4
Antiphospholipid syndrome

https://doi.org/10.1016/j.berh.2019.101463Get rights and content

Abstract

Antiphospholipid syndrome is an autoimmune systemic disorder characterized by arterial, venous, or small vessel thrombosis and/or recurrent early pregnancy loss, fetal loss, or pregnancy morbidity in the setting of documented persistent antiphospholipid antibodies that include the lupus anticoagulant, or moderate-high titer anticardiolipin, or anti-β2Glycoprotein I antibodies. Associated clinical manifestations include livedo reticularis, cutaneous ulcerations, thrombocytopenia, hemolytic anemia, valvular heart disease, and nephropathy. The degree of risk associated with antiphospholipid antibody depends on the characteristics of the antiphospholipid antibody profile and on the presence of additional thrombotic risk factors. Current standard treatment for unprovoked thrombosis is long-term warfarin or other vitamin K antagonist therapy. Treatment to prevent recurrent obstetric complications is low-dose aspirin and prophylactic heparin, usually low-molecular-weight heparin. Optimal treatment for standard therapy failures or for certain nonthrombotic manifestations is uncertain, although nonanticoagulation therapies that address multiple demonstrated mechanisms of disease are being explored.

Introduction

Although antiphospholipid syndrome (APS) is often considered a relatively new disorder, its origin dates to the early 20th century with the identification of Wasserman's antibody, which binds the phospholipid cardiolipin and was used to detect the presence of Treponema pallidum [1]. The antibody was subsequently identified in patients who did not have syphilis, giving rise to the term biologic false-positive serologic test for syphilis (BFP-STS). In the 1950s, the BFP-STS was associated with an inhibitor of coagulation termed the lupus anticoagulant (LA), so called because early case reports linked it with hemorrhage in patients with systemic lupus erythematosus (SLE) [2]. The presence of LA was subsequently associated with both thrombosis and pregnancy loss, but the intricacies of performing the LA assay (a functional clotting assay requiring fresh plasma) limited research efforts. In 1983, more easily performed and standardized ELISA tests became available that detected anticardiolipin antibody (aCL) and many reports followed describing a wide variety of clinical manifestations associated with anticardiolipin, now termed APS, including the identification of patients with APS alone (primary APS, or PAPS) and patients with acute multisystem thrombosis (catastrophic APS (CAPS)). In the 1990s, it became clear that antiphospholipid antibodies (aPL) bind primarily to the circulating plasma protein β2-glycoprotein I (β2GPI) when it is bound to phospholipid, rather than to phospholipid directly. The anti-β2GPI antibody ELISA now provides an additional test to detect the presence of aPL [1]. Understanding the role of β2GPI and other phospholipid-binding proteins has led to greater clarity regarding the multiple mechanisms involved in the characteristic manifestations of this syndrome, including cellular activation, complement activation, and both prothrombotic and antifibrinolytic effects. This multiplicity of mechanisms highlights both the spectrum of aPL-related manifestations (not all of which are the result of thrombosis) as well as the rationale for suggested future therapies (not all of which are anticoagulants).

Binding of aPL to β2GPI on cellular surfaces activates endothelial cells, monocytes, and platelets leading to proinflammatory and prothrombotic phenotypes and complement activation, with the net result leading to thrombosis and potential interference with trophoblast and decidual cells. Recent studies also suggest the involvement of neutrophils with tissue factor (TF) expression and the release of neutrophil extracellular traps (NETosis), as well as the upregulation of the mechanistic target of rapamycin (mTOR) complex on endothelial cells, which may contribute to aPL-related vasculopathy. Hemostatic reactions include both prothrombotic effects such as acquired protein C resistance and the inhibition of TF pathway inhibitor and fibrinolytic changes, such as the inhibition of tissue plasminogen inhibitor activity [3]. As a result of the ever-increasing understanding of a complex interplay of thrombosis, inflammation, and vasculopathy, new therapies may emerge to better treat a broad spectrum of APS manifestations including cardiac and renal disease. Currently, anticoagulation with warfarin remains the mainstay of therapy for thrombosis, and combination therapy with aspirin and heparin the standard treatment for obstetric complications.

Section snippets

Diagnosis of antiphospholipid syndrome

Given the tremendous surge in both basic and clinical aPL and APS research over the last thirty years, as well as the clear association of the syndrome with clinically available antibody tests, it seems it should be simple to diagnose APS. It is not always the case, however, because of the wide variation in both laboratory findings and clinical manifestations; as a result, both overdiagnosis and underdiagnosis still occur. The relatively high frequency of low titer aPL (low titers are much less

Treatment of antiphospholipid syndrome

Treatment of the most common clinical manifestations of APS, such as venous thrombosis or fetal loss, is straightforward and supported by randomized clinical studies. However, many clinical situations remain where therapy must be based on weaker clinical data or even on expert opinion. Treatment categories may be separated into primary thromboprophylaxis, secondary thromboprophylaxis, the treatment of CAPS, pregnancy prophylaxis, and the treatment of non-criteria manifestations. Treatment

Summary

APS continues to be a cause of significant morbidity and mortality among rheumatology patients. While progress has been made in treating the classic complications of thrombosis and pregnancy loss, better treatments are needed. Recurrent thromboses occur even on warfarin, and maintaining a therapeutic INR is challenging especially in the setting of a strong LA. The mortality associated with the best identified therapy for CAPS is still almost 30%, and the success of standard pregnancy therapy

Funding

No funding for this publication.

Declaration of Competing Interest

None.

References (99)

  • W.G. Jackson et al.

    Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis on antithrombotic therapy

    Blood advances

    (2017)
  • H. Cohen et al.

    Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

    The Lancet Haematology

    (2016)
  • V. Pengo et al.

    Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome

    Blood

    (2018)
  • A. Schmidt-Tanguy et al.

    Antithrombotic effects of hydroxychloroquine in primary antiphospholipid syndrome patients

    J Thromb Haemost

    (2013)
  • C. Belizna et al.

    HIBISCUS: hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome

    Autoimmun Rev

    (2018)
  • K. Legault et al.

    McMaster RARE-Best practices clinical guideline on diagnosis and management of the catastrophic antiphospholipid syndrome

    J Thromb Haemost

    (2018)
  • B.E. Lonze et al.

    Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation

    Am J Transplant

    (2014)
  • F.S. Cowchock et al.

    Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment

    Am J Obstet Gynecol

    (1992)
  • W.H. Kutteh

    Antiphospholipid antibody–associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone

    Am J Obstet Gynecol

    (1996)
  • D.W. Branch et al.

    Pregnancy Loss Study Group. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy

    Am J Obstet Gynecol

    (2000)
  • K. Bramham et al.

    First-trimester low-dose prednisolone in refractory antiphospholipid antibody–related pregnancy loss

    Blood

    (2011)
  • A. Mekinian et al.

    The efficacy of hydroxychloroquine for obstetrical outcome in anti-phospholipid syndrome: data from a European multicenter retrospective study

    Autoimmun Rev

    (2015)
  • A. Ruffatti et al.

    Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study

    J Reprod Immunol

    (2016)
  • M.D. Lockshin et al.

    History of antiphospholipid antibody

  • C.L. Conley et al.

    A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus

    J Lab Clin Invest

    (1952)
  • D. Garcia et al.

    Diagnosis and management of the antiphospholipid syndrome

    N Engl J Med

    (2018)
  • M.R. Ugolini-Lopes et al.

    Treatment of non-criteria manifestations in antiphospholipid syndrome

  • S. Zuily et al.

    15th international congress on antiphospholipid antibodies task force on antiphosphlipid syndrome classification report

  • M.L. Bertolaccini et al.

    Clinical and prognostic significance of non-criteria antiphospholipid antibody tests

  • O. Unlu et al.

    Definition and epidemiology of antiphospholipid syndrome

  • L. Andreoli et al.

    Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature

    Arthritis Care Res

    (2013)
  • S. Sciascia et al.

    The estimated frequency of antiphospholipid antibodies in young adults with cerebrovascular events: a systematic review

    Ann Rheum Dis

    (2015)
  • M.G. Tektonidou et al.

    EULAR recommendations for the management of antiphospholipid syndrome in adults

    Ann Rheum Dis

    (2019)
  • A. Martinez-Berriotxoa et al.

    Transiently positive anticardiolipin antibodies and risk of thrombosis in patients with systemic lupus erythematosus

    Lupus

    (2007)
  • M.G. Tektonidou et al.

    Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies

    Arthritis Care Res

    (2009)
  • D. Erkan et al.

    A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome

    Rheumatology

    (2002)
  • D. Erkan et al.

    Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals

    Arthritis Rheum

    (2007)
  • A. Danowski et al.

    Determinants of risk for venous and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid syndrome with systemic lupus erythematosus

    J Rheumatol

    (2009)
  • J.A. Girón-González et al.

    Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: prospective analysis of 404 individuals

    J Rheumatol

    (2004)
  • M. Kaul et al.

    Assessment of the 2006 revised antiphospholipid syndrome classification criteria

    Ann Rheum Dis

    (2007)
  • W. Lim et al.

    Management of antiphospholipid antibody syndrome: a systematic review

    J Am Med Assoc

    (2006)
  • S. Sciascia et al.

    GAPSS: the global anti-phospholipid syndrome score

    Rheumatology

    (2013)
  • S. Zuily et al.

    Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study

    Rheumatology

    (2015)
  • M.D. Lockshin et al.

    Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies

    Arthritis Rheum

    (2012)
  • A. Ruffatti et al.

    Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case–control study

    Rheumatology

    (2011)
  • S. De Carolis et al.

    Uterine artery velocity waveforms as predictors of pregnancy outcome in patients with antiphospholipid syndrome: a review

    Ann N Y Acad Sci

    (2007)
  • J. Alijotas-Reig et al.

    Is obstetric antiphospholipid syndrome a primary nonthrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies?

    Obstet Gynecol Surv

    (2010)
  • M.Y. Kim et al.

    Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies

    Ann Rheum Dis

    (2018)
  • C. Baigent et al.

    Antithrombotic Trialists'(ATT) Collaboration: aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

    Lancet

    (2009)
  • Cited by (97)

    View all citing articles on Scopus
    View full text