Current Debates in Antiphospholipid Syndrome: The Acquired Antibody-Mediated Thrombophilia
Identifieur interne : 002031 ( Istex/Corpus ); précédent : 002030; suivant : 002032Current Debates in Antiphospholipid Syndrome: The Acquired Antibody-Mediated Thrombophilia
Auteurs : M. Akif Öztürk ; Ibrahim C. Haznedaro Lu ; Mehmet Turgut ; Hakan GökerSource :
- Clinical and Applied Thrombosis/Hemostasis [ 1076-0296 ] ; 2004-04.
English descriptors
- Teeft :
- Acas, Akif, Amengual, Anionic phospholipids, Annexin, Antibody, Antibody syndrome, Anticardiolipin, Anticardiolipin antibodies, Anticoagulant, Anticoagulation, Antigenic, Antiphospholipid, Antiphospholipid antibodies, Antiphospholipid antibody syndrome, Antiphospholipid syndrome, Antithrombotic, Apoptosis, Apoptotic, Apoptotic cells, Appl, Aptt, Arthritis rheum, Aspirin, Assay, Asymptomatic, Atsumi, Autoantibody, Autoimmun, Autoimmune, Beta, Bick, Cardiolipin, Cervera, Clin, Clin appl thromb hemost, Clin pathol, Clinical features, Clinical manifestations, Clinical significance, Coagulation, Coagulation cascade, Cofactor, Cohort, Confirmatory, Current debates, Drvvt, Elisa, Endothelial, Endothelial cells, Endothelium, Epitope, Erythematosus, Fetal, Fetal loss, Gharavi, Glycoprotein, Gonadotropin, Gynecol, Haematol, Haemost, Hematol, Hemost, Hemostasis, Heparin, Hypertension, Immune, Immunoglobulin, Immunol, Immunologic, Infarction, Intravenous, Invasiveness, Ischemic, Isotype, Ivig, Kaolin, Khamashta, Laboratory diagnosis, Lipid, Lipoprotein, Lmwh, Lupus, Lupus anticoagulant, Lupus anticoagulants, Miscarriage, Monoclonal, Monocyte, Myocardial infarction, Neurologic, Normal plasma, Obstet, Obstet gynecol, Obstetric, Other hand, Oxidative, Oxidized, Pathobiology, Pathogenesis, Pathol, Pathway, Phosphatidylethanolamine, Phosphatidylserine, Phospholipid, Pierangeli, Placenta, Placental, Placental thrombosis, Platelet, Platelet activation, Pregnancy loss, Primary antiphospholipid syndrome, Procoagulant, Prophylaxis, Prothrombin, Prothrombotic, Randomized, Reprod, Rheum, Rheumatol, Rheumatology, Standardization, Subgroup, Suppl, Syndrome, Syndrome patients, Systemic, Systemic lupus erythematosus, Thromb, Thromb haemost, Thrombin, Thrombocytopenia, Thromboembolism, Thrombophilia, Thromboplastin, Thrombosis, Thrombotic, Thrombotic events, Thrombus, Tissue factor, Tissue factor pathway, Triplett, Trophoblast, Venous, Venous thrombosis, Viper, Warfarin.
Abstract
Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term “APL antibodies” represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anticoagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.
Url:
DOI: 10.1177/107602960401000201
Links to Exploration step
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<term>Annexin</term>
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<term>Antibody syndrome</term>
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<front><div type="abstract" xml:lang="en">Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term “APL antibodies” represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anticoagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.</div>
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<abstract>Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term “APL antibodies” represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anticoagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.</abstract>
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<p>Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term “APL antibodies” represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anticoagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.</p>
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<meta-value> Antiphospholipid syndrome (APL syndrome) can be called "acquired antibodymediated thrombophilia" from the clinical point of view. The hypercoagulability/thrombotic diathesis of APL syndrome can manifest in a wide variety of clinical and/or laboratory abnormal states. The expanding heterogeneous spectrum of the disor- der varies from a coincidental abnormality in the hemostasis laboratory to thromboembolic events such as a serious stroke, venous thrombosis, ar- terial occlusion, or a catastrophic obstetrical complication in the clinic (1). There are many obscurities challenging a bet- ter understanding of APL syndrome and APL an- tibodyassociated pathologic states. Difficulties are mainly present in the confusing terminology describing the disorders and antibodies, prob- lems in the hemostasis laboratory and their clin- ical relevance, still ongoing revisions in the diag- nostic criteria, heterogeneous patient presenta- tions, chaotic multisystemic involvement, unsat- isfactory treatment strategies, and, of course, the unresolved enigmatic distinct etiopathogenesis of the APL syndrome. The aim of this review is to outline current dilemmas and their present clar- ifications in the wide clinicopathologic spectrum of APL syndrome and APL antibodyrelated dis- tinct pathologic conditions. DIFFICULTIES IN THE CURRENT TERMINOLOGY OF THE APL SYNDROME The term "APL antibodies" represents a het- erogeneous group of antibodies associated with a prothrombotic state and/or a condition with high 89 State-of-the-Art Review Current Debates in Antiphospholipid Syndrome: The Acquired AntibodyMediated Thrombophilia M. Akif Öztürk, MD,* Ibrahim C. Haznedaroglu, MD, Mehmet Turgut, MD, and Hakan Göker, MD *Gazi University School of Medicine Department of Rheumatology, Hacettepe University School of Medicine Department of Hematology, Ankara, Turkey Summary: Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term "APL antibodies" represents a hetero- geneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and sub- group APL antibodies represent intersecting, but non-identical, sub- sets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understand- ing of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anti- coagulant therapy. In this review, we focused on the current dilem- mas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibodyrelated distinct patho- logic conditions. Key Words: Antiphospholipid antibody syndrome--Antiphospho- lipid antibodies--Lupus anticoagulants--Anticardiolipin antibod- ies--Terminology--Clinical features--Laboratory investigation-- Pathobiology--Management. Clin Appl Thrombosis/Hemostasis 10(2):89126, 2004 ©2004 Westminster Publications, Inc., Glen Head, NY Address correspondence and reprint requests to Dr. M. Akif Öztürk, Ostim mahallesi 89. sokak, AK-84 sitesi A2 blok no: 8, Yenimahalle, Ankara TR-06160, Turkey; e-mail: makifozturk@yahoo.com. risk of recurrent fetal loss. Currently no single assay can identify every APL antibody. While the presence of those antibodies is detected with a phospholipid-dependent coagulation reaction, they are designated as "lupus anticoagulants" (LA). When they are demonstrated with the solid phase enzyme-linked immunosorbent assay (ELISA) in which microplate wells are coated with cardiolipin, they are called "anticardiolipin antibodies" (ACA). Therefore, ACAs are detect- ed by their antigenic specificity irrespective of their functional properties. On the other hand, LAs are detected by their effect on in vitro coag- ulation irrespective of their immunologic target. Despite the famous historical name of the syn- drome, the real antigenic target for APL antibod- ies is not phospholipid itself but some phospho- lipid binding plasma proteins, mainly beta2 gly- coprotein-1 (2 GP-1) and prothrombin. 2 GP-1 is required for the binding of autoimmune ACAs to cardiolipin. Most LAs depend on the presence of prothrombin or 2 GP-1 directed against anionic phospholipids (18). Furthermore, the anionic phospholipids probably play important roles for the binding of APL antibodies to those phospho- lipid binding plasma proteins in in vivo condi- tions. It is not clear whether these antibodies rec- ognize the proteins themselves, the phospho- lipid-protein complex, or neo- or cryptic antigens eventually expressed as a result of the interac- tions. Another hypothesis is that close contact to the negatively charged surface makes clusters, providing higher antigenic density for the bind- ing of the APL antibodies that have low affinity for binding under normal conditions (3,713). Because APL antibodies represent a heteroge- nous group, each of those hypotheses could be operative in different patients. ACAs and LAs represent two intersecting, but non-identical, subsets of autoantibodies. Thus, LACs and ACAs may coexist or may occur inde- pendently (1416). From the clinical point of view, there are some patients with recurrent ve- nous and/or arterial thromboses without APL antibodies via with those "routine" assays in the absence of other autoimmune diseases. How- ever they have positivity for the more recently recognized "subgroups" of APL antibodies (i.e. antibodies against 2 GP-1, prothrombin, or an- nexin-V, and antibodies against phospholipids themselves other than cardiolipin including phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine) (1720). The term "APL antibody" describes either of those previously mentioned antibodies, whereas the term "APL syndrome" designates the presence of either of those "APL antibodies" together with the throm- botic manifestations and/or recurrent fetal loss and/or thrombocytopenia (Fig. 1). The term "LA" is improper for two major as- pects. First, the "LA" antibodies are not neces- sarily specific to patients with systemic lupus erythematosus (SLE). Many patients suffering from recurrent thrombotic events or obstetrical complications and are positive for LA do not manifest any of the major clinical or serologic features of SLE. Second, LAs prolong the in vitro coagulation assays but actually demonstrate pro- coagulant, not anticoagulant, effects in in vivo conditions. APL antibodies can be associated with clinical features of APL syndrome without any finding of an underlying connective tissue disorder (i.e., primary APL syndrome). APL syndrome can also complicate the clinical course of various connec- tive tissue disorders, most commonly SLE (18,2128), as well as some other autoimmune disorders such as Sjögren's syndrome, rheuma- toid arthritis, systemic sclerosis, systemic vas- culitis, or dermatomyositis (23). APL syndrome, however, more commonly develops in patients without any underlying disorder (18,23,2629). Presence of LA or ACAs generally defines two distinct patient populations, each of which is as- sociated with an increased risk of thrombosis (15,18). However, there appears to be an intense overlap between those disorders, challenging widespread use of the LAs and APL antibodies to- gether. Therefore, we prefer to present those two disorders together for the sake of clarity in this paper. Infection- or Drug-Related APL Antibodies APL antibodies are reported to occur in some infections such as syphilis, malaria, infectious mononucleosis, tuberculosis, human immunode- ficiency virus, and hepatitis A, B, and C (3032). Infection-related ACAs tend to be transient, of low titre, and directly bind to the cardiolipin it- self; i.e., they are not 2 GP-1 dependent, and moreover could be inhibited by 2 GP-1 (30,31). In these conditions, there is generally no appar- ently increased risk for developing manifesta- tions of APL syndrome (1,32), although certain viral infections can precede the development of APL syndrome (3336). Some drugs are associated with APL antibod- ies and LA activity. Procainamide hydrochloride, quinidine sulfate, phenytoin sodium, chlorpro- M. AKIF ÖZTÜRK ET AL90 mazine hydrochloride, valproic acid, amoxicillin, hydralazine hydrochloride, and propranolol hy- drochloride are all reported for this association. Those drug-induced APL antibodies were associ- ated with thrombotic complications in contrast to the majority of infectious-related ACAs (15,18). PATHOBIOLOGY AND GENESIS OF APL SYNDROME: AN ENIGMA FROM MOLECULES TO DISEASE Pathobiology and genesis of the APL syndrome still remain undetermined. However, there have been enormous efforts and progress for our un- derstanding the molecular pathogenesis of the APL syndrome in the past decade. The role of APL antibodies as the "primary cause" of the syndrome could be questionable, at least for some patients. APL antibodies are in- creased in patients with autoimmune hemolytic anemia (37). The APL antibodies, thus, could be "innocent bystanders" generated secondary to antibody-mediated cell injury in some disorders. Another possibility is that APL antibodies could act as a "second hit," and could be both an effect and a cause of thrombosis. In that hypothetical model, anionic phospholipids that are exposed during blood clotting could trigger immunologi- cal recognition and the formation of APL anti- bodies, promoting a vicious cycle through their thrombogenic properties (38). Finally, the APL antibodies could play direct causal roles in the generation of the clinical features of APL syn- drome. There are data supporting this final hy- pothesis. The majority of antigenic structures that are targets for the APL antibodies do play roles in the normal hemostasis. Moreover, those APL antibodies precede the thrombotic events, and the risk of developing the clinical manifes- tations of the APL syndrome correlates directly with the level of the APL antibodies (3946). Furthermore, passive transfer of immunoglobu- lins from patients with APL syndrome generates features of APL syndrome in animal models (4753). Therefore, rather than being merely an epiphenomenon, APL antibodies seem to play di- rect roles in the pathogenesis of APL syndrome. CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 91 FIG. 1. Classical diagram representing the intersecting subsets of antiphos- pholipid antibodies. Subgroup of antiphospholipid antibodies are antibodies against 2 -GP-1, prothrombin, or annexin-V, and antibodies against phospho- lipids themselves other than cardiolipin including phosphatidylserine, phos- phatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine. Although the exact pathogenetic mecha- nism(s) remain to be determined, it is likely that more than one mechanism could be operative for the development of the clinical manifestations because a wide spectrum of autoantibodies have been shown to be associated with the APL syn- drome. Thrombotic events in patients with APL syndrome segregate into venous or arterial vas- cular tree. Arterial events are generally followed by arterial events and venous events by venous events in the majority of the cases in APL syn- drome (54). Therefore, molecular mechanisms of thrombosis could differ in different clinical manifestations. For instance, venous thrombotic manifestations may be attributed to coagulation factorassociated mechanisms (i.e., secondary hemostasis), whereas disorders of platelets (i.e., primary hemostasis) might be responsible for ar- terial thromboses. The 2 GP-1 protein is the most frequently ob- served protein cofactor in the APL syndrome. However little is known regarding the physiolog- ic role(s) of this protein. The 2 GP-1 has been identified as a constituent of chylomicrons, and very-low-density and high-density lipoproteins. Roughly 40% of the circulating 2 GP-1 is bound to lipoproteins. Therefore this protein may be in- volved in lipoprotein metabolism (55). 2 GP-1 may also play a scavenging role in mediating the clearance of foreign particles and apoptotic cells in the circulation (5658). 2 GP-1 was also sug- gested as a natural anticoagulant. Circulating levels of 2 GP-1 are reduced dramatically during disseminated intravascular coagulation (DIC) along with reductions in other anticoagulant pro- teins including protein C and antithrombin III. These data suggest specific consumption of the 2 GP-1 during in vivo coagulation (59). A num- ber of in vitro studies also supported the antico- agulant role of the 2 GP-1 molecule. 2 GP-1 can inhibit various platelet functions (60,61), down- regulate the activation of the Hageman factor and the contact phase system of the coagulation cascade (62,63), prevent the binding of protein S with its plasma inhibitor, the C4b-binding pro- tein (64), and inhibit tissue factor activity (65). However, the clinical relevance of those in vitro observations remains questionable because hereditary deficiency of 2 GP-1 does not seem to be associated with thrombophilia (66). The 2 GP-1 molecule can bind to negatively charged macromolecules that are involved in the initia- tion of coagulation. However, its binding affinity is far below that of many other phospholipid- binding proteins (67). Therefore, it seems un- likely that the binding of 2 GP-1 can neutralize the initiation of coagulation cascade. Likewise, anti-prothrombin antibodies do not interfere with the coagulant properties of the prothrombin molecule itself (68). Both anti-2 GP-1 antibodies and anti-prothrombin antibodies can display LA activity (2,46,68). Hence, other than direct in- hibition of function, binding of those antibodies to their targets should have some common dy- namic influences on the coagulation cascade. Disruption of the Annexin V Shield in APL Syndrome Annexin V is found in a variety of tissues in- cluding the vascular endothelium and placenta. This protein could have potent anticoagulant properties based on its high affinity for anionic phospholipids. The capacity of annexin V to dis- place coagulation factors from phospholipid sur- faces is evident (69,70). A number of consecu- tive experiments supported this hypothesis. The decrements in the levels of annexin V induced by APL antibodies were accompanied by a shorten- ing of the coagulation time of plasma. Likewise incubating endothelial cells with antiannexin V resulted in faster coagulation of plasma. Moreover, removing annexin V from the cell sur- face by calcium chelator EGTA significantly ac- celerated the coagulation of plasma. Adding ex- ogenous annexin V increased the coagulation time of plasma applied to the cells (69). APL an- tibodies directly reduced binding of annexin-V to noncellular anionic phospholipid-coated surfaces in a 2 GP-1dependent manner interfering with its anticoagulant activity, resulting in the accel- eration of coagulation (70). Inhibition of annex- in V binding to procoagulant phospholipid sur- faces by APL antibodies was dependent upon anti-2 GP-1 antibodies. This reduction is signifi- cantly correlated with clinical thrombosis (71). The hypothesis depending on these data is used to explain the in vivo procoagulant and in vitro anticoagulant effects of APL antibodies. Based on the hypothesis, annexin V forms a crystal lattice over the anionic phospholipid surface that serves and shields it from the availability for the assem- bly of the phospholipid-dependent coagulation complexes (i.e. tissue factor, factor X, factor IX, factor V, etc.) under physiologic conditions. Annexin V, thus, has a potent anticoagulant ef- fect in vivo. During the absence of the annexin V, the complexes of APL antibodies and their antigenic targets such as 2 GP-1 or prothrombin, bind the phospholipid bilayer, reducing the ac- cess of coagulation factors to anionic phospho- M. AKIF ÖZTÜRK ET AL92 lipids in vitro. Because there is a limiting quanti- ty of anionic phospholipids, this interaction re- sults in the prolongation of the coagulation assay. However, in in vivo conditions where there is sufficient amount of annexin V, the APL antibodies disrupt the ability of annexin V to form ordered crystals on the phospholipid sur- face and inhibit the anticoagulant effect of an- nexin V. That state results in a net increase of the amount of anionic phospholipid available for promoting coagulation reactions, which estab- lishes a hypercoagulable state (38,70). This at- tractive hypothesis could link the paradoxical LA phenomenon and the in vivo thrombogenic ten- dency of the APL antibodies. However, there is some conflicting data. In a Russell's viper venom assay, co-incubation of annexin V with APL anti- body containing plasma failed to correct the clot- ting time, but even caused prolongation of the clotting time. The observed clotting time exceeds that with either annexin V or APL containing plasma alone (72). Moreover, annexin V binding was unaffected by the presence of ACA-2 GP-1 complexes. Annexin V pre-adsorbed to the bilay- ers completely prevented adsorption of ACA- 2 GP-1 complexes. None of the pre-adsorbed an- nexin V was displaced by ACA-2 GP-1 complexes (73). Therefore, displacement of the annexin V shield is not a prerequisite for the thrombotic events in patients with APL syndrome. Inhibition of the Protein C Anticoagulant Pathway in APL Syndrome The protein C anticoagulant pathway is a major regulatory mechanism of the coagulation cascade. Upon binding of thrombin to thrombo- modulin, the thrombin molecule loses its proco- agulant properties and cleaves protein C. Activated protein C then complexes with protein S and proteolyzes coagulation factors Va and VIIIa (74). A missense mutation in the factor V gene (1691 GA) (Leiden mutation) is a com- mon cause of thrombotic tendency by causing an abnormal factor V product. However, factor V Leiden mutation is not common in patients with APL syndrome (75). On the other hand, some pa- tients with APL syndrome and asymptomatic car- riers of APL antibodies may have acquired free protein S deficiency (76,77). Immunoglobulin fractions isolated from patients with APL causes acquired activated protein C resistance (78,79). The presence of LAs can interfere with the pro- tein C pathway (8083). Other APL antibodies, including anti-2 GP-1 antibodies and ACAs, were also associated with the acquired activated pro- tein C resistance phenomenon (8486). ACAs bound to protein C in the presence of cardiolipin and 2 GP-1, but not in the absence of either 2 GP-1 or cardiolipin. These data suggest that protein C could be a target of ACA by making a complex with cardiolipin and 2 GP-1, leading to protein C dysfunction (87). Autoantibodies gen- erated against the isolated components of the protein C pathway (i.e. thrombomodulin, protein C, or protein S) may also impair the protein C pathway (88,89). Different steps in the protein C anticoagulant pathway could be targets for APL antibodies. They can inhibit thrombin formation. APL antibodies interfere with the protein C acti- vation via thrombin-thrombomodulin complex. Inhibition of the protein C complex assembly takes place. Protein C activity can be downregu- lated directly or via inhibition of the activity of its cofactor, protein S. Finally, the antibodies direct- ed against the substrates of APC, factors Va and VIIIa may protect them from inactivation (90,91). A subpopulation of APL antibodies selectively inhibits the activated protein C complex as a re- sult of differences in the phospholipid require- ments of this complex as compared to those of the procoagulant complexes. Phosphatidyl- ethanolamine supports activated protein C anti- coagulant activity but has little influence on pro- thrombin activation. The inhibitory effect of LAs on activated protein C pathway was also en- hanced in the presence of phosphatidylethano- lamine (92). The rate of inhibition of the antico- agulant pathway (i.e., inactivation of factor Va) is much higher than the inhibition of the proco- agulant pathway (i.e., thrombin generation) in the presence of phosphatidylethanolamine in the system (92). Therefore, differences between membrane phospholipid requirement of the anti- coagulant and procoagulant reactions could ac- count for the selective inhibition of one pathway over the other. The variability of different LA as- says may be attributed to the differences in the phospholipid reagents inside them (93). Why the autoantibodies directed against the phospho- lipids themselves can cause hypercoagulability is possibly explained via this hypothesis. Taken together, those observations suggest that inhibition of the activated protein C antico- agulation system may be a common mechanism contributing to the prothrombotic state of APL antibodies in at least a subgroup of patients. APA and Endothelium Vascular endothelial cells play a critical pro- tective role in the whole body defense against CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 93 thrombosis. Other than being a mechanical bar- rier, the endothelium plays an active role in the physiologic regulation of hemostasis through synthesis of numerous procoagulant and antico- agulant mediators. Immunologic injury to en- dothelial cells and alterations of the endothelial cell functions could have a place in the patho- genesis of the APL syndrome. Binding of APL an- tibodies suppressed vasodilator prostacyclin re- lease by vascular endothelium. This inhibition generates an imbalance between vasodilator and vasoconstrictor prostoglandins toward the vaso- constrictor state (94). Likewise, urinary excre- tion of the major thromboxane metabolite of platelet origin (11-dehydro-thromboxane B2) is very significantly increased while the urinary metabolite reflecting the vascular production of prostacyclin (2,3-dinor-6-keto-prostaglandin F1 alpha) is much less enhanced (95). LAs induce apoptosis in endothelial cells (96,97). Apoptotic cells expose phosphatidylserine on the outer sur- face of the plasma membrane, further activating coagulation cascades (98). APL antibodies induce the production of monocyte chemoattractant pro- tein-1 in human umbilical vein endothelial cells in a 2 GP-1dependent manner, which might in turn promote thrombus formation either by en- hancing the influx of monocytes to the endothe- lium or by increasing tissue factor expression in monocytes (99). Binding of APL antibodies to the endothelial cell surface generates a functional cell activation and a procoagulant state. APL an- tibodies induce upregulation of certain cell ad- hesion molecules on the surface of endothelial cells. E-selectin, vascular cell adhesion molecule- 1 (VCAM-1), and intracellular adhesion mole- cule-1 (ICAM-1) are mediated through 2 GP-1 (100103). Anti-2 GP-1 antibodies also signifi- cantly increase the secretion of proinflammatory cytokine IL-6 and augment prostacyclin metabo- lism by endothelial cells in a dose-dependent manner (100). APL antibodies increase leukocyte adhesion to the endothelium and enhance thrombus formation as demonstrated in an in vivo model of leukocyte adhesion and microcir- culation. This increment was accompanied by en- hanced adhesion molecule expression as an in vitro marker of endothelial cell activation (104). Circulating VCAM-1 is increased in patients with primary APL syndrome, which is further evident in patients with repeated thrombotic events (105). APL antibody induced endothelial activa- tion and enhanced thrombosis is impaired in ICAM-deficient and ICAM-1/P-selectin deficient mice. These data demonstrate that pathogenic ef- fects of APL antibodies could be mediated by those cell adhesion molecules (106). Moreover, leukocyte adhesion to endothelial cells was sig- nificantly decreased after infusion of anti-VCAM- 1 antibodies (106). Taken together, those data strongly indicate that pathologic activation of the endothelium may contribute to the hypercoagu- lable state of APL syndrome. The Tissue Factor Pathway in APL Syndrome Tissue factor (TF) is the principle (patho)bio- logic initiator of the coagulation cascade. Endothelial cells and monocytes can generate tis- sue factor upon stimulation by various sub- stances. Tissue factor is inducibly synthesized in endothelium and monocytes (107). Tissue factor pathway is upregulated in the APL syndrome. Plasma tissue factor is higher in patients with APL syndrome compared to healthy people and patients with thrombosis without APL antibodies (108,109). Cell surface expression of tissue factor and tissue factor mRNA levels are also increased in the monocytes of APL syn- drome. These data suggest that circulating monocytes in APL syndrome express increased amounts of tissue factor (109,110). Moreover, APL antibodies induce tissue factor generation and enhance tissue factor activity in monocytes and vascular endothelial cells (108,111113). On the other hand, APL antibodies can also interfere with the inhibitory activity of tissue factor path- way inhibitor in a group of patients (114,115), despite the circulating tissue factor pathway in- hibitor levels were increased in APL syndrome (108). The increased levels of tissue factor path- way inhibitor could either reflect a compensato- ry response or endothelial activation or damage (108). Therefore, enhancement of the tissue fac- tor pathway either by increasing tissue factor generation and activity or by interfering with its inhibition can be an important mechanism that leads to activation of coagulation and thrombus formation in the APL syndrome. Molecular Mimicry as a Potential Triggering Mechanism in APL Syndrome Immunization with phospholipids alone does not induce the production of APL antibodies (116). However, immunization of normal mice and rabbits with purified 2 GP-1 induced pro- duction of high levels of APL antibodies in addi- tion to antibodies against 2 GP-1 (117119). Characteristics of those 2 GP-1induced APL an- tibodies were similar to those of the human au- toimmune APL antibodies (118,119). Moreover, M. AKIF ÖZTÜRK ET AL94 immunization with 2 GP-1 induced the develop- ment of the clinical and histopathologic features of APL syndrome in PL/J mice, which are genet- ically predisposed to autoimmune disease (120). A major PL-binding site of 2 GP-1, called GDKV, induced production of pathogenic APL an- tibodies alone without the rest of the 2 GP-1 molecule (121). Some common human viruses shared structural similarities with this phospho- lipid-binding region of 2 GP-1, the GDKV. Those peptides showed greater degrees of binding to PL compared to GDKV. Interestingly, immunization of mice with those peptides caused production of high levels of APL antibodies (122). A CMV pep- tide-induced monoclonal APL antibody showed significantly high binding to cardiolipin and vary- ing degrees of binding to other phospholipids in the presence of 2 GP-1. Injection of those mono- clonal APL antibodies in mice resulted in a sig- nificant increase in the number of leukocytes ad- hering to endothelial cells and enhanced throm- bus formation in vivo. These data suggest that those antibodies could be pathogenic (123). Certain viral infections can precede the develop- ment of APL syndrome (3236). Taken together, those experiments proposed that the tolerance to self 2 GP-1 could be broken after certain micro- bial exposure by molecular mimicry. This mech- anism could be operative in at least a subgroup of APL patients (124). A wide variety of diseases and immunologic alterations affect the endothe- lial phospholipids. These effects promote the pathogenicity of otherwise harmless APL anti- bodies. Therefore hypercoagulability is unpre- dictable in APL syndrome. Likewise "healthy" people with APL antibodies could remain asymp- tomatic for many years. Infection-related APL antibodies are usually transient and do not offer an increased risk for thrombotic events (1,32). The affinity of autoim- mune APL antibodies for their protein antigens in the circulation is often at most moderate, which is also a characteristic of natural autoanti- bodies (125). Indeed, patients with antibodies against either 2 GP-1 or prothrombin do usually have normal circulating levels of these proteins. Therefore, some other authors concluded that the origin of pathogenic autoimmune APL anti- bodies resides in deregulated overproduction of natural antibodies rather than in antigen-driven formation of immune antibodies (125). APL Antibodies and Apoptosis Anionic phospholipids are almost exclusively located in the intracellular surface of cell mem- branes, whereas cardiolipin is located primarily on the mitochondial membranes. Therefore, APL antibodies cannot react with their targets under normal conditions. Redistribution of the anionic phospholipids from the intracellular to the ex- tracellular compartment can occur in certain physiologic conditions such as platelet activation or apoptosis (98,126,127). Cardiolipin molecules were expressed on the surface of apoptotic cells and were recognized by APL antibodies (128). 2 GP-1 bound selectively to the surface of apop- totic cells (57,127,129). The binding of 2 GP-1 to the surface of the apoptotic cells generated an epitope for the binding of APL autoantibodies (127). Heterologous human 2 GP-1 bound to the surface of apoptotic cells induced the production of ACAs and LA activity in non-autoimmune mice (130). Importantly, neither apoptotic cells nor 2 GP-1 alone could be able to induce generation of ACAs after intravenous injection (130). Subcutaneous or intradermal administration of the heterologous 2 GP-1 molecule alone could also induce generation of APL antibodies (5,117119). Slow absorption of the 2 GP-1 over several days may induce such a phenomenon. During the sustained absorption time, 2 GP-1 could bind to apoptotic cells of the host. This in- teraction could be induced by the generation of local inflammatory response secondary to co-ad- ministration of the adjuvant (namely CFA, com- plete Freund's adjuvant) (130). Therefore apop- totic cell-bound 2 GP-1 appears to be a "true" im- munogen for the production of APL antibodies. 2 GP-1 complexed with native cardiolipin is structurally altered. Likewise, intravenous im- munization of mice with 2 GP-1 in the presence of cardiolipin vesicles induced a high level of anti-2 GP-1 antibodies, ACAs, and LA activity (131). On the other hand, binding of APL anti- bodies to apoptotic cells can occur in both in a 2 GP-1dependent and independent way (132). Taken together, these data provide evidence that exposure of phospholipids during apoptosis may be an early event in the apoptotic cellular pro- gram leading to specific interactions with circu- lating phospholipid-binding plasma proteins such as 2 GP-1. The binding of the 2 GP-1 molecule to those phospholipids exposed on the apoptotic cells could be immunogenic. That phenomenon can break tolerance and trigger the generation of APL antibodies. Once an immune response is initiated against such an immunodominant epi- tope, the immunologic response can expance to other epitopes within the complex by the process of epitope spreading. As "the end," the APL anti- CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 95 body response eventually includes autoantibod- ies against 2 GP-1 or phospholipids alone, or against a new epitope generated after the inter- action between those molecules (130,131,133). Role of Lipid Peroxidation in the Initiation and/or Propagation of APL Syndrome Oxidative injury has been suggested in the pathogenesis of a variety of disorders including vasculitic syndromes and atherosclerosis. Like- wise, a number of experiments provided evi- dence that oxidative damage could have a role in the pathobiology of the APL syndrome. Native cardiolipin, the naturally occurring form of car- diolipin, is highly susceptible to oxidation, par- ticularly upon exposure to air. In contrast, hy- drogenated cardiolipin is unable to undergo lipid peroxidation. Cardiolipin is highly sensitive to lipid peroxidation under conditions of solid- phase immunoassay. Both sera and affinity puri- fied ACA IgG from APL syndrome patients bound to oxidized cardiolipin, but did not bind to hy- drogenated cardiolipin. These data suggest that APL antibodies are directed at neoepitopes gen- erated when cardiolipin undergoes the process of peroxidation (134). Moreover, 2 GP-1 was recognized by the APL sera only when bound to oxidized cardiolipin, but not when bound to the reduced cardiolipin analog unable to undergo ox- idation (135). ACAs could bind to 2 GP-1 only when it was bound to a microtiter plate that was previously irradiated, a condition that introduces oxygen radicals (9). These data support the hy- pothesis that a simple phosholipid-2 GP-1 com- plex is not sufficient for the generation of APL antibodies unless the PL first undergoes oxida- tion. Therefore, many of the APL antibodies could actually be antibodies directed against ox- idized phospholipids (134,135). Oxidative stress is a potential component of the final common pathway leading to apoptosis. On the other hand, cells sustained progressive lipid peroxidation following an apoptotic signal (136,137). Therefore, the apoptotic cell surface is a site of increased oxidative activity. Immuno- genicity of apoptotic cell-bound 2 GP-1 depend- ed upon prolonged interaction between 2 GP-1 and the apoptotic cell surface (130). Hence both apoptosis and oxidative injury may play a dual role in the pathogenesis of APL antibodies. Antiplatelet Antibodies in APL Syndrome There is some evidence suggesting that APL autoantibodies can cross-react with platelets and can affect both their quantity and function. Platelet activation induces the exposure of an- ionic phospholipids on the outer leaflet of the membrane (126,138). Both ACAs and LAs bound to thrombin activated, but not unactivated rest- ing, platelets (139). The most likely binding site was phospholipids because there was no cross- reactivity of these antibodies with GPIIb/IIIa (139). Likewise, 2 GP-1 preferentially bound to activated platelets. Binding of ACAs to platelet surface is also 2 GP-1dependent (138,139). Moreover, some APL antibodies can induce platelet activation and aggregation (140145). Urinary excretion of the platelet-derived throm- boxane metabolite 11-dehydro-thromboxane B2 was significantly increased in patients with APL antibodies (140). Activated platelets were de- tected by flow cytometry in the majority of APL syndrome patients with neurologic involvement (146). In contrast, although APL antibodies did bind to activated platelets, they may fail to in- duce platelet activation (139,147). Therefore, the role of platelet activation in the pathobiology of thrombosis in APL syndrome is not universal. Platelets circulating in an "over-activation state" in APL syndrome could either be a "cause" or an "effect" of the thrombosis or vascular injury (148). Specific anti-platelet antibodies directed against major platelet membrane glycoproteins were higher in APL syndrome patients with thrombocytopenia compared to patients with normal platelet counts (149,150). Those anti- platelet antibodies did not demonstrate cross-re- activity with ACAs (149). Therefore, anti-platelet antibodies could represent a distinct group of auto-antibodies other than APL antibodies. They could play a significant role in the thrombocy- topenia observed in APL syndrome. However, whether binding of these anti-platelet antibodies may play a pathogenic role in thrombosis on the basis of hyperaggregability remains obscure. Heparin-induced thrombocytopenia (HIT) and APL syndrome have similar clinical presenta- tions. Enhanced platelet activation at the vascu- lar wall and endothelial injury are similar in both HIT and APL. Deposition of the immune com- plexes on slightly activated platelets further in- duces cellular activation. Likewise, generation of microvesicles provides much larger phospholipid surface area and results in enhanced thrombin generation (125,151,152). In a recent mild radi- cal-induced injury model in hamsters, anti-2 GP-1 antibodies were mainly localized within the platelet thrombus. This observation suggests that after a slight endothelial damage (first hit), acti- M. AKIF ÖZTÜRK ET AL96 vated platelets exposed negatively charged phos- pholipids, leading to deposition of APL antibody complexes perpetuating the platelet activation and thrombus growth (second hit) (125,153). Mechanisms of Pregnancy Loss in APL Syndrome Intervillous thrombosis, intravillous infarc- tions, and decidual vasculopathy disturbing pla- cental circulation were proposed as the pathobi- ologic basis of recurrent miscarriages in women with APL syndrome (154,155). The previously- mentioned hypotheses regarding the prothrom- botic state of APL syndrome could contribute to the placental thrombosis. The "disruption of the annexin V shield" hypothesis could offer a logical explanation for the placental thrombosis (69). Annexin V is normally located on the apical sur- face of syncytiotrophoblasts lining the placental villi (156,157). This protein is constitutively pro- duced to maintain the fluidity of the intervillous circulation and consequently to maintain fetal vi- ability (156,157). Infusion of anti-annexin V an- tibodies caused placental thrombosis, necrosis, and fetal loss in animal models (157). Interestingly the concentrations of this placental anticoagulant factor are markedly reduced on placental villi in APL patients with spontaneous recurrent abortion (158). Moreover, APL anti- bodies decreased the levels of villous surface an- nexin-V on placental villi (158,159). APL antibod- ies both reduced the levels of annexin V and also accelerated the coagulation of plasma on cultured trophoblasts and endothelial cells (69). Therefore, deficiency of placental surface annexin-V caused by APL antibodies may complicate the placental thrombosis observed in those patients (69,158). In contrast, ACA-2 GP-1 complexes failed to dis- place preadsorbed annexin V from lipid bilayers in another study (73). No difference was observed regarding the intensity of immunostaining for an- nexin V between placentas from women with APL syndrome and those from control subjects (160). Therefore, placental thrombosis cannot be solely attributed to the displacement of the annexin V shield, and other prothrombotic mechanisms could be operative as well. On the other hand, placental infarction is not present in all the placentae of patients with APL syndrome. Furthermore, although placental thrombosis could be responsible for late fetal losses, early miscarriages cannot be explained by placental thrombosis (155,161). Recent reports have suggested that APL antibodies could induce trophoblast dysfunction such as decreased pla- cental hormone production or trophoblast inva- sion. In a choriocarcinoma model of pregnancy, phosphatidylserine exposed during syncytium formation was targeted by APL antibodies. They inhibited the intercytotrophoblast fusion process and trophoblast invasiveness and secretion of human chorionic gonadotropin (159). APL anti- bodycontaining sera suppressed human chori- onic gonadotropin secretion by cultured tro- phoblast cells (162). Anti-annexin V antibody in- duced trophoblast apoptosis and significantly re- duced trophoblast gonadotropin secretion (163). Moreover, 2 GP-1dependent APL antibodies as well as APL antibodies against the phospholipids themselves attacked the trophoblasts, and both groups of antibodies negatively affected tro- phoblast implantation and development (164). In this regard, APL antibodies can affect tro- phoblast gonadotropin secretion and invasive- ness by binding directly to anionic phospholipids and through adhered 2 GP-1. Alternatively they can induce apoptosis and lead to the defective placentation in APL syndrome (159,163,164). Establishment of the human placenta requires invasiveness of fetal cytotrophoblast stem cells in anchoring chorionic villi. Trophoblast inva- siveness and differentiation are dependent on ad- herence to the extracellular matrix, response to external cytokine signals, and expression and the alteration of adhesion proteins. During normal cytotrophoblast differentiation along the invasive pathway, the differentiating cytotrophoblasts dramatically transform their adhesion receptor phenotype. These data suggest that a unique ad- hesion phenotype switch is required for the suc- cessful endovascular invasion and normal pla- centation (165,166). The effects of APL antibod- ies on trophoblast adhesion molecules (alpha1 and alpha5 integrins, E- and VE-cadherins) were investigated in primary cytotrophoblast cell cul- tures. APL antibodies modulated the trophoblast cadherins repertoire in vitro, suggesting that re- current pregnancy loss in APL syndrome could be associated with abnormal cytotrophoblast ex- pression of adhesion molecules (167). The Role of Genetic Predisposition in APL Syndrome Familial clustering of increased APL antibody levels has been described (168). Moreover, cer- tain polymorphisms of the 2 GP-1 molecule were associated with the presence of anti-2 GP-1 anti- bodies and APL syndrome (169,170). Associa- tions with HLA DR4, DR5, and HLA-DQ7 anti- gens and primary APL syndrome were reported (171174). Frequency of HLA-DR7 was in- CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 97 creased in SLE patients with ACAs (173,175). However, those studies were carried out in a lim- ited number of patients and genetic marker(s) for APL syndrome have not yet been demon- strated in large cohorts of subjects from differ- ent ethnic populations. Other Thrombophilic Triggers Complicating the Genesis of APL Syndrome The fibrin polymerization rate is increased in patients with APL syndrome (176). Fibrinolytic activity could be suppressed by APL antibodies. Impaired fibrinolysis could be either due to the increments in PAI-1 activity or to the inhibition of factor XII activation together with the inhibi- tion of XIIa (177,178). APL antibodies also in- hibit heparin-accelerated formation of an- tithrombin III-thrombin complexes (179). In conclusion, for the thrombophilia mecha- nism of APL syndrome, several different and/or related pathogenic mechanisms could be opera- tive concurrently, and even in the same patients to induce the generation of the features of APL antibodies. Each of the previously mentioned mechanisms could be in part operative during the pathobiologic course of APL syndrome. Moreover, it is likely that those mechanisms are tightly integrated and can display complex dual interactions as a vicious cycle. For instance, while apoptosis induces generation of APL antibodies, LAs can trigger endothelial cell apoptosis. Apoptosis is able to induce oxidative damage. Oxidative damage is a well-known inducer for apoptosis. APL antibodies can induce pathologic activation and/or injury to platelets and en- dothelium. The activation of those cells causes exposure of anionic phospholipids that can sec- ondarily amplify the generation of APL antibod- ies. Therefore, complex interactions of biologic structures and molecules are operative in the genesis of APL syndrome. A list of proposed mechanisms in the pathobiology of APL syn- drome is given in Table 1. LABORATORY DIAGNOSIS OF THE ANTIBODIES IN THE APL SYNDROME The laboratory diagnosis of APL syndrome de- pends on the detection of autoantibodies direct- ed against anionic phospholipids and/or a variety of phospholipid binding proteins. Solid-phase im- munoassays and phospholipid-dependent tests of hemostasis are used for this purpose (21,67,180 182). There still remain some problems in the detection, standardization, clinical utility, rele- vance, and significance in the laboratory diagno- sis of APL syndrome. M. AKIF ÖZTÜRK ET AL98 TABLE 1. Proposed Mechanisms in the Complicated Pathobiology of APL Syndrome Proposed Mechanism Reference Disruption of the annexin V shield 38, 69, 70 Inhibition of the protein C anticoagulant pathway 7890 Endothelial injury and/or pathological activation 9497, 99106 Alterations in the tissue factor pathway 108115 Molecular mimicry 122124 Deregulated overproduction of natural antibodies 125 Induction of apoptosis 130, 132, 133 Oxidative injury and lipid peroxydation 134, 135 Platelet activation 140146 Anti-platelet antibodies 149, 150 Genetic predisposition 168175 Induction of trophoblast dysfunction and/or trophoblast apoptosis in pregnancy 159, 162164 Modulation of cytotrophoblast expression of adhesion molecules in pregnancy 167 Increased fibrin polymerization rate 176 Impaired fibrinolytic activity 177, 178 Inhibition of formation of antithrombin III-thrombin complexes 179 Solid-Phase Tests of APL SyndromeAssociated Antibodies Solid-phase tests are developed and widely used to detect antibodies against 2 GP-1 (anti- 2 GP-1), cardiolipin (ACA), prothrombin, annex- in V, phosphatidylserine, phosphatidyletanola- mine, and many others of which their numbers are growing (180,183). Therefore, more specific measurements of antibodies associated with APL syndrome are currently available via solid-phase assays (180). A detailed summary regarding the current knowledge and clinical applications of novel antigenic targets in APL syndrome is given in "Heterogeneous clinical and laboratory mani- festations of the patient(s) with APL syndrome: a logical approach for the use of various APL anti- bodies" section of this review. Nevertheless, there are many complicated problems restricting the predictive ability of current diagnostic tests in terms of the lack of standardization, repro- ducibility, and lack of prospective and multivari- ate epidemiologic analysis (21). The inter-labo- ratory coefficient of variation for IgG APL units was found to be higher than 70%, though the within-run coefficient of variation had a median value of 10% in the First French Anticardiolipin Antibodies Standardization Workshop (184). ACA assay is currently a "routine" standard in the diagnosis of APL syndrome. However, critical laboratory tests should be repeated at least once before reaching a clinical decision in APL syn- drome (185). Another study focusing on ACA assay usefulness suggested "exceedingly high in- terlaboratory result variation, combined with a general lack of test result grading consensus and method-based variation" (185). In that study, cross-laboratory testing of samples yielded inter- laboratory coefficients of variation for lgG ACA and IgM ACA that were higher than 50% in cases. General consensus (interlaboratory agree- ment, 90% or more) was obtained in approxi- mately 40% of cases only. Different laboratories usually failed to agree on whether a sample was ACA-positive or ACA-negative. Distinct methods in various laboratories tended toward higher or lower ACA values (185). Hence, the laboratory data obtained by ACA assays should be inter- preted together with the clinical presentation of the patients, as discussed in various sections of this review. Phospholipid-Dependent Hemostatic Tests of APL Syndrome-Associated Antibodies The term LAs denotes some of the APL anti- bodies that prolong phospholipid-dependent clot- ting reactions in vitro. The main critical function of hemostasis laboratory in the diagnosis of APL syndrome is to measure LA. Essentially, a phos- pholipid-dependent screening assay such as acti- vated partial thromboplastin time (aPTT) is per- formed to test LA. If this screening test is pro- longed, normal plasma is added to the tested sample in a 1:1 mixture. If the LA is present, ad- dition of normal plasma does not correct the pro- longed assay. The next step for LA detection is to add excess phospholipid to the tested sample. Naturally, addition of those phospholipids does correct the prolonged assay. In cases of coagula- tion factor deficiency, addition of normal plasma corrects the prolonged assay at the second step of the experiment. In the presence of anti-coagula- tion factor inhibitors, prolonged assay is never corrected in all steps of the tests. Specific mea- surements of anti-factor inhibitors are mandato- ry for the diagnosis of those cases (Fig. 2) (186). The sensitivity of numerous screening or confir- matory assays for the diagnosis of LA may vary. Attention to the ratio of tested patient plasma to normal plasma is important to detect a circulat- ing inhibitor especially in a minimally prolonged aPTT. Furthermore, the normal plasma source must be "platelet poor" to maximize sensitivity in the case of a weak LA (187). Dilute Russell viper venom time (dRVVT) is an important con- firmatory test for the LA. Russell viper venom di- rectly activates factor X. Therefore, dRVVT is not affected from the intrinsic factor deficiencies be- cause they are bypassed. Thus, dRVVT is more sensitive than prolonged aPTT for the detection of LA (188) with varying reference ranges (189). The sensitivity and specificity of commercial reagents for the detection of LA may exhibit marked differences in distinct coagulometers (190). Several tests are developed for the diag- nosis of LA, including platelet neutralization pro- cedures (191), platelet-derived microvesicle based tests (192), Textarin/Ecarin ratio (193), hexagonal phase phospholipid neutralization assay (194), silica clotting time (195), kaolin clotting time (196), tissue thromboplastin inhi- bition test (197), dilute prothrombin timebased lupus ratio test (198), Taipan snake venom time (199), and lupus ratio test, a mixture of a lupus- sensitive and a lupus-insensitive aPTT-reagent with normal plasma (200). The use of platelets in confirmatory tests may lead to false-positive re- sults especially in anti-factor V and heparin-like inhibitors (201). A normal aPTT result does not exclude the presence of LA. In approximately half of APL syn- CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 99 drome cases, aPTT is prolonged. LA testing, on the other hand, is the most difficult task in the everyday practice of the hemostasis laboratory. Not only the enigmatic clinical course of the APL syndrome, but also certain technical issues com- plicate the detection of LA (201). Contamination with platelets, instrumental effects, pH drift dur- ing incubation, and difficulties in standardization represent some of the problems for LA laborato- ry identification (201). Anti-2 GP-1 and anti-pro- thrombin monoclonal antibodies offered better understanding of the mechanism by which LA prolongs in vitro clotting. LA-positive monoclon- al antibodies also improved the LA diagnosis (67). Mixing studies are widely used to identify LA or any other circulating coagulation inhibitor (187). There are some important variables in case of "mixing." The normal plasma source should be platelet-poor to maximize sensitivity as mentioned previously. The patient plasma to normal plasma ratio is extremely important, par- ticularly in the suspected APL syndrome case of a minimally prolonged aPTT (187). A hemostatic test should be optimally combined for the detec- tion of LA or exclusion of a coagulation inhibitor. Twenty-one patients who initially presented with a prolonged prothrombin time (PT) or aPTT or both were tested for the presence of LA in a study (202). The authors used a battery of coagulation tests, including both immediate and 2-hour mix- ing studies, a platelet neutralization procedure, a tissue thromboplastin inhibition test, and dRVVT. Ten percent of the patients only had a prolonged PT, 33% only had a prolonged aPTT, and in 57% both test results were abnormal. In 15 patients, inhibition was evident on immediate assay of equal-volume mixture studies of patient plasma and normal pooled plasma. However, in some patients, it was evident only after a 2-hour incu- bation period. Therefore, proper incubation is important in mixing studies for LA or inhibitor detection. Fifteen of 18 samples showed correc- tion of the abnormal screening study when platelets were used as a source of phospholipid. M. AKIF ÖZTÜRK ET AL100 FIG. 2. Simplified practical schema for the laboratory diagnosis of antiphospholipid syndrome. APL: antiphos- pholipid, ACA: anticardiolipin antibody, LA: lupus anticoagulant, ELISA: enzyme-linked immunosorbent assay. Both the tissue thromboplastin inhibition (ab- normal in 20 of 21 samples) test and dRVVT (in 13 of 14 samples) were found to be sensitive as- says (202). The dRVVT test correlates most close- ly with elevated anticardiolipin antibodies. A het- erogeneous cohort of 725 patients referred for LA detection was reviewed in a retrospective study (203). A positive LA test result was defined by abnormal results obtained by at least two techniques from the reagents used and confirmed with a platelet-neutralizing procedure. The au- thors found that a positive dRVVT test result is strongly correlated with elevated ACA (203). Sakakura and coworkers investigated kaolin clot- ting time, mixing with normal plasma in kaolin clotting time, dRVVT, dRVVT at high lipid con- centrations, APL antibodies, and ACA-2 GP-1 complex antibody in 135 patients with prolonga- tion of aPTT and diagnosed 86 patients positive for LA. In this study, the sensitivity of aPTT and dRVVT/dRVVThigh lipid concentrations ratio for LA was markedly high, but the specificity of aPTT for LA was not so remarkable. The speci- ficity, but not the sensitivity, of kaolin clotting time mixing with normal plasma in kaolin clot- ting time was also markedly high. The authors concluded that dRVVT/dRVVThigh lipid con- centrations ratio gave high sensitivity as well as specificity. Of their patients positive for LA, 25% were found to be positive for APL antibodies and 17% were positive for ACA-2 GP-1 complex anti- body (204). Clinical strategy is important for the selection of laboratory tests for the detection of LA (205,206). A decision tree can be constructed using a combination of aPTT and dRVVT with confirmatory tests, tissue thromboplastin time (TTI), platelet neutralization procedures, and mixing studies (205). Predictive values (207) and clinical associations (208,209) of all labora- tory tests may vary. Optimization of solid-phase and hemostatic tests should be performed for the rational approach to the management of APL syndrome (210,211). CLINICAL FEATURES OF THE APL SYNDROME Thrombosis is the basic pathologic process in the APL syndrome. It represents the main mech- anism behind the majority of the clinical features in patients with APL syndrome. Arterial and ve- nous thrombosis can be present in APL syn- drome. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the spectrum of clinical find- ings is extremely wide (Fig. 3). In terms of overall frequency, a recent multi- center study of a cohort of 1000 patients with APL syndrome demonstrated that the most com- mon initial manifestations were deep vein throm- bosis (31.7%), thrombocytopenia (21.9%), live- do reticularis (20.4%), stroke (13.1%), superfi- cial thrombophlebitis (9.1%), pulmonary em- bolism (9.0%), fetal loss (8.3%), transient is- chemic attack (7.0%), and hemolytic anemia (6.6%) (23). The frequencies of the majority of clinical features including recurrent thromboses and miscarriages are comparable in primary and secondary APL syndromes. However, arthritis, livedo reticularis, thrombocytopenia, and leuko- penia appear to be more common in SLE-associ- ated APL syndrome (23). Those differences could probably be attributed to the association of the manifestations with SLE itself. Likewise, the fe- male-to-male ratio was higher in the SLE-APL syndrome group (23). Venous Thrombosis in APL Syndrome Venous thrombosis most commonly involves deep and superficial venous system of the legs. Venous involvement often takes place as bilater- al and multiple (23). Deep venous thrombosis can be resulted in pulmonary thromboembolism in up to one third to half of APL syndrome pa- tients (1,23). Other less commonly involved sites of venous thrombosis include adrenal, hepatic, mesenteric, portal, splenic, subclavian, jugular, retinal, renal, skin, or upper extremity veins; su- perior and inferior vena cavae; and cerebral ve- nous sinuses (1,23). The presenting symptoms depend on the localization, extent, and acuity of the thrombosis. Thrombosis can occur sponta- neously. However, the presence of a precipitating factor such as hormone replacement therapy, oral contraceptives, immobilization, trauma, con- gestive heart failure, or pregnancy increases the risk of thrombosis (1). Neurologic Features in APL Syndrome Recurrent stroke and transient ischemic attacks are the most common neurologic manifestations of APL syndrome (23,29,212,213). Arterial thrombotic events and embolism from cardiac vegetations may represent the underlying mecha- nism (1). Ischemic events can occur in any vas- cular territory of the brain. The average age of onset of an APL-associated cerebrovascular event is approximately a decade younger than that of the typical cerebral ischemia population (45). CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 101 Some cases may lead to multiinfarct dementia. Other stroke risk factors such as cigarette smok- ing or hyperlipidemia may further complicate the risk of recurrent ischemic events in patients with APL syndrome (29). A less common cerebral vas- cular thrombotic manifestation was cerebral sinus thrombosis (1,23,212214). Other less common neurologic manifestations of APL syndrome are migraine-type headache, chorea, transverse myelopathy, myasthenia gravis, Guillain Barré syndrome, transient global amnesia, seizures, motor neuron disease, and depression. However their associations with APL syndrome have been less well-determined (29,212214). Cerebral dys- function in APL syndrome may range from mild cognitive dysfunction to severe dementia. Retinal and choroidal vessel involvement may cause acute ocular ischemia and transient blurred vision or amaurosis fugax, transient diplopia, and de- creased vision. Transient field loss may also de- velop (1,29,212216). Sudden sensorineural hearing loss has been rarely reported in APL syn- drome (217). Cardiac Features in APL Syndrome The most common cardiac manifestation of APL syndrome is valvular pathologies. They in- clude verrucous endocarditis, valvular thicken- ing, and insufficiency. Valvular stenosis is rarely seen. The mitral valve is the most com- monly affected site, followed by the aortic valve, although the tricuspid or pulmonary valve can also be affected (1,23,214,218220). A strong association between valvular abnor- malities and arterial brain infarcts in APL syn- drome patients does exist. This association re- flects the embolization from the damaged valve (219). Patients with APL syndrome have in- creased risk for myocardial infarction, in- creased risk for graft occlusion after coronary artery bypass surgery, and restenosis after an- gioplasty (18,26,214,221). APL antibodies may rarely cause myocardial infarction even in the presence of normal coronary arteries (222). In addition, there have been some reports of in- tracardiac thrombi or cardiomyopathy in asso- ciation with the APL syndrome (23,218). M. AKIF ÖZTÜRK ET AL102 FIG. 3. Schematic representation of the clinical manifestations in antiphospholipid antibody syndrome. Cutaneous Lesions in APL Syndrome Cutaneous lesions appear in approximately one third of patients with APL syndrome. Livedo reticularis is by far the most common cutaneous manifestation. It is frequently the initial clinical feature of the syndrome (23,223). Other cuta- neous findings of the APL syndrome include necrotizing vasculitis, livedoid vasculitis, throm- bophlebitis, cutaneous ulceration, necrosis, ery- thematous macules, purpura, ecchymoses, painful skin nodules, and subungual splinter he- morrhages (214,223). Pulmonary Involvement in APL Syndrome The most common pulmonary complications of APL syndrome are pulmonary thromboem- bolism and pulmonary hypertension (23,214, 224). Pulmonary embolism occurs in approxi- mately 14% to 30% of the patients. It may be the initial feature in approximately 9% of the pa- tients (23,214). Thrombosis in calf veins, inferi- or vena cava, tricuspid valve vegetations, and right-sided intracardiac thrombosis may be the source of pulmonary emboli (214). Recurrent pulmonary embolism may lead to thromboem- bolic pulmonary hypertension. Severe cases with pulmonary hypertension may be accompanied by isolated tricuspid valve insufficiency (224). Several cases of "primary" (non-thromboembol- ic) pulmonary hypertension complicating prima- ry APL syndrome have been described. The out- come in patients with pulmonary hypertension and APL syndrome is usually fatal (224). Rare cases with diffuse alveolar hemorrhage, fibros- ing alveolitis, adult respiratory distress syn- drome, and pulmonary artery thrombosis have all been reported (23,214,224). Renal Involvement in APL Syndrome Renal manifestations of the APL syndrome are relatively rare, occurring in 2.7% of all cases (23). Vasoocclusive events can occur at any level of the renal vasculature. The disease may affect the main renal artery and its branches, arterioles, glomerular capillaries, and renal veins. Characteristic histologic findings of renal APL syndrome are intrarenal vascular lesions, arte- riosclerosis, fibrous intimal hyperplasia, partial or complete vascular occlusions, and thrombotic microangiopathy. Focal cortical atrophy is an- other finding. Inflammatory vascular lesions are typically absent (225). These histopathologic findings are clinically manifested by hyperten- sion, acute or chronic renal insufficiency, pro- teinuria, nephrotic syndrome, and inconsistent hematuria in the majority of the APL syndrome patients (1,214,225,226). Among those manifes- tations, hypertension is of particular importance because it is almost invariably present among pa- tients with renal APL syndrome (225). Mild, se- vere, or even malignant hypertension may be present. All patients with APL syndrome and hy- pertension should be investigated for renal in- volvement (especially renal artery stenosis). Hypertension is often the only early clinical man- ifestation of renal APL syndrome. Other nephro- logic manifestations of APL syndrome include he- modialysis vascular access thrombosis, and pri- mary graft non-function in renal transplant re- cipients (214,226). Hematologic Manifestations in APL Syndrome Thrombocytopenia in the APL syndrome is a frequent finding, occurring in 20% to 30% of pa- tients (23,214). It is usually chronic and mild, and does not cause a severe bleeding complica- tion (23,214). On the other hand, elevated levels of APL antibodies are common in immune throm- bocytopenic purpura, and the persistent presence of APL antibodies is an important risk for the de- velopment of thrombosis or fetal loss (227). Autoimmune hemolytic anemia may develop in some patients with APL syndrome. The direct Coombs' test result is positive in 14% of patients with primary APL syndrome and 40% of patients with APL syndrome secondary to SLE. However, hemolytic anemia is not common in those pa- tients (214). Autoimmune hemolytic anemia is more common in secondary APL syndrome (23). DIC, hemolytic-uremic syndrome and thrombot- ic thrombocytopenic purpura are uncommon complications of APL syndrome. However, they represent the drastic rare clinical manifestation called catastrophic APL syndrome (1). Other Manifestations of APL Syndrome Nasal septum perforation, pancreas infarction, splenic infarction, Budd-Chiari syndrome, Addison's disease due to adrenal infarction, and pituitary failure after necrosis of the pituitary gland have all been reported in APL syndrome (1,23,228). Musculoskeletal manifestations in- cluding arthralgia or arthritis are very common (38.7% and 27.1%, respectively) (23). Avascular necrosis of bone may occur in approximately 2% of the patients (23). However, this necrotic com- plication can be detected by magnetic resonance imaging in approximately one fifth of the pa- tients with primary APL syndrome who did not receive steroids before (229). CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 103 Obstetric Complications in APL Syndrome APL syndrome is associated with both fetal and maternal complications. Fetal complications include both early abortions before the 10th week of gestation and fetal deaths at or after the 10th week of gestation. Preterm labor at or be- fore the 34th week of gestation may also take place (1,230). These obstetric features were specifically mentioned in the 1999 International Consensus Statement Classification Criteria for APL syndrome (231). Other obstetric complica- tions include intrauterine growth retardation, placental abruption, pre-eclampsia, and eclamp- sia (1,23,226,230). Association with HELLP syn- drome (hemolytic anemia, elevated liver en- zymes, low platelet count in association with pre- eclampsia) has been rarely reported (1). Catastrophic APL Syndrome Catastrophic APL syndrome is an acute and drastic manifestation of the APL syndrome char- acterized by clinical involvement of at least three different organ systems over days or weeks with histopathologic evidence of multiple occlusions of large or small vessels (232). It is fortunately a rare complication (less than 1% of all patients with APL syndrome). The mortality is as high as 50% and most patients die as a result of a com- bined cardiac and respiratory failure (232,233). Respiratory failure can develop after acute respi- ratory distress syndrome (ARDS) and diffuse alve- olar hemorrhage. Precipitating factors include in- fections, trauma, surgery, drug administration, and warfarin withdrawal in 22% of the patients with catastrophic APL syndrome. The majority of those patients develop widespread vascular oc- clusion mainly affecting small vessels of organs, particularly kidney, lungs, brain, heart, adrenal glands, and liver, causing microangiopathy. Only a minority of these patients experience occlusion of a single large vessel. Digital ischemia with frank gangrene, superficial skin necrosis, and is- chemic ulceration of the limbs may develop. Thrombocytopenia was reported in 68% of the patients, hemolytic anemia in 26%, and DIC in 28%. They all have the potential to contribute to the multiorgan thrombotic microangiopathy in catastrophic APL syndrome (232,233). HETEROGENEOUS CLINICAL AND LABORATORY MANIFESTATIONS OF THE PATIENT(S) WITH APL SYNDROME: A LOGICAL APPROACH FOR THE USE OF VARIOUS APL ANTIBODIES The spectrum of antigens and autoantibodies in the APL syndrome is expanding. Conventional approach for the detection of APL antibodies in- cludes the clotting-based assay LA and solid phase immunoassays for ACAs. However, a sig- nificant number of patients with clinical features of APL syndrome remain negative for those con- ventional APL assays. Hence, tremendous efforts are being spent to demonstrate novel antigenic targets and to develop novel laboratory assays to improve the diagnostic yield in the APL syn- drome. However, those efforts in the laboratory may adversely affect critical clinical decision making in the clinic. Therefore, a hierarchical and rational approach is necessary for effective clinical management of APL syndrome patients. Since the first documentation in 1983 (234), a large number of clinical studies documented the association between the ACAs and the develop- ment of arterial and/or venous thrombotic events (4043,235237). ACAs can also significantly in- crease the recurrence risk following an episode of vascular thrombosis (25,238,239). The risk for development of APL antibodyrelated disorders is higher in patients with high titer IgG isotype (40,41,44,45,240,241). However, IgM isotypes and low titer ACAs could be associated with an increased thrombosis risk as well (236,237). Moreover, there is growing evidence for the as- sociation of IgA isotype ACAs and APL anti- bodyrelated disorders (242,243). It is generally, however, not assayed routinely and not suggest- ed as a diagnostic criterion because other authors failed to confirm this association (244246). The association of ACAs with vascular throm- bosis is not, however, universally confirmed (15,46,241,246248). A recent meta-analysis concluded that only high-titer IgG isotype ACA is clearly associated with thrombosis. Less consis- tent results are available for IgM isotype ACAs and low titer IgG isotype ACAs (241). However, there are significant differences between those studies regarding the methods of the research, associated clinical conditions, clinical end-points, laboratory methods for the detection of ACAs, and cut-off levels for the antibodies. Thus, the comparison of studies is really problematic. The titers for APL antibodies can fluctuate. Furthermore patients who had initially had neg- ative test results for APL antibodies could have positive test results for ACAs later (20,249). Therefore, prospective well-designed studies via serial measurements of ACAs with better inter- laboratory harmonization at certain critical time points during the clinical course of APA syn- drome is strictly needed to draw more depend- able conclusions. However, in everyday clinical M. AKIF ÖZTÜRK ET AL104 practice, ACA IgG, IgM, and IgA antibodies should be searched in cases of unexplained arte- rial and/or venous thrombosis (18,26,28,250). The association of LAs and thrombosis is more significant. The risk of thrombosis is independent of the laboratory tests used to identify the LAs (46,235,241,251254). LAs are more closely as- sociated with arterial and/or venous thrombosis than ACA antibodies (235,241,253,254). Patients with SLE and LA are at approximately six times greater risk for venous thrombosis than patients without LA. On the other hand, patients with SLE and ACA antibodies have an approximate two times greater risk for venous thrombosis than pa- tients without ACA antibodies (254). A recent meta-analysis examining the risk of venous thrombosis in individuals with APA syndrome without underlying autoimmune disease or pre- vious thrombosis revealed that the risk for thrombosis is higher in patients with LA than in other patients. This risk was also higher than in patients with ACAS even when only high titers were considered (253). The closer association of the LAs with throm- bosis could be partly attributed to the lower sen- sitivity and greater specificity of LA versus ACA assays (235,250). ACA ELISA is more sensitive but less specific than the LA assay (235,250). In the cohort of 1000 well-documented patients with APL syndrome, the presence of ACA was de- tected in 879 patients and LA in 536 patients (23). Therefore, any test is neither sufficiently sensitive nor specific for screening or diagnostic purposes. Both tests should be assayed and re- peated in cases of strong suspicion for APL syn- drome (18,26,28). The presence of 2 GP-1independent benign ACAs in the general population naturally de- creases the specificity of the ACA assay for the diagnosis of APL antibody syndrome. The anti- bodies against 2 GP-1 are directed to an epitope readily available on the native protein (255). Tests specific for 2 GP-1 can help to distinguish false positive biologic test results for syphylis and true APL antibodies (256). There is a subgroup of patients who demonstrate clinical features com- patible with APL antibody syndrome but are neg- ative for conventional APL antibody assays (17,257). Therefore, antibodies against the 2 GP-1 molecule detected with solid phase ELISA could improve the specificity of conventional APL anti- body assays for the diagnosis of APL antibody syndrome. Anti-2 GP-1 antibodies may even be superior to ACA assays for the diagnosis of APL antibody syndrome based on some studies (22,258262). Some other studies suggested that anti-2 GP-1 ELISA does not give additional in- formation for a thrombotic risk than the conven- tional APL antibody assays (235,263266). A re- cent meta-analysis concluded that firm evidence for the association of anti-2 GP-1 antibodies and thrombosis is still lacking (267). Likewise, the anti-2 GP-1 antibodies are not more sensitive than conventional APL antibody assays for the diagno- sis of APL syndrome in women with recurrent fetal loss (211,268270). A potential advantage of screening for anti-2 GP-1 antibodies could be in- creasing the specificity and the positive predictive value of the ACA testing in ACA-positive patients (211,271). Moreover, the presence of anti-2 GP-1 antibodies in patients with LA and high titer ACAs could also be of prognostic importance and should alert the physician about the risk for the bad out- come of the disease (264). However, the anti- 2 GP-1 assay is not recommended for a "first-line" screening test in suspected cases for APL antibody syndrome. It could be searched if both LA and ACA remained negative and still suspicion persists (18,21,26,28,250,264). Prothrombin is another major phospholipid binding protein. The prevalence of anti-pro- thrombin antibodies ranges from 50% to 90% in APL antibodypositive patients depending on the laboratory methodology (272). Antibodies against prothrombin were demonstrated in pa- tients with LAs and severe hypoprothrombinemia or in patients with LAs and normal prothrombin levels (273275). Anti-prothrombin antibodies are associated with LA activity (4,250). They can also be determined by standard ELISA method (276). A number of clinical studies evaluated the presence of anti-prothrombin antibodies as a risk factor for arterial and/or venous thrombosis in APL syndrome. Some authors reported signifi- cant correlation with anti-prothrombin antibod- ies and thrombosis (277282), while some others did not (235,283286). Therefore, routine mea- surement of anti-prothrombin antibodies is not recommended to define their thrombotic risk in patients with APL syndrome (68,267,272). Anti- prothrombin antibodies do not interfere with the coagulant properties of prothrombin (68). More- over, most of them may react with neoepitopes generated after the binding of the prothrombin molecule to phosphatidylserine via calcium ions (68). The anti-prothrombin antibodies detected in those previously mentioned assays were di- rected against the prothrombin molecule alone. Antibodies against phosphatidylserine-prothrom- bin complex were more closely associated with CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 105 LA activity than the anti-prothrombin antibodies. They are significantly correlated with the clini- cal manifestations of the APL syndrome while anti-prothrombin antibodies were not (287,288). Therefore the place of anti-phosphatidylserine- prthrombin complex antibodies as a marker for APL syndrome remains to be elucidated. Annexin V is a tissue and circulating phospho- lipid-binding protein with anticoagulant proper- ties. It has high affinity for anionic phospholipids and can displace coagulation factors from phos- pholipid surfaces (38). Displacement of the an- nexin V shield by APL antibodies has been pro- posed in the pathogenesis of APL syndrome as discussed previously (38). Antibodies directed against the annexin V molecule do have LA prop- erties (289). Anti-annexin V antibodies have also been reported in some patients with APL syn- drome (277,290,291). Moreover anti-prothrom- bin and anti-annexin V antibodies could be more specific for the diagnosis of APA syndrome (277). Furthermore, anti-annexin V IgG antibodies were associated with higher incidences of arterial or venous thrombosis, intrauterine fetal loss, and prolonged aPTT in patients with SLE (292). However, conflicting data exist regarding the as- sociation of anti-annexin V antibodies and the clinical manifestations of the APL syndrome (291). Hence, strong evidence for the functional and clinical significance of those autoantibodies is not yet available. Low density lipoprotein (LDL) oxidation may contribute to the development of atherosclerosis in vivo (293,294). Oxidized LDL is more im- munogenic, and led to the generation of autoan- tibodies (295). Antibodies directed against oxi- dized LDL were associated with myocardial in- farction in prospective studies (296). Circulating LDL contains significant amounts of cardiolipin suggesting that many ACAs and anti-oxidized LDL antibodies may be directed at similar epi- topes (297). Moreover, APL antibodies are cross- reactive to oxidized LDL (298). On the other hand, anti-oxidized LDL antibodies are higher in patients with APL syndrome compared to healthy controls and patients with SLE without clinical features of APL syndrome (299-301). The levels of anti-oxidized LDL did not show strong correla- tion with those of anti-2 GP-1 or ACAs. Therefore anti-oxidized LDL may represent a distinct subset of antibodies (299). Elevated levels of anti-oxi- dized LDL antibodies are potential markers for the development of arterial thrombosis in patients with APL syndrome (299,300). However, follow- ing studies failed to demonstrate an association between high anti-oxidized LDL antibody levels and arterial thrombosis (301,302). On the con- trary, high anti-oxidized LDL antibody titer was correlated with venous thrombosis in another study (301). Moreover, the association of anti-ox- idized LDL antibodies and primary APL syndrome also remains controversial (301). Therefore, ad- ditional studies are needed to determine the exact clinical relevance of anti-oxidized LDL antibodies in the APL syndrome. Pathologic activation of the endothelial cells by APL antibodies contributes to the prothrom- botic state in APL syndrome as discussed previ- ously. APL antibodies themselves bind to en- dothelial cells (100,303,304). Moreover, a dis- tinct group of endothelial cell reactive antibod- ies other than well-known APL antibodies can occur in the plasma of patients with APL anti- bodies (305,306). However, whether those anti- bodies are initiators of the endothelial injury or endothelial cell surface alterations lead to the formation of those antibodies remains to be elu- cidated. Although the presence of those anti-en- dothelial antibodies was associated with a his- tory of thrombotic events (306), the utility of the anti-endothelial cell antibodies in the diag- nostic workup of the APL syndrome remains to be elucidated. There are additional potential targets for APL antibodies, including protein C and protein S, thrombomodulin, factor XI, factor XII, high-mol- ecular-weight kininogen, low-molecular-weight kininogen, tissue plasminogen activator, comple- ment component C4, complement factor H, co- agulation factor VII/VIIa, antimitochondrial an- tibody type 5, platelet-activating factor, and mal- ondialdehyde-modified lipoprotein(a) (8890, 283,307315). However, the association of those auto-antibodies and APL syndrome has not been confirmed. Accordingly a firm evidence for the clinical use of those antibodies for investigating the APL syndrome is currently absent. Cardiolipin is the most widely used phospho- lipid in the APL antibody assays. There is exten- sive cross reactivity between ACAs and antibod- ies against other phospholipids (316318). Therefore, serum anti-noncardiolipin antibodies could be identified by their cross-reactivity with ACAs. There may be no rational to perform ELISAs for other phospholipids. However, some of the antibodies against phospholipids other than cardiolipin cannot be detected by conven- tional ACA assays. ELISA methods based on car- diolipin as target antigen may not be sensitive enough to detect all APL antibody-positive sub- M. AKIF ÖZTÜRK ET AL106 jects (19,316,319323). Moreover, a significant correlation was found between those antibodies and thrombosis and thrombocytopenia (321,324, 325). Recently, a multitarget ELISA assay using a coating mixture of cardiolipin and non-cardi- olipin phospholipids including phosphatidylinos- itol, phosphatidylserine, and phosphatidylethan- olamine was suggested to enhance the ability to identify patients with APL syndrome (316). On the contrary, testing for APL antibodies other than LA and ACA is not clinically useful in the evaluation of APL syndrome (317,326). How- ever, some patients with clinical features for APL syndrome who are negative for conventional APA assays (ACA and/or LA assays) can be positive for antibodies againts non-cardiolipin phospho- lipids (316,319323). Therefore, patients whose clinical symptoms suggest APL syndrome but whose sera are negative for conventional APA as- says should be screened for antibodies against non-cardiolipin phospholipids including phos- phatidylserine, phosphatidylethanolamine, phos- phatidylglycerol, phosphatidylinositol, and phos- phatidylcholine (18,26,28). In summary, in a patient with unexplained thrombosis of any type or recurrent fetal loss both LA and ACA, all three assays should be per- formed. There is general agreement that solid- phase ELISA is the method of choice for the de- tection of ACAs (18,26,28,327). For the detec- tion of LAs, dRVVT seems to be the most sensi- tive assay (18,26,28). The titers for APL anti- bodies can fluctuate and patients who had ini- tially had negative test results for LAs or ACAs could be later positive, or patients who initially had either IgM or low IgG can develop higher levels of IgG or LAs (20,240,249). Therefore, pa- tients should be re-tested for those assays in case of strong suspicion (21). For the patients with high suspicion for APA syndrome who disclose negative results for LA and ACA assays, the pres- ence of isolated subgroup antibodies against 2 GP-1, prothrombin, annexin-V, phosphatidyl- serine, phosphatidylethanolamine, phosphatidyl- glycerol, phosphatidylinositol, or phosphatidyl- choline should be tested (18,21,26,28,250). THE "BICK CLASSIFICATION" OF APL ANTIBODYMEDIATED THROMBOSIS SYNDROMES Bick has proposed to divide the APL anti- bodymediated thrombosis syndromes into six subgroups (18,2628) (Table 2). He stated that there is little overlap (approximately 10% or less) among these subtypes. Moreover, type IV patients (mixtures of types I, II, and III) are also uncommon, with most patients fitting into one of the first three types. This classification could be important for choosing the initial and long- term therapeutic alternatives from the clinical point of view. Recommended antithrombotic therapy regimens for each subgroup is given in Table 2 and also discussed in "Clinical strategies against APL syndrome" section. DIAGNOSTIC CRITERIA OF APL SYNDROME: A STILL ONGOING PROCESS The diversity of the clinical and laboratory fea- tures of the APL syndrome necessitated a set of criteria for diagnosis. Preliminary classification criteria for APL syndrome were formulated dur- ing a post-conference workshop held in Sapporo in 1998 following the Eighth International Multidisiplinary Symposium on APL Antibodies (231) (Table 3). The workshop focused on defin- ing a category of "definite" APL syndrome. These criteria were intended to provide a uniform basis for clinical and research studies. The intention was not to guide clinical diagnosis or treatment of APL syndrome in individual patients. There- fore, the criteria encompass those clinical and laboratory features that were most closely asso- ciated with the APL syndrome in prospective clin- ical and experimental studies. IgG and IgM aCL antibodies can be detected in approximately 5% of normal subjects, while persistently elevated levels can be present in less than 2% on repeat testing (328). Hence, the persistent presence of APL antibodies for 6 or more weeks is an essen- tial requirement for APL syndrome classification. Other features of APL syndrome such as throm- bocytopenia, hemolytic anemia, transient cere- bral ischemia, transverse myelopathy, livedo reticularis, cardiac valve disease, multiple scle- rosislike syndrome, chorea, and migrane was not included in the Sapporo criteria because their associations were not strongly confirmed by clin- ical and experimental investigations. Likewise, anti-2 GP-1 antibodies, low-positive titers of IgG or IgM ACAs, IgA isotype of ACA, and antibodies against other phospholipids or phospholipid- binding proteins were not included as criteria in this classification (231,329). Recently, the Sapporo criteria for APL syn- drome were tested by experienced clinicians. Two hundred forty-three consecutive patients CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 107 who had clinical diagnoses of primary APL syn- drome (n=49), secondary APL syndrome (n=26), systemic lupus erythematosus (SLE) without clinical APL syndrome (n=131), and lupus-like disease without clinical APL syndrome (n=37) were classified according to the classifi- cation criteria. Sensitivity, specificity, positive predictive value, and negative predictive value were found to be 0.71, 0.98, 0.95, and 0.88, re- spectively (330). Specificity and positive predic- tive value were high and these preliminary crite- ria could be useful for clinical studies. Sensitivity and negative predictive value were lower com- pared with physician-diagnosed APL syndrome because some other diagnostic features of the disease such as livedo reticularis, thrombocy- topenia, low-titer aCL, IgA ACA, or anti-2 GP-1 were not included in the criteria for definite APL M. AKIF ÖZTÜRK ET AL108 Data from references 18, 2628. *Antithrombotic therapy should not be stopped unless the ACAs has been absent for the preceding 4 to 6 months. Based on The FDA Safety Information and Adverse Event Reporting Program, 2002 Safety Alert-Lovenox. Deep venous thrombosis with or without pulmonary embolus · Acute treatment with heparin/LMWH followed by long-term* self-administration of subcutaneous porcine heparin/LMWH · Clopidogrel (long term if stable) Type I syndrome Coronary artery thrombosis Peripheral artery thrombosis Aortic thrombosis Carotid artery thrombosis · Acute treatment with heparin/LMWH followed by long-term* self-administration of subcutaneous porcine heparin/LMWH · Clopidogrel (long term if stable) Type II syndrome Retinal artery thrombosis Retinal vein thrombosis Cerebrovascular thrombosis Transient ischemic attacks Cerebrovascular · Long-term (clopidogrel) plus long-term* self-admin- istration of subcutaneous porcine heparin/LMWH Retinal · Clopidogrel;if failure, add long-term* self-adminis- tration of subcutaneous porcine heparin/LMWH Type III syndrome Mixtures of types I, II, and III · Therapy depends on types and sites of thrombosis, as per preceding recommendations Type IV syndrome Placental vascular thrombosis Fetal wastage common in first trimester Fetal wastage can occur in second and third trimesters Maternal thrombocytopenia (uncommon) · Low dose aspirin (81 mg/day) before conception and add fixed, low dose porcine heparin at 5000 U every 12 hours immediately after conception, Dalteparin (but not enoxaparin) Type V (fetal wastage) syndrome Antiphospholipid antibody No apparent clinical manifestations · No clear indications for antithrombotic therapyType VI syndrome TABLE 2. "Bick Classification" of APL Antibody-Mediated Thrombosis Syndromes and Recommended Antithrombotic Therapy Regimens Type of Thrombotic Syndrome Clinical Presentation Recommended Antithrombotic Therapy syndrome. Therefore, classification criteria for "probable" or "possible" APL syndrome should be described to better understand the boundaries of APL syndrome and the full spectrum of "true" APL syndrome (329). At the subsequent work- shop on classification criteria held in Tours, France in September 2000, no alterations were added to the Sapporo criteria. However, future efforts should be focused on the following to im- prove them: 1) further evaluation of the interna- tional (Sapporo) criteria for definite APL syn- drome; 2) definition of other categories of APL syndrome, such as "probable" and "possible" APL syndrome; 3) guidelines for the clinical diagnosis as distinct from classification of APL syndrome; 4) strategies to improve the compliance of labo- ratories worldwide, with recommended proce- dures for LA and ACA assays; 5) development of monoclonal antibody standard reagents for ACA and LA assays; and 6) refinement and subse- quent evaluation of anti-2 GP-1 assays for use in identification of APL syndrome (331). Because the major features of primary and secondary APL syndromes are similar and SLE is by far the most CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 109 TABLE 3. Preliminary Criteria for Classification of Definite APL Syndrome Definite antiphospholipid antibody syndrome is considered to be present if at least 1 of the clinical criteria and 1 of the laboratory criteria are met. Clinical criteria 1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis must be confirmed by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathologic confirmation, thrombosis should be present without significant inflammation in the vessel wall. 2. Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or 2. (b) One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or 2. (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. In studies of populations of patients who have more than 1 type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above. Laboratory criteria 1. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on 2 or more occasions, at least 6 weeks apart, measured by a standardized enzyme-linked immunosorbent assay for beta2 glycoprotein I-dependent anticardiolipin antibodies. 2. Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulants/Phospholipid- Dependent Antibodies), in the following steps: (a) Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g. activated partial thromboplastin time, kaolin clotting time, dilute Russell's viper venom time, dilute prothrombin time, Textarin time. 2. (b) Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma. 2. (c) Shortening or correction of the prolonged coagulation time on the screening test by addition of excess phospholipid. 2. (d) Exclusion of other coagulopathies, e.g. factor VIII inhibitor or heparin, as appropriate. Data from reference 231. No exclusions other than those contained within the above criteria are needed. However, because of the likelihood that thrombosis may be multifactorial in patients with the APL syndrome, the workshop participants recommend that (a) patient populations being studied should be assessed for other contributing causes of thrombosis, and (b) such populations should be stratified according to identifiable or probable risk factors, e.g., age or comorbidities. Specific limits were not placed on the interval between the clinical event and the positive laboratory findings. However, it was the view of many at the workshop that (a) information about such intervals should be assessed when relevant, and (b) the relatively strict definition of laboratory criteria (including the requirement that results again be positive on repeat tests performed at least 6 weeks after the initial test) would help to exclude antiphospholipid antibody positivity that represents an epiphenomenon to the clinical events. common cause of secondary APL syndrome, ex- clusion criteria have been proposed for the diag- nosis of primary APL syndrome (Table 4) (332). CLINICAL STRATEGIES AGAINST APL SYNDROME: OBSERVATION AND RATIONAL CLINICAL MANAGEMENT Despite tremendous advances in our under- standing the pathogenesis of APL syndrome, the mainstay of the management is still anticoagula- tion. Available data for making a decision on how to treat APL syndrome patients largely come from retrospective studies, and data from prospective clinical trials are limited. Moreover, there is no consensus regarding the duration and intensity of anticoagulant therapy after the thrombotic event occurred. Management strate- gies based on "Bick classification of APL syn- drome" have been given in Table 2. This classifi- cation offers a useful tool for the management of APL in clinical practice. Whether or not to treat asymptomatic healthy individuals with APL antibodies (type VI disease in Bick's classification) is also a matter of debate. A weakly or transiently elevated positive APL an- tibody test result needs no prophylaxis. Asymp- tomatic healthy subjects with persistently posi- tive moderate-to-high titer APL antibodies are generally given low-dose aspirin (ASA 75100 mg/day). Low-dose aspirin alone could offer some benefit in recurrent miscarriage syndrome with APL antibodies (333335). Aspirin prophy- laxis could also provide protection against post- partum nonpregnancy-related vascular throm- bosis in APL syndrome patients who present with pregnancy loss as their only manifestation (336). Prophylactic aspirin is suggested to all patients with SLE to prevent both arterial and venous thrombotic manifestations, especially those with APL antibodies (337). On the other hand, the use of low dose aspirin in people with ACAs did not protect against deep venous thrombosis or pul- monary embolism (41). Currently there is still no satisfactory prospective evidence that low-dose aspirin provides an adequate prophylaxis against thrombosis especially in venous site in asympto- matic carriers of APL antibodies. Hydroxychloro- quine can decrease the titers of APL antibodies and could protect against thrombotic risk in SLE patients. It was also tried in primary APL syn- drome in some studies (338,339). However, use- fulness in asymptomatic carriers of APL antibod- ies has not been proven by prospective trials. Moreover, the majority of asymptomatic carriers of APL antibodies do not develop thrombotic manifestations. Therefore targeted education and close monitoring of those persons would be ap- propriate (18,26,340). Clearly, any acquired pro- thrombotic risk factors should be removed if pos- sible. Asymptomatic individuals with APL anti- bodies should be examined for the co-existence of hereditary thrombophilia (factor V Leiden, prothrombin 20210A, MHTFR, and others) and a strong family history of arterial and/or venous M. AKIF ÖZTÜRK ET AL110 TABLE 4. Proposed Empirical Exclusion Criteria to Distinguish Primary and SLE Related APL Syndrome The presence of any of these criteria excludes the diagnosis of primary APL syndrome: Malar rash Discoid rash Oral or pharyngeal ulceration, excluding nasal septum ulceration or perforation Frank arthritis Pleuritis, in the absence of pulmonary embolism or left-sided heart failure Pericarditis, in the absence of myocardial infarction or uremia Persistent proteinuria greater than 0.5 gram per day, due to biopsy-proven immune complex-related glomerulonephritis Lymphopenia less than 1.000/µL Antibodies to native DNA, by radioimmunoassay or Crithidia fluorescence Antiextractable nuclear antigen antibodies ANA of more than 1:320 Treatment of drugs known to induce APL antibodies A follow-up longer than 5 years after the first clinical manifestation is necessary to rule out the subsequent emergence of SLE Data from reference 332. thrombotic tendency. Selected cases among that specific subpopulation are subject to long-term low-dose aspirin prophylaxis. Likewise, if any asymptomatic subject does develop some clinical features of APL syndrome such as migraine, livedo reticularis, dizzy or confusional episodes, nonspe- cific visual disturbance, or very early pregnancy loss, low-dose aspirin may be given (340,341). Treatment of acute thrombotic events of pa- tients with APL syndrome is not different than treatment of acute thrombosis in the general population. Those patients should be anticoagu- lated with standard heparin protocol (339,342). However, initial management of acute arterial thrombosis, particularly cerebrovascular events, must include careful differential diagnosis. Stroke during the course of APL syndrome could either be in situ thrombotic or be embolized from the cardiac valves. A hemorrhagic stroke must be ruled out in patients who are already on warfarin prophylaxis. In cases of secondary APL syndrome associated with SLE, possibility of a neurologic involvement due to SLE may further complicate the clinical situation (339). There are anecdotal reports for successful results with thrombolytic agents or angioplasty in patients with APL syn- drome and acute myocardial infarction (343 345). However, reocclusion is a major problem and thrombolytic agents are often unhelpful in acute thrombotic events in APL syndrome as well as serious hemorrhagic complications (340). There is almost always an increased risk of re- currence of thrombosis in APL syndrome unless effective antithrombotic prophylaxis is given (1,18,2628,54,148,238,252,339,346,347). Cor- ticosteroids or immunosuppresants have no room in reducing thrombotic risk in patients with pri- mary APL syndrome. The immunosuppression generally will not alleviate propensity to throm- bosis in secondary APL syndrome patients (18,26,348). Therefore, long-term anticoagula- tion as a secondary prophylaxis is mandatory in APL syndrome, although the duration and inten- sity is still controversial. Initial data from large retrospective trials concluded that lifelong high- intensity warfarin (i.e. INR 3.0) is necessary for preventing recurrences (51,346). However, se- vere hemorrhagic complication appears to be an important problem particularly with high INRs (54,342,346,349). The risk of major bleeding in- creases by 42% with every increase in INR by one point (350). Some small studies suggest that in- termediate intensity warfarin therapy (i.e. INR value between 2.0 and 3.0) can be equally effec- tive and safer (238,252,347). Efficacy of inter- mediate-dose warfarin was also supported by its capacity to suppress in vivo markers of coagula- tion activation, i.e. prothrombin fragments 1+2 (PF 1.2) in patients with SLE and APL antibodies (351). Recently a randomized, double-blind trial of 114 patients with a mean follow-up period of 2.7 years demonstrated that high-intensity war- farin was not superior to moderate-intensity war- farin for thromboprophylaxis in patients with APL syndrome (352). Another potential problem with warfarin anticoagulation is dose monitoring because LAs may prolong the PT. In such pa- tients, the INR may not reflect the true level of anticoagulation (353,354). Lastly, warfarin fail- ure is not uncommon. Some authors reported that up to 50% of APL patients on adequate doses of warfarin experienced recurrent throm- bosis (18,2628), although warfarin failure could result from inappropriate use or drug interac- tions (339). Aspirin may be added to warfarin if there are ongoing symptoms of ischemia despite high-intensity warfarin. However, care should be taken for the increased risk of bleeding in this special therapeutic situation (339). Low-dose he- parin or low-molecular-weight heparin have been suggested as the more effective and safer alternatives to warfarin in the prevention of thrombotic recurrences (18,26,28,355). Heparin enhances plasmin-mediated inactivation of 2 GP-1 (356). Therefore, some authors prefer to use long-term low-molecular-weight heparin (LMWH) therapy for preventing thrombotic re- currences (18,26,28,355). This LMWH approach may be particularly useful for patients with arte- rial thrombosis. There is no consensus on the duration of anti- coagulation. Although initial reports suggested lifelong oral anticoagulation, this approach could carry a high risk of bleeding (54,346). Therefore, the risk to benefit ratio and the risk of thrombo- sis versus bleeding should be evaluated with maximum caution from the clinical point of view. Aspirin alone is an insufficient prophylaxis for the prevention of recurrent arterial or venous thrombosis (346). Clopidogrel has been effective in stable patients not failing to respond to LMWH (18,26). Therefore, long-term clopidogrel may be an alternative to long-term anticoagulation, par- ticularly in arterial thrombosis (18,26). The du- ration of antithrombotic treatment may be con- cluded depending on the clinical severity of the initial thrombotic event and the persistence of antibodies. Some experts prefer to change anti- coagulant treatment to antiaggregant prophylax- is with either low-dose aspirin or clopidogrel CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 111 after 6 months of thrombosis-free and antibody- free period (18,26). Anticoagulant therapy should be individual- ized in APL patients depending on the severity of the clinical condition and the localization and na- ture of the initial thrombus. The Bick classifica- tion of APL antibodyassociated thrombotic syn- dromes offers a very useful guide for choosing appropriate therapy for the clinician against the very heterogenous presentations of APL syn- drome (Table 2). Thrombocytopenia Thrombocytopenia rarely causes clinical prob- lem of hemorrhage in APL syndrome. However, it is essential to achieve a platelet count above 50,000 per mm3 (54) before warfarin therapy to reduce the risk of hemorrhage. Prednisone is the most common approach for management of au- toimmune thrombocytopenia in APL syndrome. Intravenous immunoglobulin (IVIG), chloro- quine, low-dose heparin, cyclosporin A, dapsone, and danazol have been used to correct thrombo- cytopenia in APL syndrome in selected cases (339,341,357359). Aspirin administration should be given with caution for the damaged function of already low-count platelets in throm- bocytopenic APL syndrome. Splenectomy might be indicated, but is occasionally ineffective (148,339). Management of Pregnancy in APL Syndrome Women with APL syndrome have a high risk of recurrent fetal loss. Therefore, therapy with aspirin, heparin, prednisone, intravenous im- munoglobulin (IVIG), and their combinations have been tried in the obstetric APL syndrome with varying success (226,230,360). There is a general consensus that women with APL syndrome and a history of thrombosis should receive heparin for thromboprophylaxis during the gestational period because pregnan- cy represents a hypercoagulable state (340,361). However there is no agreement regarding the management of the pregnancies of women with APL antibodies and recurrent miscarriages but had not experienced any previous thrombotic event. There are conflicting data concerning this difficult topic. Earlier non-randomized trials sug- gested that low-dose aspirin alone is beneficial (333,334). A recent randomized controlled trial supported this observation. This trial demon- strated that a high success rate can be achieved with low-dose aspirin only, while LMWH addi- tion do not significantly improve pregnancy out- come (335). On the other hand, treatment with aspirin plus heparin led to a significantly higher rate of live births in women with APL syndrome than that achieved with aspirin alone in other prospective studies (362,363). At the end of the research spectrum, a placebo-controlled study claimed that low-dose aspirin has no additional benefit when added to supportive care for women for whom recurrent early fetal loss is the only sequela of the APL syndrome (364). However, most of those studies investigated a limited number of subjects and there are some limitations in the research design. Further large randomized placebo controlled trials are needed to identify the optimal treatment for this group of women, although the heterogeneous nature and critical clinical points in fetal and maternal life can limit their performance. Currently, he- parin administered to pregnant women after ul- trasonographic demonstration of a live embryo is the treatment of choice (1). LMWH can also be used instead of standard heparin to reduce the risk of osteoporosis and heparin-induced throm- bocytopenia (1,365). However, maximum care should be taken while choosing the LMWH dur- ing pregnancy. Enoxaparin prophylaxis resulted in prosthetic valve thrombosis in two of the seven pregnant women with prosthetic heart valves leading to maternal and fetal deaths. There are other similar postmarketing reports of complica- tions of enoxaparin treatment miscarriages (The FDA Safety Information and Adverse Event Reporting Program, 2002 Safety Alert-Lovenox). Therefore, enoxaparin should not be recom- mended to manage the pregnancy in APL anti- body positive women with a history of recurrent miscarriages. Dalteparin may represent a safer alternative as a LMWH in this setting of APL syn- drome complicating pregnancies. Damage to the developing trophoblast occurs early in the pregnancy. Hence, in most of the ex- perienced centers, aspirin is being started before conception (18,26,361). The success rate of preg- nancy using low-dose aspirin and low-dose he- parin combination could be as high as 97% (18,26,366). Therefore, this approach should be accepted as "standard of care" until further in- vestigations would be performed focusing on pregnancy and APL syndrome. Some in vitro observations provide evidence for the rationale of using heparin and aspirin in APL syndrome. APL antibodies affect the inva- siveness and differentiation of cytotrophoblast cells after binding to the cell surface. LMWH sig- nificantly reduces the immunoglobulin G bind- M. AKIF ÖZTÜRK ET AL112 ing to trophoblast cells and restores in vitro pla- cental invasiveness and differentiation in a dose- dependent manner. Such an effect is not ob- served in the presence of acetylsalicylic acid (367). LMWH at pharmacologic doses signifi- cantly reduces the APL antibody binding and re- stores gonadotropin releasing hormoneinduced human chorionic gonadotropin (hCG) secretion in presence of APL antibody containing sera. Low dose aspirin does not modify APL antibody bind- ing, but partially restores hCG secretion (368). Therefore, LMWH together with low-dose ASA offers not only a simple antithrombotic approach but also have the potential to modify the pathobi- ology of the pregnancy loss due to APL syndrome. There is also no general agreement on the du- ration of postpartum thromboprophylaxis. Those women are usually suggested to hold the heparin therapy but to continue low-dose aspirin after delivery depending on the individual clinical sit- uation (18,26). There is an increased risk for nonpregnancy-related vascular thrombosis in APL syndrome patients who present with preg- nancy loss as their only manifestation of APL syn- drome. Recently a retrospective study suggested that aspirin alone is effective as a prophylaxis in this subgroup of APL syndrome patients (336). Prednisone administration during pregnancy of women with APL syndrome provided no ben- efit over either low-dose heparin or low-dose as- pirin. Moreover, steroid use resulted in signifi- cant maternal morbidity including gestational di- abetes, hypertension, osteoporosis, and preterm labor (333,369,370). Therefore, steroid admin- istration should be restricted to patients with thrombocytopenia or coexistent lupus (361). Earlier studies with small numbers of patients implied that addition of IVIG to either aspirin or heparin is safe and might improve the pregnancy outcomes (371,372). However, results of a re- cent multicenter study demonstrated that IVIG failed to improve obstetric or neonatal outcomes beyond those achieved with a heparin and low dose aspirin regimen (373). Moreover, a more recent randomized study exhibited that APL syn- drome women treated with LMWH plus low-dose aspirin had a higher rate of live births than those treated with IVIG (374). The additional cost of IVIG is also a matter of debate. Therefore, IVIG therapy should only be considered in serious pregnancy-related patient morbidity that is re- fractory to aspirin plus heparin (230,360). APL syndrome is now accepted as a treatable cause of recurrent pregnancy loss (1). Seventy- four percent of women who became pregnant in the recently published cohort of 1000 APL pa- tients succeeded in having one or more live births (437 of 590 women). This represents the advances in the treatment and follow-up of APL pregnants (23). Clinical approach to women with APL anti- bodies without any symptom of APL syndrome during their first pregnancy is also a matter of debate. The common practice in such cases is low-dose aspirin, although remains to be largely unconfirmed. A small study investigating the ef- ficacy of low-dose aspirin in persistently APL pos- itive women with "low risk" pregnancy (i.e. no associated signs or symptoms of the APL syn- drome, thrombosis or thrombocytopenia and no or just one prior spontaneous abortion) failed to demonstrate any advantage of aspirin adminis- tration in such pregnants. However, the frequen- cy of complications was so low that at least 600 women were needed for the investigation as to whether low-dose aspirin would be beneficial treatment during a pregnancy (375). Management of Catastrophic APL Syndrome Catastrophic APL syndrome is a life-threaten- ing medical emergency that requires high-level clinical awareness. Varying combinations of an- ticoagulants, steroids, plasmapheresis, cyclophos- phamide, and IVIG were administered for the management of this condition (232,233). Among the 20 patients who received a combination of antithrombotics, steroids, and plasmapheresis or IVIG, recovery occurred in 14 (70%) patients in a previous study (232). Fibrinolytic agents have been tried to treat acute thrombotic microan- giopathy (232). Recently, an international con- sensus statement for treatment guidelines for cat- astrophic APL syndrome was established by the Catastrophic APL Syndrome Registry Project Group during the presymposium workshop on APL syndrome consensus, held in Taormina at the tenth International Congress on APL syn- drome in September 2002. The optimal manage- ment of catastrophic APL syndrome must have three clear aims according to this consensus re- port: to treat any precipitating factors (prompt use of antibiotics if infection is suspected, ampu- tation for any necrotic organ, high awareness in patients with APL syndrome who undergo an op- eration or an invasive procedure); to prevent and to treat the ongoing thrombotic events; and to suppress the excessive cytokine "storm." Stand- ard anticoagulation protocol (usually intra- venous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous CURRENT DEBATES IN ANTIPHOSPHOLIPID SYNDROME 113 gammaglobulins and, if associated with lupus flare, cyclophosphamide, are the most common- ly used treatments for catastrophic APL syn- drome patients (376). FUTURE PROSPECTS Better standardization of diagnostic tests is mandatory particularly for the detection of clin- ically suspected cases. Moreover, we still need better predictive assays to differentiate disease- associated APL antibodies to identify which pa- tients with APL antibodies are truly at risk for thrombotic events. Identification of peptide mimetics for each immunologically distinct pro- thrombotic APL antibodies seem to help us for this aim (377). Molecular markers of thrombo- sis, such as PF 1.2, could be investigated with prospective large trials in asymptomatic carriers of APL antibodies to identify the "high-risk" sub- jects (378). The prospective study of aspirin as compared with placebo, and the trial of aspirin as compared with low-dose warfarin plus aspirin would give us more dependable answers to the question of whether to treat individuals with APL antibodies in the clinically "gray" zone (379,380). Results of ongoing large collaborative prospective randomized double-blind studies (such as (WAPS, PAPRE, WARSS, APASS, PRE- CLUDE trials) are being awaited for more effi- cient and less toxic therapeutic approaches (339,347,381). Statins blocked APL antibodyin- duced endothelial cell activation in vitro and di- minished APL antibodymediated thrombosis and endothelial cell activation in an in vivo ani- mal model (382,383). Hence, statins might serve as complementary medicines for the manage- ment of APL syndrome. Focusing on better un- derstanding of the pathobiology of the APL syn- drome may further provide new therapeutic strategies. For instance, intensive antioxidant therapy, antithrombotic strategies that more specifically target the tissue factor pathway of co- agulation such as recombinant tissue factor path- way inhibitor or anti-tissue factor antibodies, or a 2 GP-1specific B cell toleragen, LJP 1082, may be tried for more specific targeted therapy (299,384,385). 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<mods version="3.6"><titleInfo lang="en"><title>Current Debates in Antiphospholipid Syndrome: The Acquired Antibody-Mediated Thrombophilia</title>
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<titleInfo type="alternative" lang="en" contentType="CDATA"><title>Current Debates in Antiphospholipid Syndrome: The Acquired Antibody-Mediated Thrombophilia</title>
</titleInfo>
<name type="personal"><namePart type="given">M. Akif</namePart>
<namePart type="family">Öztürk</namePart>
<namePart type="termsOfAddress">MD</namePart>
<affiliation>Gazi University School of Medicine, Department of Rheumatology</affiliation>
</name>
<name type="personal"><namePart type="given">Ibrahim C.</namePart>
<namePart type="family">Haznedaroğlu</namePart>
<namePart type="termsOfAddress">MD</namePart>
<affiliation>Hacettepe University School of Medicine, Department of Hematology, Ankara, Turkey</affiliation>
</name>
<name type="personal"><namePart type="given">Mehmet</namePart>
<namePart type="family">Turgut</namePart>
<namePart type="termsOfAddress">MD</namePart>
<affiliation>Hacettepe University School of Medicine, Department of Hematology, Ankara, Turkey</affiliation>
</name>
<name type="personal"><namePart type="given">Hakan</namePart>
<namePart type="family">Göker</namePart>
<namePart type="termsOfAddress">MD</namePart>
<affiliation>Hacettepe University School of Medicine, Department of Hematology, Ankara, Turkey</affiliation>
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<abstract lang="en">Antiphospholipid (APL) syndrome is the most common form of acquired thrombophilia. It can cause significant morbidity and even mortality. The term “APL antibodies” represents a heterogeneous group of antibodies associated with this disorder. Currently no single assay can identify every APL antibody. Clinically relevant APL antibodies are mainly anticardiolipin antibodies (ACA) detected by solid phase enzyme-linked immunosorbent assay (ELISA) and lupus anticoagulants (LA) demonstrated by in vitro coagulation assay. However, there are some other antibodies associated with the APL syndrome (i.e., subgroup APL antibodies). ACAs, LAs, and subgroup APL antibodies represent intersecting, but non-identical, subsets of autoantibodies. Thus, those autoantibodies may coexist or may occur independently. Any organ system and any size of vessel can be affected during the clinical course of the disease. Therefore, the APL syndrome can manifest itself in a wide variety of clinical thrombotic features. Fetal loss and pregnancy morbidity represent a specific challenge. Despite tremendous advances in the understanding of the pathogenesis of APL syndrome during the past decade, the mainstay of management is still anticoagulation. However, there is no general agreement regarding the duration and intensity of anticoagulant therapy. In this review, we focused on the current dilemmas and their present clarifications in the wide clinicopathologic spectrum of APL syndrome and APL antibody-related distinct pathologic conditions.</abstract>
<subject><genre>keywords</genre>
<topic>Antiphospholipid antibody syndrome</topic>
<topic>Antiphospholipid antibodies</topic>
<topic>Lupus anticoagulants</topic>
<topic>Anticardiolipin antibodies</topic>
<topic>Terminology</topic>
<topic>Clinical features</topic>
<topic>Laboratory investigation</topic>
<topic>Pathobiology</topic>
<topic>Management</topic>
</subject>
<relatedItem type="host"><titleInfo><title>Clinical and Applied Thrombosis/Hemostasis</title>
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<identifier type="ISSN">1076-0296</identifier>
<identifier type="eISSN">1938-2723</identifier>
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<part><date>2004</date>
<detail type="volume"><caption>vol.</caption>
<number>10</number>
</detail>
<detail type="issue"><caption>no.</caption>
<number>2</number>
</detail>
<extent unit="pages"><start>89</start>
<end>126</end>
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