Antiphospholipid Syndrome in Systemic Lupus Erythematosus: Is the Whole Greater Than the Sum of Its Parts?

This article compares the manifestations of systemic lupus erythematosus (SLE) in the presence and absence of antiphospholipid antibodies (aPLs), the hallmark autoantibodies of antiphospholipid syndrome (APS). The combination of SLE and APS appears to be of greater concern than either entity alone. APS complicates SLE by adding a vaso-occlusive factor to the inflammatory component that adversely affects the prognosis of those who have lupus and aPLs. The increase in both morbidity and mortality when both are present has significant therapeutic implications. Anticoagulation may be a safer and more appropriate therapeutic option than instituting a regimen of corticosteroids and immunosuppressive agents with all their attendant adverse effects. It falls upon the physician to clearly define the disease entity and fully evaluate the disease process.     

Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by thromboembolic events and/or fetal loss in the presence of antiphospholipid antibodies (aPLs). The mechanisms underlying the pathogenicity of aPLs are still poorly understood. Here we show that 3 human monoclonal aPLs as well as IgG fractions from patients with the APS increase mRNA expression of the intracellular toll-like receptor (TLR) 7 in plasmacytoid dendritic cells and TLR8 in monocytes. Simultaneously they induce the translocation of TLR7 or TLR8 from the endoplasmic reticulum to the endosome. These effects depend on the uptake of aPLs into the endosome, subsequent activation of endosomal NADPH oxidase, and generation of superoxide. As a consequence cells are dramatically sensitized to ligands for TLR7 and TLR8. This observation delineates a novel signal transduction pathway in innate immunity originating from the endosome. Because the overexpression of TLR7 can also be detected in plasmacytoid dendritic cells from patients with the APS ex vivo, our results provide an explanation for proinflammatory and procoagulant effects of aPLs. Because inappropriate expression of TLR7 has been implicated in the development of systemic autoimmunity, these findings may also be relevant for the understanding of autoimmunity.     

Antiphospholipid syndrome: state of the art with emphasis on laboratory evaluation

Antiphospholipid antibodies (aPLs) are associated with arterial and venous thrombosis, recurrent pregnancy loss and thrombocytopenia. Although aPLs have not yet been conclusively shown to be causal in thrombosis and miscarriage, they are useful laboratory markers for the antiphospholipid syndrome (APS). The syndrome can complicate another autoimmune disease, most commonly systemic lupus erythematosus, but more often occurs alone -- primary APS. Identification of the syndrome is clinically important because of the risk of recurrent thrombosis and the need for antithrombotic therapy in many cases. Diagnosis and treatment of APS represent significant challenges, however, owing to the protean clinical manifestations and associations, limitations of currently available laboratory tests for aPLs, and the lack of clear evidence-based guidance on optimal management.     

The contribution of antiphosphatidylethanolamine antibodies in the diagnosis of the antiphospholipid syndrome

The diagnosis of seronegative antiphospholipid syndrome (APS) has been proposed for patients with well-defined clinical APS but persistently negative for the routinely tested antiphospholipid antibodies (aPLs): antibodies to cardiolipin (aCL) and to β(2) glycoprotein I (aβ(2)GPI) and lupus anticoagulant (LA). Antibodies directed to phosphatidylethanolamine (aPE) have been described as the sole aPLs in some patients with clinical manifestations of APS. Here, we briefly summarize the available data on the clinical associations of aPEs and propose their investigation in patients with a clinical profile highly suggestive of seronegative APS.     

Obstetric and vascular APS: same autoantibodies but different diseases?

Beta2 glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are the main pathogenic autoantibody population and at the same time the laboratory diagnostic tool for the antiphospholipid syndrome (APS). These antibodies are responsible for both the vascular and the obstetric manifestations of the syndrome but the pathogenic mechanisms behind these manifestations are not the same. For example, thrombotic events do not appear to play a major role in APS miscarriages and a direct reactivity of β2GPI-dependent aPLs on decidual and trophoblast cells was reported. A local expression of β2GPI on these tissues was reported both in physiological conditions and in APS women, thus explaining the local tropism of the autoantibodies. The two hit hypothesis was suggested to explain why the vascular manifestations of APS may occur only occasionally in spite of the persistent presence of aPLs. This is not apparently the case for the obstetric variant of the syndrome, making the difference even more striking. A different pathogenesis may also provide the rationale for the well-known fact that the vascular and the obstetric manifestations may occur independently although in a minority of cases.     

Management of Obstetric Antiphospholipid Syndrome

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.     

The Management of Stroke in Antiphospholipid Syndrome

Ischemic stroke is one of the most common complications of the antiphospholipid syndrome (APS). Because of the relative lack of definitive prospective studies, there is still some debate as to whether the persistent presence of antiphospholipid antibodies (aPLs) increases the risk of recurrent stroke. There is more evidence for aPLs as a risk factor for first stroke. The mechanisms of ischemic stroke are considered to be thrombotic and embolic. APS patients with thrombotic stroke frequently have other, often conventional vascular risk factors. Transesophageal echocardiogram is strongly recommended in APS patients with ischemic stroke because of the high yield of valvular abnormalities. The appropriate management of thrombosis in patients with APS is still controversial because of limited randomized clinical trial data. This review discusses the current evidence for antithrombotic therapy in patients who are aPL positive but do not fulfill criteria for APS, and in APS patients. Alternative and emerging therapies including low molecular weight heparin, new oral anticoagulants (including direct thrombin inhibitors), hydroxychloroquine, statins, and rituximab, are also addressed.     

Antiphospholipid antibodies do not a syndrome make

The association of antiphospholipid antibodies (aPLs) with a poor obstetric history and/or thrombotic event is typical of the antiphospholipid syndrome (APS). We report four cases of poor pregnancy outcome where a diagnostic label of APS resulted in delayed recognition of other causes of pregnancy loss. Pregnancy outcomes in these women were not improved with antithrombotic therapy alone. Successful outcomes were achieved only when other causes of recurrent miscarriage were considered and treated.     

The systemic nature of the antiphospholipid syndrome

Antiphospholipid syndrome (APS, Hughes' syndrome) is a systemic autoimmune disorder characterized by arterial and/or venous thrombosis and recurrent foetal loss, accompanied by mild to moderate thrombocytopaenia and elevated titres of antiphospholipid antibodies (aPLs): lupus anticoagulant (LAC) and/or anticardiolipin (aCL) antibodies. APS was defined originally in 1983 in systemic lupus erythematosus (SLE) patients, but later it was found that APS can be primary or secondary to other autoimmune diseases or malignancy. During the past 20 years many organs have been reported to be involved in this syndrome and the clinical manifestations are seen in every medical field. Moreover, many aPLs have been found in APS besides aCLs and LACs, which bind to the autoantigen beta-2-glycoprotein I (beta2GPI). Treatment for APS, based on antiplatelet and anticoagulation drugs, is dependent on various parameters, including whether SLE is also present, classical vs non-classical manifestations of the diseases, women with APS based on pregnancy morbidity, the presence of elevated aCL antibody titres in the absence of clinical manifestations, and catastrophic APS.     

Which antiphospholipid antibodies should be measured in the antiphospholipid syndrome?

The results of an analysis of studies published over a 10-year period that addressed the association between antiphospholipid antibodies (aPLs) and thromboembolic events in patients with the antiphospholipid syndrome (APS) are reported. It would appear that lupus anticoagulants are the strongest risk factor for thromboembolic events in aPL-positive patients. Consequently, it is suggested that all patients with clinical manifestations of APS should be tested for these antibodies. On the other hand, the results do not unequivocally show that measurement of anticardiolipin antibodies is of help in defining the thrombotic risk of patients. Furthermore, they only partially support the notion that anti-beta 2-glycoprotein I and antiprothrombin antibodies may be independent risk factors for thrombosis.     

Cardiac involvement in the antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease, associated with a hypercoagulable state and fetal loss and with other clinical manifestations including cardiac involvement. Cardiac manifestations of APS are valve abnormalities (valve thickening and vegetations), occlusive arterial disease (atherosclerosis and myocardial infarction), intracardiac emboli, ventricular dysfunction, and pulmonary hypertension. Antiphospholipid antibodies (aPLs) may have a role in the accelerated atherosclerotic arterial disease observed in APS, related to their ability to induce endothelial activation. aPLs have been incriminated in the pathogenesis of heart valve lesions in APS patients. Markers of endothelial cell activation are up-regulated with prominent deposition of aPL in heart valves, suggesting aPL deposition initiates an inflammatory process that recruits complement leading to the valve lesion. Autoantibody-mediated endothelial cell activation probably plays a role in sustaining a proadhesive, proinflammatory, and procoagulant phenotype. The heterogeneity of APS clinical manifestations is likely linked to the varied effects that aPL can induce on endothelial cells and to the different functions that endothelial cells display depending on the anatomic localization.     

Evaluation of the clinical relevance of anti-annexin-A5 antibodies in Chinese patients with antiphospholipid syndrome

A hallmark feature of antiphospholipid syndrome (APS) is the presence of antiphospholipid antibodies (aPLs). Few studies have addressed the clinical relevance of anti-annexin A5 antibodies (aANXA5) in Chinese patients with APS. In this study, we evaluated the clinical performance of aANXA5 in the diagnosis of APS. Sera from 313 subjects were tested, including 170 samples from patients with APS, 104 samples from patients with non-APS diseases as disease controls (DC), and 39 healthy controls (HC). Serum IgG and IgM aANXA5 were determined by ELISA. Overall, the levels of both IgG and IgM aANXA5 were significantly increased in patients with primary APS (PAPS) and APS associated to other diseases (APSAOD) compared with DC and HC. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IgG and IgM aANXA5 in the diagnosis of APS were 33.5 and 15.3, 99.0 and 99.0, 98.3 and 96.3, and 47.7 and 41.7%, respectively. Significant associations between IgG aANXA5 and arterial thrombotic events (OR, 2.60; 95% CI, 1.44–4.71) and between IgG aANXA5 and venous thrombotic events (OR, 2.80; 95% CI, 1.55–5.06) were identified. No correlations were identified between IgG or IgM aANXA5 and obstetric complications. Our data suggest that aANXA5 could serve as a diagnosis biomarker for patients with APS. More importantly, our data highlighted a potential role of IgG aANXA5 in identifying APS patients with high risk of thrombosis.     

Grossesse et syndrome des antiphospholipides

Antiphospholipid syndrome (APS) is associated with a risk of obstetrical complications, affecting both the mother and the fetus. Obstetrical APS is defined by a history of three consecutive spontaneous miscarriages before 10 weeks of gestation (WG), an intra-uterine fetal death after 10 WG, or a premature birth before 34 WG because of severe pre-eclampsia, eclampsia or placental adverse outcomes (intrauterine growth retardation, oligohydramnios). Pregnancy in women with a diagnosis of obstetric APS is at increased risk for placental abruption, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome and thrombosis that may be part of a catastrophic antiphospholipid syndrome (CAPS). A previous thrombosis and the presence of a lupus anticoagulant are risk factors for pregnancy failure. A multidisciplinary approach, associating the internist, the anesthesiologist and the obstetrician, is recommended for these high-risk pregnancies. Preconception counseling is proposed to identify pregnancy contraindications, and to define and adapt the treatment prior and during the upcoming pregnancy. Heparin and low-dose aspirin are the main treatments. The choice between therapeutic or prophylactic doses of heparin will depend on the patient's medical history. The anticoagulant therapeutic window for delivery should be as narrow as possible and adapted to maternal thrombotic risk. There is a persistent maternal risk in the postpartum period (thrombosis, HELLP syndrome, CAPS) justifying an antithrombotic coverage during this period. We suggest a monthly clinical and biological monitoring which can be more frequent towards the end of pregnancy. The persistence of notches at the Doppler-ultrasound evaluation seems to be the best predictor for a higher risk of placental vascular complications. Treatment optimization and multidisciplinary antenatal care improve the prognosis of pregnancies in women with obstetric APS, leading to a favorable outcome most of the time.     

Arterial compliance: is it reduced in antiphospholipid syndrome?

To assess vascular compliance in patients with antiphospholipid syndrome (APS), or antiphospholipid antibodies (aPLs) positivity in comparison to healthy people and diabetes mellitus patients. Twenty-five patients with APS or aPLs, 33 healthy people (HP), 28 patients with diabetes mellitus (DM) underwent pulse wave analysis. Data calculated included the small artery elasticity (SAE), large artery elasticity (LAE) and systemic vascular resistance (SVR). Statistical analysis was performed as appropriate. The patient group was divided into two subgroups: APS-1 with warfarin treatment, and APS-2 without warfarin treatment. All patients and healthy subjects were matched by gender, body mass index and lipid profiles. Patients in APS-1 group were significantly younger in comparison to three other groups. After the adjustment for age, we found that SAE in APS-1 group did not differ from SAE in the HP group (6.4+/-1.8 ml/mmHg x 100 and 5.54+/-3.4 ml/mmHg x 100, respectively, P>0.05). In contrast, SAE in the group APS-2 was significantly lower (3.41+/-1.2 ml/mmHg x 100) than in the APS-1 and was almost equal to SAE in the DM group (4.2+/-2.37 ml/mmHg x 100). The SAE in the APS-2, DM and HP groups was inversely correlated with age, whereas in the APS-1 group we did not find such correlation. This pilot study showed abnormal small vascular elasticity in the patients with positive aPL, relative to the healthy subjects. The APS patients, treated with warfarin had the normal vascular function. This data support the hypothesis that APS may be associated with diffuse changes in the arterial wall, and may be a risk factor for atherosclerotic disease.     

Pathogenesis of the antiphospholipid syndrome

The presence of pathogenic antiphospholipid antibodies (aPL) is the characterizing feature of the antiphospholipid syndrome (APS), mediating the recurrent pregnancy loss and thrombosis typical of the disease, through their action on various antigenic targets. Despite the available knowledge regarding the mechanisms by which aPL induce a procoagulant phenotype in the vasculature and abnormal cellular proliferation and differentiation in placental tissues to cause the typical clinical features, these processes still remain incompletely understood. It is also known that inflammation serves as a necessary link between the observed procoagulant phenotype and actual thrombus development, and is an important mediator of the placental injury in APS patients. Even less well understood are the processes underlying the ontogeny of these pathogenic antibodies. This review seeks to highlight what is known about the mechanisms that contribute to the origin of pathogenic aPL and to the action of these antibodies on target antigens that produce the pathological features of APS. We will also examine the feasibility of classifying patients in clinical phenotypes related to underlying pathophysiological mechanisms, and how this could impact the management of patients with novel "targeted" therapeutic strategies.     

Thrombophilias and vascular placental pathology. A survey of the literature

PURPOSE: Hereditary thrombophilia as antiphospholipid syndrome (APS) may represent a new risk factor for placental vascular diseases. CURRENT KNOWLEDGE AND KEY POINTS: General screening for biological abnormalities related to thrombophilia is poorly associated with placental vascular diseases and therefore, may be unwarranted. Women with an history of thrombotic diseases may be at risk for late fetal loss or preeclampsia. Adverse obstetric outcomes are particularly high despite anticoagulation regimens in patients with APS. A high frequency for biological abnormalities related to thrombophilia was detected in pregnancies complicated by late fetal loss in comparison with controls. However, no beneficial strategy prevention was clearly reported and therefore, a selective testing was actually debated for these patients. FUTURE PROSPECTS AND PROJECTS: Searching for acceptable treatment alternatives in patients with APS in order to reduce the high rate for pregnancy complications which may be persistent despite anticoagulation regimens. To determine by controlled studies the role for a prophylactic low molecular weight heparin regimens in patients with haemostatic abnormalities and previous pregnancy complications.     

A study of 75 pregnancies in patients with antiphospholipid syndrome

OBJECTIVE: To describe a French tertiary referral center experience in the treatment of pregnancies in patients with the antiphospholipid syndrome (APS). METHODS: Retrospective review of the data of 75 consecutive pregnancies in 47 women. RESULTS: After exclusion of induced abortions and pregnancies occurring before APS onset, the prior live birth rate was 7.9%. Forty-nine pregnancies occurred in women with history of vascular thrombosis, 17 with history of thrombocytopenia. Heparin was prescribed in 39 pregnancies, associated with aspirin in 35 cases, and aspirin alone was used in 36 as first-line therapy. Corticosteroids were prescribed in 38 pregnancies. Three pregnancies by in vitro fertilization led to one embryonic loss, one full term birth, and one premature birth. Six pregnancies treated with immunoglobulin ended in one fetal death, 2 premature and 3 full term deliveries. The outcome of the other 66 pregnancies was one embryonic loss, 8 fetal deaths, 16 prematurates, and 38 full term births. Use of corticosteroids correlated with severe prematurity (p = 0.005), preeclampsia (p = 0.014), intrauterine growth retardation (p = 0.005), and presence of disease associated to APS (p = 0.009). After exclusion of one fetal death associated with congenital anomaly, live birth rate was 72.9%. There was a trend for higher rate of fetal survival in patients without history of vascular thrombosis (84.6 vs 66.4%; p = 0.11). CONCLUSION: Obstetrical prognosis in APS was improved by antithrombotic therapy. Studies are needed to define individual risk and specific significance of the various antiphospholipid antibodies, in order to improve the respective indications for aspirin alone or with heparin in women without thrombotic events.     

The relation between antiphospholipid syndrome-related pregnancy morbidity and non-gravid vascular thrombosis: A review of the literature and management strategies

The antiphospholipid syndrome (APS) is associated with pregnancy morbidity and vascular thrombosis in the presence of circulating antiphospholipid (aPL) antibodies. Clinical manifestations of aPL antibodies represent a spectrum (asymptomatic, pregnancy events, vascular events, or both pregnancy and vascular events), and APS should not be considered a single disease with a predictable outcome. Patients with aPL antibodies are at increased risk of vascular thrombotic events during pregnancy, the postpartum period, and even during long-term follow-up after an APS-related pregnancy event. Therefore, the purpose of this paper is to review the relation between APS-related pregnancy morbidity and vascular thrombosis, and to address the importance of prophylactic therapy during and after APS pregnancies to prevent maternal thrombotic complications. During pregnancy, low-dose aspirin (LDA) should be considered for all patients with aPL antibodies and heparin should be added to LDA in patients fulfilling the Sapporo criteria for definite APS. During delivery, especially with caesarian section, periods without anticoagulation should be kept to an absolute minimum. Some data suggest that LDA might be effective against future non-gravid vascular thrombosis in patients with APS and a history of only pregnancy morbidity.     

The Michael Mason Prize: Pathogenic antiphospholipid antibodies, stressed out antigens and the deployment of decoys

The antiphospholipid syndrome is a common autoimmune cause of vascular thrombosis and recurrent miscarriages. aPLs that target the N-terminal domain [Domain I (DI)] of the phospholipid binding protein ?2-glycoprotein I (?2GPI) represent the key sub-population of aPLs that promote thrombosis. This review describes two research arms relating to the study of this autoantigen. The first arm describes recent novel biochemical and functional insights into the molecular structure of ?2GPI in vivo and how this may be altered in APS. These findings support the emerging hypothesis that redox modification of ?2GPI may be relevant to the pathogenesis of APS and the development of pathogenic anti-?2GPI antibodies. The second arm describes how a recombinant DI peptide engineered using a bacterial expression system was used to delineate the fine immunodominant epitopes on DI that pathogenic anti-?2GPI antibodies target. The epitope was found to be conformational and revolve around arginine (R) 39 within DI. Thus, whole recombinant DI was used in an in vivo mouse model as a novel decoy peptide inhibitor of anti-?2GPI antibodies. DI and a high binding mutant completely abrogated the pathogenic effects of aPL in this murine model, with loss of inhibition of pathogenicity observed upon mutating the residue R39 to serine. This proof-of-principle study supports the ongoing development of recombinant DI as a novel therapeutic inhibitory peptide for patients with APS.