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Cited by 114Systemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis MechanismsVasculitis and related conditions

Antiphospholipid syndrome: multiple mechanisms

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MACKWORTH-YOUNG, C G·2004·Clinical and Experimental Immunology
DOI 10.1111/j.1365-2249.2004.02497.xPMC PMC1809064
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Abstract

It is 20 years since the use of a radioimmunoassay enabled an association to be described between antibodies to the anionic phospholipid cardiolipin and a set of clinical features [1]. These features, which included thrombosis – both venous and arterial – and recurrent foetal loss, subsequently became known as the antiphospholipid syndrome (APS) [2–4]. They had previously been shown to be associated with positive Venereal Disease Reference laboratory (VDRL) and lupus anticoagulant (LA) tests, both of which detect antiphospholipid antibodies [5–8]. However, the radioimmunoassay, and the enzyme-linked assays (ELISA) derived from it [9], are considerably more sensitive, and their use enabled the clinical syndrome to be clearly defined. Many additional clinical features have been described, such as neurological disorders, migraine, livedo reticularis and thrombocytopenia [10–12]. Some of these remain controversial, and may be features of associated connective tissue diseases such as systemic lupus erythematosus (SLE), with which APS frequently coexists. They are not all directly related to thrombosis. APS can occur as an isolated, primary condition [13–15]. It has emerged as the most common cause of acquired thrombophilia, and is a major cause of pregnancy morbidity. Because thrombosis in APS can occur at almost any site, it is a condition that is seen in almost all medical specialities. Central to our understanding of antiphospholipid syndrome has been the demonstration that the autoantibodies in the condition probably play a direct role in pathogenesis. Strong evidence for this has come from murine models. Passive transfer of antiphospholipid antibodies (aPL) to normal mice can generally [16–19], though not always [20], produce features resembling human APS, notably impairment of foetal development. Similar results have been obtained by immunizing mice with aPL [21]. In a murine model of venous injury the addition of aPL results in increased local clot formation [22]. Another critical discovery was that antibodies to phospholipid appear to represent part of a large family of autoantibodies, many of which recognize phospholipid-binding plasma proteins either alone, or in combination with phospholipid. The first of these proteins to be recognized was beta-2-glycoprotein I (β2GPI) [23,24]. This molecule has number of physiological functions, which include a regulatory role within coagulation pathways. Prothrombin is another important protein recognized by sera of patients with APS. Others include annexin V, high and low molecular weight kininogens, protein C and protein S (see Table 1). Antigen specificities of antibodies that have been detected in the serum of patients with antiphospholipid syndrome. Antigen specificities of antibodies that have been detected in the serum of patients with antiphospholipid syndrome. In general, aPL found in patients with antiphospholipid syndrome require the presence of β2GPI for binding to cardiolipin. Indeed, most of these antibodies appear to bind to β2GPI itself (reviewed in [25]). This may be through an epitope on native, unbound β2GPI. However, antibodies to β2GPI are generally of low affinity [25], and it has been proposed that the binding of anionic phospholipid, such as cardiolipin, to β2GPI enhances this affinity: this enhancement may occur through the revealing of a cryptic epitope on the β2GPI molecule [26]. Furthermore, there is evidence for the binding of aPL to different domains of β2GPI, although binding to domain I may predominate (reviewed in [26]). These conflicting results may simply reflect the existence of different subpopulations of aPL within the sera of individuals with APS. What is clear is that, for the majority of so-called antiphospholipid antibodies that are detected by ELISA in the serum of patients with APS, anionic phospholipid such as cardiolipin is not the antigen to which those antibodies are actually binding. By contrast, anticardiolipin antibodies that arise as a consequence of infection – and are not normally associated with the syndrome – do not tend to be dependent on β2GPI for binding to phospholipid [25,27–29]. The picture that has emerged is of an autoimmune condition in which antibodies are expressed in the serum against a variety of phospholipid and protein antigens. Not only are different specificities found in different patients [30], but there may be great heterogeneity within an individual [31,32]. How is it that some of these antibodies appear to cause clinical disease? The central feature of APS is thrombosis. Several theories have emerged to explain the association between raised serum anticardiolipin levels and vascular pathology. Many of these have built on the intimate association between phospholipid-binding proteins and antibodies found in the syndrome. The regulation of haemostasis is complex, and occurs at a number of levels. These include platelet and endothelial cell (EC) activity, as well as the coagulation and fibri

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  • Preclinical evidence from animal models has demonstrated that the presence of LA-related autoantibodies alone is insufficient for causing overt thrombosis, and a "second hit" such as inflammation or infection may be necessary to transform the prothrombotic potential induced by LA-related autoantibodies into overt thrombosis.

    “Second, preclinical evidence from animal models has demonstrated that the presence of LA-related autoantibodies alone is insufficient for causing overt thrombosis, and a “second hit” such as inflammation or infection may be necessary to transform the prothrombotic potential induced by LA-related autoantibodies into overt thrombosis [35].”

    From Cardiovascular risk factors are major determinants of thrombotic risk in patients with the lupus anticoagulant (2017) · cites this paper as [35]

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  1. [5]Laurell B-B, Nilsson IM. Hypergammaglobulinaemia, circulating anticoagulant, and biologic false positive Wassermann reaction. J Laboratory Clin Med. 1957;49:694–707. [PubMed] [Google Scholar]
  2. [9]Loizou S, McCrea JD, Rudge AC, et al. Measurement of anticardiolipin antibodies by enzyme linked immunosorbent assay: standardisation and quantitation of results. Clin Exp Immunol. 1985;62:738–44. [PMC free article] [PubMed] [Google Scholar]
  3. [29]Gharavi AE, Sammaritano LR, Wen J, et al. Characteristics of HIV and chlorpromazine induced antiphospholipid antibodies: effect of β2-glycoprotein I on binding to phospholipid. J Rheumatol. 1984;21:94–9. [PubMed] [Google Scholar]
  4. [61]Comp PC, DeBault LE, Esmon NL, Esmon CT. Human thrombomodulin is inhibited by IgG from two patients with non-specific anticoagulants. Blood. 1983;62:299a. [Google Scholar]

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Authors
MACKWORTH-YOUNG, C. G.
Affiliations
Kennedy Institute of Rheumatology (GB)
Corresponding author
MACKWORTH-YOUNG, C G
Venue
Clinical and Experimental Immunology
Publisher
Oxford University Press (OUP)
Published
2004-05-04
Volume
136
Issue
3
Pages
393-401
ISSN
  • 0009-9104 (ISSN-L)
  • 1365-2249
DOI
10.1111/j.1365-2249.2004.02497.x
PMC
PMC1809064
OpenAlex
W2024804378
Cited by
114
References
143
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 6
FWCI
2.04
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Clinical & Experimental Immunology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Vasculitis and related conditions
Keywords
antiphospholipid syndrome, antiphospholipid antibodies, anticardiolipin antibodies, beta2-glycoprotein I, lupus anticoagulant, thrombosis, acquired thrombophilia, pregnancy morbidity, systemic lupus erythematosus, autoantibody pathogenesis, passive transfer, mouse model, thrombocytopenia
MeSH terms
Abortion, Spontaneous, Arteriosclerosis, Endothelium, Vascular, Female, Glycoproteins, Hemostasis, Humans, Male, Pregnancy, Protein C, Thrombosis, Lupus Coagulation Inhibitor, Antiphospholipid Syndrome, Antibodies, Anticardiolipin, beta 2-Glycoprotein I

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