Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of “Non-criteria” Antiphospholipid Antibodies

Objective.Most clinicians use the 2006 Sydney classification criteria to evaluate patients suspected of having antiphospholipid syndrome (APS). Although sensitive and specific for APS, many patients fulfilling clinical criteria for the syndrome are persistently negative for the specific serological tests (“laboratory criteria”). These “seronegative APS” (SN-APS) patients can go undiagnosed and untreated until they experience serious clinical events. This study’s objective was to describe antibody profiles of SN-APS patients using non-criteria markers, assess the clinical utility of these markers separately and in combination, and suggest incorporation into guidelines for patients suspected of APS.Methods.We categorized 175 consecutive patients suspected of APS into 2 subgroups: 107 fulfilling Sydney APS classification for seropositive APS (SP-APS) and 68 with clinical manifestations suggestive of APS but having negative serology, on 2 occasions, for criteria markers (SN-APS). On study inclusion, samples were retested for criteria and 11 non-criteria markers, including antiphosphatidylserine/prothrombin antibodies.Results.Using 4 of 11 non-criteria tests, a cumulative 30.9% of SN-APS patients were detected. Combining results of all 11 non-criteria tests, 25 SN-APS (36.8%) and 89 SP-APS (83.2%) were positive for 1 or more non-criteria antibodies.Conclusion.Failure to diagnose APS can result in severe clinical consequences. Patients displaying clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria biomarkers. In our cohort, around one-third of SN-APS patients showed reactivity to 1 or more non-criteria markers. An update to the current classification criteria incorporating new serological markers should be considered to identify and stratify patients with APS for more effective treatment and management.

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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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Isolated IgA Anti-β2 Glycoprotein I Antibodies in Patients with Clinical Criteria for Antiphospholipid Syndrome

Journal of Immunology Research ◽

10.1155/2014/704395 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 34

Author(s):

Raquel Ruiz-García ◽

Manuel Serrano ◽

José Ángel Martínez-Flores ◽

Sergio Mora ◽

Luis Morillas ◽

...

Keyword(s):

Autoimmune Disease ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Clinical Manifestations ◽

Diagnostic Systems ◽

Clinical Criteria ◽

Glycoprotein I ◽

Standardized Diagnostic ◽

Disease Present

Seronegative antiphospholipid syndrome (SNAPS) is an autoimmune disease present in patients with clinical manifestations highly suggestive of Antiphospholipid Syndrome (APS) but with persistently negative consensus antiphospholipid antibodies (a-PL). IgA anti-β2 Glycoprotein I (aB2-GPI) antibodies are associated with APS. However, they are not currently considered to be laboratory criteria due to the heterogeneity of published works and the use of poor standardized diagnostic systems. We have aimed to assess aPL antibodies in a group of patients with clinical manifestations of APS (C-APS) to evaluate the importance of the presence of IgA aB2GPI antibodies in APS and its relation with other aPL antibodies. Only 14% of patients with C-APS were positive for any consensus antibody, whereas the presence of isolated IgA aB2GPI antibodies was found in 22% of C-APS patients. In patients with arterial thrombosis IgA aB2GPI, antibodies were the only aPL antibodies present. Serologic profile in primary APS (PAPS) is different from systemic autoimmune disorders associated APS (SAD-APS). IgA aB2GPI antibodies are more prevalent in PAPS and IgG aB2GPI antibodies are predominant in SAD-APS. The analysis of IgA aB2GPI antibodies in patients with clinical manifestations of PAPS might avoid underdiagnosed patients and provide a better diagnosis in patients with SAD-APS. Laboratory consensus criteria might consider including analysis of IgA aB2GPI for APS diagnosis.

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The Antiphospholipid Syndrome: The Mount Sinai Hematology Perspective.

Blood ◽

10.1182/blood.v106.11.2154.2154 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2154-2154

Author(s):

Maria Teresa De Sancho ◽

Gonzalo Estupinan ◽

Ilene Schulman ◽

Mayra Lema ◽

Jacob Rand

Keyword(s):

Antiphospholipid Syndrome ◽

Antithrombotic Therapy ◽

High Titer ◽

Clinical Manifestations ◽

Factor V Leiden ◽

Protein S ◽

Factor V ◽

Recurrent Thrombosis ◽

Clinical Criteria ◽

Chronic Therapy

Abstract Objective: To evaluate the clinical manifestations, type and persistence of antiphospholipid (aPL) antibodies, and outcomes of patients evaluated in a hematology practice clinic for the diagnosis of antiphospholipid syndrome (APLS). Methods: We systematically reviewed the medical records of all patients referred to our Hemostasis and Thrombosis Practice Clinic for evaluation of APLS from January 1995 to July 2005. APLS was defined by the Sapporo criteria. 180 patients were identified who either had APLS as defined by the Sapporo criteria or had documented aPL antibodies on 2 separate occasions at least 6 weeks apart without any clinical manifestation for APLS. Data collected included demographics, clinical manifestations, type of aPL antibodies, presence or absence of lupus anticoagulant (LAC), persistence or fluctuation of the aPL antibodies, presence of other thrombophilias, antithrombotic therapy, and outcomes. Results: Of the 180 patients, 141 were females and 39 were males. The age range was 21 to 89 yr. 119 patients (66%) fulfilled the clinical criteria for APLS and 61(34%) did not. Among the 119 patients with APLS, the clinical manifestations included arterial thromboembolism (ATE) in 53 (46 idiopathic, 7 secondary), venous thromboembolism (VTE) in 44 (31 idiopathic, 13 secondary), both ATE and VTE in 7 and pregnancy losses (PL) in 30. Among the 30 patients with PL, 19 had recurrent PL before the 10th week of gestation and 11 had PL after the 10th week of gestation. 5 patients with PL also had ATE and/or VTE. 94 patients had anticardiolipin (aCL) antibody (medium titer IgG isotype), 57 had aCL antibody (high titer IgG), 29 had antiphosphatidylserine (aPS) antibody (medium titer IgG), 27 had aPS antibody (high titer IgG), 11 had anti-β2 glycoprotein I (anti-β2GPI) antibody (medium titer), 13 had anti-β2GPI antibody (high titer), 47 had aCL antibody (medium titer IgM), 15 had aCL antibody (high titer IgM), 74 had aPS antibody (medium titer IgM), 43 had aPS antibody (high titer IgM), 20 had anti-β2GPI medium titer IgM, 12 had anti-β2GPI high titer IgM, 10 had anti-β2GPI medium titer IgA isotype, 6 had anti-β2GPI high titer IgA isotype and 36 had LAC. 115 patients had persistent aPLA and 65 had fluctuating aPLA. 33 patients had other thrombophilias: factor V Leiden (n=5), prothrombin gene mutation (G20210A) (n=6), protein S deficiency (n=4), increased homocysteine level (>12 mcmol/L) (n=9), hyperfibrinogenemia (n=3), elevated factor VIII (n=4) and factor XI (n=1) and plasminogen deficiency (n=1). Antithrombotic therapy included warfarin in 71 patients, aspirin in 85, clopidogrel in 3, and LMWH in 36 (2 on chronic therapy and 34 during pregnancy). 21 patients were on no antithrombotic medications. Of the 180 patients, 110 patients had succesful outcomes defined as either absence of recurrent thrombosis or pregnancy losses. 7 patients had recurrent PL while 10 had recurrent thrombosis. 1 patient died. 52 patients were lost to follow-up. Conclusions: The majority of our patients with APLS were women. The most common clinical manifestations were ATE, followed by VTE and PL. The most prevalent aPL antibody was aCL medium titer IgG isotype and the least common was anti-β2GPI high titer IgA. Antithrombotic therapy resulted in successful outcomes in approximately 2/3 of patients.

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DIAGNOSIS OF ANTIPHOSPHOLIPID SYNDROME IN PEOPLE WITH CLINICAL CRITERIA OF THE DISEASE. EXPERIENCE OF A SEPARATE OUTPATIENT CENTER

Atherothrombosis Journal ◽

10.21518/2307-1109-2019-1-92-98 ◽

2019 ◽

pp. 92-98

Author(s):

T. V. Vavilova ◽

L. A. Isaeva ◽

K. Yu. Grinchenko ◽

Ju. D. Bogatenkova ◽

V. A. Sorokoumov

Keyword(s):

Antiphospholipid Syndrome ◽

Laboratory Tests ◽

Clinical Signs ◽

Clinical Manifestations ◽

Final Diagnosis ◽

Diagnostic Process ◽

Clinical Criteria ◽

Laboratory Confirmation ◽

Diagnostic Center ◽

Open Question

Antiphospholipid syndrome (APS) is an immune-mediated violation of coagulation, the diagnosis of which requires mandatory laboratory confirmation. Since the clinical manifestations of APS are extremely diverse, various specialists are involved in the diagnostic process – neurology, cardiologists, surgeons, hematologists, endocrinologists, laboratory medicine specialists, etc. So far, it remains an open question what specialist exactly should make the final diagnosis and supervise patient with APS. The experience of a separate diagnostic center shows the distribution of prescriptions and their compliance with the international recommendations. This study also provides data on the frequency of prescribing laboratory tests to confirm APS, which is 1.2% of all coagulation tests. Among the patients with suspected APS on the basis of clinical signs, only 12.2% of the diagnosis was confirmed. Presents the dangers of obtaining false-positive results that should be taken into account when prescribing laboratory tests.

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ANTIPHOSPHOLIPID SYNDROME

Health and Ecology Issues ◽

10.51523/2708-6011.2017-14-4-1 ◽

2017 ◽

pp. 4-11

Author(s):

E. V. Makarenko

Keyword(s):

Blood Plasma ◽

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Arterial Thrombosis ◽

Lupus Anticoagulant ◽

Pregnancy Complication ◽

Classification Criteria ◽

Clinical Criteria ◽

Glycoprotein I ◽

Acquired Thrombophilia

Antiphospholipid syndrome is autoimmune acquired thrombophilia associated with the formation of antibodies to phospholipids, which is manifested by recurrent venous or arterial thrombosis and/or pathology of pregnancy. Antiphospholipid antibodies are a heterogeneous group of autoantibodies interacting with phospholipids, which are components of cell membranes and phospholipid-binding proteins of blood plasma. Antiphospholipid syndrome can affect vessels of any caliber and localization, with thrombosis accompanied by no morphological signs of inflammation in the wall of the vessel. Obstetrical pathology is manifested by loss of the fetus, which can occur at any time of pregnancy, as well as other complications of pregnancy, such as preeclampsia and placental insufficiency. Based on the classification criteria, antiphospholipid syndrome is diagnosed if one of the clinical criteria (thrombosis or pregnancy complication) and one of the laboratory criteria including the lupus anticoagulant, antibodies to cardiolipin or β2-glycoprotein I, are revealed. The main tactic of the treatment of patients with antiphospholipid syndrome is to prevent thrombosis. For this purpose, the traditional therapy with anticoagulants and antiaggregants is applied. In addition, new medicines are being developed and evaluated

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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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Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset

Lupus ◽

10.1177/09612033211014248 ◽

2021 ◽

pp. 096120332110142

Author(s):

Marwa Elkhalifa ◽

Ana-Maria Orbai ◽

Laurence S Magder ◽

Michelle Petri ◽

Graciela S Alarcón ◽

...

Keyword(s):

Rheumatic Diseases ◽

African Descent ◽

Clinical Manifestations ◽

Classification Criteria ◽

The Other ◽

Clinical Criteria ◽

American College Of Rheumatology ◽

Glycoprotein I ◽

Beta 2 ◽

The Difference

Objective Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE. Methods The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations. Results The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant. Conclusion We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.

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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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Antiphospholipid syndrome

Hämostaseologie ◽

10.1055/s-0037-1619044 ◽

2010 ◽

Vol 30 (03) ◽

pp. 139-143 ◽

Cited By ~ 3

Author(s):

G. M. A. van Os ◽

R. T. Urbanus ◽

C. Agar ◽

J. C. M. Meijers ◽

P. G. de Groot

Keyword(s):

Antiphospholipid Syndrome ◽

Solid Phase ◽

Clinical Manifestations ◽

Consensus Meeting ◽

Classification Criteria ◽

International Consensus ◽

Pregnancy Morbidity ◽

Antibody Assays ◽

Long Time ◽

Antibody Elisa

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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Challenges in the Diagnosis of the Antiphospholipid Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2009.133678 ◽

2010 ◽

Vol 56 (6) ◽

pp. 930-940 ◽

Cited By ~ 55

Author(s):

Katrien Devreese ◽

Marc F Hoylaerts

Keyword(s):

Antiphospholipid Syndrome ◽

Antiphospholipid Antibodies ◽

Lupus Anticoagulant ◽

Complex Disease ◽

Clinical Manifestations ◽

Clinical Role ◽

Clinical Criteria ◽

Pregnancy Morbidity ◽

Glycoprotein I ◽

Coagulation Tests

Abstract Background: The antiphospholipid syndrome (APS) is an important cause of acquired thromboembolic complications and pregnancy morbidity. Its diagnosis is based on clinical and laboratory criteria, defined by strict guidelines. The original clinical and laboratory criteria for the identification of APS patients were published in 1999, in the so-called Sapporo criteria. In 2006 these criteria were revised, and recently more precise guidelines for analysis of the lupus anticoagulant have been provided. However, several questions related to the diagnosis of APS remain unanswered. Content: In addition to providing a historical perspective, this review covers several challenges in the diagnosis of APS with respect to clinical and laboratory features, while highlighting pathogenic pathways of the syndrome. We discuss ongoing dilemmas in the diagnosis of this complex disease. Although antiphospholipid antibodies are found in association with various clinical manifestations, the older established clinical criteria were not substantively altered in the 2006 update. Several laboratory tests recommended in the latest criteria, including phospholipid-dependent coagulation tests for the detection of the lupus anticoagulant and ELISAs for measuring anticardiolipin and β2-glycoprotein I antibodies, still show methodological and diagnostic shortcomings. In addition, antiphospholipid antibodies have been described against other antigens, but their clinical role remains uncertain. Conclusions: Despite updated APS criteria, diagnosis of this syndrome remains challenging. Further research on clinically relevant antibodies and standardization of their detection are needed to improve clinical risk assessment in APS.

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