa, N. et al. (1998) Human β2glycoprotein I binds to endothelial cells through a cluster of lysine residues that are critical for anionic phospholipids binding and offers epitopes for anti-β2glycoprotein I antibodies. J Immunol 160, 5572-5578CrossRefGoogle Scholar
92Vega Ostertag, M. et al. (2006) A peptide that mimics the Vth region of β2glycoprotein I reverses antiphospholipid-mediated thrombosis in mice. Lupus 15, 358-365CrossRefGoogle Scholar
93Ma, K. et al. (2000) High affinity binding of β2glycoprotein I to human endothelial cells is mediated by Annexin II. J Biol Chem 275, 15541-15548Google Scholar
94Zhang, J. and McCrae, K.R. (2005) Annexin A2 mediates endothelial cell activation by antiphospholipid/β2Glycoprotein I antibodies. Blood 105, 1964-1969CrossRefGoogle Scholar
95Akira, S., Takeda, K. and Kaisho, T. (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2, 675-680CrossRefGoogle ScholarPubMed
96Raschi, E. et al. (2003) Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood 101, 3495-3500CrossRefGoogle ScholarPubMed
97Pierangeli, S.S. et al. (2007) Toll like receptor 4 is involved in Antiphospholipid-mediated thrombosis: in vivo studies. Ann Rheum Dis [Epub ahead of print]Google Scholar
98Pierangeli, S.S. et al. (1995) Induction of thrombosis in a mouse model by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemost 74, 1361-1367Google Scholar
99Sammaritano, L.R. et al. (1997) Anticardiolipin IgG subclasses: association with IgG2 with arterial and/or venous thrombosis. Arthritis Rheum 40, 1998-2006Google Scholar
100Romay-Penabad, Z. et al. (2007) C5a receptor-deficient micer are protected from thrombophilia and endothelial cell activation induced by some antiphospholipid antibodies. Ann NY Acad Sci 1108, 554-566CrossRefGoogle Scholar
101Munakata, Y. et al. (2000) Detection of complement-fixing antiphospholipid antibodies in association with thrombosis. Thromb Haemost 83, 728-731Google Scholar
102Carbone, J. et al. (1999) Immunological abnormalities in primary APS evolving into SLE: 6 years follow-up in women with repeated pregnancy loss. Lupus 8, 274-278Google Scholar
103Davis, W.D. and Brey, R.L. (1992) Antiphospholipid antibodies and complement activation in patients with cerebral ischemia. Clin Exp Immunol 10, 455-460Google ScholarPubMed
104Potti, A. et al. (2006) Gene-expression patterns predict phenotypes of immune-mediated thrombosis. Blood 107, 1391-1396Google Scholar

Further reading, resources and contacts

The eMedicine entries for antiphospholipid syndrome (APS) by Elise Belilos and by Barry L. Myones are updated practical guides for physicians that include relevant information on clinical manifestations and current treatment in APS, a brief synopsis on history and pathophysiology, and updated classification criteria for definite APS:

http://www.emedicine.com/ped/topic118.htmGoogle Scholar
http://www.apsfa.org/aps.htmlGoogle Scholar
http://www.apscore.orgGoogle Scholar