A brief history of antiphospholipid antibodies and antiphospholipid syndrome

  • Henrique Luiz Staub Professor of the disciplines General Medicine, Clinical Immunology, and Adult and Elderly Health Practice of the School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS). Porto Alegre, RS
  • Lia Portella Staub Luteran University of Brazil, Canoas-RS
Keywords: anti-phospholipid antibody syndrome, antiphospholipid syndrome, Hughes syndrome, thrombosis, pregnancy complication.


AIMS: To review the historical reports on antiphospholipid antibodies (aPL) from the early years of the 20th century; to outline the cardinal features of the antiphospholipid syndrome (APS) from 1983 on, including clinical criteria, etiopathogenesis and current therapy.

METHODS: Literature review using PubMed. Articles on the history of aPL and APS were selected.

RESULTS: The original aPL were described in patients with syphilis yet in 1906 by Wassermann. A first definition of lupus anticoagulant was proposed in 1963,while the anticardiolipin antibody (aCL) test was depicted twenty years later. The APS, initially reported by Hughes in 1985as the “aCL syndrome”, is one of the most prevalent acquired thrombophilia. Venous and arterial thrombosis, associated or not to pregnancy morbidity, comprise the main features. It is a novel disorder firstly associated to systemic lupus erythematosus. A primary form of APS was put forward in 1989, and many APS variants are currently known. Lifelong, full-dose anticoagulation is the mainstream for treatment of thrombotic APS. In obstetric APS, the combination of acetil-salicilic acid and enoxoparin has been a mostly effective therapy.

CONCLUSIONS: The sequential characterization of aPL since Wassermann in 1906, and later of the APS in the 1980-thies, is a rather interesting example of how a new entity is sketched step by step. APS is an intriguing novel cause of autoimmune thrombophilia, with a complex pathogenesis and a plethora of clinical and laboratory abnormalities. Treatment is based on life-long anticoagulation.



Download data is not yet available.

Author Biography

Henrique Luiz Staub, Professor of the disciplines General Medicine, Clinical Immunology, and Adult and Elderly Health Practice of the School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS). Porto Alegre, RS


Armstrong EM, Bellone JM, Hornsby LB,Treadway S,Phillippe HM. Acquired thrombophilia. J Pharm Pract. 2014;27:234-42. https://doi.org/10.1177/0897190014530424

Jayakody Arachchillage D, Greaves M. The chequered history of the antiphospholipid syndrome. Br J Haematol. 2014;165:609-17. https://doi.org/10.1111/bjh.12848

Wassermann A, Neisser A, Bruck C. Eine serodiagnostische Reaktion bei Syphilis. Deutsche medicinische Wochenschrift (Berlin). 1906;32:745-6. https://doi.org/10.1055/s-0028-1142018

Eagle H. Studies in the serology of syphilis: the induction of antibodies to tissue lipoids (a positive Wassermann reaction) in normal rabbits. J Exp Med. 1932;55:667-81. https://doi.org/10.1084/jem.55.4.667

Bialynicki-Birula R. The 100th anniversary of Wassermann-Neisser-Bruckreaction. ClinDermatol. 2008;26:79-88. https://doi.org/10.1016/j.clindermatol.2007.09.020

Castro AR, Morril WE, Gale DC, Park MM, Pelegrino-Ferreira LA, Bazzo ML, Pope V. Use of Synthetic Cardiolipin and Lecithin in the Antigen Used by the Venereal Disease Research Laboratory Test for Serodiagnosis of Syphilis. Clin Diagn Lab Immunol. 2000;7:658-61. https://doi.org/10.1128/CDLI.7.4.658-661.2000

Harris A, Rosenberg AA, Riedel LM. A microflocculation test for syphilis using cardiolipin antigen: preliminary report. J Vener Dis Inform. 1946;27:159-72.

Harris EN, Gharavi AE, Wasley GD, Hughes GR. Use of an enzyme-linked immunosorbent assay and of inhibition studies to distinguish between antibodies to cardiolipin from patients with syphilis or autoimmune disorders. J Infect Dis. 1988;157:23-31. https://doi.org/10.1093/infdis/157.1.23

Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus. 1992;1:75-81. https://doi.org/10.1177/096120339200100204

Ortel TL. Laboratory diagnosis of the lupus anticoagulant. Curr Rheumatol Rep. 2012;14:64-70. https://doi.org/10.1007/s11926-011-0225-3

Conley CL. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest. 1952;31:621-2.

Campana C, Clausi-Schetiini G, Brunetti M. Hemorrhagic syndrome caused by circulating anticoagulants during systemic lupus erythematosus. Prog Med (Napoli). 1963;19:95-100.

Bowie EJ, Thompson JH Jr, Pascuzzi CA, Owen CA Jr. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med. 1963;62:416-30.

Johansson EA, Lassus A. The occurrence of circulating anticoagulants in patients with syphilitic and biologically false positive antilipoidal antibodies. Ann Clin Res. 1974;6:105-8.

Nilsson IM, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant ("antithromboplastin"). Acta Med Scand. 1975;197:153-9. https://doi.org/10.1111/j.0954-6820.1975.tb04897.x

Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant.Br Med J. 1983;287:1088-9. https://doi.org/10.1136/bmj.287.6399.1088

Boey ML, Colaco CB, Gharavi AE, Elkon KB, Loizou S, Hughes GR. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant.Br Med J. 1983;287:1021-3. https://doi.org/10.1136/bmj.287.6398.1021

Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211-4. https://doi.org/10.1016/S0140-6736(83)91267-9

Hughes GR. The anticardiolipin syndrome.ClinExpRheumatol. 1985;3:285-6.

Gharavi AE, Harris EN, Asherson RA, Hughes GR. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis. 1987;46:1-6. https://doi.org/10.1136/ard.46.1.1

Harris EN. Syndrome of the black swan.Br J Rheumatol. 1987;26:324-6. https://doi.org/10.1093/rheumatology/26.5.324

Staub HL, Harris EN, Khamashta MA, Savidge G, Chahade WH, Hughes GR. Antibody to phosphatidylethanolamine in a patient with lupus anticoagulant and thrombosis. Ann RheumDis. 1989;48:166-9. https://doi.org/10.1136/ard.48.2.166

Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, Outt HH, Harris EN, Vilardell-Torres M, Hughes GR..The "primary" antiphospholipid syndrome: major clinical and serological features.Medicine (Baltimore). 1989;68:366-74. https://doi.org/10.1097/00005792-198911000-00004

Sheng Y, Kandiah DA, Krilis SA. Beta2-glycoprotein I: target antigen for 'antiphospholipid' antibodies. Immunological and molecular aspects.Lupus. 1998;7 Suppl 2:S5-9. https://doi.org/10.1177/096120339800700202

Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, Brey R, Derksen R, Harris EN, Hughes GR, Triplett DA, Khamashta MA. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42:1309-11. https://doi.org/10.1002/1529-0131(199907)42:7<1309::AID-ANR1>3.0.CO;2-F

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J ThrombHaemost. 2006;4:295-306. https://doi.org/10.1111/j.1538-7836.2006.01753.x

do Prado AD, Piovesan DM, Staub HL, Horta BL. Association of anticardiolipin antibodies with preeclampsia: a systematic review and meta-analysis. Obstet Gynecol. 2010;116:1433-43. https://doi.org/10.1097/AOG.0b013e3181fe02ec

D'Ippolito S, Meroni PL, Koike T, Veglia M, Scambia G, Di Simone N. Obstetric antiphospholipid syndrome: a recent classification for an old defined disorder. Autoimmun Rev. 2014;13:901-8. https://doi.org/10.1016/j.autrev.2014.05.004

Biggioggero M, Meroni PL. The geoepidemiologyof the antiphospholipid antibody syndrome. Autoimmun Rev. 2016;15:433-9.

Cervera R. Antiphospholipid syndrome. Thromb Res. 2017;151 Suppl 1:S43-S47. https://doi.org/10.1016/S0049-3848(17)30066-X

Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramón E, Buonaiuto V, Jacobsen S, Zeher MM, Tarr T, Tincani A, Taglietti M, Theodossiades G, Nomikou E, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quéré I, Hachulla E, Vasconcelos C, Fernández-Nebro A, Haro M, Amoura Z, Miyara M, Tektonidou M, Espinosa G, Bertolaccini ML, Khamashta MA; Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies).Morbidity and mortality in the APS during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011-18. https://doi.org/10.1136/annrheumdis-2013-204838

Sebastiani GD, Iuliano A, Cantarini L, Galeazzi M. Genetic aspects of the antiphospholipid syndrome: an update. Autoimmun Rev. 2016;15:433-9. https://doi.org/10.1016/j.autrev.2016.01.005

Castro-Marrero J, Balada E, Vilardell-Tarrés M, Ordi-Ros J. Genetic risk factors of thrombosis in the antiphospholipid syndrome. Br J Haematol. 2009;147:289-96. https://doi.org/10.1111/j.1365-2141.2009.07831.x

Iverson GM, von Mühlen CA, Staub HL, Lassen AJ, Binder W, Norman GL. Patients with atherosclerotic syndrome, negative in anti-cardiolipin assays, make IgA autoantibodies that preferentially target domain 4 of beta2-GPI. J Autoimmun. 2006;27:266-71. https://doi.org/10.1016/j.jaut.2006.09.007

Sherer Y, Blank M, Shoenfeld Y. Antiphospholipid syndrome (APS): where does it come from? Best Pract Res Clin Rheumatol. 2007;21:1071-8. https://doi.org/10.1016/j.berh.2007.09.005

Verthelyi D, Ansar Ahmed S. Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice. J Autoimmun. 1997;10:115-25. https://doi.org/10.1006/jaut.1996.0121

Mehdi AA, Uthman, Khamashta M. Antiphospholipid syndrome: pathogenesis and a window of treatment opportunities in the future. Eur J Clin Invest. 2010;40:451-64. https://doi.org/10.1111/j.1365-2362.2010.02281.x

Döring Y, Hurst J, Lorenz M, Prinz N, Clemens N, Drechsler MD, Bauer S, Chapman J, Shoenfeld Y, Blank M, Lackner KJ, von Landenberg P. Human antiphospholipid antibodies induce TNF alpha in monocytes via Toll-like receptor 8. Immunobiology. 2010;215:230-41. https://doi.org/10.1016/j.imbio.2009.03.002

Karakantza M, Theodorou GL, Meimaris N, Mouzaki A, John E, Andonopoulos AP, Maniatis A. Type 1 and type 2 cytokine-producing CD4+ and CD8+ T cells in primary antiphospholipid syndrome. Ann Hematol. 2004;83:704-11. https://doi.org/10.1007/s00277-004-0910-7

Oku K, Nakamura H, Kono M, Ohmura K, Kato M, Bohgaki T, Horita T, Yasuda S, Amengual O, Atsumi T. Complement and thrombosis in the antiphospholipid syndrome. Autoimmun Rev. 2016;15:1001-4. https://doi.org/10.1016/j.autrev.2016.07.020

Di Simone N, Luigi MP, Marco D, Fiorella DN, Silvia D, Clara DM, Alessandro C. Pregnancies complicated with antiphospholipid syndrome: the pathogenic mechanism of antiphospholipid antibodies: a review of the literature. Ann N Y Acad Sci. 2007;1108:505-14. https://doi.org/10.1196/annals.1422.054

Dal Ben ER, do Prado CH, Baptista TS, Bauer ME, Staub HL. Decreased levels of circulating CD4+CD25+Foxp3+ regulatory T cells in patients with primary antiphospholipid syndrome. J Clin Immunol. 2013;33:876-9. https://doi.org/10.1007/s10875-012-9857-y

Dal Ben ER, do Prado CH, Baptista TS, Bauer ME, Staub HL. Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome have decreased numbers of circulating CD4+CD25+FoxP3+ Treg and CD3-CD19+ B cells. Rev Bras Reumatol. 2014;54:241-6.

Emmi G, Silvestri E, Squatrito D, Ciucciarelli L, Cameli AM, Denas G, D'Elios MM, Pengo V, Emmi L, Prisco D. An approach to differential diagnosis of antiphospholipid antibody syndrome and related conditions. Scientific World Journal. 2014;2014:341342. https://doi.org/10.1155/2014/341342

Asherson, RA. The catastrophic antiphospholipid (Asherson's) syndrome. Autoimmun Rev. 2006;6:64-7. https://doi.org/10.1016/j.autrev.2006.06.005

Cervera R. CAPS Registry. Lupus. 2012;21:755-7. https://doi.org/10.1177/0961203312436866

Asherson, RA. New subsets of the antiphospholipid syndrome in 2006: "PRE-APS" (probable APS) and microangiopathic antiphospholipid syndromes ("MAPS"). Autoimmun Rev. 2006;6:76-80. https://doi.org/10.1016/j.autrev.2006.06.008

Dusse LM, Alpoim PN, Silva JT, Rios DR, Brandão AH, Cabral AC. Revisiting HELLP syndrome. Clin Chim Acta. 2015;451:117-20. https://doi.org/10.1016/j.cca.2015.10.024

Avcin T, Jazbec J, Kuhar M, Zupancic M, Rozman B. Evans syndrome associated with antiphospholipid antibodies. J Pediatr Hematol Oncol. 2003;25:755-6. https://doi.org/10.1097/00043426-200309000-00017

Sneddon, IB. Cerebrovascular lesions and livedo reticularis. Brit J Dermatol. 1965;77:180-5. https://doi.org/10.1111/j.1365-2133.1965.tb14628.x

Dutra LA, Braga-Neto P, Pedroso JL, Barsottini OG. Sneddon's syndrome: case report and review of its relationship with antiphospholipid syndrome. Einstein (Sao Paulo). 2012;10:230-2. https://doi.org/10.1590/S1679-45082012000200018

Lima I, Melo A, Brandi IV, Costa O, Santiago M. Lupoid sclerosis: what is the role of antiphospholipid antibodies? J Clin Rheumatol. 2007;13:85-6. https://doi.org/10.1097/01.rhu.0000260637.95695.40

Schmoeller DG, da Silva BM, Staub HL. Cocaine abuse, retiform purpura and antiphospholipid syndrome. Rheumatology (Oxford). 2015;54:1533-4. https://doi.org/10.1093/rheumatology/kev219

Tuthill JI, Khamashta MA. Management of APS. J Autoimmun. 2009;33:92-8. https://doi.org/10.1016/j.jaut.2009.05.002

Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the APS. Engl J Med. 1995;332:993-7. https://doi.org/10.1056/NEJM199504133321504

Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum. 2007;57:1487-95. https://doi.org/10.1002/art.23109

Espinosa G, Cervera R. Current treatment of antiphospholipid syndrome: lights and shadows. Nat Rev Rheumatol. 2015;11:586-96. https://doi.org/10.1038/nrrheum.2015.88

Andrade D, Tektonidou M. Emerging therapies in APS.http://www.ncbi.nlm.nih.gov/pubmed/26995745. CurrRheumatol Rep. 2016;18:22.

Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic APS. Curr Rheumatol Rep. 2010;12:70-6. https://doi.org/10.1007/s11926-009-0073-6

Pierangeli SS, Erkan D. APS treatment beyond anticoagulation: are we there yet? Lupus. 2010;19:475-85. https://doi.org/10.1177/0961203310361489

Skrzypczak J. The management of pregnant women with APS. Pol Arch Med Wewn. 2007;117 Suppl:50-3.

Esteve-Valverde E, Ferrer-Oliveras R, Alijotas-Reig J. Obstetric antiphospholipid syndrome. Rev Clin Esp. 2016;216:135-45. https://doi.org/10.1016/j.rce.2015.09.003

Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or LA. Cochrane Database Syst Rev. 2005;18;(2):CD002859.

Erkan D, Patel S, Nuzzo M, Gerosa M, Meroni PL, Tincani A, Lockshin MD. Management of the controversial aspects of the APS pregnancies: a guide for clinicians and researchers. Rheumatology (Oxford). 2008;47 Suppl 3:iii23-7. https://doi.org/10.1093/rheumatology/ken181

Scoble T, Wijetilleka S, Khamashta MA. Management of refractory APS. Autoimmun Rev. 2011;10:669-73. https://doi.org/10.1016/j.autrev.2011.04.030

Hughes GR. Hughes Syndrome (the antiphospholipid syndrome): ten clinical lessons. Autoimmun Rev. 2008;7:262-6. https://doi.org/10.1016/j.autrev.2007.11.017

How to Cite
Staub, H. L., & Staub, L. P. (2018). A brief history of antiphospholipid antibodies and antiphospholipid syndrome. Scientia Medica, 28(3), ID31097. https://doi.org/10.15448/1980-6108.2018.3.31097
History of Medicine