Hematology

Pathogenesis of the antiphospholipid syndrome

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

Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Tue Feb 02 00:00:00 GMT 2010 (More)

INTRODUCTION — 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 from a diverse list of potential disease manifestations. The most common of these clinical manifestations are categorized as venous or arterial thromboses, recurrent fetal loss, or thrombocytopenia.

 

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 ß2 glycoprotein-I
  • Other antibodies, including those to prothrombin, annexin V, phosphatidylserine, phosphatidylinositol, and others

 

APS occurs either as a primary condition or in the setting of an underlying disease, particularly disorders in the spectrum of systemic lupus erythematosus (SLE). In the latter case, the condition is termed secondary APS.

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 either phospholipids or plasma proteins that are bound to phospholipids. The antigens against which the aPL are directed and the mechanisms by which aPL cause thrombosis are not completely understood.

APL are 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].

There are a variety of tests that can detect APL:

 

  • Anticardiolipin antibodies
  • Functional assays for the detection of aPL with lupus anticoagulant activity
  • Anti-ß2-glycoprotein-I antibodies

 

These tests vary in their sensitivity and specificity and have substantial overlap. As an example, both anticardiolipin antibodies and anti-ß2-glycoprotein-I antibodies can be associated with lupus anticoagulant activity.

The standard types of aPL assays performed are enzyme-linked immunoassays (ELISAs) for anticardiolipin antibodies (aCL) and coagulation tests designed to detect lupus anticoagulants (LAs). When the APS is suspected despite the absence of aPL detected by these conventional tests, additional assays such as those for antibodies to ß2-glycoprotein-I (ß2-GP-I), prothrombin, phosphatidylinositol, and other antigens may be considered. However, assays for these antibodies are not standardized for clinical use, and their clinical utility is not well characterized (see ‘Additional aPL’ below).

Anticardiolipin antibodies — ACL react with cardiolipin but may also react with phosphatidylserine, phosphatidylinositol, phosphotidylglycerol, ß2-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 test 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 have been replaced by specific antitreponemal tests in many laboratories.

In the APS, a reaction against this molecule can be interpreted incorrectly as being directed against a treponemal antigen. 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 ß2-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 ß2-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 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-ß2-glycoprotein-I antibodies — ß2-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 ß2-GP-I [18]. ß2-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 ß2-GP-I are found in a large percentage of patients with primary or secondary APS [21]. Although antibodies to ß2-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 ß2-GP-I, other antibodies may be associated with the APS. These include antibodies to:

 

  • Prothrombin
  • Annexin V
  • Phosphatidylserine
  • Phosphatidylinositol
  • Phosphatidylethanolamine

 

In general, assays for these antibodies are not standardized for clinical use. 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.

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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 ß2-GP-I play an important role in the thrombotic events associated with APS. The range of findings is summarized by the following points:

 

  • ß2-GP-I helps maintain adequate plasma levels of free protein S [39]. Antibodies to ß2-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 ß2-GP-I [44]. Depletion of these T cells significantly reduces anti-ß2-GP-I antibody production.
  • Complexes of ß2-GP-I and aCL bind to platelet phospholipids, upregulating coagulation and stimulating platelet aggregation [45]. Antibody binding to ß2-GP-I attached to the platelet glycoprotein Ib-IX-V receptor may lead to platelet activation [46].
  • Antibodies to ß2-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, ß2-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 ß2-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 ß2-GP-I transfers disease [63]. Some data indicate that one ß2-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 ß2-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 ß2-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 ß2-GP-I [70].
  • Antibodies to ß2-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-ß2-GP-I antibodies, which may explain why they do not become hypercoagulable [40,66,67].
  • Patients with antibodies to ß2-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 overexpress 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 overexpress 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 ß2-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”.)

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 ß2-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-ß2-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).
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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 from a diverse list of potential disease manifestations. The most common of these clinical manifestations are categorized as either venous or arterial thromboses, recurrent fetal loss, or thrombocytopenia.

 

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 ß2 glycoprotein-I

 

In addition to aCL, LAs, and antibodies to ß2-GP-I, other antibodies may be associated with the APS. 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 ß2-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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