Annu. Rev. Med. 2003. 54:40924 doi: 10.1146/annurev.med.54.101601.152412 Copyright c 2003 by Annual Reviews.

All rights reserved First published online as a Review in Advance on Oct. 24, 2002

THE ANTIPHOSPHOLIPID SYNDROME

Jacob H. Rand
Thrombosis and Hemostasis Section, and Hematology and Coagulation Laboratories, Department of Medicine, Hematology Division, Mount Sinai School of Medicine, New York, New York 10029; e-mail: jacobrand@aol.com

Key Words thrombophilia, thrombosis, pregnancy loss, stroke, systemic lupus erythematosus, autoimmunity s Abstract The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that bind to phospholipids. There have been signicant advances in the recognition of the role of phospholipid-binding cofactors, primarily 2GPI, as the true immunologic targets of the antibodies. Recent evidence suggests that the antibodies disrupt phospholipid-dependent anticoagulant mechanisms and/or that aPL antibodies induce the expression of procoagulant and proadhesive molecules on endothelial cells. Current diagnosis is based on clinical ndings and empirically derived tests, such as assays for antibodies that bind to phospholipids or putative cofactors and coagulation assays that detect inhibition of phospholipiddependent coagulation reactions. Current treatment relies primarily on anticoagulant therapy. Research advances are expected to bring mechanistically based diagnostic tests and improved therapy that target the roots of the disease process.

INTRODUCTION
The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that recognize phospholipids or phospholipidbinding protein cofactors. Alternative names for the disorder include antiphospholipid cofactors syndrome (because the antigenic targets are generally thought to be phospholipid-binding cofactor proteins), antibody-mediated thrombosis syndrome (because there is general agreement that antibodies play a central role in this process), and Hughes syndrome [honoring the investigator who rst proposed it and also avoiding semantic prejudgment of the mechanism(s)]. The antibodies are detected through enzyme-linked immunosorbant assays using solid-phase phospholipids (most commonly cardiolipin or phosphatidyl serine) and protein cofactors (most commonly 2GPI) as antigenic targets, or with coagulation assays that reect the inhibition of phospholipid-dependent coagulation reactions, i.e., the lupus anticoagulant (LA) phenomenon. The disorder is classied as primary when it occurs in the absence of systemic lupus erythematosus (SLE) and
0066-4219/03/0218-0409$14.00

409

410

RAND

secondary in its presence. The clinical presentations and courses of thrombosis in the primary and secondary disorders appear similar (1, 2). Specic criteriaknown as the Sapporo Investigational Criteriahave been developed to dene the aPL syndrome for research purposes (3). These include (a) clinical history of one or more episodes of vascular thrombosis (involving any site), or history of pregnancy morbidity, and (b) laboratory evidence of a positive LA test, or a medium- or high-titer anticardiolipin (aCL) IgG and/or IgM antibody measured by a standard assay for 2 glycoprotein I ( 2GPI)dependent aCL antibodies. The laboratory abnormalities should be present on two or more occasions at least six weeks apart. However, in clinical practice, patients may be suspected of having this disorder without meeting the stringent criteria.

PATHOPHYSIOLOGY
It is not yet understood how aPL antibodies arise in patients with the syndrome. Genetic factors may play a role (4). The antibodies generated in patients with the aPL syndrome appear to recognize epitopes on phospholipid-binding proteins, unlike the antibodies that arise following infections such as syphilis and Lyme disease, which recognize phospholipids directly. Infection may play a role in stimulating the aPL thrombotic disorder. In a mouse model, immunization with Haemophilus inuenzae, Neisseria gonorrhoeae, or tetanus toxoid resulted in the development of antibodies against 2GPI (5); infusion of these antibodies into pregnant mice resulted in manifestations of the aPL syndrome, including thrombocytopenia, prolonged activated partial thromboplastin time, and increased fetal loss. In humans, infections with HIV-1, hepatitis A, hepatitis B, and hepatitis C are also associated with increased prevalence of aCL antibodies, most of which are not cofactor-dependent (6). Reports of association of aCL antibodies and/or LA with viral infections, including hepatitis C virus, HIV-1, cytomegalovirus, varicella zoster, Epstein-Barr virus, adenovirus, and parvovirus Bsome of which were associated with thrombosishave been reviewed (7). aPL syndrome with thrombosis has also been reported after infection with varicella (810). 2GPI, a member of the complement control protein or short consensus repeat (SCR) superfamily, appears to be a major epitope recognized by aPL antibodies (reviewed in Reference 11). The crystal structure of the protein, with 326 amino acids in ve repeating SCR stretches of 60 amino acid residues, has been solved (12, 13). The structure (13) suggests that the protein binds the phospholipid bilayer with the cationic portion of its fth SCR domain. aPL antibody recognition of the protein, possibly via domains I and II, near the amino terminus, increases the binding of the protein to membrane phospholipid (12) by the formation of divalent IgG- 2GPI complexes that have increased afnity for the phospholipid bilayer (14). The biologic function of 2GPI has not been established (15). 2GPI deciency has been identied in humans and does not appear to be associated with disease

ANTIPHOSPHOLIPID SYNDROME

411

(16, 17). One case report of a patient with a mutated nonfunctional 2GPI who had severe thrombotic problems (18) suggested a possible protective role against thrombosis. Homozygous 2GPI-null mice appeared anatomically and histologically normal (19). 2GPI binds to endothelial cells via annexin II, a protein that also serves as a receptor for plasminogen and tissue plasminogen activator (20). In addition to 2GPI, prothrombin (coagulation factor II), coagulation factor V, protein C, protein S, annexin-V, high-molecular-weight kininogen, and lowmolecular-weight kininogen may also be recognized by aPL antibodies in various patients (21). Antibodies of some aPL syndrome patients recognize heparin and inhibit the formation of antithrombin IIIthrombin complexes (22).

ETIOLOGY AND PATHOGENESIS

The concept that aPL antibodies play a direct causal role in the development of thrombotic manifestations is supported by signicant data from experimental animal models. Mice immunized against 2GPI develop aPL antibodies and pregnancy wastage (23). Mice that have been passively or actively immunized with aPL antibodies also develop pregnancy wastage (24, 25). Mice infused with aPL antibodies exhibited greater venous thrombosis after experimental vascular injury than mice infused with control antibodies (2628). Atherosclerosis was accelerated in a susceptible mouse model, the low-density-lipoproteinreceptor knockout mouse, by immunization with human aCL antibodies (29). Several pathogenic mechanisms, the biological validities of which remain to be determined, have been proposed for the aPL syndrome. These include aPLantibodymediated interference with phospholipid-dependent antithrombotic mechanisms, consequences of aPL antibody binding to cell membranes, and other mechanisms.

Antiphospholipid-AntibodyMediated Interference with Phospholipid-Dependent Antithrombotic Mechanisms

Disruption of the annexin-V anticoagulant shield, caused by aPL antibodies, is a proposed mechanism for thrombosis. Annexin-V is a phospholipid-binding protein whose potent anticoagulant properties result from its forming two-dimensional crystalline lattices over phospholipid surfaces (30, 31), which shield the phospholipid from availability for coagulation reactions. Annexin-V on cultured human trophoblasts and endothelial cells is reduced by IgG fractions from aPL syndrome patients; also, plasma incubated with these cells coagulates more rapidly (32). A monoclonal antiphosphatidylserine antibody reduced the level of annexin-V on cultured syncytialized BeWo trophoblasts and allowed prothrombin to bind to these cells (33). The aPL-antibodymediated reduction of annexin-V occurs via displacement by aPL antibodies, requires the presence of 2-GPI (34), and accelerates coagulation (35). IgG fractions isolated from patients with aPL antibodies reduce the binding of annexin-V to phospholipid-coated

412

RAND

microtiter plates; this reduction of annexin-V binding depends on anti- 2GPI antibodies and correlates with clinical thrombosis (36). aPL sera also reduce annexin-V binding to platelets (37). One group was unable to show that aPL IgG antibodies reduce annexin-V binding (38) or annexin-V-mediated anticoagulant activity (39). Antiphospholipid antibodies may also interfere with various components of the protein C antithrombotic pathway. aPL antibodies interfere with several aspects of the protein C system, inhibiting the formation of thrombin (through the inhibition of prothrombinase activity), decreasing protein C activation by the thrombomodulinthrombin complex, inhibiting assembly of the protein C complex, inhibiting activated protein C activity, and binding to factors Va and VIIIa in ways that protect them from proteolysis by activated protein C (40). Protein C can be a target of aCL in the presence of cardiolipin and 2GPI, leading to protein C dysfunction (41). In addition to these effects, patients with the aPL syndrome frequently have protein S deciency (42, 43). Thrombosis with acquired activated protein C resistance may be associated with antibodies against phosphatidyl ethanolamine (44). Interestingly, oxidation of phosphatidyl ethanolamine may enhance the anticoagulant activity of activated protein C; inhibition of this process by aPL may thereby promote thrombin generation (45). Antiphospholipid antibodies can also recognize heparin and heparinoid molecules, perhaps on the basis of anionic charge, and thereby inhibit antithrombin-III activity (22). There are conicting data on whether aPL antibodies do (46) or do not (47) alter the balance of eicosanoid synthesis toward prothrombotic moieties. aPL antibodies can activate platelets (48) and stimulate platelet aggregation (49).

Consequences of Antiphospholipid Antibody Binding to Cell Membranes

Several effects of aPL antibodies on vascular endothelium have been described. aPL antibodies interact with cultured human vascular endothelial cells with resultant injury and/or activation (5052). Incubation of cultured endothelial cells with aPL antibodies increases the expression of cell adhesion molecules (53), an effect that is mediated by 2GPI (54) and may promote leukocyte adhesion to the endothelial surface. aPL antibodies have thrombogenic effects that are mediated by intercellular cell adhesion molecule1, vascular cell adhesion molecule1, and P-selectin (55). Tissue factor expression is increased in cultured endothelial cells incubated with aPL (56, 57). aPL antibodies with reactivity against annexin-V induce apoptosis in endothelial cells (58). Lupus anticoagulants (LAs) have also been shown to stimulate the release of microparticles and possible prothrombotic activity from endothelial cells (59, 60). aPL antibodies can also promote tissue factor synthesis by leukocytes (61). Stimulation of peripheral blood monocytes from aPL syndrome patients with 2GPI induced substantial monocyte tissue factor activity (62). aPL antibodies may also increase tissue factor activity via inhibition of tissue factor pathway inhibitor activity (63).

ANTIPHOSPHOLIPID SYNDROME

413

Other Pathogenic Mechanisms for the Antiphospholipid Syndrome

Antiphospholipid antibodies show cross-reactivity against oxidized LDL (64, 65) and may thereby be associated with an increased risk of atherosclerosis (66). Fibrinolysis may be impaired via elevation of plasminogen activator inhibitor-1 levels (42) and via anti- 2GPImediated inhibition of the autoactivation of factor XII (67). An additional thrombotic mechanism that has been proposed for the aPL syndrome is the localization of an increased concentration of prothrombin by noninhibitory antiprothrombin antibodies; these antibodies may localize the protein to phospholipid membranes and increase prothrombin activity under dened conditions (68, 69).

CLINICAL MANIFESTATIONS
Initial presentation with the thrombosis usually occurs in the fourth or fth decades (70) and rarely later in life (71). Men and women are equally prone to develop aPL syndrome (70).

Thrombosis and Embolism

Although most patients present with deep vein thrombosis of the lower extremities (72), the syndrome should be especially suspected in patients who develop thrombosis in unusual anatomic sites or experience recurrent thrombotic episodes without another established cause (73). In a series of aPL syndrome patients, 59% had radiologically proven thrombi limited to the venous circulation, 28% had thrombi limited to the arterial tree, and 13% had both types of events (73). Thrombosis may occur without identiable provocation or in the setting of a predisposing factor such as estrogen hormone replacement therapy, oral contraceptives (74), vascular stasis, surgery, or trauma. Women are at particularly high risk for venous thrombosis during and after pregnancy (2). Some patientsgenerally those with venous rather than arterial thrombosis (75)also have concurrent genetic thrombophilic conditions, such as heterozygosity for the factor V Leiden polymorphism (7577). Having a history of a previous thromboembolic event is a major risk factor for future thromboembolism. The risk of recurrence in patients with aCL antibodies after the rst episode of venous thromboembolism is about 30% (78). The risk of recurrence correlates with the titer of antibodies (78). A history of thrombosis is probably the most important risk factor for predicting future thrombosis in this disorder. A prospective study of patients with aPL antibodies concluded that history of thrombosis and an elevated aCL titer of over 40 U are independent predictors of thrombosis (79). The importance of clinical history was further illustrated by a multicenter study of about 500 end-stage renal disease patients awaiting transplantation (80), of which 19% had elevated levels of aCL antibodies, but only about one fourth of these had a history of thrombotic disorders

414

RAND

or SLE. In that study, all 7 patients with thrombotic histories who were transplanted without anticoagulant treatment lost their grafts within one week as a result of renal thrombosis, whereas 3 of the 4 patients treated with anticoagulants maintained their grafts. None of the patients with elevated aCL antibodies, but without thrombotic histories or SLE, who were transplanted (n = 37) lost their grafts because of thrombosis despite their not being anticoagulated. This suggested that only a minority of patients with elevated aCL antibodies truly have the aPL syndrome.

Systemic Lupus Erythematosus and Other Autoimmune Disorders

As mentioned above, aPL syndrome in patients with SLE is referred to as secondary aPL syndrome. Additional autoimmune conditions associated with aPL syndrome include immune thrombocytopenia (see below), myasthenia gravis (81), Graves disease (82), autoimmune hemolytic anemia, Evans syndrome (83), and progressive systemic sclerosis (84). Elevation of aPL antibodies has also been observed in the course of vasculitic conditions, e.g., giant cell arteritis (85), Takayasu arteritis (86), and polyarteritis nodosa (86). However, it is not clear whether, in the absence of thrombosis, these are part of the thrombophilic syndrome.

Thrombocytopenia
Most cases of thrombocytopenia in the aPL syndrome appear to be immunemediated and probably reect a common autoimmune background rather than being attributable to phospholipid/cofactor epitopes (87, 88). The thrombocytopenia is usually mild or moderate, is rarely associated with bleeding complications, and occurs in 20%40% of patients with the aPL syndrome (89). Among patients presenting with immune-mediated thrombocytopenia, aPL antibodies and antibodies against platelet membrane glycoprotein are both present in 70% (90).

Catastrophic Antiphospholipid Syndrome

Rare patients present with severe disseminated vascular occlusions with multiorgan ischemia and infarction, a condition called the catastrophic aPL syndrome (91). These patients may experience massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzymes, renal impairment, adrenal insufciency, and areas of cutaneous infarction. The respiratory failure is usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Laboratory evidence for disseminated intravascular coagulation and histopathologic evidence for microvascular thrombosis are frequently present. A minority of patients experience large-vessel occlusions. Mortality is about 50%.

Neurologic Manifestations
Elevated levels of aCL and aPS antiphospholipid antibodies are associated with increased risk for developing stroke (92, 93). The aPL syndrome should be suspected in young patients with transient ischemic attacks or stroke, especially when other

ANTIPHOSPHOLIPID SYNDROME

415

known risk factors for cerebrovascular disease are absent (94). About two thirds of children with idiopathic cerebral ischemia (95) and with acute cerebral infarction (96) have evidence of elevated aPL antibodies. High levels of aCL IgG antibodies, above 40 GPL units, in patients with cerebrovascular events were associated with an increased risk of recurrence and death (97). In a signicant minority of aPL syndrome patients, the stroke is due to cerebral venous infarction (98) and may occur in additional conjunction with factor V Leiden heterozygosity. The syndrome is also associated with retinal vaso-occlusion (99102).

Clinical Associations
Approximately 35% of patients with primary aPL syndrome have cardiac valvular abnormalities (103), and 20% of cardiac patients with valvular heart disease have evidence for aPL antibodies compared with 10% of matched control subjects (104). About half of patients with SLE and aPL antibodies have some demonstrable valvular abnormality (105). Histologically, the lesions consist mainly of supercial or intravalvular brin deposits in association with variable degrees of vascular proliferation, broblast inux, brosis, and calcication, without prominent evidence of inammation (106); immunoglobulins and complement component deposits are commonly found (107). Additional manifestations of the aPL syndrome include bone marrow necrosis (108), adrenal infarction (109), and adrenal hemorrhage (110, 111). Acute sensorineural hearing loss may be a manifestation of the aPL syndrome (112).

DIAGNOSIS
Although general agreement has not been reached as to which specic LA tests should be used for diagnosis, consensus criteria for dening the LA phenomenon have been developed (113). These include (a) the prolongation of a phospholipiddependent coagulation test, (b) evidence of inhibitor activity in the test plasma determined by mixing tests with pooled normal plasma, and (c) conrmation that the inhibitory effect is due to blocking phospholipid-dependent coagulation (i.e., neutralization of the inhibitory effect by addition of excess phospholipids or by changing the source of phospholipid). Remarkably, the LA effect is associated with thrombosis and not associated with susceptibility to bleeding. An explanation for this paradox has been proposed (34, 35). When a bleeding diathesis is encountered in an aPL syndrome patient, another coagulopathy needs to identied. These include acquired hypoprothrombinemia (114), acquired platelet function disorders, thrombocytopathies, associated thrombocytopenia (usually immune-mediated), and acquired inhibitors against specic coagulation factors. The LA may predict the risk of thrombosis better than immunoassays (115). A meta-analysis of the risk for aPL-associated venous thromboembolism in individuals who had aPL antibodies without underlying autoimmune disease or previous

416

RAND

thrombosis, who were followed for a 15-year period, showed the mean odds ratios for thrombosis to be 1.6 for aCL antibodies, 3.2 for high titers of aCL, and 11.0 for LA (116). The dilute Russell viper venom time (dRVVT) is considered to be one of the most sensitive LA tests (117). RVV directly activates coagulation factor X, leading to the formation of brin clot. LA prolongs the dRVVT by interfering with assembly of the prothrombinase complex. To conrm that the prolongation of the clotting time is not due to a coagulation-factor deciency, a mixture of patient and control plasma is also tested. LAs are a frequent cause of prolonged aPTT (activated partial thromboplastin time) tests (118), especially in patients lacking a history of bleeding. The currently available aPTT reagents vary in their sensitivities to LAs and can be exploited to aid diagnosis; e.g., if the aPTT is normalized when an LA-insensitive aPTT reagent is used or when frozen washed platelets are added to the aPTT assay (the platelet neutralization procedure) then an LA effect is likely present. Also, incubating a mixture of patient and normal plasma at 37 C may help distinguish antibodies against factor VIII (aPTT is prolonged further after incubation) from LA (aPTT is usually unaffected by incubation). It should be recognized that both LA and specic coagulation-factor inhibitors may coexist in rare patients. Other LA tests, used mainly as secondary conrmatory tests, include the kaolin clotting time, the tissue thromboplastin inhibition test, the hexagonal-phase phospholipid neutralization test, and the textarin/ecarin test.

Anticardiolipin Antibody Assays

Elevated levels of aCL antibodies are predictive of an increased risk of thrombosis. During a 10-year follow-up of asymptomatic patients with raised aCL antibody levels, 50% of patients developed clinical manifestations of the syndrome (119). Also, the presence of elevated titers of aCL antibodies six months after an episode of venous thromboembolism was associated with an increased risk of recurrence and death (119). Women who have IgM antibodies, an IgG aCL antibody titer of <20 IgG binding units, and a negative LA do not appear to be at risk for aPL syndrome, whereas women with an IgG aCL titer of >20 binding units or a positive LA are more likely to develop complications (120). aPL syndrome has been described primarily with elevated aCL IgG antibodies, but it also occurs with elevated IgM antibodies and infrequently with IgA antibodies (121). aCL antibody isotype distributions may vary in different ethnic groups (122). Patients with syphilis, Lyme disease, kala-azar, leptospirosis, and other infections, who have coincident thrombosis, could be misdiagnosed with the aPL syndrome on the basis of elevated aCL antibodies alone. Elevated aCL antibodies in these disorders are not associated with risk for thrombotic complications. Antibodies induced by infection generally recognize phospholipids directly and not via protein cofactors such as 2GPI. aPS antibodies correlate more specically with aPL syndrome than aCL antibodies (123125). It may be that aPS (located on the plasma membrane of cells)

ANTIPHOSPHOLIPID SYNDROME

417

is a more pathophysiologically relevant phospholipid antigen for testing for the antibodies than cardiolipin (located on intracellular membranes not exposed to plasma). The risk of stroke with elevated aPS antibodies is comparable to the risk with aCL antibodies (93). Although 2GPI is believed to be the major protein cofactor for the aPL antibodies (126), elevated 2GPI antibodies alone cannot be relied on for the diagnosis because of their low sensitivity (40%50%), despite their higher specicity for the aPL syndrome (98%) and high positive predictive value (90%) (127). Prothrombin is the second major cofactor for aPL antibodies. Although antiprothrombin antibodies occur in 30% of patients with SLE and were previously reported to be signicantly associated with thrombosis (128), a recent study has questioned their usefulness (129). The presence of these antibodies correlates with hypoprothrombinemia and with thrombocytopenia (130).

TREATMENT
Current evidence indicates that the treatment for patients with thrombosis associated with the aPL syndrome should be the same as for patients with thromboses of other etiologies. In patients whose LA interferes with aPTT monitoring for intravenous unfractionated heparin, heparin levels may be followed using LAinsensitive aPTT reagents or specic heparin assays, or using the activated coagulation time test. These patients may also be treated with weight-adjusted doses of a low-molecular-weight heparin. Prospective studies have concluded that patients with spontaneous thromboembolism and the aPL syndrome should be treated with long-term oral anticoagulant therapy to an international normalization ratio (INR) range of 2.03.0 (115) or 2.02.85 (78). However, in one retrospective study, 6/16 patients (37%) followed over 642 months developed deep venous thrombosis despite oral anticoagulation (INR 1.53.0) (131). Several large prospective trials are in progress. Recently, the National Institutes of Health have funded a National Registry on Antiphospholipid Syndrome (principal investigator: Dr. Robert A.S. Roubey, email: apscore@med.unc.edu), which is expected to yield signicant new information on the syndrome and on the signicance of abnormal test results in otherwise healthy individuals.

CONCLUSION
Although the etiology and pathophysiology of the aPL syndrome remain unidentied, there have been major advances in the recognition of the role of protein cofactors, primarily 2GPI, as immunologic targets. Also, several intriguing leads are being pursued, including those involving antibody-mediated disruption of phospholipid-dependent anticoagulant mechanisms and antibody-mediated induction of procoagulant and proadhesive pathways. Current diagnosis is based on clinical manifestations and empirically derived tests, and current treatment

418

RAND

relies primarily on conventional anticoagulant therapy. It is expected that research advances will bring mechanistically based diagnostic tests and improved therapy targeting the disease process.
The Annual Review of Medicine is online at http://med.annualreviews.org

LITERATURE CITED
1. Vianna JL, Khamashta MA, Ordi Ros J, et al. 1994. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am. J. Med. 96:39 2. Krnic BS, OConnor CR, Looney SW, et al. 1997. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors inuencing recurrent thrombosis. Arch. Intern. Med. 157:2101 8 3. Wilson WA, Gharavi AE, Koike T, et al. 1999. International consensus statement on preliminary classication criteria for denite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 42:130911 4. Radway-Bright EL, Ravirajan CT, Isenberg DA. 2000. The prevalence of antibodies to anionic phospholipids in patients with the primary antiphospholipid syndrome, systemic lupus erythematosus and their relatives and spouses. Rheumatology (Oxford ) 39:42731 5. Blank M, Krause I, Fridkin M, et al. 2002. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J. Clin. Invest. 109:797804 6. Guglielmone H, Vitozzi S, Elbarcha O, et al. 2001. Cofactor dependence and isotype distribution of anticardiolipin antibodies in viral infections. Ann. Rheum. Dis. 60:5004 7. Uthman IW, Gharavi AE. 2002. Viral infections and antiphospholipid antibodies. Semin. Arthritis Rheum. 31:25663 8. Manco Johnson MJ, Nuss R, Key N, et al. 1996. Lupus anticoagulant and protein S deciency in children with postvaricella purpura fulminans or thrombosis. J. Pediatr. 128:31923 Barcat D, Constans J, Seigneur M, et al. 1998. Deep venous thrombosis in an adult with varicella. Rev. Med. Interne 19:509 11 Peyton BD, Cutler BS, Stewart FM. 1998. Spontaneous tibial artery thrombosis associated with varicella pneumonia and free protein S deciency. J. Vasc. Surg. 27:56367 Schultz DR. 1997. Antiphospholipid antibodies: basic immunology and assays. Semin. Arthritis Rheum. 26:72439 Bouma B, de Groot PG, van den Elsen JM, et al. 1999. Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids based on its crystal structure. EMBO J. 18:516674 Schwarzenbacher R, Zeth K, Diederichs K, et al. 1999. Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome. EMBO J. 18:622839 Willems GM, Janssen MP, Pelsers MM, et al. 1996. Role of divalency in the high-afnity binding of anticardiolipin antibody-beta 2 glycoprotein I complexes to lipid membranes. Biochemistry 35:1383342 Manfredi AA, Rovere P, Galati G, et al. 1998. Apoptotic cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum. 41:20514 Yasuda S, Tsutsumi A, Chiba H, et al. 2000. beta(2)-glycoprotein I deciency: prevalence, genetic background and

9.

10.

11.

12.

13.

14.

15.

16.

ANTIPHOSPHOLIPID SYNDROME effects on plasma lipoprotein metabolism and hemostasis. Atherosclerosis 152:337 46 Bancsi LF, van der Linden IK, Bertina RM. 1992. Beta 2-glycoprotein I deciency and the risk of thrombosis. Thromb. Haemost. 67:64953 Gushiken FC, Arnett FC, Thiagarajan P. 2000. Primary antiphospholipid antibody syndrome with mutations in the phospholipid binding domain of beta(2)glycoprotein I. Am. J. Hematol. 65:160 65 Sheng Y, Reddel SW, Herzog H, et al. 2001. Impaired thrombin generation in beta 2-glycoprotein I null mice. J. Biol. Chem. 276:1381721 Ma K, Simantov R, Zhang JC, et al. 2000. High afnity binding of beta 2glycoprotein I to human endothelial cells is mediated by annexin II. J. Biol. Chem. 275:1554148 de Groot PG, Horbach DA, Derksen RH. 1996. Protein C and other cofactors involved in the binding of antiphospholipid antibodies: relation to the pathogenesis of thrombosis. Lupus 5:48893 Shibata S, Harpel PC, Gharavi A, et al. 1994. Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes. Blood 83:2532 40 Garcia CO, Kanbour-Shakir A, Tang H, et al. 1997. Induction of experimental antiphospholipid antibody syndrome in PL /J mice following immunization with beta 2 GPI. Am. J. Reprod. Immunol. 37: 11824 Branch DW, Scott JR, Kochenour NK, et al. 1985. Obstetric complications associated with the lupus anticoagulant. N. Engl. J. Med. 313:132226 Blank M, Faden D, Tincani A, et al. 1994. Immunization with anticardiolipin cofactor (beta-2-glycoprotein I ) induces experimental antiphospholipid syndrome in naive mice. J. Autoimmun. 7:44155

419

17.

18.

19.

20.

21.

22.

23.

24.

25.

26. Pierangeli SS, Harris EN. 1996. In vivo models of thrombosis for the antiphospholipid syndrome. Lupus 5:45155 27. Pierangeli SS, Barker JH, Stikovac D, et al. 1994. Effect of human IgG antiphospholipid antibodies on an in vivo thrombosis model in mice. Thromb. Haemost. 71:67074 28. Olee T, Pierangeli SS, Handley HH, et al. 1996. A monoclonal IgG anticardiolipin antibody from a patient with the antiphospholipid syndrome is thrombogenic in mice. Proc. Natl. Acad. Sci. USA 93: 860611 29. George J, Afek A, Gilburd B, et al. 1997. Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies. Lupus 6:72329 30. Mosser G, Ravanat C, Freyssinet JM, et al. 1991. Sub-domain structure of lipidbound annexin-V resolved by electron image analysis. J. Mol. Biol. 217:24145 31. Voges D, Berendes R, Burger A, et al. 1994. Three-dimensional structure of membrane-bound annexin V. A correlative electron microscopy-X-ray crystallography study. J. Mol. Biol. 238:199213 32. Rand JH, Wu XX, Andree HA, et al. 1997. Pregnancy loss in the antiphospholipidantibody syndromea possible thrombogenic mechanism. N. Engl. J. Med. 337:15460 33. Vogt E, Ng AK, Rote NS. 1997. Antiphosphatidylserine antibody removes annexin-V and facilitates the binding of prothrombin at the surface of a choriocarcinoma model of trophoblast differentiation. Am. J. Obstet. Gynecol. 177:96472 34. Rand JH, Wu XX, Andree HAM, et al. 1998. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a lupus procoagulant phenomenon. Blood 92:165260 35. Rand JH, Wu XX, Giesen P. 1999. A possible solution to the paradox of the lupus anticoagulant: antiphospholipid

420

RAND antibodies accelerate thrombin generation by inhibiting annexin-V. Thromb. Haemost. 82:137677 Hanly JG, Smith SA. 2000. Anti-beta2glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome. Clin. Exp. Immunol. 120:537 43 Tomer A. 2002. Antiphospholipid antibody syndrome: rapid, sensitive, and specic ow cytometric assay for determination of anti-platelet phospholipid autoantibodies. J. Lab. Clin. Med. 139:147 54 Willems GM, Janssen MP, Comfurius P, et al. 2000. Competition of annexin V and anticardiolipin antibodies for binding to phosphatidylserine containing membranes. Biochemistry 39:198289 Bevers EM, Janssen MP, Willems GM, et al. 2000. No evidence for enhanced thrombin formation through displacement of annexin V by antiphospholipid antibodies. Thromb. Haemost. 83:79294 de-Groot PG, Horbach DA, Derksen RH. 1996. Protein C and other cofactors involved in the binding of antiphospholipid antibodies: relation to the pathogenesis of thrombosis. Lupus 5:48893 Atsumi T, Khamashta MA, Amengual O, et al. 1998. Binding of anticardiolipin antibodies to protein C via beta2glycoprotein I (beta2-GPI): a possible mechanism in the inhibitory effect of antiphospholipid antibodies on the protein C system. Clin. Exp. Immunol. 112:32533 Ames PR, Tommasino C, Iannaccone L, et al. 1996. Coagulation activation and brinolytic imbalance in subjects with idiopathic antiphospholipid antibodies a crucial role for acquired free protein S deciency. Thromb. Haemost. 76:19094 Crowther MA, Johnston M, Weitz J, et al. 1996. Free protein S deciency may be found in patients with antiphospholipid antibodies who do not have systemic lupus erythematosus. Thromb. Haemost. 76:68991 44. Esmon NL, Smirnov MD, Esmon CT. 1997. Lupus anticoagulants and thrombosis: the role of phospholipids. Haematologica 82:47477 45. Esmon NL, Safa O, Smirnov MD, et al. 2000. Antiphospholipid antibodies and the protein C pathway. J. Autoimmun. 15:22125 46. Lellouche F, Martinuzzo M, Said P, et al. 1991. Imbalance of thromboxane/prostacyclin biosynthesis in patients with lupus anticoagulant. Blood 78:289499 47. Hasselaar P, Derksen RH, Blokzijl L, et al. 1988. Thrombosis associated with antiphospholipid antibodies cannot be explained by effects on endothelial and platelet prostanoid synthesis. Thromb. Haemost. 59:8085 48. Emmi L, Bergamini C, Spinelli A, et al. 1997. Possible pathogenetic role of activated platelets in the primary antiphospholipid syndrome involving the central nervous system. Ann. NY Acad. Sci. 823:188200 49. Hughes GR, Harris NN, Gharavi AE. 1986. The anticardiolipin syndrome. J. Rheumatol. 13:48689 50. Dueymes M, Levy Y, Ziporen L, et al. 1996. Do some antiphospholipid antibodies target endothelial cells? Ann. Med. Interne Paris 147(Suppl. 1):2223 51. Matsuda J, Gotoh M, Gohchi K, et al. 1997. Anti-endothelial cell antibodies to the endothelial hybridoma cell line (EAhy926) in systemic lupus erythematosus patients with antiphospholipid antibodies. Br. J. Haematol. 97:22732 52. Navarro M, Cervera R, Teixido M, et al. 1996. Antibodies to endothelial cells and to beta 2-glycoprotein I in the antiphospholipid syndrome: prevalence and isotype distribution. Br. J. Rheumatol. 35: 52328 53. Simantov R, LaSala JM, Lo SK, et al. 1995. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J. Clin. Invest. 96:221119 54. Meroni PL, Raschi E, Camera M, et al.

36.

37.

38.

39.

40.

41.

42.

43.

ANTIPHOSPHOLIPID SYNDROME 2000. Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome. J. Autoimmun. 15:23740 Pierangeli SS, Espinola RG, Liu X, et al. 2001. Thrombogenic effects of antiphospholipid antibodies are mediated by intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and Pselectin. Circ. Res. 88:24550 Branch DW, Rodgers GM. 1993. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: a possible mechanism of thrombosis. Am. J. Obstet. Gynecol. 168:20610 Oosting JD, Derksen RH, Blokzijl L, et al. 1992. Antiphospholipid antibody positive sera enhance endothelial cell procoagulant activitystudies in a thrombosis model. Thromb. Haemost. 68:27884 Nakamura N, Ban T, Yamaji K, et al. 1998. Localization of the apoptosis-inducing activity of lupus anticoagulant in an annexin V-binding antibody subset. J. Clin. Invest. 101:195159 Combes V, Simon AC, Grau GE, et al. 1999. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J. Clin. Invest. 104:93102 Kornberg A, Renaudineau Y, Blank M, et al. 2000. Anti-beta 2-glycoprotein I antibodies and anti-endothelial cell antibodies induce tissue factor in endothelial cells. Isr. Med. Assoc. J. 2(Suppl.):2731 Martini F, Farsi A, Gori AM, Gori et al. 1996. Antiphospholipid antibodies (aPL) increase the potential monocyte procoagulant activity in patients with systemic lupus erythematosus. Lupus 5:20611 Visvanathan S, Geczy CL, Harmer JA, et al. 2000. Monocyte tissue factor induction by activation of beta 2-glycoproteinI-specic T lymphocytes is associated with thrombosis and fetal loss in patients with antiphospholipid antibodies. J. Immunol. 165:225862

421

55.

56.

57.

58.

59.

60.

61.

62.

63. Salemink I, Blezer R, Willems GM, et al. 2000. Antibodies to beta2-glycoprotein I associated with antiphospholipid syndrome suppress the inhibitory activity of tissue factor pathway inhibitor. Thromb. Haemost. 84:65356 64. Witztum JL, Horkko S. 1997. The role of oxidized LDL in atherogenesis: immunological response and anti-phospholipid antibodies. Ann. NY Acad. Sci. 811:8896 65. Horkko S, Miller E, Dudl E, et al. 1996. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein. J. Clin. Invest. 98:81525 66. Vaarala O. 1996. Antiphospholipid antibodies and atherosclerosis. Lupus 5:442 47 67. Schousboe I, Rasmussen MS. 1995. Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and antibeta 2-glycoprotein I. Thromb. Haemost. 73:798804 68. Rao LV, Hoang AD, Rapaport SI. 1996. Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipid. Blood 88:4173 82 69. Field SL, Chesterman CN, Dai YP, et al. 2001. Lupus antibody bivalency is required to enhance prothrombin binding to phospholipid. J. Immunol. 166:611825 70. Stone JH, Amend WJ, Criswell LA. 1997. Outcome of renal transplantation in systemic lupus erythematosus. Semin. Arthritis Rheum. 27:1726 71. Piette JC, Cacoub P. 1998. Antiphospholipid syndrome in the elderly: caution. Circulation 97:219596 72. Martinelli I, Cattaneo M, Panzeri D, et al. 1997. Risk factors for deep venous thrombosis of the upper extremities. Ann. Intern. Med. 126:70711 73. Provenzale JM, Ortel TL, Allen NB. 1998. Systemic thrombosis in patients

422

RAND with antiphospholipid antibodies: lesion distribution and imaging ndings. Am. J. Roentgenol. 170:28590 Girolami A, Zanon E, Zanardi S, et al. 1996. Thromboembolic disease developing during oral contraceptive therapy in young females with antiphospholipid antibodies. Blood Coagul. Fibrinolysis 7:497501 Montaruli B, Borchiellini A, Tamponi G, et al. 1996. Factor V Arg506 Gln mutation in patients with antiphospholipid antibodies. Lupus 5:3036 Schutt M, Kluter H, Hagedorn GM, et al. 1998. Familial coexistence of primary antiphospholipid syndrome and factor V Leiden. Lupus 7:17682 Brenner B, Vulfsons SL, Lanir N, et al. 1996. Coexistence of familial antiphospholipid syndrome and factor V Leiden: impact on thrombotic diathesis. Br. J. Haematol. 94:16667 Schulman S, Svenungsson E, Granqvist S. 1998. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am. J. Med. 104:332 38 Finazzi G, Brancaccio V, Moia M, et al. 1996. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am. J. Med. 100:53036 Vaidya S, Sellers R, Gugliuzza K, et al. 2001. Therapy in ESRD patients with antiphospholipid antibody syndrome. Transpl. Proc 33:125758 Shoenfeld Y, Lorber M, Yucel T, et al. 1997. Primary antiphospholipid syndrome emerging following thymectomy for myasthenia gravis: additional evidence for the kaleidoscope of autoimmunity [see comments]. Lupus 6:47476 Hofbauer LC, Spitzweg C, Heufelder AE. 1996. Graves disease associated with the primary antiphospholipid syndrome. J. Rheumatol. 23:143537 Frolow M, Jankowski M, Swadzba J, et al. 1996. Evans syndrome with antiphospholipid-protein antibodies. Pol Merkuriusz Lek 1:34445 (in Polish; abstr. in English) Chun WH, Bang D, Lee SK. 1996. Antiphospholipid syndrome associated with progressive systemic sclerosis. J. Dermatol. 23:34751 Meyer O, Nicaise P, Moreau S, et al. 1996. Antibodies to cardiolipin and beta 2 glycoprotein I in patients with polymyalgia rheumatica and giant cell arteritis. Rev. Rhum. Engl. Ed. 63:24147 Dasgupta B, Almond MK, Tanqueray A. 1997. Polyarteritis nodosa and the antiphospholipid syndrome. Br. J. Rheumatol. 36:121012 Macchi L, Rispal P, Clofent SG, et al. 1997. Anti-platelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid antibody syndrome: their relationship with the observed thrombocytopenia. Br. J. Haematol. 98:33641 Panzer S, Gschwandtner ME, Hutter D, et al. 1997. Specicities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome. Ann. Hematol. 74:23942 Galli M, Finazzi G, Barbui T. 1996. Thrombocytopenia in the antiphospholipid syndrome. Br. J. Haematol. 93:15 Lipp E, von-Felten A, Sax H, et al. 1998. Antibodies against platelet glycoproteins and antiphospholipid antibodies in autoimmune thrombocytopenia. Eur. J. Haematol. 60:28388 Asherson RA, Cervera R, Piette JC, et al. 1998. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 77:195207 The Antiphospholipid Antibodies and Stroke Study Group (APASS). 1997. Anticardiolipin antibodies and the risk of

83.

74.

84.

75.

85.

76.

86.

77.

87.

78.

88.

79.

89.

90.

80.

81.

91.

92.

82.

ANTIPHOSPHOLIPID SYNDROME recurrent thrombo-occlusive events and death. Neurology 48:9194 Tuhrim S, Rand JH, Wu XX, et al. 1999. Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 30:156165 Weingarten K, Filippi C, Barbut D, et al. 1997. The neuroimaging features of the cardiolipin antibody syndrome. Clin. Imaging 21:612 Ravelli A, Martini A. 1997. Antiphospholipid antibody syndrome in pediatric patients. Rheum. Dis. Clin. North Am. 23:65776 Baca V, Garcia RR, Ramirez LM, et al. 1996. Cerebral infarction and antiphospholipid syndrome in children. J. Rheumatol. 23:142831 Levine SR, Salowich-Palm L, Sawaya KL, et al. 1997. IgG anticardiolipin antibody titer >40 GPL and the risk of subsequent thrombo-occlusive events and death. A prospective cohort study. Stroke 28:166065 Carhuapoma JR, Mitsias P, Levine SR. 1997. Cerebral venous thrombosis and anticardiolipin antibodies. Stroke 28:2363 69 Dunn JP, Noorily SW, Petri M, et al. 1996. Antiphospholipid antibodies and retinal vascular disease. Lupus 5:31322 Coniglio M, Platania A, Di Nucci GD, et al. 1996. Antiphospholipid-protein antibodies are not an uncommon feature in retinal venous occlusions. Thromb. Res. 83:18388 Abu-el AA, al-Momen AK, al-Amro S, et al. 1996. Prothrombotic states associated with retinal venous occlusion in young adults. Int. Ophthalmol. 20:197 204 Glacet BA, Bayani N, Chretien P, et al. 1994. Antiphospholipid antibodies in retinal vascular occlusions. A prospective study of 75 patients. Arch. Ophthalmol. 112:79095 Niaz A, Butany J. 1998. Antiphospholipid

423

93.

104.

94.

105.

95.

106.

96.

107.

97.

108.

98.

109.

99.

100.

110.

101.

111.

102.

112.

103.

antibody syndrome with involvement of a bioprosthetic heart valve. Can. J. Cardiol. 14:95154 Bouillanne O, Millaire A, de Groote P, et al. 1996. Prevalence and clinical significance of antiphospholipid antibodies in heart valve disease: a case-control study. Am. Heart. J. 132:79095 Nesher G, Ilany J, Rosenmann D, et al. 1997. Valvular dysfunction in antiphospholipid syndrome: prevalence, clinical features, and treatment. Semin. Arthritis Rheum. 27:2735 Garcia TR, Amigo MC, de-la-Rosa A, et al. 1996. Valvular heart disease in primary antiphospholipid syndrome (PAPS): clinical and morphological ndings. Lupus 5:5661 Ziporen L, Goldberg I, Arad M, et al. 1996. Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic ndings in deformed heart valves. Lupus 5:196205 Paydas S, Kocak R, Zorludemir S, et al. 1997. Bone marrow necrosis in antiphospholipid syndrome. J. Clin. Pathol. 50: 26162 Marie I, Levesque H, Heron F, et al. 1997. Acute adrenal failure secondary to bilateral infarction of the adrenal glands as the rst manifestation of primary antiphospholipid antibody syndrome [letter]. Ann. Rheum. Dis. 56:56768 Caron P, Chabannier MH, Cambus JP, et al. 1998. Denitive adrenal insufciency due to bilateral adrenal hemorrhage and primary antiphospholipid syndrome. J. Clin. Endocrinol. Metab. 83:143739 Hsu B, Udden MM, Lynch EC. 1997. Autoimmune hemolytic anemia, primary adrenal insufciency, and the antiphospholipid syndrome. Am. J. Med. Sci 314: 4143 Naarendorp M, Spiera H. 1998. Sudden sensorineural hearing loss in patients with systemic lupus erythematosus or lupuslike syndromes and antiphospholipid antibodies. J. Rheumatol. 25:58992

424

RAND antibody isotype distribution in 3 geographic populations of patients with systemic lupus erythematosus. J. Rheumatol. 24:29196 Colaco CB, Male DK. 1985. Antiphospholipid antibodies in syphilis and a thrombotic subset of SLE: distinct proles of epitope specicity. Clin. Exp. Immunol. 59:44956 Branch DW, Rote NS, Dostal DA, et al. 1987. Association of lupus anticoagulant with antibody against phosphatidylserine. Clin. Immunol. Immunopathol. 42:6375 Harris EN. 1990. Antiphospholipid antibodies. Br. J. Haematol. 74:19 Alarcon-Segovia D, Mestanza M, Cabiedes J, et al. 1997. The antiphospholipid/cofactor syndromes. II. A variant in patients with systemic lupus erythematosus with antibodies to beta 2-glycoprotein I but no antibodies detectable in standard antiphospholipid assays. J. Rheumatol. 24:154551 Sanmarco M, Soler C, Christides C, et al. 1997. Prevalence and clinical signicance of IgG isotype anti-beta 2-glycoprotein I antibodies in antiphospholipid syndrome: a comparative study with anticardiolipin antibodies. J. Lab. Clin. Med. 129:499 506 Puurunen M, Vaarala O, Julkunen H, et al. 1996. Antibodies to phospholipidbinding plasma proteins and occurrence of thrombosis in patients with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 80:1622 Galli M. 2000. Should we include antiprothrombin antibodies in the screening for the antiphospholipid syndrome? J. Autoimmun. 15:1015 Galli M, Barbui T. 1998. Prothrombin as cofactor for antiphospholipids. Lupus 7(Suppl. 2):S3740 Urfer C, Pichler WJ, Helbling A. 1996. Antiphospholipid antibodies syndrome: follow-up of patients with a high antiphospholipid antibodies titer. Schweiz. Med. Wochenschr. 126:213640

113. Brandt JT, Triplett DA, Alving B, et al. 1995. Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientic and Standardisation Committee of the ISTH. Thromb. Haemost. 74:1185 90 114. Vivaldi P, Rossetti G, Galli M, et al. 1997. Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome. Case report and review of literature. Haematologica 82:34547 115. Ginsberg JS, Wells PS, Brill-Edwards P, et al. 1995. Antiphospholipid antibodies and venous thromboembolism. Blood 86:368591 116. Wahl DG, Guillemin F, De-Maistre E, et al. 1998. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 7:1522 117. Thiagarajan P, Pengo V, Shapiro SS. 1986. The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants. Blood 68:86974 118. Kitchens CS. 1988. Prolonged activated partial thromboplastin time of unknown etiology: a prospective study of 100 consecutive cases referred for consultation. Am. J. Hematol. 27:3845 119. Shah NM, Khamashta MA, Atsumi T, et al. 1998. Outcome of patients with anticardiolipin antibodies: a 10 year followup of 52 patients. Lupus 7:36 120. Silver RM, Porter TF, van Leeuween I, et al. 1996. Anticardiolipin antibodies: clinical consequences of low titers. Obstet. Gynecol. 87:494500 121. Selva-OCallaghan A, Ordi-Ros J, Monegal-Ferran F, et al. 1998. IgA anticardiolipin antibodiesrelation with other antiphospholipid antibodies and clinical signicance. Thromb. Haemost. 79: 28285 122. Molina JF, Gutierrez US, Molina J, et al. 1997. Variability of anticardiolipin

123.

124.

125. 126.

127.

128.

129.

130.

131.