The Antiphospholipid Story

The Antiphospholipid Story
DONATO ALARCÓN-SEGOVIA, MD, MS, PhD,
Investigator,
Department of Immunology and Rheumatology,
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,
Vasco de Quiroga 15, 14000 Mexico DF, Mexico.
Address reprint requests to Dr. Alarcón-Segovia.
J Rheumatol. 2003 Sep;30(9):1893-6.
________________________________________
Throughout the history of humanity, and except for a few contributions by true pioneers, each bit of new knowledge or new development has been based on the work of many others, often unknown, who have helped build the corresponding edifice. Each milestone takes up so many yards, inches, centimeters, or millimeters according to the relative importance of the apparent new knowledge. However, the lack of even an apparently millimetric step, in this same sense, might prevent reaching the milestone. Stephenson may not have thought about it, but his invention of the railroad steam engine was only possible because throughout history people had learned to harness fire, including the unknown primitive humans who first learned to produce and keep it.
I will attempt to recount the saga of the antiphospholipid syndrome (APS), including my own experiences, with the precision of the scientist, the insight of one who has lived through it, and the emotion of one who sees in this story a wonderful example of the sum of contributions made for the sake of knowledge and helping fellow humans. Interest in this topic should not falter if we are to understand it fully, and with this understanding be able to provide our patients with a definitive solution.
I would like to take you as far back as 1906, to Wassermann and his coworkers1, who developed serological reactions for the diagnosis of syphilis utilizing phospholipid-rich tissues as antigens, later to be termed cardiolipin by Pangborn (1941)2. The finding of individuals who were positive for these reactions, but who were either too pious or too young to be suspected of having acquired syphilis, first brought about the possibility of false positive serological reactions for this disease, and tests were developed to distinguish these from the true positive reactions.
The first milestone resulted from the attempt to determine who, and perhaps why, some individuals had such false positive reactions for syphilis, and the finding that the majority were women who, when followed by Moore and Lutz (1955)3 for enough time, developed systemic lupus erythematosus (SLE). Interestingly, 3 of their 21 lupus patients with antecedent false positive tests for syphilis had had major unexplained thrombophlebitis. Here we should acknowledge the contributions, albeit indirect, of Hargraves, Richmond, and Morton (1948)4, who found LE cells that permitted a more ample diagnosis of SLE, and of Edmund Dubois (1953)5, who helped us recognize its wider clinical spectrum.
The second milestone resulted from the search for the cause of bleeding in a patient by Conley and Hartmann (1952)6, with the resulting finding of an inhibitor of coagulation that was subsequently related by Sánchez-Medal and Lisker (1959)7 from our own institute to patients with SLE, most of whom did not bleed.
The paradox encountered by Bowie and his coworkers (1963)8 of a frequent occurrence of thrombosis, rather than bleeding, in patients with SLE who had this inhibitor of coagulation, subsequently termed lupus anticoagulant by Feinstein and Rapaport (1977)9, marks the initiation of the concept of APS, particularly when somewhat later Thiagarajan, et al (1980)10, found that at least some of the lupus anticoagulants actually were antiphospholipid antibodies (aPL).
Shortly after the study of Bowie and his coworkers, and stemming from the same institution, Alarcón-Segovia and Osmundson (1965)11 described 11 patients with SLE who had peripheral vascular syndromes. Some of these are particularly interesting: one had chronic ulcers of the legs and livedo reticularis, clinical manifestations later found to be associated with aPL, and both circulating anticoagulant and false positive serologic tests for syphilis; another patient had had 4 miscarriages, thrombophlebitis, livedo reticularis, thrombosis of the left ulnar artery, convulsions, and long-standing false positive tests for syphilis; a third patient had false positive tests for syphilis, recurrent superficial thrombophlebitis, leg ulcers, intermittent claudication with evidence of popliteal artery occlusion, a vascular lesion of the brain stem, and a terminal occlusion of a basilar artery.
Shortly thereafter (1967) in a letter to Lancet, I insisted on the association of a circulating anticoagulant with infarction rather than bleeding12. Somewhat later (1974) Johansson and Lassus13 would indicate the concurrent findings of circulating anticoagulants and false positive tests for syphilis as in our described patient.
In 1980 Soulier and Boffa14 recorded the occurrence of recurrent abortions, thromboses, and a circulating anticoagulant in patients not having a primary condition, and in 1981 Carreras and his coworkers15 studied the possible role of inhibition of prostacyclin formation by the lupus anticoagulant in the causation of thrombosis.
The next milestones in the antiphospholipid story resulted from the development of more sensitive tests for aPL: in 1980 radioimmunoassays by Smolarsky16, by Harris and coworkers in 198317, and more practical, an ELISA developed by Loizou and his coworkers, using cardiolipin as antigen (1985)18. The more ample use of these tests permitted Hughes19 to propose the occurrence of an anticardiolipin syndrome in patients with SLE (1985). In some of his writings at that time Hughes mentioned that there were some patients with this syndrome who had no lupus, but he did not actually describe such patients.
The notion that within SLE there might be patients with a set of manifestations caused by one of their multiple autoantibodies and thus have a specific syndrome seemed interesting enough to me to try to confirm it. I therefore wrote Graham Hughes requesting some specific instructions on their anticardiolipin ELISA. I obtained a prompt response from Nigel Harris with instructions as well as anticardiolipin positive sera. Carmen Oria, a Venezuelan chemist working in our laboratory, was then able to reproduce the method, with modifications (1988)20. Meanwhile, with the help of Margarita Delezé, an enthusiastic rheumatologist who had come to our department after her hospital was destroyed in the 1985 Mexico City earthquake, we had started a cohort of consecutive lupus patients who were to be repeatedly tested for anticardiolipin antibodies. When the cohort reached 500 patients with a mean followup of more than 7 months and at least 5 antiphospholipid antibody tests of IgG, IgM, and/or IgA isotypes, we published our results21 confirming the existence of an APS in patients with SLE and documenting the clinical manifestations associated with high levels of aPL (1989). We would subsequently extend our cohort to 667 lupus patients, and after 3.5 years of followup, we proposed classification criteria for the APS (1992)22. Consensus criteria for the APS were later proposed (1999)23.
Analyzing our findings in the initial cohort of the 500 lupus patients, it became clear to me that there were patients who had the same clinical manifestations and high concentrations of anticardiolipin antibodies but who had no other clinical or serologic evidence of SLE. A search of the literature did not reveal any descriptions of this, although there were isolated reports of patients with some of these manifestations and those who had a circulating anticoagulant, as also described by Soulier and Boffa, whom we cited14.
With the help of Jorge Sánchez-Guerrero I prepared a description of 9 patients with what we termed primary antiphospholipid syndrome. Eventually, after some unexpected delays, on September 12, 1988, we submitted our manuscript to The Journal of Rheumatology; it was ultimately published early in 1989, and became one of its most highly cited articles24. At the end of 1988, however, Asherson published an editorial on the same topic in The Journal25. It was supposed to have accompanied our paper.
About 3 months later a paper by Mackworth-Young and coworkers appeared describing a series of patients with the same syndrome26, and later in the same year a larger multicenter series coordinated by Asherson was also published27. Our paper24 was already cited in their publication27. On July 5, 1993, Graham Hughes and I shared the Ciba-Geigy–International League Against Rheumatism Award, given to us at its international congress in Barcelona, for our contributions to knowledge on the APS.
A further milestone was reached in 1990 at the antiphospholipid meeting in Sirmione, Italy, when Monica Galli proposed that antibodies detected by ELISA tests with cardiolipin as antigen were not directed to the phospholipid but to a protein cofactor present in the bovine serum used to block the plates. This was supported by Steven Krilis, who had actually determined that the protein cofactor was ß2-glycoprotein-I (ß2-GPI), which had natural anticoagulant properties and high affinity for anionic molecules such as cardiolipin. Moreover, as noted by Takao Koike, pathogenic antibodies can be distinguished from those present in infectious disease (e.g., syphilis). The pathogenic antibodies require the presence of bovine serum with such cofactor, the infectious antibodies do not, he said. The corresponding articles were published that same year (1990)28-30.
At a ß2-GPI symposium in Milan in 1992, Cabral and his coworkers described the presence of anti-ß2-GPI antibodies in a group of patients with primary APS31; this finding was also published by Viard, et al that year32. That these antibodies may have the most important role in the causation of the APS, particularly its thrombotic component, was evidenced by their systematic fall at the time of thrombosis, as found by Gómez-Pacheco and coworkers33 in 1999.
An important study by Matsuura, Koike, and their coworkers34 (1995) revealed that the so-called anticardiolipin antibodies could bind to ß2-GPI in the absence of cardiolipin if the ELISA plates were oxidized by irradiation. This procedure was considered by Roubey and coworkers in 199535 to cause higher antigen density and permit bivalent binding. In 1995 Cabiedes, et al36 found that manifestations of APS associated more strongly with antibodies to ß2-GPI determined in non-irradiated plates versus those with anticardiolipin, and Cabral, myself, and our respective coworkers subsequently (1996, 1997)37 described groups of patients with clinical manifestations of APS who had persistently negative anticardiolipin antibodies when studied in conventional assays, but persistently positive anti-ß2-GPI antibodies determined in non-irradiated plates.
In 1988, early in the antiphospholipid story, I began inquiring about the pathogenic potential of aPL in an editorial38, and participated in a series of studies on their role in deficiencies of natural anticoagulants, headed by Guillermo and Alejandro Ruiz-Argüelles (1989)39, in a study by Vázquez-Mellado, et al (1994)40 on their role in thrombocytopenia by recognizing ß2-GPI that had bound to anionic phospholipids switched to the outer leaflet of platelets upon their activation or aggregation, as well as in a study by Cabral, et al41, where we found a role for an IgM natural autoantibody to phosphatidylcholine in the causation of hemolytic anemia (1990).
The synergism between aPL and antiendothelial cell antibodies in the causation of vascular damage in the APS began to be explored by Meroni and coworkers (1992)42, and a potential role of aPL in the causation of atherosclerosis stemmed from the seminal work by Vaarala and coworkers on the crossreactivity between anticardiolipin antibodies with oxidized low density lipoprotein (1993)43.
But perhaps the most important milestone for determining the pathogenicity of antiphospholipid antibodies came with the elegant series of studies by Shoenfeld and his group (1991)44,45, i.e., animal models of the APS induced both by passive and by active immunization, as well as their therapeutic manipulation (1999)46. In addition, these workers identified a hexapeptide that is recognized specifically by pathogenic anti-ß2-GPI antibodies and by antibodies produced on immunization of mice with microbial preparations. Naive mice infused with the antipeptide antibody produced by these immunizations developed clinical evidence of an antiphospholipid syndrome, indicating that molecular mimicry elicited by infections may lead to the development of pathogenic anti-ß2-GPI antibodies reactive with this peptide (2002)47.
The presence of autoreactive interleukin 6 producing CD4+ T cell clones to ß2-GPI in patients with APS was recently identified by Kuwana and his group (2001). These cells recognized at least 4 different epitopes, but the majority recognized a 15 amino acid peptide in the phospholipid-binding fifth domain. Most of these T cells stimulated autologous blood B cells to promote anti-ß2-GPI production in the presence of recombinant ß2-GPI. In a subsequent study they found that such autoreactive T cells had restricted T cell receptor ß-chain usage (Vß7 and Vß8) (2002)48.
Some of these findings may have implications regarding potential forms of treatment. Other avenues of treatment reside in the induction of tolerance of anti-ß2-GPI-producing B cells or in anionic blockade of the phospholipid-binding sites of ß2-GPI by means of heparin or other compounds, as proposed by Guerin and coworkers (2002)49.
Before the concept of an antiphospholipid syndrome originated, lupus patients with venous occlusions and particularly those with arterial occlusions were treated mainly with corticosteroids and immunosuppressives. In addition, patients with primary APS were often diagnosed as lupus and met classification criteria for this disease. This could have been considered reasonable were it not for the unnecessary steroid treatment they received instead of merely anticoagulant and/or platelet antiaggregant treatment.
We have come a long way in our understanding of the antiphospholipid syndrome. In looking back, I cannot help but feel that the wheels of the antiphospholipid story are turning more slowly, and at times even seem to stop. It might be only natural that the previous large scope of studies would now tend to be reduced. However, many unknowns await our renewed vigor. Only with vigor can we attain a brighter future for our patients.
REFERENCES
1. Wasserman A, Neisser A, Bruck C. Eine serodiagnostiche reaktion bei syphilis. Dtsch Med Wochenschr 1906;32:745-9.
2. Pangborn MC. A new serologically active phospholipid from beef heart. Proc Soc Exper Biol Med 1941;48:484-6.
3. Moore JE, Lutz WB. Natural history of systemic lupus erythematosus: approach to its study through chronic biologic false positive reactors. J Chron Dis 1955;1:297-316.
4. Hargraves MM, Richmond H, Morton R. Presentation of 2 bone marrow elements: the "Tart" cell and the "LE" cell. Proc Staff Meet Mayo Clin 1948;23:25-8.
5. Dubois EL. Effect of LE cell on clinical picture of systemic lupus erythematosus. Ann Intern Med 1953;93:1265-94.
6. Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Lab Clin Invest 1952;31:621-2.
7. Sánchez-Medal L, Lisker R. Circulating anticoagulants in disseminated lupus erythematosus. Br J Haematol 1959;5:284-93.
8. 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.
9. Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemostas Thromb 1972;1:75-95.
10. Thiagarajan P, Shapiro SS, De Marco L. Monoclonal immunoglobulin M lambda coagulation inhibitor with phospholipid specificity. Mechanism of lupus anticoagulant. J Clin Invest 1980;66:397-405.
11. Alarcón-Segovia D, Osmundson PJ. Peripheral vascular syndromes associated with systemic lupus erythematosus. Ann Intern Med 1965;62:907-19.
12. Alarcón-Segovia D. Infarction and circulating anticoagulant. Lancet 1967;2:43-4.
13. 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.
14. Soulier JP, Boffa MC. Avortements á repetition, thromboses et anticoagulant circulant antithromboplastine. Nouv Presse Med 1980;9:859-64.
15. Carreras LO, Defreyn G, Machin SJ, et al. Arterial thrombosis, intrauterine death and "lupus" anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981;i:244-6.
16. Smolarsky MA. A simple radioimmunoassay to determine binding of antibodies to lipid antigens. J Immunol Methods 1980;38:85-93.
17. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983;2:1211-4.
18. Loizou S, McCrea JD, Rudge A, Reynolds A, Boyle CC, Harris EN. Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985;62:738-45. [MEDLINE]
19. Hughes GRV. The anticardiolipin syndrome. Clin Exp Rheumatol 1985;3:285-6.
20. Delezé M, Oria CV, Alarcón-Segovia D. Occurrence of both hemolytic anemia and thrombocytopenic purpura (Evans' syndrome) in systemic lupus erythematosus. Relationship to antiphospholipid antibodies. J Rheumatol 1988;15:611-5.
21. Alarcón-Segovia D, Delezé M, Oria CV, et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. A prospective analysis of 500 consecutive patients. Medicine (Baltimore) 1989;68:353-65.
22. Alarcón-Segovia D, Pérez-Vázquez ME, Villa AR, Drenkard C, Cabiedes J. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Semin Arthritis Rheum 1992;21:275-85.
23. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 1999;42:1309-11.
24. Alarcón-Segovia D, Sánchez-Guerrero J. Primary antiphospholipid syndrome. J Rheumatol 1989;16:482-8.
25. Asherson RA. A "primary" antiphospholipid syndrome? J Rheumatol 1988;15:1742-6.
26. Mackworth-Young CG, Loizou S, David J, Walport MJ. Primary antiphospholipid syndrome: features of patients with raised anticardiolipin antibodies and no other disorder. Ann Rheum Dis 1989;48:362-7.
27. Asherson RA, Khamashta MA, Ordi-Ros J, et al. The "primary" antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989;68:366-74.
28. Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990;335:1544-7.
29. McNeil HD, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta-2- glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990;87:4120-4.
30. Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990;336:177-8.
31. Shoenfeld Y, Meroni PL. The beta-2-glycoprotein I and antiphospholipid antibodies. Clin Exp Rheumatol 1992;10:205-9.
32. Viard JP, Amoura Z, Bach JF. Association of anti-beta2- glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992;93:181-6.
33. Gómez-Pacheco L, Villa AR, Drenkard C, Cabiedes J, Cabral AR, Alarcón-Segovia D. Serum anti-beta 2-glycoprotein-I and anticardiolipin antibodies during thrombosis in systemic lupus erythematosus patients. Am J Med 1999;106:417-23.
34. Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994;179:457-62.
35. Roubey RAS, Eisenberg R, Harper MF, Winfield JB. "Anticardiolipin" autoantibodies recognize beta 2-glycoprotein I in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995;154:954-60.
36. Cabiedes J, Cabral AR, Alarcón-Segovia D. Clinical manifestations of the antiphospholipid syndrome in systemic lupus erythematosus patients associate more strongly with anti-beta 2-glycoprotein-I than with antiphospholipid antibodies. J Rheumatol 1995; 22:1899-906.
37. Alarcon-Segovia D, Cabral AR. Antiphospholipid/cofactor syndromes. J Rheumatol 1996;23:1319-22.
38. Alarcon-Segovia D. Pathogenetic potential of antiphospholipid antibodies. J Rheumatol 1988;15:890-3.
39. Ruiz-Arguelles GJ, Ruíz-Argüelles A, Alarcón-Segovia D, et al. Natural anticoagulants in systemic lupus erythematosus. Deficiency of protein S bound to C4bp with recent history of venous thromboses, antiphospholipid antibodies, and the antiphospholipid syndrome. J Rheumatol 1991;18:552-8.
40. Vazquez-Mellado J, Llorente L, Alarcón-Segovia D. Exposure of anionic phospholipid upon platelet activation permits binding of beta 2-glycoprotein-I and through it that of IgG antiphospholipid antibodies. Studies in platelets from patients with antiphospholipid syndrome and normal subjects. J Autoimmun 1994;7:335-48.
41. Cabral AR, Cabiedes J, Alarcón-Segovia D. Hemolytic anemia related to an IgM autoantibody to phosphatidylcholine that binds in vitro to stored and to bromelain-treated human erythrocytes. J Autoimmun 1990;3:773-87.
42. Del Papa N, Meroni PL, Tincani A, et al. Relationship between anti-phospholipid and anti-endothelial cell antibodies: further characterization of the reactivity on resting and cytokine-activated endothelial cells. Clin Exp Rheumatol 1992;10:37-42.
43. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho K, Palosuo T. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993;341:923-5.
44. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome by passive transfer of anti-cardiolipin antibodies. Proc Nat Acad Sci USA 1991;88:3069-73.
45. Blank M, Faden D, Tincani A, et al. Immunization with anticardiolipin cofactor (beta 2 GP-I) induces experimental antiphospholipid syndrome in naive mice. J Autoimmun 1994;7:441-55.
46. Blank M, Shoenfeld Y, Cabilly S, Heldman Y, Fridkin M, Katchalski-Katzir E. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Nat Acad Sci USA 1999;96:5164-8.
47. Blank M, Krause I, Fridkin M, et al. Bacterial induction of autoantibodies to beta 2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 2002; 109:797-804.
48. Yoshida K, Arai T, Kaburaki J, Ikeda Y, Kawakami Y, Kuwana M. Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta 2-glycoprotein I in patients with antiphospholipid syndrome. Blood 2002;99:2499-504.
49. Guerin J, Sheng Y, Reddel S, Iverson GM, Chapman MG, Krilis S. Heparin inhibits the binding of beta 2-glycoprotein I to phospholipids and promotes the plasmin-mediated inactivation of this blood protein. J Biol Chem 2002;277:1-6.

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Volume 12 of the APSFA Newsletter - "Antiphospho...What?" is NOW Available!

Volume 12 of the APSFA Newsletter - "Antiphospho...What?" is NOW Available!

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The WINTER/SPRING 2009 volume of our quarterly newsletter, "Antiphospho...What??" is ready to be downloaded. You can download it at the following link: http://www.apsfa.org/docs/APSFAVol12WinSpr2009.pdf

The next volume will be coming out in late Spring, early Summer, 2009.

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Keywords: APSFA, APS Foundation, antiphospholipid antibody syndrome, lupus, stroke, dvt, pe, thrombosis, clot, migraine, hughes syndrome, miscarriage, america, usa, anticoagulant, heart attack, APS, newsletter