ARTIGOS DE REVISÃO / REVIEW ARTICLES

Antiphospholipid syndrome

Síndrome antifosfolipídica

Ricard Cervera, Gerard Espinosa

Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Catalonia, Spain

Correspondência

 

ABSTRACT

The antiphospholipid syndrome (APS) is defined by the development of venous and/or arterial thromboses, often multiple, and pregnancy morbidity (mainly, recurrent fetal losses), in the presence of antiphospholipid antibodies (aPL). Some estimates indicate that the incidence of the APS is around 5 new cases per 100 000 persons per year and the prevalence around 40-50 cases per 100 000 persons. The aPL are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis and 6% of patients with pregnancy morbidity.

Currently, there is consensus in treating APS patients with thrombosis with long-term oral anticoagulation and to prevent obstetric manifestations with the use of aspirin and heparin. This review summarizes the main knowledge on the clinical and therapeutic aspects of this syndrome.

Keywords: Antibodies, Anticardiolipin; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Stroke

 

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RESUMO

A síndrome antifosfolipídica (SAF) carateriza-se pelo desenvolvimento de tromboses venosas e/ou arteriais, muitas vezes múltiplas, e pela morbidade gestacional (por perdas fetais recorrentes), na presença de anticorpos antifosfolipídicos. As estimativas indicam que a incidência da SAF é de cerca de 5 novos casos por 100 000 pessoas por ano e a prevalência é de cerca de 40-50 casos por 100 000 pessoas. Os aPL são positivos em aproximadamente 13% dos pacientes com acidente vascular cerebral, 11% com enfarte do miocárdio, 9,5% dos pacientes com trombose venosa profunda e 6% dos pacientes com morbidade gestacional.

Atualmente, há consenso no tratamento de pacientes com SAF com trombose com anticoagulação oral de longa duração e para evitar manifestações obstétricas com o uso de aspirina e heparina. Esta revisão resume os principais conhecimentos sobre os aspectos clínicos e terapêuticos desta síndrome.

Palavras-chave: Acidente Vascular Cerebral; Anticorpos Anticardiolipina; Anticorpos Antifosfolipídeos; Síndrome Antifosfolipídica

 

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Introduction

The antiphospholipid syndrome (APS) is characterized by the development of venous and/or arterial thromboses, often multiple, and pregnancy morbidity (mainly, recurrent fetal losses), in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-ß2glycoprotein-I (ß2GPI) antibodies.^1-4

The APS can be found in patients having neither clinical nor laboratory evidence of another definable condition (primary APS) or it may be associated with other diseases, mainly systemic lupus erythematosus (SLE), but occasionally with other autoimmune conditions,¹ infections,² drugs,¹ and malignancies.³ A minority of APS patients can develop a devastating variant termed catastrophic APS.⁵

Epidemiology

The aPL can appear in different scenarios, such as asymptomatic aPL carrier patients, thrombotic APS with recurrent venous and/or arterial thrombosis, obstetric APS affecting otherwise healthy women with recurrent pregnancy loss, patients with non-APS classification criteria manifestations (i.e, thrombocytopenia, hemolytic anemia or livedo reticularis) or with catastrophic APS.⁵

Prevalence of the aPL in the general population ranges between 1% - 5%. However, only a minout together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS ("CAPS Registry") was crerity of these individuals develop the APS. Some estimates indicate that the incidence of the APS is around 5 new cases per 100 000 persons per year and the prevalence around 40-50 cases per 100 000 persons.⁶ Specifically, aPL are positive in approximately 13% of patients with stroke, 11% with myocardial infarction (MI), 9.5% of patients with deep vein thrombosis (DVT) and 6% of patients with pregnancy morbidity.⁷

The prevalence of the catastrophic APS is scarce (less than 1% of all cases of APS).^5,8,9 In order to pated in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory and therapeutic data of more than 500 patients.⁵

Pathogenesis

Autoantibodies associated with APS are directed against a number of proteins of the plasma or 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 are the basis for possible mechanisms by which aPL may develop thrombotic events in patients with APS. In depth reviews of these mechanisms can be found elsewhere.^10,11

Clinical Manifestations

The clinical picture of the APS is characterized by venous and arterial thromboses, pregnancy morbidity (mainly, fetal losses) and moderate thrombocytopenia. Single vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Any combination of vascular occlusive events may occur in the same individual and the time interval between them also varies considerably from weeks to months or even years.^12-14 The prevalence of the main manifestations in a cohort of 1000 patients with APS (“Euro-Phospholipid Project”) are collected in Table 1.¹²

Several attempts have been made in order to identify the individual risk of thrombosis in aPL positive patients.^15,16 A study of pregnant women with APS reported that patients with triple aPL positivity (ie, positivity for LA, aCL, and anti-ß2GPI) and/or previous thromboembolism had an increased likelihood of poor neonatal outcomes than patients with double or single aPL positivity and no thrombosis history.¹⁵ More recently, a global APS score (GAPSS) was developed in a cohort of 211 SLE from a single centre after the combination of several independent risk factors for both thrombosis and pregnancy loss. The final score includes 6 factors with different weights: IgG/IgM aCL (5 points), IgG/IgM anti-ß2GPI antibodies (4 points), LA (4 points), IgG/ IgM anti-phosphatidylserine–prothrombin complex antibodies (3 points), hyperlipidemia (3 points) and arterial hypertension (1 point). A GAPSS cut-off value higher than 10 points appears to have the best prognostic yield.¹⁶

Classification Criteria

A preliminary classification set of criteria was established after an expert workshop held in Sapporo, Japan, in 1999.¹⁷ These classification criteria were updated in another workshop was held in Sydney, Australia, in 2006 in which the experts proposed the inclusion of anti-ß2GPI antibodies. Although no new clinical criteria were added, some particular features were remarked on, such as associated APS features, including cardiac valve involvement, livedo reticularis, thrombocytopenia, APS nephropathy, and non-thrombotic central nervous system manifestations (i.e. cognitive dysfunction)¹⁸ (Table 2).

This revised APS classification criteria¹⁹ provide a more uniform basis for selecting patients for APS research by emphasising risk stratification. They strongly recommend investigating coexisting inherited and acquired thrombosis risk factors in patients with APS, especially in those who are included in clinical trials. An assessment of these 2006 revised APS classification criteria has shown that only 59% of the patients meeting the 1999 APS Sapporo classification criteria met the revised criteria.¹⁹

The preliminary classification criteria for catastrophic APS were formulated at a workshop in Taormina, Italy, in 2002, during the 10th International Congress on aPL (Table 3).²⁰ A validation study showed that they have a sensitivity of 90.3%, a specificity of 99.4%, a positive predictive value of 99.4% and a negative predictive value of 91.1%.²¹ A recent evidence-based set of guidelines for the diagnosis and management of catastrophic APS has formulated the recommendation that these classification criteria can be also used as diagnostic criteria.²²

Treatment

Treatment of thrombosis in APS patients is based on long-term oral anticoagulation and treatment of obstetric manifestations on the use of aspirin and heparin.²³ These recommendations are based on randomized controlled trials and observational studies (Table 4). In detail, patients with definite APS with first venous thrombosis have to be treated with prolonged oral anticoagulation at a target international normalized ratio (INR) of 2.0-3.0. Anticoagulation at INR of 3.0-4.0, isolated antiaggregation, anticoagulation at INR 2.0-3.0 or anticoagulation at INR 2.0-3.0 plus antiaggregation have been proposed for definite APS patients with arterial thrombosis. Regarding obstetric APS, although combined therapy with low-dose aspirin and low-molecular-weight heparin is the mainstay of treatment in women with obstetric APS, the strength of evidence of its efficacy is under discussion.²⁴

Otherwise, in the field of APS there are grey areas where the evidence is scarce and where the management of certain patients is difficult. Some examples are patients with “seronegative” APS, those who do not display formal (clinical or laboratory) classification criteria for APS, those with refractory APS despite optimal treatment (recurrent thrombotic events despite optimal anticoagulation or recurrent fetal losses despite the combination of aspirin and low molecular weight heparin), and the treatment of clinical manifestations not included in the classification criteria such as hematologic manifestations (thrombocytopenia and haemolytic anemia), neurologic manifestations (chorea, myelitis or multiple sclerosis-like lesions), nephropathy and heart valve disease associated with antiphospholipid antibodies. In these cases, the recommendations are based on the common sense since the published evidence is scarce or it does not exist.²³

In cases of catastrophic APS, an aggressive treatment is required (Fig 1). Therefore, early diagnosis is very important to start adequate therapy and decrease the high mortality rate of these patients. Once the diagnosis is made or suspected, searching and treating the precipitating factor, mainly infection, is the first step of treatment. The specific therapy of catastrophic APS is the combination of anticoagulation with heparin, and corticosteroids as first line of treatment. Additionally adding intravenous immunoglobulins and/or plasma exchange have to be considered in life-threatening cases. In patients with associated SLE, intravenous cyclophosphamide has demonstrated be beneficial. In refractory cases, rituximab or eculizumab should be added.^22,25

Outcome and Organ Damage

Given that APS affect predominantly young patients, assesment of organ damage is crucial but evidence in that field is limited. A retrospective analysis was published that focused in morbidity, mortality, and organ damage in 135 APS patients (89 primary APS and 46 with secondary APS).²⁶ Patients were clustered according to the initial event: arterial thrombosis, DVT or pregnancy morbidity. One-fourth of the patients progressed to organ damage in a mean time of 10 years from disease onset. The highest morbidity was attributed to neurologic damage, which was more common among patients with arterial thrombosis as an initial manifestation.

During the follow-up study period of the “Euro-Phospholipid Project”, a 10-year survival rate of 91% was reported.¹⁴ During this follow-up period, 93 (9.3%) patients died. The main causes of death were thrombosis (36.5%) and infections (26.9%).

Patients with APS still develop significant morbidity and mortality despite current treatment (mainly oral anticoagulants and/ or antiaggregant agents); therefore, it is imperative to increase the effort in determining optimal prognostic markers and therapeutic measures to prevent these important complications of the APS.

 

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Correspondência:Marta Vaz Batista martafilipavaz@gmail.com
Serviço de Medicina 1, Hospital Professor Doutor Fernando Fonseca, Amadora, Portugal
IC 19 - 2720-276 Amadora

 

Conflitos de Interesse: Os autores declaram a inexistência de conflitos de interesse na realização do presente trabalho.

Fontes de Financiamento: Não existiram fontes externas de financiamento para a realização deste artigo.

Conflicts of interest: The authors have no conflicts of interest to declare.

Financing Support: This work has not received any contribution, grant or scholarship.

 

Recebido: 09/09/2018

Aceite:30/09/2018