Elsevier

Blood Reviews

Volume 31, Issue 6, November 2017, Pages 406-417
Blood Reviews

Review
Diagnosis and management of the antiphospholipid syndrome

https://doi.org/10.1016/j.blre.2017.07.006Get rights and content

Abstract

Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy complications in the presence of persistent antiphospholipid antibodies (APLA). Laboratory diagnosis of APLA depends upon the detection of a lupus anticoagulant, which prolongs phospholipid-dependent anticoagulation tests, and/or anticardiolipin (aCL) and anti-β2-glycoprotein-1 (β2GPI) antibodies. APLA are primarily directed toward phospholipid binding proteins. Pathophysiologic mechanisms underlying thrombosis and pregnancy loss in APS include APLA induced cellular activation, inhibition of natural anticoagulant and fibrinolytic systems, and complement activation, among others. There is a high rate of recurrent thrombosis in APS, especially in triple positive patients (patients with lupus anticoagulant, aCL and anti-β2GPI antibodies), and indefinite anticoagulation with a vitamin K antagonist is the standard of care for thrombotic APS. There is currently insufficient evidence to recommend the routine use of direct oral anticoagulants (DOAC) in thrombotic APS. Aspirin with low molecular weight or unfractionated heparin may reduce the incidence of pregnancy loss in obstetric APS. Recent insights into the pathogenesis of APS have led to the identification of new potential therapeutic interventions, including anti-inflammatory and immunomodulatory therapies. Additional research is needed to better understand the effects of APLA on activation of signaling pathways in vascular cells, to identify more predictive biomarkers that define patients at greatest risk for a first or recurrent APLA-related clinical event, and to determine the safety and efficacy of DOACs and novel anti-inflammatory and immune-modulatory therapies for refractory APS.

Introduction

The anti-phospholipid syndrome (APS) is a systemic autoimmune disorder characterized by recurrent thrombosis and/or obstetrical morbidity along with persistent anti-phospholipid antibodies (APLA), including lupus anticoagulant (LA), anti-β2-glycoprotein I (anti-β2GPI) and/or anti-cardiolipin (aCL) antibodies [1]. APS is one of the most common acquired thrombophilias, and unlike most of the genetic thrombophilias, is associated with both venous and arterial thrombosis. The deep veins of the lower extremities and the cerebral arterial circulation are the most commonly affected venous and arterial sites, respectively [2]. Thrombosis can also occur in more unusual locations such as the hepatic veins, visceral veins, or cerebral venous circulation. Indeed, development of thrombosis at unusual sites should prompt an evaluation for antiphospholipid antibodies as positive studies may inform therapy. A small number of patients (< 1%) develop catastrophic anti-phospholipid syndrome (CAPS) [1], [3], [4], defined as small vessel thrombosis in three or more organs in less than one week in the presence of APLA, with histopathologic confirmation of small vessel thrombosis in the absence of inflammation [4]. CAPS, which is often triggered by a precipitating event such as infection [5], [6], is associated with high (50%) mortality, mostly due to cerebral and cardiac thrombosis, infections and multi-organ failure [3], [7]. Obstetrical morbidity in APS includes the unexplained death of one or more morphologically normal fetuses at or beyond the 10th week of gestation, the premature birth of one or more morphologically normal neonates before the 34th week of gestation because of either eclampsia or severe preeclampsia, and/or three or more unexplained, consecutive spontaneous abortions before the 10th week of gestation [1]. Other ‘non-criteria’ clinical associations of APLA include thrombocytopenia, livedo reticularis, skin ulcers, and transient ischemic attacks [7]. These symptoms, along with thrombosis or pregnancy loss, should alert clinicians to this diagnosis.

While much knowledge concerning the clinical manifestations of APS has been acquired, the pathogenesis of this disorder remains poorly understood. For example, it is difficult to predict who will develop APS, or why. Though specific serological characteristics of APLA provide insight into which patients with these antibodies are more likely to develop clinical manifestations, our ability to accurately risk-stratify patients with these antibodies remains limited. Finally, a number of mechanisms by which APLA may induce thrombosis have been reported, although whether these are truly distinct, reflective of antibody heterogeneity, or represent different manifestations of a single, central pathway that has not been defined has remained elusive.

Section snippets

Diagnosis of APS

The Sapporo classification criteria for APS were first proposed in 1999 [8], and updated at the Eleventh International Congress on Antiphospholipid Antibodies in Sydney in 2006 [1]. While these are often used in practice as diagnostic criteria, it should be noted that they were originally developed to define a uniform cohort of APS patients for clinical studies rather than to provide a system for clinical diagnosis. Patient must have both clinical and laboratory criteria to meet a diagnosis of

Antiphospholipid antibodies

APLA were originally thought to react with anionic phospholipids such as cardiolipin, however, it is now known that that most APLA are directed against phospholipid binding proteins expressed on, or bound to, an appropriate surface such as a cellular membrane [36]. Anti-β2GPI antibodies appear to be central to the pathogenesis of APS [12], [37], although other antigenic targets such as prothrombin have been described [12], [38], [39]. Affinity-purified anti-β2GPI antibodies from patients with

Thrombotic risk assessment in APS

Thrombotic risk prediction in APS is challenging. While sufficient information may be gleaned from antiphospholipid antibody laboratory testing to provide an approximate odds ratio for thrombosis prediction, direct extrapolation of these ratios to a specific individual is difficult. A major problem in the APS field is the identification of robust, easily measurable clinical and laboratory biomarkers that accurately predict the risk of cardiovascular events.

Management of thrombosis in APS

Since most studies imply a high rate of recurrent thrombosis in patients with APS, long-term anticoagulation with a vitamin K antagonist (VKA) is the standard of care for patients who develop thrombosis [138]. Garcia et al. conducted a careful systematic review of 8 prospective studies that evaluated patients with a first APS-related thrombotic event and reported that the rate of recurrent thrombosis after stopping anticoagulation in patients with APLA was 40% higher than in those with VTE

Treatment of catastrophic APS

CAPS can be a challenging diagnosis to make in patients without a known history of APLA and delays in diagnosis can have lethal consequences Early diagnosis is essential to rescue patients with this rapidly progressive, potentially fatal condition. Prospective trials for treatments of CAPS have not been conducted, and are not expected for this rare disorder. The optimal treatment of CAPS is unknown. Based on observational data and expert opinion, anticoagulation with heparin and high dose

Management of obstetric APS

The management of obstetrical APS remains controversial, largely because numerous observational and randomized studies used different definitions of recurrent miscarriage, pre-eclampsia or placental insufficiency, and different APLA were tested, with variability in cut-off values for positive tests and in APLA profiles. A prospective observational study reported live births in 71% of pregnancies treated with aspirin in combination with either heparin or LMWH [165]. Two randomized studies

Non-anticoagulant therapeutic approaches

Insights into the pathogenic mechanisms involved in APS have identified novel targeted therapeutic approaches including inhibition of specific signaling pathways, and immunomodulatory therapies, which may be particularly useful in patients with refractory thrombotic APS and underlying SLE. Case reports of CAPS as well as studies in animal models suggest that plasma exchange, defibrotide and complement directed therapies may also be effective.

Asymptomatic antiphospholipid antibodies

Asymptomatic APLA are present in 1% to 5% of healthy individuals without a history of thrombotic events and as many as 11% to 86% of individuals with SLE; these wide estimates reflect in part the use of different assays and non-standardized approaches to APLA detection. It is difficult to predict the rate of first thrombosis in these patients although a prospective study of triple-positive APLA carriers reported a 5.3% annual incidence of thromboembolism that was not diminished by the use of

Conclusions and future directions

APS is an autoimmune, inflammatory disorder associated with a substantial incidence of thrombosis, pregnancy morbidity, and potentially devastating complications such as catastrophic APS. APLA are common in the general population and identifying individuals at greatest risk of clinical events remains very challenging. Anti-β2GPI-Domain1 antibodies and β2GPI specific LA are potentially more specific markers of thrombotic risk but are not widely available outside of the research setting. The

Practice points

  • “Sydney” classification criteria for APS classification require the persistent presence of an antiphospholipid antibody accompanied by thrombosis or pregnancy morbidity.

  • Laboratory evaluation of APLA can be challenging; APLA assays are affected by patient factors (inflammation, anticoagulants) and inter-laboratory variability.

  • Long-term anticoagulation with a vitamin K antagonist is the standard of care for patients with thrombotic APS.

  • The optimal management of patients with APLA who develop

Research agenda

  • Continued efforts toward universal standardization of APLA assays.

  • Development of enhanced biomarkers with better predictive value for primary and recurrent thrombosis, and adverse pregnancy outcomes in patients with APLA.

  • Improved characterization of the mechanisms and signaling pathways underlying altered cellular functions in APS, including defining interactions between diverse signaling pathways, and characterization of the roles of multiple receptors and how they may interact.

  • Further

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

SC and KRM drafted and edited the manuscript and both authors approved the final version submitted for publication. This work was supported in part by HL123416 and an ASH Bridge grant (to KRM) and an ASH RTAF (to SC).

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