76

Antiphospholipid Syndrome
Doruk Erkan JanE E. Salmon michaEl D. lockShin

KEY POINTS
Antiphospholipid antibodies (aPLs) are a family of autoantibodies directed against phospholipid-binding plasma proteins, most commonly 2-glycoprotein I. The origin of aPLs is unknown but is hypothesized to be an incidental exposure to infectious agents that induce autoantibodies in susceptible individuals. The clinical manifestations of aPLs range from asymptomatic to catastrophic antiphospholipid syndrome (APS); thus, patients should not be evaluated and managed as if they had a single disease. Stroke is the most common presentation of arterial thrombosis; deep vein thrombosis is the most common venous manifestation of APS. Pregnancy losses in patients with aPLs typically occur after 10 weeks gestation (fetal loss), but earlier losses also occur. Catastrophic APS is a rare, abrupt, life-threatening complication that consists of multiple thromboses of medium and small arteries occurring over days. The diagnosis of APS should be made in the presence of characteristic clinical manifestations and persistently positive aPLs (measured at least 12 weeks apart). The prevention of secondary thrombosis in persistently aPL-positive individuals lacks a risk-stratified approach; the effectiveness of high-intensity anticoagulation in APS patients with vascular events is not supported by prospective controlled studies. A common strategy to prevent fetal loss in aPL-positive patients with a history of pregnancy morbidities is low-dose aspirin and heparin; if patients fail this regimen, the next step is to add intravenous immunoglobulin (IVIG), although this approach is not supported by controlled studies. Prevention of primary thrombosis in persistently aPL-positive individuals lacks an evidence-based approach; elimination of reversible thrombosis risk factors and prophylaxis during high-risk periods (e.g., surgical procedures) are crucial. Currently, there is no evidence that anticoagulation is effective for nonthrombotic manifestations of aPLs, such as livedo reticularis, thrombocytopenia, hemolytic anemia, or heart valve disease. Catastrophic APS patients usually receive a combination of anticoagulation, corticosteroids, IVIG, and plasma exchange.

DEFINITION
Diagnosis of the antiphospholipid syndrome (APS) requires that a patient have both a clinical event (thrombosis or pregnancy morbidity) and the persistent presence of antiphospholipid antibody (aPL), documented by a solid-phase serum assay (anticardiolipin or anti2-glycoprotein I [anti-2GPI] immunoglobulin [Ig] G or M), a coagulation assay (inhibitor of phospholipid-dependent clottingthe lupus anticoagulant test), or both. Preliminary (Sapporo) classification criteria for APS,1 revised in 2004,2 are listed in Table 76-1. Certain factors are not included as criteria but may be helpful in the diagnosis of individual patients. These include IgA anticardiolipin or anti-2GPI, valvular heart disease, thrombocytopenia, early preeclampsia, and livedo reticularis (Table 76-2). These factors are rare, nonstandardized, or nonspecific phenomena that are too unreliable for use in clinical studies but occur in a sufficient number of patients to support a suspected diagnosis. A false-positive test for syphilis does not fulfill the laboratory criterion. APS can occur as an isolated diagnosis, or it can be associated with systemic lupus erythematosus (SLE) or another rheumatic disease. Antiphospholipid antibodies, but probably not the syndrome, can be induced by drugs and infections.3

EPIDEMIOLOGY
Low-titer, usually transient, anticardiolipin occurs in up to 10% of normal blood donors,4,5 and moderate- to high-titer anticardiolipin or a positive lupus anticoagulant test occurs in less than 1%. The prevalence of positive aPL tests increases with age. Ten percent to 40% of SLE patients5 and approximately 20% of rheumatoid arthritis patients6 have positive aPL tests. Based on a limited number of uncontrolled and nonriskstratified studies, asymptomatic (no history of vascular or pregnancy events) aPL-positive patients have a 0% to 4% annual risk of thrombosis; patients with other autoimmune diseases such as SLE are at the higher end of the range.7,8 The aPL profile (low versus high risk for thrombosis) and patients clinical characteristics (presence or absence of other acquired or genetic thrombosis risk factors) influence the individual risk of thrombosis.9 Ten percent of first-stroke victims have aPLs,10 especially those who are young (up to 29%),5,11 as do up to 20% of women who have suffered three or more consecutive fetal losses.12 Fourteen percent of patients with recurrent venous thromboembolic disease have aPLs.13

CAUSE
The main antigen to which aPLs bind is not a phospholipid but rather a phospholipid-binding plasma proteinnamely, 2GPI (apolipoprotein H). 2GPI is normally present at a
Supplemental images available on the Expert Consult Premium Edition website.

1301

1302

Erkan

antiphospholipid syndromE

Table 76-1 revised sapporo Classification Criteria for antiphospholipid syndrome

Clinical Criteria 1. Vascular thrombosis* one or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. 2. pregnancy morbidity (a) one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or (b) one or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency, or (c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded. Laboratory Criteria 1. lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the international society on thrombosis and hemostasis 2. anticardiolipin antibody of immunoglobulin (ig) G or igm isotype in serum or plasma, present in medium or high titer (>40 Gpl or mpl, or >99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (Elisa). 3. anti2-glycoprotein i antibody of igG or igm isotype in serum or plasma (in titer >99th percentile) present on two or more occasions at least 12 weeks apart, measured by a standardized Elisa. definite antiphospholipid syndrome (aps) is present if at least one of the clinical criteria and one of the laboratory criteria are met. Classification of aps should be avoided if less than 12 weeks or more than 5 years separate the positive antiphospholipid antibody test and the clinical manifestation. in studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above. *Coexisting inherited or acquired factors for thrombosis are not reasons to exclude patients from APS trials. However, two subgroups of APS patients should be recognized, based on the presence and absence of additional risk factors for thrombosis. Indicative (but not exhaustive) cases include age (>55 yr in men and >65 yr in women) and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated low-density lipoprotein or low high-density lipoprotein cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index >30 kg/m2, microalbuminuria, estimated glomerular filtration rate <60 mL/min), inherited thrombophilias, oral contraceptive use, nephritic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfill criteria should be stratified according to contributing causes of thrombosis. A thrombotic episode in the past can be considered a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found. Superficial venous thrombosis is not included in the clinical criteria. Generally accepted features of placental insufficiency include an abnormal or nonreassuring fetal surveillance test (e.g., nonreactive nonstress test) suggestive of fetal hypoxemia, an abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-diastolic flow in the umbilical artery), oligohydramnios (e.g., amniotic fluid index 5 cm), or a postnatal birth weight less than the 10th percentile for gestational age. Investigators are strongly advised to classify APS patients participating in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, only lupus anticoagulant present; IIb, only anticardiolipin antibody present; IIc, only anti-2-glycoprotein I antibody present. From Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 4:295-306, 2006.

Table 76-2 other Features suggesting the presence of antiphospholipid antibodies

Clinical livedo reticularis thrombocytopenia (usually 50,000-100,000 platelets/mm3) autoimmune hemolytic anemia Cardiac valve disease (vegetations or thickening) multiple sclerosislike syndrome, chorea, or other myelopathy Laboratory immunoglobulin a anticardiolipin antibody immunoglobulin a anti2-glycoprotein i

concentration of 200 mg/mL, is a member of the complement control protein family, and has five repeating domains and several alleles. An octapeptide in the fifth domain and critical cysteine bonds are necessary for both phospholipid binding and antigenicity14; a first-domain site activates platelets.15,16 In vivo, 2GPI binds to phosphatidylserine on activated or apoptotic cell membranes, including those of trophoblasts, platelets, and endothelial cells. Under physiologic conditions, 2GPI may function in the elimination of apoptotic cells17 and as a natural anticoagulant.18 Other, less relevant antigens targeted by aPLs are prothrombin, annexin V, protein C, protein S, high- and lowmolecular-weight kininogens, tissue plasminogen activator, factor VII, factor XI, factor XII, complement component C4, and complement factor H.19 In experimental animal models, passive or active immunization with viral peptides,20 bacterial peptides,21 and heterologous 2GPI22 induces polyclonal aPLs and clinical events associated with APS. These data suggest that pathologic autoimmune aPL is induced in susceptible humans by infections via molecular mimicry. However, infection-induced aPLs (syphilitic and nonsyphilitic Treponema, Borrelia burgdorferi, human immunodeficiency virus, Leptospira, or parasites) are usually 2GPI independent and bind phospholipids directly.23 Drugs (chlorpromazine, procainamide, quinidine, and phenytoin) and malignancies (lymphoproliferative disorders) can also induce 2GPI-independent aPLs. Conversely, autoimmune aPLs bind 2GPI or other phospholipid-binding plasma proteins, which in turn bind negatively charged phospholipids such as cardiolipin (2GPI-dependent aPLs). Low levels of aPLs may be present normally; one of the functions of normal aPLs may be to participate in the physiologic removal of oxidized lipids.

PATHOGENESIS
Antiphospholipid antibody is most likely related to thrombosis through multiple mechanisms; a proposed pathogenesis is illustrated in Figure 76-1. The process begins with activation or apoptosis of platelets, endothelial cells, or trophoblasts, during which phosphatidylserine (a negatively charged phospholipid) migrates from the inner to the normally electrically neutral outer cell membrane. Circulating 2GPI binds to phosphatidylserine, and then aPL binds to a 2GPI dimer.24 Antiphospholipid antibody2GPI dimer binding activates the complement cascade extracellularly; initiates an

part 11

systEmiC lUpUs ErythEmatosUs and rElatEd syndromEs

1303

C5aR C5a C5aR Platelet Monocyte aPL

C5aR

PMN 2-GPI surface receptor? Outer layer 2-GPI Adhesion molecules TF TNF-

PS PC Inner layer p38MAPK NFB Cell activation Nucleus Figure 76-1 Proposed mechanism of antiphospholipid antibody (aPL)related thrombosis and placental injury. the negatively charged phospholipid phosphatidylserine (ps, yellow circles) migrates from the inner to the outer cell membrane during activation or apoptosis of platelets and endothelial cells, and it is normally present on trophoblasts. the neutral phospholipid phosphatidylcholine (pC, red circles) is the major constituent of the outer layer of unactivated cells. dimeric 2-glycoprotein i (2Gpi) then binds to ps (probably via 2Gpi surface receptors such as apoEr2, annexin a2, or a toll-like receptor), and apl binds to 2Gpi, activating the classic complement pathway and leading to the generation of C5a, which induces (a) expression of adhesion molecules (e.g., intracellular adhesion molecule [iCam]-1) and tissue factor [tF]) and (b) activation of monocytes, polymorphonuclear (pmn) cells, and platelets, resulting in the release of proinflammatory mediators (e.g., tumor necrosis factor [tnF]-, vascular endothelial growth factor receptor-1 [VEGFr1]) and the prothrombotic stage. Both nuclear factor B (nFB) and p38 mitogen-activated protein kinase (p38mapk) may play a role in the intracellular signaling cascade. antiphospholipid antibodies also downregulate the expression of trophoblast signal transducer and activator of transcription 5 (stat-5), reducing the endometrial stromal cell production of prolactin (prl) and insulin growth factor binding protein-1 (iGFBp-1). IGFBP-1 PRL STAT-5 Inflammation Tissue damage Fetal death Thrombus

intracellular signaling cascade, probably through the C5a and 2GPI surface receptors; and recruits and activates inflammatory effector cells, including monocytes, neutrophils, and platelets, leading to the release of proinflammatory products (e.g., tumor necrosis factor [TNF]-, oxidants, proteases) and the induction of a prothrombotic phenotype.25-27 The putative receptor of 2GPI binding protein that transduces signals from the cell membrane to the nucleus is not yet identified and may vary among cells. The following candidates have been suggested: apoER2 (a member of the low-density lipoprotein receptor superfamily), annexin A2, and a Toll-like receptor.28,29 Both nuclear factor B and p38 mitogen-activated protein kinase may play a role in the intracellular signaling cascade30,31 In addition, through downregulation of the signal transducer and activator of transcription 5 (Stat5), aPLs inhibit the production of placental prolactin and insulin growth factor binding protein-1,32 and they adversely affect the formation of a trophoblast syncytium, placental apoptosis, and trophoblast invasionall processes that are required for the normal establishment of placental function.

Other possible contributory mechanisms of aPL-mediated thrombosis include inhibition of coagulation cascade reactions catalyzed by phospholipids (e.g., activation of circulating procoagulant proteins or inhibition of protein C and S activation), induction of tissue factor (a physiologic initiator of coagulation) expression on monocytes, reduction of fibrinolysis, and interaction with the annexin V anticoagulant shield in the placenta.29 In experimental animal models, aPLs cause fetal resorption and increase the size and duration of trauma-induced venous and arterial thrombi.33,34 Inhibiting complement activation prevents experimental aPL-induced fetal death, and C5 knockout mice carry pregnancies normally despite aPL,35 implying that a complement-mediated effector mechanism is an absolute requirement for fetal death to occur. Complement activation is also required for experimental thrombosis.36 Because high-level aPLs may persist for years in asymptomatic persons, it is likely that vascular injury, endothelial cell activation, or both immediately precede the occurrence of thrombosis in those bearing the antibody (second-hit

1304

Erkan

antiphospholipid syndromE

hypothesis). Of note, at least 50% of APS patients with vascular factors possess other acquired thrombosis risk factors at the time of their events.37,38 Both persons congenitally lacking 2GPI39 and 2GPI knockout mice appear normal.40 2GPI polymorphisms influence the generation of aPLs in individuals, but they have only a weak relationship to the occurrence of APS.41 A cluster of 50 upregulated genes may have an effect on the occurrence of thrombosis in aPL-positive individuals.42

CLINICAL FEATURES
The clinical manifestations range from asymptomatic aPL positivity (no history of vascular or pregnancy events) to catastrophic APS (multiple thromboses occurring over days). Thus, patients should not be evaluated and managed as if they have a single disease. VASCULAR OCCLUSION APS affects all organ systems. Its principal manifestations are venous or arterial thromboses and pregnancy loss (see Table 76-1). Except for their severity, the youth of affected patients, and the unusual anatomic locations (Budd-Chiari syndrome; sagittal sinus and upper extremity thromboses), venous thromboses in APS do not differ clinically from thromboses attributable to other causes. Similarly, arterial thromboses differ from nonaPL-associated thromboses only by their recurrent nature, unusual locations, and occurrence in young patients. Deep vein thrombosis and stroke are the most common clinical manifestations of APS. Renal thrombotic microangiopathy, glomerular capillary endothelial cell injury, and thrombosis of renal vessels cause proteinuria without celluria or hypocomplementemia and may lead to severe hypertension, renal failure, or both.43 PREGNANCY MORBIDITY Pregnancy losses in patients with aPLs typically occur after 10 weeks gestation (fetal loss), although earlier losses also occur. However, these pre-embryonic or embryonic pregnancy losses (<10 weeks gestation) are more commonly due to chromosomal and other genetic defects. Pregnancy in those with APS is often normal until the second trimester, when fetal growth slows and amniotic fluid volume decreases. APS patients may develop severe, early preeclampsia or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Placental infarction is a cause of fetal growth restriction or death; nonthrombotic mechanisms of placental dysfunction also occur.44 Prior late pregnancy losses predict future losses, independent of the aPL profile. MISCELLANEOUS MANIFESTATIONS Many patients have livedo reticularis (Fig. 76-2), although this is not specific for APS. Cardiac valve disease (vegetations, thickening, or both), a late manifestation, may necessitate valve replacement. Its pathogenesis in APS is unknown. Recent studies suggest that APS does not add to the risk of atherosclerosis imparted by SLE.45 Pulmonary hypertension may develop due to recurrent pulmonary
Figure 76-2 livedo reticularis in antiphospholipid syndrome.

embolism or small vessel thrombosis; rarely, aPL-positive patients may present with diffuse pulmonary hemorrhage. Some patients develop nonfocal neurologic symptoms such as lack of concentration, forgetfulness, and dizzy spells. Multiple small, hyperintense lesions seen on magnetic resonance imaging (MRI), primarily in the periventricular white matter, do not correlate well with clinical symptoms. Rarely, high-affinity antiprothrombin antibodies may cause hemorrhage by depleting prothrombin (lupus anticoagulant hypoprothrombinemia syndrome).46 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME Catastrophic APS is a rare, abrupt, life-threatening complication. It consists of multiple thromboses of medium and small arteries occurring (despite apparently adequate anticoagulation) over a period of days and causing stroke; cardiac, hepatic, adrenal, renal, and intestinal infarction; and peripheral gangrene.4,47 In a review of 220 patients with catastrophic APS, the main clinical manifestations included renal involvement in 154 patients (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%).48 Acute adrenal failure may be the initial clinical event. Proposed formal criteria for this syndrome are shown in Table 76-3.49 Patients often have moderate thrombocytopenia; erythrocytes are less fragmented than in the hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, and fibrin split products are not strikingly elevated. Renal failure and pulmonary hemorrhage may occur. Tissue biopsies show noninflammatory vascular occlusion.

DIAGNOSIS AND DIAGNOSTIC TESTS

LABORATORY STUDIES The diagnosis of APS requires a positive lupus anticoagulant test or a moderate- to high-titer anticardiolipin IgG or IgM test in patients with characteristic clinical manifestations. Patients with negative lupus anticoagulant and anticardiolipin tests should be tested for IgA anticardiolipin and IgG, IgM, or IgA anti-2GPI when there is a high suspicion for APS. Positive aPL results require a repeat test after 12 or more weeks to exclude a transient, clinically unimportant

part 11

systEmiC lUpUs ErythEmatosUs and rElatEd syndromEs

1305

Table 76-3 preliminary Criteria for the Classification of Catastrophic antiphospholipid syndrome (aps)
1. Evidence of involvement of three or more organs, systems, or tissues* 2. development of manifestations simultaneously or in less than 1 wk 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue 4. laboratory confirmation of the presence of antiphospholipid antibody (lupus anticoagulant or anticardiolipin or anti2glycoprotein i antibodies) Definite Catastrophic APS all 4 criteria Probable Catastrophic APS Criteria 2 through 4 and two organs, systems, or tissues involved Criteria 1 through 3, except no confirmation 6 wk apart due to early death of patient not tested before catastrophic episode Criteria 1, 2, and 4 Criteria 1, 3, and 4 and development of a third event more than 1 wk but less than 1 mo after the first, despite anticoagulation *Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension, proteinuria, or some combination of these. For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally. If the patient had not previously been diagnosed with APS, laboratory confirmation requires that the presence of antiphospholipid antibody be detected on two or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of APS. From Asherson RA, Cervera R, de Groot PG, et al: Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus 12:530-534, 2003.

noncardiolipin phospholipids (phosphatidylserine, phosphatidylethanolamine) have no proven relationship to APS. The ELISA tests other than anticardiolipin and anti-2GPI are neither standardized nor widely accepted as predictors of clinical illness. Whether to test persons with venous occlusive disease or recurrent fetal loss simultaneously for protein C, protein S, and antithrombin III deficiency or for the factor V Leiden and prothrombin mutations is a matter of economics and clinical likelihood; such testing is advisable when feasible. It is useful to test persons with arterial occlusive disease for hyperhomocysteinemia. Antinuclear and anti-DNA antibodies occur in approximately 45% of patients clinically diagnosed as having primary APS without an accompanying illness55; these antibodies do not mandate the additional diagnosis of SLE if the patient has no clinical indicators of SLE. Thrombocytopenia in APS is usually modest (>50,000/mm3); proteinuria and renal insufficiency occur in patients with thrombotic microangiopathy. Pathologic examination demonstrates small artery and glomerular thrombi and recanalization (Fig. 76-3). Hypocomplementemia, erythrocyte casts, and pyuria are not characteristic of thrombotic microangiopathy and, when present, imply lupus glomerulonephritis. Erythrocyte sedimentation rate, hemoglobin, and leukocyte count are usually normal in patients with uncomplicated primary APS, except during acute thrombosis. Prothrombin fragment 1 + 2 and other markers of coagulation activation do not predict impending thrombosis. IMAGING STUDIES MRI shows vascular occlusion and infarction consistent with clinical symptoms, with no special characteristics (other than multiple, otherwise unexplained cerebral infarctions in a young person). Multiple small, hyperintense white-matter lesions are common and do not unequivocally imply brain infarction. Occlusions usually occur in vessels below the resolution limits of angiography; hence, angiography or magnetic resonance angiography is not indicated unless clinical findings suggest medium- or large-vessel disease. Echocardiography or cardiac MRI may show severe Libman-Sacks endocarditis and intracardiac thrombi.56 PATHOLOGY Skin, renal, and other tissues show noninflammatory occlusion of all caliber arteries and veins, acute and chronic endothelial injury and its sequelae, and recanalization in late lesions. Uteroplacental insufficiency was once thought to be due to thrombosis or spiral artery vasculopathy (atherosis, intimal thickening, fibrinoid necrosis, and absence of physiologic changes in the spiral arteries).57 Consistent with the importance of inflammation in murine models of APS, recent findings demonstrate inflammatory infiltrates, particularly macrophages, and suggest that inflammation contributes to placental injury in patients.58 The finding of necrotizing vasculitis suggests concomitant lupus or other connective tissue disease. There are no other diagnostic immunofluorescence or electron microscopic findings.

antibody. The diagnosis of APS should be questioned if less than 12 weeks or more than 5 years separate the positive aPL test from the clinical manifestation.2 The lupus anticoagulant test is a more specific but less sensitive predictor of thromboses than is anticardiolipin; it correlates better with aPL-related clinical events.50 Documentation of a lupus anticoagulant requires a fourstep process: (1) demonstration of a prolonged phospholipid-dependent coagulation screening test, such as activated partial thromboplastin time or dilute Russell viper venom time (however, low-level abnormalities are not clearly linked to APS); (2) failure to correct the prolonged screening test by mixing the patients plasma with normal platelet-poor plasma, demonstrating the presence of an inhibitor; (3) shortening or correction of the prolonged screening test by the addition of excess phospholipid, demonstrating phospholipid dependency; and (4) exclusion of other inhibitors.51 Approximately 80% of patients with lupus anticoagulant have anticardiolipin, and 20% of patients positive for anticardiolipin have lupus anticoagulant.52 The anticardiolipin enzyme-linked immunosorbent assay (ELISA) is sensitive but not specific for the diagnosis of APS.53 Although the widely available ELISA test for IgG and IgM anticardiolipin is standardized, considerable variability exists among commercial laboratories that perform the test, especially for the IgA isotype.54 Low-titer anticardiolipin or anti-2GPI, transient aPLs, and antibody to

1306

Erkan

antiphospholipid syndromE

Figure 76-3 Renal thrombotic microangiopathy in antiphospholipid syndrome (APS). A, kidney biopsy from a 35-year-old woman with primary aps, microhematuria, and non-nephrotic proteinuria. the glomerulus contains microthrombi, occluding capillary lumina, and there is endothelial swelling. B, the same patients small renal artery contains organized thrombus, with recanalization and arteriosclerosis (periodic acidschiff, 100). C, autopsy specimen from a 45-year-old man with primary aps. note the thrombus in various stages of organization, intact elastic lamina with focal reduplication, and medial thickening (elastic Verhoeff stain, 100). D, the same patients medium-sized peripheral artery. note the organized thrombus with recanalization, severe fibrointimal thickening, medial hypertrophy, and extreme stenosis of lumen (hematoxylin and eosin, 75). (Courtesy of Dr. Surya V. Seshan.)

DIFFERENTIAL DIAGNOSIS Infection-induced anticardiolipin is usually transient and is more commonly IgM than IgG.59 Transient aPLs or lowtiter anticardiolipin is inconclusive for diagnosis. Research laboratories can distinguish autoimmune from infectioninduced aPLs by determining the antibodys 2GPI dependence. In a patient who has lupus or lupus-like disease, livedo reticularis, or long-standing thrombocytopenia and who has a persistently positive aPL test, it is usually unnecessary to exclude other diagnoses. Because the prevalence of aPL-positive ELISA tests increases with age, and because the differential diagnosis of vascular occlusion is broader than it is in young adults, particular care is necessary in diagnosing APS in patients older than 60 years. Sustained high-titer anticardiolipin IgG, livedo reticularis, thrombocytopenia, coexisting rheumatic disease, and absence of other causes support a diagnosis of APS. Five percent to 21% of women with recurrent pregnancy losses, and 0.5% to 2% of normal pregnant women, have aPLs. Heritable deficiency of protein C, protein S, and antithrombin III and the presence of the factor V Leiden (A506G), prothrombin (G20210A), and methylene tetrahydrofolate reductase (MTHFR, C677T) mutations are less

common causes of fetal loss.60 Attribution of pregnancy loss to APS is most certain when there is no coexisting plausible explanation, when the loss occurs after the demonstration of a fetal heartbeat (10 weeks), when a significant aPL profile is repeatedly positive before and after pregnancy, and when the placenta shows vasculopathy and infarction. A single pregnancy loss before 10 weeks gestation in a patient with a lowpositive anticardiolipin test is more likely to be attributable to fetal chromosomal abnormalities, infection, or maternal hormonal or anatomic abnormalities. Independent coagulopathies may further increase the thrombotic risk in patients with aPLs. These and other acquired thrombotic risk factors (hypertension, diabetes, nephrotic syndrome, venous insufficiency, immobility) are alternative causes of thromboembolic disease. Arterial occlusion occurs in patients with thrombotic thrombocytopenic purpura, infected or sterile emboli of cardiac or vascular origin, septicemia, hyperhomocysteinemia, myxoma, Takayasus arteritis, polyarteritis nodosa, and severe Raynauds disease. The relationship of Sneddons syndrome (stroke and livedo reticularis, with or without aPLs) to APS is uncertain. Catastrophic APS has few mimics. Among them are sepsis, disseminated intravascular coagulation, thrombotic

part 11

systEmiC lUpUs ErythEmatosUs and rElatEd syndromEs

1307

thrombocytopenic purpura, hemolytic uremic syndrome, polyarteritis nodosa, and disseminated embolization from myxoma, atrial thrombus, or atherosclerotic plaque. Small vessel occlusions occurring in rapid succession suggest disseminated intravascular coagulation. Severe cerebral and renal disease suggests thrombotic thrombocytopenic purpura; renal failure and hemolysis suggest hemolytic uremic syndrome. Antiphospholipid antibodies are rarely present in patients with the alternative diagnoses. Acute adrenal insufficiency is characteristic of APS and WaterhouseFriderichsen syndrome.

Table 76-4 treatment recommendations for persistently antiphospholipid antibodypositive individuals

Clinical Circumstance asymptomatic Venous thrombosis arterial thrombosis recurrent thrombosis Recommendation no treatment* Warfarin inr 2.5 indefinitely Warfarin inr 2.5 indefinitely Warfarin inr 3 to 4 + low-dose aspirin

TREATMENT
THROMBOSIS Treatment recommendations are summarized in Table 76-4. Anticoagulation with heparin is the treatment for acute thrombosis in APS patients. Warfarin, occasionally in association with low-dose aspirin, is used for secondary thrombosis prophylaxis. Two randomized, controlled trials demonstrated that moderate warfarin (international normalized ratio [INR] 2 to 3) and high-intensity warfarin (INR 3 to 4) are equally protective against recurrence in APS patients after the first thrombosis.61,62 The intensity of anticoagulation for aPL-related arterial thrombosis is still a matter for debate, because in both studies, patients with arterial events constituted less than half the study population. Although APS patients with arterial thrombosis who are at high risk for recurrence may require high-intensity anticoagulation, in the absence of risk-stratified studies, high risk has no consensus definition and is currently based solely on clinical judgment. Aspirin is the standard of care after an ischemic stroke or transient ischemic attack to prevent a recurrence in aPLnegative patients. Although most aPL-positive patients with ischemic strokes receive warfarin, the Antiphospholipid Antibody in Stroke Study (APASS) concluded that for selected aPL-positive patients who do not have atrial fibrillation or high-grade stenosis, aspirin and warfarin (target INR 2.2) are equivalent in terms of both efficacy and major bleeding complications.63 The APASS results probably do not apply to conventionally defined APS, because the average age of study participants was much higher than that of the average APS population; in addition, the aPL determination was performed only once at study entry, and the titer cutoff for assigning a patient to the positive anticardiolipin group was very low. However, aspirin is an option for older aPL-positive patients who have a single low-titer anticardiolipin test and whose presentation is one stroke. Some patients require larger than expected doses of both heparin and warfarin to achieve therapeutic anticoagulation. Uncommonly, positive lupus anticoagulant tests cause the INR to be unreliable.64 Such patients may be treated with high-dose warfarin or unfractionated or lowmolecular-weight heparin, monitored by the measurement of antifactor Xa activity or other appropriate assay. For well-anticoagulated patients who continue to have thromboses, aspirin (81 to 325 mg/day), hydroxychloroquine, a statin drug, intravenous immunoglobulin (IVIG), and plasmapheresis have theoretical bases for efficacy, and all have been used.65 Corticosteroids have no established role in the treatment of APS but are used for rheumatic

pregnancy First pregnancy no treatment* single pregnancy loss at no treatment* <10 wk 1 Fetal or 3 (pre) embryonic prophylactic heparin + low-dose loss, no thrombosis aspirin throughout pregnancy, discontinue 6-12 wk post partum thrombosis regardless of therapeutic heparin or low-dose pregnancy history aspirin throughout pregnancy, warfarin post partum Valve nodules or deformity no known effective treatment; full anticoagulation if emboli or intracardiac thrombi demonstrated

thrombocytopenia >50,000/mm3 no treatment thrombocytopenia <50,000/mm3 prednisone, iViG Catastrophic aps anticoagulation + corticosteroids + iViG or plasmapheresis

*Aspirin (81 mg/day) may be given. Enoxaparin 0.5 mg/kg subcutaneously once daily. Enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily. APS, antiphospholipid syndrome; INR, international normalized ratio; IVIG, intravenous immunoglobulin.

symptoms in patients with accompanying systemic autoimmune illness. However, high doses of corticosteroids are usually given empirically to patients with severe thrombocytopenia, hemolytic anemia, and catastrophic APS. No controlled studies in APS patients have been published for clopidogrel, pentoxifylline, aspirin-dipyridamole, argatroban, hirudin, and other new anticoagulant agents. Neither hirudin nor fondaparinux inactivates complement, and neither drug protects mice with experimental APS against pregnancy loss, so they may be ineffective in human disease. Clinical experience suggests that thrombolytic agents for acute thrombosis are unhelpful, because reocclusion occurs rapidly. Currently available data, although retrospective and not risk-stratified, indicate that lifelong anticoagulation of APS patients with vascular events is appropriate.66 However, the recent recognition that some patients have full remission of antibody and that most thrombotic events have recognizable triggers raises the possibility of discontinuing anticoagulation in highly selected patients when the triggers are eliminated. PREGNANCY MORBIDITY Heparin anticoagulation is indicated at the diagnosis of pregnancy in an aPL-positive woman who has had prior pregnancy losses attributable to APS. Because warfarin is teratogenic, only unfractionated or low-molecular-weight

1308

Erkan

antiphospholipid syndromE

heparin is used for the treatment of affected pregnancies in the United States; in other countries, converting to warfarin after the first trimester may be considered acceptable.67 Most physicians with a special interest in this field now use low-molecular-weight heparin owing to the decreased risk of thrombocytopenia and osteoporosis. Patients with prior fetal losses later than 10 gestational weeks should be treated with prophylactic heparin (enoxaparin 30 to 40 mg subcutaneously once daily), together with low-dose aspirin; this regimen increases the fetal survival rate from 50% (untreated) to 80%.68,69 Women who have had prior thromboses must be fully anticoagulated (enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily) throughout pregnancy, because the risk of new thrombosis markedly increases both during pregnancy and post partum. Even with treatment, prematurity and fetal growth restriction still occur. Clopidogrel and newer antithrombotic agents are not cleared for use in pregnancy, but together with IVIG and hydroxychloroquine, they may be considered in patients who are unable to use heparin or who fail heparin treatment. In aPL-positive women with prior thrombosis, warfarin is changed to heparin or low-molecular-weight heparin before conception, if possible, or at the first missed menstrual period. In aPL-positive women without prior thrombosis, heparin treatment begins after confirmation of pregnancy, continues until 48 hours before anticipated delivery (to allow epidural anesthesia), and resumes for 8 to 12 weeks post partum. Some physicians recommend the initiation of heparin before conception; no clinical trial supports this recommendation, however, and the risk of longer-duration heparin therapy is considerable. Patients in most published series received low-dose aspirin as well as heparin, but the benefit of adding aspirin is unknown. Because of the risk of postpartum thrombosis, it is prudent to continue anticoagulation for 8 to 12 weeks post partum and then discontinue it by tapering the doses. If desired, conversion from heparin to warfarin may be accomplished after the first or second postpartum week. Breastfeeding is permissible with both heparin and warfarin. No studies unequivocally justify the treatment of women with aPLs during a first pregnancy, women with only very early losses, or women whose aPL titers are low or transient. Nonetheless, it is common to offer such patients low-dose aspirin. ASYMPTOMATIC ANTIPHOSPHOLIPID ANTIBODYPOSITIVE INDIVIDUALS Persistence of aPLs for decades without clinical events is well documented. The probability that an asymptomatic person incidentally found to have aPLs will eventually develop the syndrome is likely low.7 Anticoagulation is not indicated for the prophylactic treatment of asymptomatic aPL-positive individuals. For those with moderate- to hightiter anticardiolipin and persistent aPLs, education about the meaning of abnormal tests is appropriate, as is a discussion of warning signs to report. Elimination of reversible thrombosis risk factors and prophylaxis during high-risk periods, such as surgical procedures, are crucial. Ongoing prospective clinical trials will determine whether asymptomatic persons with high-titer aPLs should be treated prophylactically.

Although drugs that induce lupus (hydralazine, phenytoin) may also induce aPLs, if no alternatives are available, they may be prescribed for patients with aPLs. Drugs that promote thrombosis (estrogen and estrogen-containing oral contraceptives) are not currently deemed safe, even for asymptomatic women serendipitously known to have hightiter antibodies. This advice does not translate to a recommendation to test all normal women before the prescription of such medications, but it does suggest that special attention and further evaluation be provided to those with family histories or clinical suggestions of rheumatic disease, livedo reticularis, biologic false-positive tests for syphilis, or borderline thrombocytopenia. There is no reliable information regarding the safety of progestin-only contraception, morning after contraception, or the use of raloxifene, bromocriptine, or leuprolide in APS patients. A small retrospective review of women undergoing artificial reproductive technology (in vitro fertilization) procedures demonstrated no thrombotic events.70 ANTIPHOSPHOLIPID ANTIBODYPOSITIVE INDIVIDUALS WITH AMBIGUOUS EVENTS Some patients with positive aPL tests have clinical events of ambiguous meaning (dizzy or confusional episodes, nonspecific visual disturbance, very early pregnancy loss). There is no consensus for the treatment of such persons. Because full anticoagulation carries high risk, many physicians prescribe lowdose (81 mg) aspirin, hydroxychloroquine, or both daily. No published data support or repudiate this recommendation. Based on the presumed pathogenesis, some physicians prescribe anticoagulation for patients with livedo reticularis, thrombocytopenia, leg ulcers, thrombotic microangiopathy, or valvulopathy. The efficacy of anticoagulation is unknown in these conditions. One small, descriptive, cross-sectional study provides evidence that B cell depletion with rituximab is well tolerated and can be effective for refractory thrombocytopenia and skin ulcers in aPL-positive patients.71 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME The onset of catastrophic APS is usually sudden and immediately life threatening. Early diagnosis can be a challenge, but it is critical because, in contrast to other causes of multiple organ dysfunction syndrome, appropriate therapy includes anticoagulation and corticosteroids in combination with repeated plasma exchange, IVIG, and, in desperate situations, other modalities such as cyclophosphamide or rituximab. However, mortality remains as high as 48% despite all attempts at effective therapy.72 There are no systematic studies of the treatment of catastrophic APS owing to the rarity of the condition. ANTIPHOSPHOLIPID ANTIBODYNEGATIVE INDIVIDUALS WITH A CLINICAL EVENT In patients clinically suspected of having APS but with normal anticardiolipin, lupus anticoagulant, and anti-2GPI tests, alternative causes of clotting must be sought. Even among patients with concomitant rheumatic disease, APS may not be the cause of recurrent thromboembolism or pregnancy loss. Patients with SLE develop emboli from

part 11

systEmiC lUpUs ErythEmatosUs and rElatEd syndromEs

1309

SLE-related cardiac valvular disease, vasculitis, or atheroma. Other patients have factor V Leiden or some other procoagulant mutation. Recurrent pregnancy losses may be caused by chromosomal abnormalities, uterine infection, diabetes, hypertension, or non-aPL coagulopathy. The concept of seronegative APS is not recognized.

PROGNOSIS
Pulmonary hypertension, neurologic involvement, myocardial ischemia, nephropathy, gangrene of extremities, and catastrophic APS are associated with a worse prognosis. During long-term follow-up, serious morbidity and disability occur in an unpredictable proportion of primary APS patients who experience major vascular events and in those who have delays in diagnosis and treatment. Thus, the long-term functional outcome of primary APS patients is poor; at 10 years, one third of patients develop permanent organ damage, and one fifth are unable to perform everyday activities.73 In a retrospective study of obstetric APS patients without thrombosis, 35% developed aPL-related clinical events during 8 years of follow-up. The studied populations were highly selected referral populations that may have been biased toward severe disease, but follow-up studies of obstetric patients with autoantibodies show similar results.74 Long-term outcomes of children born of APS pregnancies are not known. In many patients with long-standing APS, the development of severe cardiac valvular disease necessitates valve replacement, and rare patients develop renal failure due to thrombotic microangiopathy. Immediate thrombosis may cause loss of a transplanted kidney or other organ; aPL positivity correlates with poor graft survival after renal transplantation in SLE patients.75 Serious perioperative complications may occur despite prophylaxis in aPL-positive patients, because they are at additional risk for thrombosis when undergoing surgical procedures. Thus, perioperative strategies should be clearly identified before any surgical procedure, pharmacologic and physical antithrombosis interventions should be vigorously employed, periods without anticoagulation should be kept to an absolute minimum, intravascular manipulation for access and monitoring should be minimized, and any deviation from a normal course should be considered a potential disease-related event.76 REFERENCES
1. Wilson WA, Gharavi AE, Koike T, et al: International consensus statement on preliminary classification criteria for antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 42:1309-1311, 1999. 2. miyakis S, lockshin mD, atsumi T, et al: international consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb haemost 4:295-306, 2006. 3. Gharavi AE, Sammaritano LR, Wen J, et al: Characteristics of human immunodeficiency virus and chlorpromazine-induced antiphospholipid antibodies: Effect of beta 2 glycoprotein I on binding to phospholipid. J Rheumatol 21:94-99, 1994. 4. Vila P, Hernandez MC, Lopez-Fernandez MF, et al: Prevalence, follow-up and clinical significance of the aCL in normal subjects. Thromb Haemost 72:209-213, 1994. 5. Petri M: Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 15:145-151, 2000. 6. Olech E, Merrill JT: The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis. Curr Rheumatol Rep 8:100-108, 2006.

7. Giron-Gonzalez JA, Garcia del Rio E, Rodriguez C, et al: Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: Prospective analysis of 404 individuals. J Rheumatol 31:1560-1567, 2004. 8. Somers E, Magder LS, Petri ML: Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 29:2531-2536, 2002. 9. Erkan D, Harrison MJ, Levy R, et al: APLASAa randomized double-blind placebo-controlled primary thrombosis prevention trial in asymptomatic persistently antiphospholipid antibody (APL)-positive individuals with aspirin (ASA) [abstract]. Clin Exp Rheumatol 25:14, 2007. 10. The Antiphospholipid Antibody Stroke Study (APASS) Group: Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 43:2069-2073, 1993. 11. Levine SR, Brey RL, Sawaya KL, et al: Recurrent stroke and thromboocclusive events in the antiphospholipid syndrome. Ann Neurol 38:119-124, 1995. 12. Stephenson MD: Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 66:24-29, 1996. 13. Ginsberg JS, Wells PS, Brill-Edwards P, et al: Antiphospholipid antibodies and venous thromboembolism. Blood 86:3685-3691, 1995. 14. Koike T, Ichikawa K, Kasahara H: Epitopes on beta2-GPI recognized by anticardiolipin antibodies. Lupus 7(Suppl 2):S14, 1998. 15. Shi T, Giannakopoulos B, Yan X, et al: Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Arthritis Rheum 54:2558-2567, 2006. 16. Reddel SW, Wang YX, Sheng YH, et al: Epitope studies with anti-beta 2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimmun 15:91-96, 2000. 17. Casciola-Rosen L, Rosen A, Petri M, et al: Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: Implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A 93:1624-1629, 1996. 18. Mori T, Takeya H, Nishioka J, et al: Beta 2-glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemost 75:49-55, 1996. 19. Bertolaccini ML, Hughes GR: Antiphospholipid antibody testing: Which are most useful for diagnosis? Rheum Dis Clin North Am 32:455-463, 2006. 20. Gharavi AE, Pierangeli SS, Harris EN: Origin of antiphospholipid antibodies. Rheum Dis Clin North Am 27:551-563, 2001. 21. Blank m, krause i, Fridkin m, et al: Bacterial induction of autoantibodies to beta2-glycoprotein-i accounts for the infectious etiology of antiphospholipid syndrome. J clin invest 109:797-804, 2002. 22. Gharavi AE, Sammaritano LR, Wen J, et al: Induction of antiphospholipid antibodies by immunization with beta 2 glycoprotein I (apolipoprotein H). J Clin Invest 90:1105-1109, 1992. 23. Arvieux J, Renaudineau Y, Mane I, et al: Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome. Thromb Haemost 87:599-605, 2002. 24. Lutters BC, Derksen RH, Tekelenburg WL, et al: Dimers of beta 2-glycoprotein 1 increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2. J Biol Chem 278:33831-33838, 2003. 25. Bordron A, Dueymes MY, Levy Y, et al: Anti-endothelial cell antibody binding makes negatively charged phospholipids accessible to antiphospholipid antibodies. Arthritis Rheum 41:1738-1747, 1998. 26. Simantov R, LaSala J, Lo SK, et al: Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 96:2211-2219, 1996. 27. Font J, Espinosa G, Tassies D, et al: Effects of 2-glycoprotein I and monoclonal anticardiolipin antibodies in platelet interaction with subendothelium under flow conditions. Arthritis Rheum 46: 3283-3289, 2002. 28. van Lummel M, Pennings MT, Derksen RH, et al: The binding site in 2-glycoprotein I for ApoER2 on platelets is located in domain V. J Biol Chem 280:36729-36736, 2005. 29. Erkan D, Lockshin MD: What is antiphospholipid syndrome? Curr Rheumatol Rep 6:451-457, 2004. 30. Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B, et al: NFkappaB is an essential intermediate in the activation of endothelial cells by anti-beta2-glycoprotein 1 antibodies. Thromb Haemost 88:851-857, 2002.

1310

Erkan

antiphospholipid syndromE 54. Erkan D, Derksen WJ, Kaplan V, et al: Real world experience with antiphospholipid antibody tests: How stable are results over time? Ann Rheum Dis 64:1321-1325, 2005. 55. Lockshin MD, Sammaritano LR, Schwartzman S: Brief report: Validation of the Sapporo criteria for antiphospholipid antibody syndrome. Arthritis Rheum 43:440-443, 2000. 56. Erel H, Erkan D, Lehman TJ, et al: Diagnostic usefulness of 3 dimensional gadolinium enhanced magnetic resonance venography in antiphospholipid syndrome. J Rheumatol 29:1338-1339, 2002. 57. Khong TY, De Wolf F, Robertson WB, et al: Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational-age infants. Br J Obstet Gynaecol 93:1049-1059, 1986. 58. Stone S, Pijnenborg R, Vercruysse L, et al: The placental bed in pregnancies complicated by primary antiphospholipid syndrome. Placenta 27:457-467, 2006. 59. Levy RA, Gharavi AE, Sammaritano LR, et al: Characteristics of IgG antiphospholipid antibodies in patients with systemic lupus erythematosus and syphilis. J Rheumatol 17:1036-1041, 1990. 60. Kupferminc MJ, Eldo A, Steinman N, et al: Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:9-13, 1999. 61. crowther ma, Ginsberg JS, Julian J, et al: comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. n Engl J med 349:1133-1138, 2003. 62. Finazzi G, marchioli r, Brancaccio V, et al: a randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WaPS). J Thromb haemost 3:848853, 2005. 63. Levine SR, Brey RL, Tilley BC, et al: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291:576-584, 2004. 64. Ortel TL, Moll S: Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 127:177-185, 1997. 65. Erkan D, Lockshin MD: New treatments for antiphospholipid syndrome. Rheum Dis Clin North Am 32:129-148, 2006. 66. Brunner HI, Chan WS, Ginsberg JS, et al: Long term anticoagulation is preferable for patients with antiphospholipid antibody syndrome: Result of a decision analysis. J Rheumatol 29:490-501, 2002. 67. Vilela VS, de Jesus NR, Levy RA: Prevention of thrombosis during pregnancy. Isr Med Assoc J 4:794-797, 2002. 68. kutteh Wh: antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. am J obstet Gynecol 174:1584-1589, 1996. 69. rai r, cohen h, Dave m, et al: randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BmJ 314:253-257, 1997. 70. Guballa N, Sammaritano L, Schwartzman S, et al: Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum 43:550-556, 2000. 71. Tenedios F, Erkan D, Lockshin MD: Rituximab in the primary antiphospholipid syndrome (PAPS) [abstract]. Arthritis Rheum 52:4078, 2005. 72. Vero S, Asherson RA, Erkan D: Critical care review: Catastrophic antiphospholipid syndrome. J Intensive Care Med 21:144-159, 2006. 73. Erkan D, Yazici Y, Sobel R, et al: Primary antiphospholipid syndrome: Functional outcome after 10 years. J Rheumatol 27:2817-2821, 2000. 74. Erkan D, Merrill JT, Yazici Y, et al: High thrombosis rate after fetal loss in antiphospholipid syndrome: Effective prophylaxis with aspirin. Arthritis Rheum 44:1466-1467, 2001. 75. Raklyar I, DeMarco PJ, Wu J, et al: Anticardiolipin antibody correlates with poor graft survival in renal transplantation for systemic lupus erythematosus. Arthritis Rheum 52:S384, 2005. 76. Erkan D, leibowitz E, Berman J, lockshin mD: Perioperative medical management of antiphospholipid syndrome: hospital for Special Surgery experience, review of the literature and recommendations. J rheumatol 29:843-849, 2002.

31. Pierangeli SS, Vega-Ostertag M, Harris EN: Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: A pathway to targeted therapies. Thromb Res 114:467-476, 2004. 32. Mak IYH, Brosens JJ, Christian M, et al: Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 87:2581-2587, 2002. 33. Pierangeli SS, Liu XW, Barker JH, et al: Induction of thrombosis in a mouse model by IgG, IgM, and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemost 74:1361-1367, 1995. 34. Jankowski M, Vreys I, Wittevrongel C, et al: Thrombogenicity of 2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically-induced thrombosis model in the hamster. Blood 101: 157-162, 2003. 35. Girardi G, Bulla r, Salmon JE, et al: The complement system in the pathophysiology of pregnancy. mol immunol 43:68-77, 2006. 36. Fleming SD, Egan RP, Chai C, et al: Anti-phospholipid antibodies restore mesenteric ischemia/reperfusion-induced injury in complement receptor 2/complement receptor 1-deficient mice. J Immunol 173:7055-7061, 2004. 37. Kaul M, Erkan D, Sammaritano L, et al: Assessment of the 2006 revised antiphospholipid syndrome (APS) classification criteria [abstract]. Arthritis Rheum 54:S796, 2006. 38. Erkan D, Yazici Y, Peterson MG, et al: A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 41:924-929, 2002. 39. Bancsi LF, van der Linden IK, Bertina RM: Beta 2-glycoprotein I deficiency and the risk of thrombosis. Thromb Haemost 67:649-653, 1992. 40. Sheng Y, Reddel SW, Herzog H, et al: Impaired thrombin generation in beta 2-glycoprotein I null mice. J Biol Chem 276:13817-13821, 2001. 41. Kamboh MI, Manzi S, Mehdi H, et al: Genetic variation in apolipoprotein H (beta2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus. Lupus 8:742-750, 1999. 42. Potti A, Bild A, Dressman HK, et al: Gene-expression patterns predict phenotypes of immune-mediated thrombosis. Blood 107:1391-1396, 2006. 43. Bhandari S, Harnden P, Brownjohn AM, et al: Association of anticardiolipin antibodies with intraglomerular thrombi and renal dysfunction in lupus nephritis. QJM 91:401-409, 1998. 44. Rand JH, Wu X, Andree HAM, et al: Pregnancy loss in the antiphospholipid-antibody syndrome: A possible thrombogenic mechanism. N Engl J Med 337:154-160, 1997. 45. Roman MJ, Shanker BA, Davis A, et al: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2399-2406, 2003. 46. Erkan D, Bateman H, Lockshin MD: Lupus-anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: Report of 2 cases and review of literature. Lupus 8:560-564, 1999. 47. Erkan D, Cervera R, Asherson RA: Catastrophic antiphospholipid syndrome: Where do we stand? Arthritis Rheum 48:3320-3327, 2003. 48. Cervera R, Font J, Gomez-Puerta JA, et al: Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis 64:1205-1209, 2005. 49. asherson ra, cervera r, de Groot PG, et al: catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. lupus 12:530-534, 2003. 50. Galli m, luciani D, Bertolini G, et al: lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 101:1827-1832, 2003. 51. Brandt JT, Triplett DA, Alving B, et al: Criteria for the diagnosis of lupus anticoagulants: An update. Thromb Haemost 74:1185-1190, 1995. 52. Cervera R, Piette JC, Font J, et al: Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 46:1019-1027, 2002. 53. Day HM, Thiagarajan P, Ahn C, et al: Autoantibodies to 2glycoprotein I in systemic lupus erythematosus and primary antiphospholipid syndrome: Clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol 25:667-674, 1998.