Antiphospholipid syndrome

SummaryThe antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL) in the plasma of patients with vascular thrombosis, recurrent complications of pregnancy, or both (1, 2). The presence of aPL in plasma of patients can be detected with either a prolongation of phospholipid dependent coagulation tests (lupus anticoagulant, LAC), or with solid phase immune assays against the protein β2-glycoprotein I (β2-GPI) or the phospholipid cardiolipin (anti-β2-GPI antibody ELISA and anti-cardiolipin antibody ELISA, respectively) (3). For a long time there was a lot of confusion on who had the syndrome and who not. To solve this dispute, an international consensus meeting was organized in Sapporo in 1999 to formulate classification criteria for patients with the antiphospholipid syndrome (4). These criteria have been updated in 2004 at another international consensus meeting in Sydney (5). The classification criteria were defined for scientific purposes and were aimed to be used as inclusion criteria in patient related studies. They were specifically not defined for diagnostic purposes. However, current practice is that these criteria are used as a diagnostic tool. This is very unfortunate because the specificity of the different aPL assays to detect the clinical manifestations that characterize APS are disputable. One of the aims of defining the criteria was to initiate studies to determine the value of the different anti-phospholipid antibody assays to serve as biomarker for the risk of thrombosis and pregnancy morbidity. The recent progress made on this important topic will be discussed.

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Non-Criteria Manifestations of Juvenile Antiphospholipid Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10061240 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1240

Author(s):

Takako Miyamae ◽

Tomohiro Kawabe

Keyword(s):

Heart Disease ◽

Antiphospholipid Syndrome ◽

Valvular Heart Disease ◽

Antiphospholipid Antibodies ◽

Clinical Manifestations ◽

Autoimmune Disorder ◽

Classification Criteria ◽

Neurologic Manifestations ◽

Test Results ◽

Pregnancy Morbidity

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder mainly characterised by increased risks of thrombosis and pregnancy morbidity and persistent positive test results for antiphospholipid antibodies (aPLs). The criteria for diagnosing juvenile APS have yet to be validated, while the Sydney classification criteria do not contain several non-thrombotic clinical manifestations associated with the presence of aPLs. As such, difficulties have been encountered in the diagnosis of patients who have no certain thrombotic occlusions. Moreover, extra-criteria manifestations (i.e., clinical manifestations not listed in the classification criteria), including neurologic manifestations (chorea, myelitis and migraine), haematologic manifestations (thrombocytopenia and haemolytic anaemia), livedo reticularis, nephropathy and valvular heart disease have been reported, which suggests that the clinical spectrum of aPL-related manifestations extends beyond that indicated in the classification criteria. Studies have demonstrated that more than 40% of children with aPLs demonstrated non-thrombotic aPL-related clinical manifestations alone. Moreover, our results showed that the pathogenesis of non-criteria manifestations is characterised by “APS vasculopathy”. The present review introduces the characteristics and findings of non-criteria manifestations observed in juvenile APS.

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Antiphospholipid syndrome: a case report with an unusual wide spectrum of clinical manifestations

Autoimmunity Highlights ◽

10.1186/s13317-019-0119-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Carmela Mazzoccoli ◽

Domenico Comitangelo ◽

Alessia D’Introno ◽

Valeria Mastropierro ◽

Carlo Sabbà ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Symptoms ◽

Wide Spectrum ◽

Clinical Manifestations ◽

Classification Criteria ◽

Inflammation Markers ◽

Case Presentation ◽

Pregnancy Morbidity ◽

Generalized Seizures ◽

Laboratory Examinations

Abstract Background Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of venous and/or arterial thrombosis, and the detection of circulating antiphospholipid antibodies. The classification criteria for definite APS are actually met when at least one clinical criterion (thrombosis or pregnancy morbidity) is present in association of one laboratory criterion (LAC, aCL antibody or aβ2GPI antibody present on two or more occasions, at least 12 weeks a part), and thrombosis should be confirmed by objective validated criteria. The average age of primary APS patients has been reported to be about 35–40 years and the disease is more common in women than in men. Case presentation In this report, we described a rare case of an adult male who presented over a period of 9 years with a wide spectrum of clinical manifestations involving different organs that were not initially diagnosed as APS. Dizziness and syncope were his first clinical symptoms, and a non-bacterial thrombotic endocarditis (NBTE) involving the mitral valve was at first diagnosed. Subsequently, the patient also presented with generalized seizures and subsequent head injury. When the patient was admitted to our clinic with bilateral epistaxis and fever, thrombocytopenia was revealed. Moreover, laboratory examinations showed acute pancreatitis with an increase of levels of inflammation markers. Conclusion Based on the patient’s medical history and all the examination results, it was possible to make a diagnosis of primary APS and, starting from diagnosis of thrombocytopenia, we were allowed to conclude that all of manifestation were epi-phenomena of a unique clinical entity, rather than unrelated diseases. Though APS is one of the most common thrombocytophilias, unfortunately, it is not recognized often enough. The lack of prevention in undiagnosed patients may cause severe complications which can in turn result in the death of those patients.

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Is There an Additional Value in Detecting Anticardiolipin and Anti-β2 glycoprotein I IgA Antibodies in the Antiphospholipid Syndrome?

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714653 ◽

2020 ◽

Vol 120 (11) ◽

pp. 1557-1568

Author(s):

Walid Chayoua ◽

Dong-mei Yin ◽

Hilde Kelchtermans ◽

Gary W. Moore ◽

Jean-Christophe Gris ◽

...

Keyword(s):

Antiphospholipid Syndrome ◽

Immunoglobulin A ◽

Clinical Manifestations ◽

Pregnancy Morbidity ◽

Medical Centers ◽

Glycoprotein I ◽

Iga Antibodies ◽

Obstetric Aps ◽

Current Criterion ◽

Additional Value

Abstract Background Anticardiolipin (aCL) and anti-β2 glycoprotein I (aβ2GPI) immunoglobulin A (IgA) antiphospholipid antibodies (aPL) have shown to associate with thrombosis and pregnancy morbidity. However, inclusion of IgA aPL in the classification criteria of the antiphospholipid syndrome (APS) has been debated. We investigated the value of aCL and aβ2GPI IgA aPL in the detection of thrombosis and pregnancy morbidity in addition to the current aPL panel for APS. Methods We included 1,068 patients from eight European medical centers: 259 thrombotic APS patients, 122 obstetric APS patients, 204 non-APS thrombosis patients, 33 non-APS obstetric patients, 60 APS patients with unspecified clinical manifestations, 196 patients with autoimmune diseases, and 194 controls. aCL and aβ2GPI IgG/M/A were detected with four commercial assays and lupus anticoagulant was determined by the local center. Results Positivity for IgA aPL was found in 17 to 26% of the patients with clinical manifestations of APS and in 6 to 13% of the control population. Both aCL and aβ2GPI IgA were significantly associated with thrombosis and pregnancy morbidity. Isolated IgA positivity was rare in patients with clinical manifestations of APS (0.3–5%) and not associated with thrombosis and/or pregnancy morbidity. Addition of IgA to the current criterion panel did not increase odds ratios for thrombosis nor pregnancy morbidity. Conclusion aCL and aβ2GPI IgA are associated with clinical manifestations of APS. However, isolated IgA positivity was rare and not associated with thrombosis or pregnancy morbidity. These data do not support testing for aCL and aβ2GPI IgA subsequent to conventional aPL assays in identifying patients with thrombosis or pregnancy morbidity.

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Pathophysiological insights into the antiphospholipid syndrome

Hämostaseologie ◽

10.5482/hamo-16-07-0020 ◽

2017 ◽

Vol 37 (03) ◽

pp. 202-207 ◽

Cited By ~ 1

Author(s):

Davit Manukyan ◽

Nadine Müller-Calleja ◽

Karl Lackner

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Future Research ◽

Scientific Debate ◽

Pregnancy Morbidity ◽

Anionic Phospholipids ◽

The Third ◽

Glycoprotein I ◽

Underlying Mechanisms

SummaryThe antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis and severe pregnancy morbidity in presence of antiphospholipid antibodies (aPL). While there is compelling evidence that aPL cause the clinical manifestations of APS, the underlying mechanisms are still a matter of scientific debate. This is mainly related to the broad heterogeneity of aPL. There are three major types of aPL: The first one binds to (anionic) phospholipids, e.g. cardiolipin, in absence of other factors (cofactor independent aPL). The second type binds to phospholipids only in presence of protein cofactors, e.g. ß2-glycoprotein I (ß2GPI) (cofactor dependent aPL). The third type binds to cofactor proteins directly without need for phospholipids. It is widely believed that cofactor independent aPL (type 1) are associated with infections and, more importantly, non-pathogenic, while pathogenic aPL belong to the second and in particular to the third type. This view, in particular with regard to type 1 aPL, has not been undisputed and novel research data have shown that it is in fact untenable. We summarize the available data on the pathogenetic role of aPL and the implications for diagnosis of APS and future research.

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Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study

Blood ◽

10.1182/blood-2010-05-283507 ◽

2010 ◽

Vol 116 (16) ◽

pp. 3058-3063 ◽

Cited By ~ 34

Author(s):

Lucía Comellas-Kirkerup ◽

Gabriela Hernández-Molina ◽

Antonio R. Cabral

Keyword(s):

Hemolytic Anemia ◽

Antiphospholipid Syndrome ◽

Autoimmune Hemolytic Anemia ◽

Lupus Anticoagulant ◽

Thrombotic Event ◽

Classification Criteria ◽

Response To Treatment ◽

Primary Antiphospholipid Syndrome ◽

Pregnancy Morbidity

Abstract The updated Sapporo classification criteria for antiphospholipid syndrome (APS) only include thrombosis or pregnancy morbidity as clinical criteria. To test this notion, we studied 55 patients (80% women) with hematologic manifestations. All fulfilled the laboratory criteria for primary APS. Thirty-five patients (64%) had thrombocytopenia, 14 (25%) had autoimmune hemolytic anemia, and 6 (11%) had both. Twenty-five patients (22 women, 88%) also fulfilled one clinical criterion for APS after a median follow-up of 13.2 years (range, 1.45-37 years), whereas the remaining 30 patients (22 women, 73%) have not had any thrombotic event nor pregnancy morbidity after a median follow-up of 5.4 years (range, 0.12-24 years). No patient developed systemic lupus erythematosus during follow-up. The hematologic manifestation was asynchronous with the APS onset in 84% of patients. The response to treatment was similar regardless of the APS status. Patients with definite APS were more frequently positive for the lupus anticoagulant (63%) than lupus anticoagulant-positive patients without APS (30%; odds ratio, 3.5; 95% confidence interval, 1.07-11.4; P < .02). Anticardiolipin or anti–β2-glycoprotein-I antibodies were highly prevalent among the study groups. Our study suggests that, depending upon their antiphospholipid profile, patients with hemocytopenias appear to comprise a peculiar subset of patients with APS; some develop thrombotic and/or obstetric APS whereas others continue with hematologic APS.

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Antiphospholipid Syndrome: A Review

Haematology Journal of Bangladesh ◽

10.37545/haematoljbd201824 ◽

2018 ◽

Vol 2 (02) ◽

pp. 51-58

Author(s):

Md. Motahar Hossain ◽

Md. Akhter Hossain ◽

Yasmin Rahman ◽

Md. Kamrul Hasan

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Anticardiolipin Antibodies ◽

Vitamin K Antagonist ◽

Classification Criteria ◽

Antiphospholipid Antibody ◽

Antiphospholipid Antibody Syndrome ◽

Pregnancy Morbidity ◽

Pregnancy And Postpartum

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous thromboembolism, arterial thrombosis, and obstetric morbidities in the setting of persistently positive levels of antiphospholipid antibodies. It may be primary or secondary. The latest classification criteria (Sydney 2006) recognize just three tests to define this syndrome- lupus anticoagulant, anticardiolipin antibodies and anti-?2-glycoprotein-1 antibodies. Treatment of thrombotic events involves lifelong anticoagulation with vitamin K antagonist warfarin. Antiphospholipid antibody syndrome (APS) with only pregnancy morbidity is treated with thromboprophylaxis with heparin during pregnancy and postpartum for 6 weeks. In this review we discuss the pathogenesis, diagnosis, treatment and prognosis of the APS.

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Treatment of Thrombotic Antiphospholipid Syndrome: The Rationale of Current Management—An Insight into Future Approaches

Journal of Immunology Research ◽

10.1155/2015/951424 ◽

2015 ◽

Vol 2015 ◽

pp. 1-20 ◽

Cited By ~ 33

Author(s):

Cecilia Beatrice Chighizola ◽

Tania Ubiali ◽

Pier Luigi Meroni

Keyword(s):

Antiphospholipid Syndrome ◽

Clinical Manifestations ◽

Controversial Issues ◽

Current Management ◽

Pharmacological Agents ◽

Future Studies ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

The Impact ◽

Insight Into

Vascular thrombosis and pregnancy morbidity represent the clinical manifestations of antiphospholipid syndrome (APS), which is serologically characterized by the persistent positivity of antiphospholipid antibodies (aPL). Antiplatelet and anticoagulant agents currently provide the mainstay of APS treatment. However, the debate is still open: controversies involve the intensity and the duration of anticoagulation and the treatment of stroke and refractory cases. Unfortunately, the literature cannot provide definite answers to these controversial issues as it is flawed by many limitations, mainly due to the recruitment of patients not fulfilling laboratory and clinical criteria for APS. The recommended therapeutic management of different aPL-related clinical manifestations is hereby presented, with a critical appraisal of the evidence supporting such approaches. Cutting edge therapeutic strategies are also discussed, presenting the pioneer reports about the efficacy of novel pharmacological agents in APS. Thanks to a better understanding of aPL pathogenic mechanisms, new therapeutic targets will soon be explored. Much work is still to be done to unravel the most controversial issues about APS management: future studies are warranted to define the optimal management according to aPL risk profile and to assess the impact of a strict control of cardiovascular risk factors on disease control.

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Morbidity, Mortality, and Organ Damage in Patients with Antiphospholipid Syndrome

The Journal of Rheumatology ◽

10.3899/jrheum.110800 ◽

2012 ◽

Vol 39 (3) ◽

pp. 516-523 ◽

Cited By ~ 27

Author(s):

ELEFTHERIA P. GRIKA ◽

PANAYIOTIS D. ZIAKAS ◽

ELIAS ZINTZARAS ◽

HARALAMPOS M. MOUTSOPOULOS ◽

PANAYIOTIS G. VLACHOYIANNOPOULOS

Keyword(s):

Antiphospholipid Syndrome ◽

Lupus Erythematosus ◽

Descriptive Analysis ◽

Disease Onset ◽

Clinical Manifestations ◽

Organ Damage ◽

Systemic Lupus ◽

Pregnancy Morbidity ◽

Initial Event ◽

Unit Increase

Objective.To describe morbidity, organ damage, mortality, and cause of death in patients with antiphospholipid syndrome (APS).Methods.Descriptive analysis of 135 patients. Patients were clustered according to initial event: arterial thrombosis including stroke (AT; n = 46), venous thrombosis including pulmonary emboli (VT; n = 53), or pregnancy morbidity (PM; n = 36). Disease progression according to initial event and prevalence of organ damage was observed.Results.APS occurs among young individuals (mean age 33.3 ± 11.9 yrs). One-third of the patients have APS secondary to systemic lupus erythematosus (SLE) or SLE-like disease. A broad spectrum of clinical manifestations mark the disease onset even before diagnosis. The pattern of initial presentation is preserved with regard to second event; VT is followed by VT (84%), AT is followed by AT (95%), and PM is followed by PM (88.9%). The highest morbidity is attributed to neurologic damage. PM is more likely to be followed by a second event, yet is associated with less organ damage than AT and VT. After a mean followup of 7.55 years, 29% of patients experienced organ damage and 5 died, with Systemic Lupus International Collaborating Clinics score associated with increased mortality (HR 1.31, 95% CI 1.07–1.60, p = 0.01, per 1-unit increase); hematological malignancies occurred in 2 patients after a cumulative followup of 1020 person-years. Coexistent SLE adds significant damage in patients with APS.Conclusion.APS is a disease of young individuals, who experience increased morbidity. Neurologic damage is the most common cause of morbidity. AT at presentation as well as coexistent SLE are associated with poor outcome.

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Diagnosis and management of non-criteria obstetric antiphospholipid syndrome

Thrombosis and Haemostasis ◽

10.1160/th14-05-0416 ◽

2015 ◽

Vol 113 (01) ◽

pp. 13-19 ◽

Cited By ~ 39

Author(s):

Samuel J. Machin ◽

Ian J. Mackie ◽

Hannah Cohen ◽

Deepa R. Jayakody Arachchillage

Keyword(s):

Antiphospholipid Syndrome ◽

In Vitro Fertilisation ◽

International Consensus ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Retrospective Cohort Studies ◽

Obstetric Antiphospholipid Syndrome ◽

Obstetric Aps

SummaryAccurate diagnosis of obstetric antiphospholipid syndrome (APS) is a prerequisite for optimal clinical management. The international consensus (revised Sapporo) criteria for obstetric APS do not include low positive anticardiolipin (aCL) and anti β2 glycoprotein I (aβ2GPI) antibodies (> 99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late preeclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. In this review we examine the available evidence to address the question of whether patients who exhibit non-criteria clinical and/or laboratory manifestations should be included within the spectrum of obstetric APS. Prospective and retrospective cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM aβ2GPI, or low positive positive aCL or aβ2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such prospective and retrospective studies also suggest that women with non-criteria obstetric APS may benefit from standard treatment for obstetric APS with low-molecular-weight heparin plus low-dose aspirin, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches. Women with obstetric APS appear to be at a higher risk than other women of pre-eclampsia, placenta- mediated complications and neonatal mortality, and also at increased long-term risk of thrombotic events. The applicability of these observations to outcomes in women with non-criteria obstetric APS remains to be determined.

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IgG Autoantibodies againstβ2-Glycoprotein I Complexed with a Lipid Ligand Derived from Oxidized Low-Density Lipoprotein are Associated with Arterial Thrombosis in Antiphospholipid Syndrome

Clinical and Developmental Immunology ◽

10.1080/10446670310001642113 ◽

2003 ◽

Vol 10 (2-4) ◽

pp. 203-211 ◽

Cited By ~ 40

Author(s):

Daniel Lopez ◽

Kazuko Kobayashi ◽

Joan T. Merrill ◽

E. Matsuura ◽

Luis R. Lopez

Keyword(s):

Venous Thrombosis ◽

Antiphospholipid Syndrome ◽

Arterial Thrombosis ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Clinical Manifestations ◽

Density Lipoprotein ◽

Healthy Individuals ◽

Pregnancy Morbidity ◽

Glycoprotein I

We recently reported [J. Lipid Res.42(2001), 697;43(2002), 1486;44(2003), 716] thatβ2-glycoprotein I (β2GPI) forms complexes with oxidized LDL (oxLDL) and autoantibodies against these complexes are present in patients with SLE and antiphospholipid syndrome (APS). The relationship ofβ2GPI/oxLDL complexes and IgG autoantibodies againstβ2GPI complexed with oxLig-1 (an oxLDL-derived ligand) with clinical manifestations of APS was studied in 150 APS and SLE patients. Theβ2GPI/oxLDL levels of APS patients were similar to those of SLE patients without APS, but they were significantly higher than healthy individuals. There was no difference in the complex levels among the patients with arterial, venous thrombosis, or pregnancy morbidity. IgG anti-β2GPI/oxLig-1 levels of APS were significantly higher than those of SLE without APS and healthy individuals. Further, antibody levels of APS patients with arterial thrombosis were significantly higher than those patients with venous thrombosis and pregnancy morbidity. Thus, oxidation of LDL leads the complex formation withβ2GPI in SLE and APS patients. In contrast, anti-β2GPI/oxLig-1 autoantibodies were generated only in APS and were strongly associated with arterial thrombosis. These results suggest that autoantibodies againstβ2GPI/oxLDL complexes are etiologically important in the development of atherosclerosis in APS.

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