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Pathogenesis of the antiphospholipid syndrome
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Pathogenesis of the antiphospholipid syndrome
Authors
Bonnie L Bermas, MD
Peter H Schur, MD
Section Editor
David S Pisetsky, MD, PhD
Deputy Editor
Paul L Romain, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2012. |This topic last updated: Sep 11, 2012.
INTRODUCTION The antiphospholipid antibody syndrome (APS) is defined by the presence of two
major components:
Presence in the plasma of at least one type of autoantibody known as an antiphospholipid
antibody (aPL).
The occurrence of at least one of the following clinical manifestations: venous or arterial
thromboses, or pregnancy morbidity.
Although the clinical manifestations of APS occur in other disease populations, in the APS they occur by
definition in the context of aPL. aPL, which are directed against plasma proteins bound to anionic
phospholipids, may be detected as:
Lupus anticoagulants
Anticardiolipin antibodies
Antibodies to 2 glycoprotein-I
The full clinical significance of other autoantibodies, including those directed against prothrombin, annexin
V, phosphatidylserine, and phosphatidylinositol, remain unclear.
APS occurs either as a primary condition or in the setting of an underlying disease, particularly systemic
lupus erythematosus (SLE).
The pathogenesis of the APS will be reviewed here. The clinical manifestations, diagnosis, and treatment
of the APS are discussed separately. (See "Clinical manifestations of the antiphospholipid syndrome" and
"Diagnosis of the antiphospholipid syndrome" and "Treatment of the antiphospholipid syndrome" and
"Obstetrical manifestations of the antiphospholipid syndrome".)
ANTIPHOSPHOLIPID ANTIBODIES The APS is characterized by antibodies directed against epitopes
on plasma proteins that are uncovered or generated by the binding of these proteins to phospholipids;
they do not bind directly to anionic phospholipids [1,2]. The mechanisms by which aPL cause thrombosis
are not completely understood.
There are a variety of tests that can detect aPL:
Anticardiolipin antibodies
Functional assays for the detection of aPL with lupus anticoagulant activity
Anti-2-glycoprotein-I antibodies
These tests vary in their sensitivity and specificity.
The standard types of aPL assays performed are enzyme-linked immunoassays (ELISAs) for
anticardiolipin antibodies (aCL) and antibodies to 2-glycoprotein-I (2-GP-I), and coagulation tests
designed to detect lupus anticoagulants (LAs).
Anticardiolipin antibodies aCL react with cardiolipin but may also react with phosphatidylserine,
phosphatidylinositol, phosphatidylglycerol, 2-GP-I, prothrombin, or annexin V [3].
The concordance between the presence of an LA and aCL is approximately 85 percent. In many cases,
however, LAs comprises a separate population of antibodies from aCL [1,4,5]. Thus, testing should be
performed for both LAs and aCL if APS is suspected on a clinical basis. (See "Diagnosis of the
antiphospholipid syndrome".)
Elevated levels of IgG aCL confer a greater risk of thrombosis than do other immunoglobulin isotypes [6].
However, IgM and IgA aCL isotypes may be associated with the APS [7].
False positive serologic test for syphilis The biologic false positive test for syphilis (BFPTS)
phenomenon occurs because the syphilis antigen used in the VDRL and RPR tests is cardiolipin mixed
with cephaline and cholesterol. Examples of BFPTS are positive rapid plasma reagin (RPR) or Venereal
Disease Research Laboratory (VDRL) tests that are not confirmed by specific treponemal assays. These
tests for the diagnosis of syphilis have been replaced by specific antitreponemal tests in most
laboratories.
RPR and VDRL assays, if available, are not appropriate screening tests for aPL because of their low
sensitivities and specificities [8]. (See "Diagnostic testing for syphilis", section on 'Interpretation of
serologic testing'.)
Lupus anticoagulants LAs are antibodies directed against plasma proteins such as 2-GP-I,
prothrombin, or annexin V that are bound to anionic phospholipids [9-12]. The phrase "the lupus
anticoagulant" is a misnomer, for three reasons:
The presence of an LA is generally associated with a clotting tendency, not an anticoagulant
effect. (See "Clinical manifestations of the antiphospholipid syndrome", section on
'Thrombosis'.)
More than one antibody is associated with LA activity. As examples, both aCL and
antibodies to 2-GP-I can have LA activity.
Only about 50 percent of individuals with an LA meet the American College of
Rheumatology criteria for the classification of SLE. (See "Clinical manifestations of the
antiphospholipid syndrome", section on 'Primary APS versus APS with SLE'.)
Because there is more than one LA and not all antibodies with APS are associated with anticoagulant
activity, the detection of LAs occurs through functional clotting tests, not through enzyme-linked
immunosorbent assays (ELISAs). LAs block in vitro assembly of the prothrombinase complex, resulting in
a prolongation of in vitro clotting assays such as the activated partial thromboplastin time (aPTT), the
dilute Russell viper venom time (dRVVT), the kaolin clotting time and, infrequently, the prothrombin time.
(See "Clinical use of coagulation tests" and "Diagnosis of the antiphospholipid syndrome", section on
'Lupus anticoagulant'.)
Prolongation of clotting times Clotting factor deficiencies that lead to prolongation of coagulation
assays are reversed when the patient's plasma is diluted 1:1 with normal platelet-free plasma. Such a
procedure is known as a mixing study. (See "Clinical use of coagulation tests", section on 'Mixing
studies'.)
In contrast, abnormalities of coagulation assays are not reversed when the cause is an LA [1,9].
However, they can be reversed by incubation of the patient's plasma with a hexagonal phase
phospholipid that neutralizes the inhibitor [1,4,9].
Abnormal bleeding times Many patients with LAs have prolonged bleeding times despite adequate
platelet counts [13,14]. Although these changes suggest impaired coagulation, patients with an LA have a
paradoxical increase in the frequency of arterial and venous thrombotic events [15,16].
Anti-2-glycoprotein-I antibodies 2-GP-I (apolipoprotein H) is a naturally occurring inhibitor of
coagulation and platelet aggregation [17]. The properties of this protein as a clotting inhibitor could
explain why neutralizing antibodies promote thrombosis. Consistent with this hypothesis is the
observation that aPL prolong the aPTT if added to normal plasma but not to plasma depleted of 2-GP-I
[18]. 2-GP-I binds to negatively-charged phospholipids such as phosphatidylserine and
phosphatidylinositol and inhibits both contact activation of the clotting cascade and the conversion of
prothrombin to thrombin [19,20].
Antibodies to 2-GP-I are found in a large percentage of patients with primary or secondary APS [21].
Although antibodies to 2-GP-I are usually found in association with other aPL, they are the sole aPL
detectable in approximately 11 percent of such patients [21]. (See "Diagnosis of the antiphospholipid
syndrome".)
Additional aPL In addition to aCL, LAs, and antibodies to 2-GP-I, other antibodies have been
reported in association with clinical features of the APS. These include antibodies to:
Prothrombin
Annexin V
Phosphatidylserine
Phosphatidylinositol
Phosphatidylethanolamine
In general, assays for these antibodies are not standardized for clinical use. Their interpretation and
relevance to clinical practice remains unclear. Among these additional aPL, the largest amount of
literature relates to antiprothrombin antibodies.
Antiprothrombin antibodies Antiprothrombin antibodies have been described in association with both
clotting and hemorrhage [22]. The presence of prothrombin antibodies should be suspected when a
patient with known aPL develops a bleeding tendency. (See "Acquired inhibitors of coagulation", section
on 'Other coagulation factor inhibitors'.)
Antiprothrombin antibodies have been described in 50 percent of patients with aPL, 34 percent of patients
with SLE, and 57 percent of patients with Sneddon's syndrome (livedo reticularis with stroke or transient
ischemic attacks) [23-25].
Antibodies directed against prothrombin may interfere with coagulation in conjunction with other aPL [23].
As an example, antibodies to a complex of phosphatidylserine and prothrombin appear to be more
significant in terms of the risk of clinical events than antibodies to prothrombin alone [26,27]. (See
"Acquired inhibitors of coagulation", section on 'Prothrombin inhibitors'.)
Antiprothrombin antibodies are also associated with an increased likelihood of recurrent venous
thromboembolic disease that is independent of the presence of aCL or LA. In one study of 236
consecutive patients with acute venous thrombotic events, the following observations were made [28]:
aPL were found in 85 (36 percent), of whom 24 (10 percent of the overall cohort) had
antiprothrombin antibodies.
A history of previous thromboembolism was identified in nearly one-quarter of the patients.
In a multivariate analysis, antiprothrombin antibodies were associated with previous
thromboembolism (odds ratio 3.3).
Future studies and further refinement of APS assays are likely to clarify the role of antibodies to
prothrombin, annexin V, phosphatidylserine, and other aPL targets.
PATHOGENESIS The pathogenesis of the APS associated clinical manifestations appears to result
from a variety of aPL effects upon pathways of coagulation, including the procoagulant actions of these
antibodies upon protein C, annexin V, platelets, serum proteases, toll-like receptors, tissue factor, and via
impaired fibrinolysis [29-36]. In addition to heightening the risk of vascular thrombosis, aPL increase
vascular tone, thereby increasing the susceptibility to atherosclerosis, fetal loss, and neurological damage
[37].
The most commonly accepted explanation for the development of aPL is that they occur in susceptible
individuals following incidental exposure to infectious agents. However, aside from the milieu of rheumatic
diseases such as SLE, the conditions creating such susceptibility remain largely undefined.
Current thinking about the pathogenesis of the APS holds that once aPL are present, a "second-hit" is
required for the development of the full-blown syndrome [38]. Potential candidates for the delivery of such
a second hit are smoking, prolonged immobilization, pregnancy and the post-partum period, oral
contraceptive use, hormone replacement therapy, malignancy, nephrotic syndrome, hypertension, and
hyperlipidemia.
Clues to the pathogenesis of the APS derive from in vitro experiments, animal models, and clinical
studies in humans.
In vitro experiments Multiple in vitro experiments suggest that antibodies to 2-GP-I play an
important role in the thrombotic events associated with APS. The range of findings is summarized by the
following points:
2-GP-I helps maintain adequate plasma levels of free protein S [39]. Antibodies to 2-GP-I
may cause thrombosis by interfering with the activity of protein S. (See "Protein S
deficiency", section on 'Physiology of protein S'.)
Other aPL may have similar effects on protein C and other coagulation factors through
binding to these proteins or receptors on endothelial cell surfaces [40-43]. (See "Protein C
deficiency", section on 'Physiology of protein C'.)
Specific T cells in APS patients respond to stimulation with 2-GP-I [44]. Depletion of these
T cells significantly reduces anti-2-GP-I antibody production.
Complexes of 2-GP-I and aCL bind to platelet phospholipids, upregulating coagulation and
stimulating platelet aggregation [45]. Antibody binding to 2-GP-I attached to the platelet
glycoprotein Ib-IX-V receptor may lead to platelet activation [46].
Antibodies to 2-GP-I may cross-react with antigenic determinants on endothelial cell CD40
[47]. CD40 ligation in vitro causes endothelial cell activation characterized in part by
increased surface expression of adhesion molecules [48].
APL may lead to platelet activation and facilitate the adherence of platelets to endothelium
[40,49]. This effect may be enhanced by the presence of antibodies to both aCL, 2-GP-I,
and phosphatidylserine/prothrombin complexes [50], as well as by the presence of thrombin
[51].
APL may activate vascular endothelium, resulting in increased binding of monocytes and
activated platelets and the expression of tissue factor, chemokines, and growth factors [52-
55].
Animal models The following data from animal models that are relevant to the pathogenesis of the
APS include:
Findings in a mouse model of APS challenge the dogma that this syndrome is entirely a
noninflammatory, thrombotic disease, and provide evidence that complement activation is
critical for APS pregnancy complications [56,57].
In the same mouse model, aPL-induced fetal loss may be inhibited by treatment with
heparin [58], and some evidence in humans suggests that similar findings apply to patients
with the APS [59]. (See 'Clinical studies' below.)
The infusion of human or murine aCL or immunization with a monoclonal human aCL
prolongs the PTT and increases the rate of fetal loss in mice [60,61].
Data from a mouse model suggest that antibodies directed against an antigenic hexapeptide
derived from 2-GP-I may cross-react with bacterial proteins containing the same motif (ie,
possible molecular mimicry) [62]. Passive transfer of purified antibodies to the hexapeptide
was associated with decreased platelets counts, fetal resorption, and prolongation of the
activated partial tissue thromboplastin time.
In other mouse experiments, antibodies to a 15 amino acid peptide derived from 2-GP-I
transfer disease [63]. Some data indicate that one 2-GP-I domain (domain I) plays a role in
human disease [64].
Clinical studies Clinical studies in humans are consistent with findings from in vitro and animal model
experiments about the importance of complement activation and antibodies to 2-GP-I in disease
pathogenesis:
Patients with primary APS had lower levels of CH50, C3 and C4 than controls; they also had
increased levels of complement fragments indicative of complement activation (ie, C3a and
C4a) [65].
When immunohistochemical analyses were performed on placentas from 47 patients with
aPL and 23 healthy controls, there was evidence of increased complement deposition within
the trophoblast cytoplasm, trophoblastic cell and basement membrane, and extravillous
trophoblasts of placentas from aPL patients [59]. These findings are consistent with murine
studies implicating complement as a critical factor in fetal tissue injury [56-58].
However, it remains uncertain whether complement activation causes a hypercoagulable state, or, results
from it.
Antibodies to 2-GP-I correlate better with the development of APS than do aCL or LAs
alone [1,66-70]. As an example, in a study of 100 patients with an LA, 12 of the 14 who
developed a thromboembolic event had prolongations of their dilute Russell viper venom
time (dRVVT) assay, a coagulation test that is highly sensitive for antibodies to 2-GP-I [70].
Antibodies to 2-GP-I were found in 35 of 39 lupus patients with features of APS compared
with only two of 55 patients without APS [66,67]. As noted above, patients with syphilis and
other infections that often lead to aCL production do not form anti-2-GP-I antibodies, which
may explain why they do not become hypercoagulable [40,66,67].
Patients with antibodies to 2-GP-I but without either LA or aCL can display the clinical
features of APS, including venous and/or arterial thromboses [21,71].
APS patients express greater quantities of tissue factor, the major initiator of coagulation in
vivo, on the surfaces of monocytes. In one report, enhanced monocyte expression of tissue
factor was observed in patients with primary APS and a history of thrombosis, but not in
patients with aPL without thrombosis or in patients with thrombosis but without aPL [72].
Monocytes from patients with thromboembolic phenomena also appear to over-express
potentially procoagulant proteins including: annexin I and II, protein disulfide isomerase,
Nedd8, RhoA, and heat shock protein-60 on their surfaces; in contrast, monocytes from
patients with recurrent abortions reportedly over-express fibrinogen and hemoglobin [73].
Interaction with other antibodies APL may also exert their effects through complex interactions with
other antibodies. As examples, patients with aPL may also have antibodies directed against
heparin/heparan sulfate, platelet-activating factor, tissue-type plasminogen activator, annexins (2, IV, and
V), thromboplastin, oxidized low density lipoproteins, thrombomodulin, kininogen, and coagulation factors
VII, VIIa, and XII [23,24,37,74-87].
Microparticles Microparticles are fragments of cell surface membranes that are released from
apoptotic, activated, and damaged cells. The plasma concentration of microparticles that are derived from
endothelial cells is increased among patients with APS when compared to people with aPL without
thrombotic events and to healthy controls [88-90]. (See "Endothelial dysfunction", section on
'Microparticles'.)
GENETIC PREDISPOSITION Although genetic studies of the APS are in their infancy, genetic risk
factors such as concurrence of coagulation factor mutations heighten the risk of aPL-associated
thrombosis. In different studies, factor V Leiden and the prothrombin gene mutation and activated protein
C resistance were associated with an increased risk of venous thromboembolism in patients with aPL
[91,92]. (See appropriate topic reviews on the different hypercoagulable states).
Several other types of studies have implicated genetic factors in the pathogenesis of the APS. The
following are illustrative:
Relatives of probands with aPL are more likely to have aPL. In a series of 23 patients with
aCL, for example, 29 of their 87 relatives (33 percent) also had aCL [93].
There is a strong association of aPL with HLA-DR7 in Canadian, German, Italian, and
Mexican patients, and with HLA-DQ7 in American and Spanish patients [94].
Weaker associations have been noted between various polymorphisms of the
immunoglobulin receptor (Fcgamma RIIA) and platelet glycoproteins [95,96].
The inheritance of certain polymorphisms of the 2-GP-I gene and of the HLA-DMA and
HLA-DMB genes may also enhance the risk of aPL [97,98].
An increased incidence of arterial thrombosis may be associated with certain platelet
glycoprotein polymorphisms [96].
Genetic associations between two genes known to be associated with the risk of SLE (ie,
STAT4 gene and BLK gene) were noted in a study of 133 patients with primary APS.
However, two other SLE-associated genes were not associated with APS (ie, BANK1 gene
and IRF5 gene) [99].
PREVALENCE IN DIFFERENT CONDITIONS In addition to their occurrence in primary APS, aPL are
found in many other clinical settings. Their clinical significance varies widely in the conditions outlined
below.
Healthy individuals A minority of healthy individuals have aPL. In most cases, the aPL are not
present upon retesting. However, in some individuals, the presence of aPL is associated with an
increased risk of developing the APS. (See "Diagnosis of the antiphospholipid syndrome", section on
'Initial laboratory testing'.)
Autoimmune and rheumatic diseases The most important rheumatic disease associated with aPL is
SLE. aPL occur in a substantial proportion of patients with SLE [100-103]:
Approximately 31 percent of patients have an LA
23 to 47 percent have an aCL
20 percent have antibodies to 2-GP-I
Conversely, approximately 50 percent of patients with an LA have SLE [5,102].
Both LAs and aCL have also been found in patients with a variety of other autoimmune and rheumatic
diseases (eg, scleroderma, psoriatic arthritis) but, in the absence of clinical events associated with the
APS, their significance is not clear [102,104].
Infections APL have also been noted in patients with infections. These are usually IgM aCL, which
may occasionally result in thrombotic events [102,105]. Furthermore, these antibodies usually do not
have anti-2-GP-I antibody activity [106,107].
The infections that have been associated with aPL include [104,106-114]:
Bacterial infections Bacterial septicemia, leptospirosis, syphilis, Lyme disease
(borreliosis), tuberculosis, leprosy, infective endocarditis, post-streptococcal rheumatic fever,
and Klebsiella infections.
Viral infections Hepatitis A, B, and C, mumps, HIV, HTLV-I, cytomegalovirus, varicella-
zoster, Epstein-Barr virus, adenovirus parvovirus, and rubella. Several earlier studies had
reported an association between infection with hepatitis C virus and aPL [109-111].
However, more recent studies suggest no link between the two disorders [112]. As a result,
the correlation between hepatitis C virus infection and aPL, if present, is weak and may not
have underlying pathogenic significance.
Parasitic infections Malaria, Pneumocystis jirovecii, and visceral leishmaniasis (also
known as kala-azar).
Medications A number of medications have been associated with aPL. These include phenothiazines
(chlorpromazine), phenytoin, hydralazine, procainamide, quinidine, quinine, dilantin, ethosuximide, alpha
interferon, amoxicillin, chlorothiazide, oral contraceptives, and propranolol [104,105,115]. The aPL are
usually transient, often of the IgM isotype, and rarely associated with thrombosis. The mechanism of
drug-induced aPL is not known.
Neoplasms Associations with malignant neoplasms have been reported including solid tumors of the
lung, colon, cervix, prostate, kidney, ovary, breast, and bone; with Hodgkin's and non-Hodgkin
lymphomas; and with myelofibrosis, polycythemia vera, myeloid and lymphocytic leukemias [104].
Other associations APL have been noted in association with immune thrombocytopenia, sickle cell
anemia, pernicious anemia, diabetes mellitus, inflammatory bowel disease, dialysis, and Klinefelter
syndrome [104].
SUMMARY
The antiphospholipid antibody syndrome (APS) is defined by two major components:
Presence in the plasma of at least one type of autoantibody known as an antiphospholipid
antibody (aPL).
The occurrence of at least one clinical feature: either venous or arterial thromboses, or
pregnancy morbidity.
Although the clinical manifestations of APS occur in other disease populations, in the APS they occur by
definition in the context of aPL. aPL, which are directed against plasma proteins bound to anionic
phospholipids, may be detected as:
Lupus anticoagulants
Anticardiolipin antibodies
Antibodies to 2 glycoprotein-I
In addition to aCL, LAs, and antibodies to 2-GP-I, other antibodies have been reported to be associated
with thrombosis. Their relevance in the APS remains uncertain. Antiprothrombin antibodies may be
associated with a bleeding tendency as well as thrombosis. (See 'Additional aPL' above.)
The pathogenesis of the APS associated clinical manifestations appears to result from a variety of aPL
effects upon pathways of coagulation, including the procoagulant actions of these antibodies upon protein
C, annexin V, platelets, and fibrinolysis. (See 'Pathogenesis' above.)
The most commonly accepted explanation for the development of aPL is that they occur in susceptible
individuals following incidental exposure to infectious agents. However, aside from the milieu of rheumatic
diseases such as SLE, the conditions creating such susceptibility remain largely undefined.
Current thinking about the pathogenesis of the APS holds that once aPL are present, a "second-hit" is
required for the development of the full-blown syndrome.
Multiple in vitro experiments suggest that antibodies to 2-GP-I play an important role in the APS.
Findings in a mouse model of APS provide evidence that complement activation is critical for APS
pregnancy complications.
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TOPIC OUTLINE
SUMMARY
INTRODUCTION
ANTIPHOSPHOLIPID ANTIBODIES
Anticardiolipin antibodies
- False positive serologic test for syphilis
Lupus anticoagulants
- Prolongation of clotting times
- Abnormal bleeding times
Anti-2-glycoprotein-I antibodies
Additional aPL
- Antiprothrombin antibodies
PATHOGENESIS
In vitro experiments
Animal models
Clinical studies
Interaction with other antibodies
Microparticles
GENETIC PREDISPOSITION
PREVALENCE IN DIFFERENT CONDITIONS
Healthy individuals
Autoimmune and rheumatic diseases
Infections
Medications
Neoplasms
Other associations
SUMMARY
REFERENCES
RELATED TOPICS
Acquired inhibitors of coagulation
Clinical manifestations of the antiphospholipid syndrome
Clinical use of coagulation tests
Diagnosis of the antiphospholipid syndrome
Diagnostic testing for syphilis
Endothelial dysfunction
Obstetrical manifestations of the antiphospholipid syndrome
Protein C deficiency
Protein S deficiency
Treatment of the antiphospholipid syndrome
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