Antiphospholipid syndrome: pathogenic mechanisms

Autoimmunity Reviews 2 (2003) 86–93 Antiphospholipid syndrome: pathogenic mechanisms Gerard Espinosaa, Ricard Cerveraa,*, Josep Fonta, Yehuda Shoenfeldb a ´ ´ Department of Autoimmune Diseases, Institut Clınic d’Infeccions i Immunologia, Hospital Clınic, Villarroel 170, 08036 Barcelona, Catalonia, Spain b Department of Medicine ‘B’ and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Received 13 November 2002; accepted 12 December 2002 Abstract Despite the strong association between antiphospholipid antibodies (aPL) and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Proposed pathophysiological mechanisms may be categorized into two types. First, aPL may act in vivo by disrupting the kinetics of the normal procoagulant and anticoagulant reactions occurring on cell membranes. Second, aPL may stimulate certain cells thereby altering the expression and secretion of various molecules. In this article, we review the mechanisms by which aPL may develop thrombotic events. 䊚 2002 Elsevier Science B.V. All rights reserved. Keywords: Antiphospholipid antibodies; Antiphospholipid syndrome; Thrombosis; Pathogenic mechanisms 1. Introduction The antiphospholipid syndrome (APS) is diagnosed when arterial or venous thrombosis or recurrent miscarriages occur in a person in whom laboratory tests for antiphospholipid antibodies (aPL) (anticardiolipin antibodies (aCL), lupus anticoagulant (LA), or both) are positive w1x. It is known that aPL are directed against phospholipidbinding proteins expressed on, or bound to, the Abbreviations: aCL, anticardiolipin antibodies; APC, activated protein C; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; b2GPI, b2-glycoprotein I; HUVEC, human umbilical vein endothelial cells; LA, lupus anticoagulant; PGI2, prostacyclin; TXA2, thromboxane A2 *Corresponding author. Tel.yfax: q34-93-2275774. E-mail address: [email protected] (R. Cervera). surface of vascular endothelial cells or platelets w2x. The main protein associated with aCL activity is b2-glycoprotein I (b2GPI) bound to phospholipids w3x. The APS is now accepted as an example of an autoantibody-mediated disease w4x. Given the heterogeneity of clinical manifestations in APS it is likely that more than one pathophysiological process may play a role. Proposed pathophysiological mechanisms may be categorized into two types (Table 1). First, aPL may act in vivo by disrupting hemostatic reactions occurring on cell membranes. The aPL may alter the kinetics of the normal procoagulant and anticoagulant reactions by crosslinking membrane-bound proteins, by blocking protein–protein interactions, andyor by blocking the access of other proteins to the phospholipid 1568-9972/03/$ - see front matter 䊚 2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S1568-9972(02)00144-1 G. Espinosa et al. / Autoimmunity Reviews 2 (2003) 86–93 87 Table 1 Possible mechanisms of autoantibody-mediated thrombosis in APS Inhibition of anticoagulant reactions Inhibition of the protein C pathway (a) Inhibition of protein C activation (b) Inhibition of APC Inhibition of antithrombin activity Displacement of annexin A5 Inhibition of b2GPI anticoagulant activity Cell-mediated events On monocytes On endothelial cells On platelets (a) Expression of tissue factor (a) Enhanced endothelial cell procoagulant activity (1) Expression of tissue factor (2) Expression of adhesion molecules (b) Impaired fibrinolysis (c) Dysregulation of eicosanoids (1) Decreased endothelial cell PGI2 production (2) Increased platelet thromboxan A2 production (a) Enhanced platelet activationyaggregation Adapted from: Roubey RAS. Tissue factor, protein C pathway, and other hemostasis abnormalities in the pathogenesis of the APS. In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y, editors. The APS II. Autommune thrombosis, Elsevier; 2002. membrane. Second, aPL may stimulate certain cells thereby altering the expression and secretion of various molecules. In this article, we review (Fig. 1) the mechanisms by which aPL may develop thrombotic events. of b2GPI. These results suggest that aPL-induced protein C dysfunction is mediated by b2GPI. Autoantibodies directed against thrombomodulin w8x, protein C, and protein S w9x have been detected in some APS patients. 2. Inhibition of anticoagulant reactions 2.2. Inhibition of antithrombin activity 2.1. Inhibition of the protein C pathway Antithrombin is the major inhibitor of factors IXa, Xa, and thrombin. An APS patient with normal antigenic levels of antithrombin, but low functional activity, has been reported w10x. Protein C becomes activated when thrombin binds to thrombomodulin, a constitutively expressed protein on the surface of vascular endothelial cells. Activated protein C (APC) is a physiological anticoagulant through its potential to inactivate clotting factors Va and VIIIa. Protein S amplifies the activity of APC, and the assembly of the APC-protein S complexes on anionic phospholipid surfaces is essential for the catalytic activity. Inhibition of both protein C activation and the function of APC have been observed in association with APS w5x. The aPL can interfere with the protein C system in different ways w6x. Purified b2GPI inhibits the binding of protein C to phospholipids much better than the binding of prothrombin, resulting in a prothrombotic state w7x. The aPL recognize protein C only in the presence 2.3. Displacement of annexin A5 Annexin A5 is a potent anticoagulant protein whose activity is consequence of its high affinity for anionic phospholipids and the inhibition of phospholipid-dependent coagulation reactions. Annexin A5 appears to play a thrombomodulatory role in the placental circulation where it is necessary for maintenance of placental integrity w11x. Some patients with the APS have evidence for antibodies that specifically recognize annexin A5 and the presence of these antibodies has also been reported to be increased in patients with thrombo- 88 G. Espinosa et al. / Autoimmunity Reviews 2 (2003) 86–93 Fig. 1. Model of hemostasis pathways (coagulation and fibrinolysis) showing possible sites of action of aPL involved in the thrombosis in APS. APC, activated protein C; factor VIIa, activated factor VII; PAI-1, type-1 tissue-type plasminogen activator inhibitor; PS, protein S; tPA, tissue-type plasminogen activator; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin. sis w12x. However, other studies did not find this association w13,14x, and one group found no significant associations between anti-annexin V antibodies and any clinical manifestation w15x. associated thrombosis. The aPL may enhance the affinity of b2GPI to phospholipids and then b2GPI may become a real competitor to phospholipiddependent hemostasis reactions. 2.4. Inhibition of b2GPI anticoagulant activity 3. Cell-mediated events b2GPI is a highly glycosylated single-chainprotein present in plasma that avidly binds to negatively charged phospholipids. The physiological function of b2GPI is uncertain. This protein exhibits anticoagulant properties w16–19x. However, familial deficiency of b2GPI is not a risk factor for thrombosis. It has been suggested that b2GPI may contribute to the pathogenesis of APS- 3.1. On monocytes: expression of tissue factor Tissue factor is a single chain transmembrane protein that is widely accepted to be a major physiological initiator of blood coagulation in vitro. Tissue factor is normally not expressed by intravascular cells but can be induced in monocytes and endothelial cells by different physiological or G. Espinosa et al. / Autoimmunity Reviews 2 (2003) 86–93 nonphysiological stimuli. Induced tissue factor forms a tissue factoryactivated factor VII complex in the presence of phospholipids and activates rapidly factors IX and X. The tissue factor pathway is modulated by the tissue factor pathway inhibitor. Tissue factor pathway inhibitor inhibits factors VIIa and Xa. Kornberg et al. have found an increased procoagulant activity attributed to tissue factor expression on monocytes induced by murine monoclonal aCL that can induce APS w20x. Subsequently, Cuadrado et al. w21,22x have shown that tissue factor-related procoagulant activity and tissue factor mRNA levels in monocytes are increased in primary APS patients with thrombosis when compared with those without thrombosis. Clinically, increased tissue factor was associated with IgG aCL and a history of thrombosis. Our group have shown that purified IgG aCL from three APS patients with previous thrombotic episodes induce a significant increase in both monocyte procoagulant activity and tissue factor expression, as compared with purified IgG aCL from two SLE individuals without thrombosis w23x. Moreover, we have also reported an increase on tissue factor expression on normal monocytes using affinity-purified IgM aCL (with anti-b2GPI activity) from two APS patients with a history of thrombosis w24x. Functional anti-tissue factor pathway inhibitor activity was detected in a subset of APS patients. Roubey et al. w25x have recently detected autoantibodies directed against tissue factor pathway inhibitor in APS patient sera and found an association between these antibodies and arterial thrombosis and stroke. 3.2. On endothelial cells 3.2.1. Enhanced procoagulant activity: expression of tissue factor and adhesion molecules Endothelium is now emerging as a major site of regulation of hemostasis. When perturbed, endothelial cells serve as a surface that can support many steps in the coagulation cascade by producing tissue factor and plasminogen activators inhib- 89 itors and synthesizing specific bindings sites for several coagulation factors. Potentiation of human umbilical vein endothelial cells (HUVEC) procoagulant activity by aPLcontaining sera from SLE patients is strongly decreased after depleting IgG from sera w26x. Fractions of human APS sera containing monomeric IgG, IgM, or IgA, as well as high molecular weight-IgG, each cause HUVEC to increase procoagulant activity characteristic of tissue factor w26,27x. These results indicate that the factor responsible for the induction of tissue factor activity resides, at least in part, in the IgG fraction of the serum. More recently, human anti-b2GPI IgM monoclonal antibodies as well as polyclonal antib2GPI antibodies have been shown to induce tissue factor at both protein and mRNA level in HUVEC monolayers in vitro w28x. Endothelial cells incubated in the presence of aPL preparations were shown to up-regulate adhesion molecules (E-selectin, ICAM-1 and VCAM1) expression and pro-inflammatory cytokines (IL-1b and IL-6) secretion w29x. Increased plasma levels of soluble VCAM-1 were found in primary APS patients with recurrent thrombotic events, and elevated levels of tissue plasminogen activator and von Willebrand factor (as endothelial perturbation markers) were associated with aPL in systemic lupus erythematosus. In contrast to these findings, Frijns et al. w30x did not find any significant difference in soluble adhesion molecules, soluble thrombomodulin and von Willebrand factor plasma levels in APS secondary to systemic lupus erythematosus. 3.2.2. Impaired fibrinolysis The different population of autoantibodies observed in APS may disturb fibrinolysis and contribute thereby to vascular complications. Thrombosis may therefore result from an impaired or insufficient fibrinolytic cellular response to vascular injury provoked by autoantibodies. Some reports demonstrated the existence of impaired fibrinolysis associated with thrombosis and aPL in systemic lupus erythematosus. In recent studies, it has been shown that the hypofibrinolysis detected in these patients is most probably a manifestation of endothelial cell dysfunction, as indicated by 90 G. Espinosa et al. / Autoimmunity Reviews 2 (2003) 86–93 increased plasma levels of type-1 plasminogen activator inhibitor and tissue-type plasminogen activator antigens w31x. These manifestations of endothelial cell dysfunction have been found in association with antibodies directed against endothelial cells, or with the presence of immune complexes, thus suggesting that endothelial cells are important sites of action for antibodies that have a role in the pathogenesis of thrombosis. Similar manifestations of endothelial dysfunction have also been found in primary APS w32x, though at present there are no solid arguments to propose a direct association between aPL and impaired fibrinolysis in the thrombotic manifestation of APS. 3.2.3. Dysregulation of eicosanoids: decreased endothelial cell prostacyclin production and increased platelet thromboxan A2 production Decreased endothelial cell prostacyclin (PGI2) production and increased thromboxane A2 (TXA2) production by platelets have both been implicated as mechanisms predisposing to thrombosis in patients with APS. PGI2 is the most important natural inhibitor of platelet aggregation and it is also a vasodilator, being considered as one of the antithrombotic mechanisms of vascular endothelium. Its effect is contrary to that of TXA2. It was suggested that LA could interfere with arachidonic acid release from phospholipid membranes because the effect was abolished in the presence of arachidonic acid. ¨ et al. have demonstrated that some purified Schorer aPL inhibit the enzymatic activity of phospholipase A2 w33x. In contrast, some authors obtained discrepant results reporting no inhibition or even an increase of the production of PGI2 by HUVEC w34x. Data demonstrating that aPL enhance platelet TXA2 production are more consistent w34,35x. In patients with APS, there is an imbalance of the normal TXA2 yPGI2 equilibrium. In a study reported in 1991, Carreras’ group. w35x showed that in patients with LA, platelet activation may occur without a compensatory increment in the vascular biosynthesis of PGI2. 3.3. On platelets: enhanced platelet activationy aggregation Platelets play a central role in primary hemostasis involving adhesion to the injured blood vessel wall, followed by platelet activation, granule release, shape change, and rearrangement of the outer membrane phospholipids and proteins transforming them into a highly efficient procoagulant surface. The interaction of aPL with platelets can occur in at least three different ways. First, immunoglobulins may bind through the Fab fragment with specific platelet antigens in a classic antigen– antibody reaction; second, immune complexes may bind to platelets via FcgRII receptor; and third, aPL, like other immunoglobulins, may bind to platelets in a non-specific manner by mechanisms not well characterized but probably related to platelet membrane injury. The last mechanism does not seem to have a pathophysiological role in APS-related thrombosis. Some studies have demonstrated that aPL may bind to platelet surface, and this binding is higher on activated or damaged platelets than in resting ones. Shi et al. w36x observed that human aCL only can bind to activated platelets but not to resting platelets and this binding was in a b2GPIdependent way. Our group demonstrated that monoclonal aCL obtained from patients with APS increased platelet interaction with the subendothelium under flow conditions w24x. The only FcgR molecules present on platelets are the FcgRII. Activation of the FcgRII receptor causes platelet activation and granule release. With these results, the following hypothesis has been proposed. Small initial platelet activation is produced by physiological or pathological conditions resulting in the expression of phospholipids on the platelet surface. The binding of b2GPI to these phospholipids may occur. The aPL subsequently may bind to the formed b2GPI-phospholipid complexes, and then, interact with their Fc portion with the platelet surface FcgRII receptors. Through these interaction, platelets may be activated and a vicious circle G. Espinosa et al. / Autoimmunity Reviews 2 (2003) 86–93 of cellular activation may be created finally ending in a thrombotic event. Recently, we demonstrated that three monoclonal aCL with anti-b2GPI activity promoted platelet interaction with collagen-rich subendothelium under flow conditions with a clear b2GPI dependence w37x. The FcgRII receptor have high affinity for the Fc portion of IgG contained in immune complexes or to IgG bound to an antigen on the platelet surface. For this reason, it is probable that the monoclonal aCL bound to b2GPI-phospholipid complexes on platelet membranes exert their action through complement activation, besides of activation of Fcg receptor II. The complement generated in presence of aPL bound to negatively charged phospholipids may cause platelet activation and eventually, platelet destruction. This hypothesis has been supported by some findings. On the one hand, increased levels of inactivated terminal membrane attack complex (C5b-9) were found in patients with APS and cerebral ischemia w38x, and decreased levels of serum complement were detected in patients with aPL w39x. Furthermore, the complement generated in presence of aPL bound to b2GPI-phospholipid complexes may cause platelet activation. In addition, it has been demonstrated that C5b-9 action may increase the transbilayer migration of phosphatidylserine in the platelet membrane w40x causing increased binding of b2GPI, and then C5b-9 activation, and in a vicious circle, platelet activation. In conclusion, despite the strong association between aPL and thrombosis, the pathogenic role of aPL in the development of thrombosis has not been fully elucidated. Recent data indicate that many of the autoantibodies associated with APS are directed against a number of plasma proteins and proteins expressed on, or bound to, the surface of vascular endothelial cells or platelets. The involvement of aPL in clinically important normal procoagulant and anticoagulant reactions and on certain cells altering the expression and secretion of various molecules may offer a basis for definitive investigations of possible mechanisms by which aPL may develop thrombotic events in patients with APS. 91 Take-home messages ● The APS is an example of an autoantibodymediated disease. Given the heterogeneity of clinical manifestations it is likely that more than one pathophysiological process may play a role. ● Two types of pathophysiological mechanisms for the aPL have been proposed. First, the aPL may act in vivo by disrupting hemostatic reactions occurring on cell membranes. 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Contribution of platelet microparticle formation and granule secretion to the transmembrane migration of phosphatidylserine. J Biol Chem 1993;268:7171 –8. The World of Autoimmunity; Literature Synopsis Epidemiology of systemic lupus Erythematosus In a recent report by M. Petri (Best Prac Res Clin Rheum 2002;16:847–858), she updates us on the recent changes, trends, and practices in systemic lupus erythematosus (SLE). It appears that the incidence of SLE is on the rise although there is not an absolute consensus. This may be due to the fact that SLE is identified earlier or that milder cases are already recognized. Prevalence is higher, but this is not surprising given the improvement of survival since the 1950’s and 1960’s. Clusters of SLE cases were thought to help identify possible environmental factors in its pathogenesis, however nothing in particular was found. Women are more often afflicted than men, possibly due to estrogen, which is known to stimulate lymphocytes. Certain studies have shown that exogenous exposure to estrogen may increase SLE incidence. Men by contrast, suffer more from morbidity such as renal insufficiency, thrombosis, hypertension, hemolytic anemia, seizures, but have less Sjogren’s and lupus nephritis. There are also racial differences. African Americans, African Caribbeans, Aborigines, and Asians have a greater incidence of SLE versus Caucasians. The newest minority group demonstrating an increased incidence is Hispanics. Racial differences are thought to be genetic although there is disagreement on whether socioeconomic factors affect renal failure or general mortality. Age of onset among Caucasians was 33.2 years and 31.3 among African Americans, and occurs earlier in women than men. Studies have tried to ascertain whether changes in serological test could be used to predict future disease flares, however no predictive values were found. During actual flares the most common finding was a decline in anti-dsDNA, and during renal or hematological flares, a decline in C3 and C4. Morbidity was mostly due to either direct or indirect effects of corticosteroids. General survival increased drastically in the 1950’s and 1960’s, but plateaued in the 1980’s. Many studies have shown an improvement in overall survival over time, however minority groups still suffer the greatest mortality. Finally, the leading causes of death are cardiovascular disease (the leading cause of death in late SLE) and infection (the leading cause of death in the Third World).