Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome

Sciascia, Savino; Bertolaccini, Maria Laura

doi:10.1177/0961203314538332

Cited by 18 publications

(13 citation statements)

References 31 publications

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“…Specifically, some IgG aPS/PT require a significant structural reorganization of the antigen for proper recognition in solution, whereas IgG aPT-A target epitopes that are constitutively exposed to the solvent in both closed and open forms of prothrombin. [37][38][39] Given that IgG aPS/PT, and not IgG aPT-A, significantly correlate with thrombosis and obstetric complications, 13,14,20 these findings also raise the interesting hypothesis that excessive stabilization of the open form of prothrombin in vivo may contribute to the onset and progression of APS. Second, we discovered that IgG aPS/PT are heterogeneous, and APS patients positive for IgG aPS/PT can be classified into 2 groups (group A and group B) according to their autoantibody profile.…”

Section: Discussionmentioning

confidence: 97%

“…[12][13][14][15] Using enzyme-linked immunosorbent assays (ELISA), aPS/PT have been found primarily in 2 types of APS patients: (1) patients positive solely for lupus anticoagulant 13,[16][17][18] (as discussed in Table 1 of the review by Amengual et al 19 ); and (2) patients positive for lupus anticoagulant, anti-cardiolipin (aCL), and anti-b 2 -glycoprotein I (anti-b 2 GPI) antibodies who carry the highest risk of thrombosis and recurrence, the so-called "triple-positive." 12,14,20 Because of these clinical observations and earlier research conducted in animal models of APS-induced thrombosis, [21][22][23] it has been hypothesized that aPS/ PT may be responsible for some of the vascular and obstetric manifestations observed in patients with APS; testing for aPS/PT could therefore be requested by physicians to confirm or reinforce an APS diagnosis in selected patients or even adopted as a new test to identify novel APS patients at higher risk of thrombosis who would otherwise go undetected with the use of current testing methods.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis

et al. 2019

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Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are often detected in patients with antiphospholipid syndrome (APS), but how aPS/PT engage prothrombin at the molecular level remains unknown. Here, the antigenic determinants of immunoglobulin G aPS/PT were investigated in 24 triple-positive APS patients at high risk of thrombosis by using prothrombin mutants biochemically trapped in closed and open conformations, and relevant fragments spanning the entire length of prothrombin. Two novel unexpected findings emerged from these studies. First, we discovered that some aPS/PT are unique among other anti-prothrombin antibodies insofar as they efficiently recognize prothrombin in solution after a conformational change requiring exposure of fragment-1 to the solvent. Second, we identified and characterized 2 previously unknown subpopulations of aPS/PT, namely type I and type II, which engage fragment-1 of prothrombin at different epitopes and with different mechanisms. Type I target a discontinuous density-dependent epitope, whereas type II engage the C-terminal portion of the Gla-domain, which remains available for binding even when prothrombin is bound to the phospholipids. Based on these findings, APS patients positive for aPS/PT were classified into 2 groups, group A and group B, according to their autoantibody profile. Group A contains mostly type I antibodies whereas group B contains both type I and type II antibodies. In conclusion, this study offers a first encouraging step toward unveiling the heterogeneity of anti-prothrombin antibodies in correlation with thrombosis, shedding new light on the mechanisms of antigen–autoantibody recognition in APS.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis

et al. 2019

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“…While the diagnostic utility of these antibodies is in evolution, there are numerous studies on their association with thrombosis or antiphospholipid antibody syndrome, or both. 2,3 Most recently, a systematic review (N = 7,000) concluded that prothrombin antibodies (aPT, aPS/PT) were strong risk factors for thrombosis (odds ratio 2.3, 95% confi dence interval 1.72-3.5). 4 The revised Sapporo (Sydney) guidelines referenced by the authors addressed these "non-criteria" antiphospholipid antibodies.…”

Section: To the Editormentioning

confidence: 99%

In reply: ‘Non-criteria’ antiphospholipid antibodies and thrombosis (February 2018)

Serhal

Gornik

Evans

2018

CCJM

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“…phosphatidylinositol, phosphatidylserine) while others react with phospholipid binding proteins (e.g. distinct domains of β2GP1, prothrombin, annexin-V) [17][18][19] . The pathogenic role of non-criteria aPLs as well as their importance in defining APS phenotypes is yet to be revealed.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, such roles were described for some non-criteria aPLs, for instance antiphosphatidylethanolamine (aPE) and anti-phosphatidylserine (aPS) with recurrent pregnancy losses [17][18][19][20][21] or anti-phosphatidylserine/prothrombin (aPS/PT) with thrombosis 21 . Notably, inconsistencies regarding criteria and non-criteria aPLs have been reported 16 and most studies evaluated a single or a few non-criteria aPLs, frequently using different diagnostic platforms, which may be difficult to compare.…”

Section: Introductionmentioning

confidence: 99%

Profiles of criteria and non-criteria anti-phospholipid autoantibodies are associated with clinical phenotypes of the antiphospholipid syndrome

Levin

Volkov

Seguro

et al. 2020

Preprint

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Background: Specific anti-phospholipids antibodies (aPLs) are used as classification criteria of the antiphospholipid syndrome (APS). These aPLs, although essential for diagnosis, do not predict disease phenotypes, which may require specific therapies. Non-criteria aPLs are rarely evaluated and their role is yet to be defined. In the current study, we aimed to examine the association between criteria and non-criteria aPLs and APS phenotypes.Methods: Serum samples from 188 subjects, 130 APS patients and 58 controls were analyzed for the presence of 20 aPLs (IgG and IgM isotypes to cardiolipin(CL), beta2-glycoprotein1(β2GP1), phosphatidic acid(P-acid), phosphatidylcholine(PC), phosphatidylethanolamine(PE), phosphatidylglycerol(PG), phosphatidylinositol(PI), phosphatidylserine(PS), annexin-5(AN) and prothrombin(PT) using a line immunoassay (GA Generic Assays, Germany). Sero-positivity to the different aPLs/aPLs profiles was correlated to APS phenotypes (i.e. arterial thrombosis, CNS manifestations, venous thrombosis, relapsing disease, obstetric morbidity). Results: In this cohort, arterial thrombosis was associated with accumulative number of ≥7/20 aPLs evaluated (OR 4.1; CI95% 1.9-96, p=0.001) as well as the sole presence of aPT(IgG) (OR 2.3;CI 95% 1.1-5.1, p=0.03). CNS manifestations were linked with a profile of 4 aPLs(IgG): aPT, aPG, aPI and aAN (OR 2.6;CI 95% 1.1-6.3, p=0.03). Symptom-free period of ≥3 years was linked with lower number of aPLs and the presence of aPI(IgG) (OR 3.0;CI 95% 1.08-8.1, p<0.05) or aAN(IgG) (OR 3.4;CI 95% 1.08-10.9, p<0.05). APS related pregnancy morbidity correlated with a profile of 2 aPLs(IgG): aCL and aPS (OR 2.9; CI95% 1.3-6.5, p<0.05) or the sole presence of aAN(IgG) (OR 2.8; CI95% 1.02-8, p=0.05). Conclusion: In this study, we observed an association between specific criteria/non-criteria aPLs or aPLs profiles and clinical phenotypes of APS. Our data suggest that examination of a wider variety of aPLs may allow better characterization of APS.

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Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome

Cited by 18 publications

References 31 publications

Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis

Discovery and characterization of 2 novel subpopulations of aPS/PT antibodies in patients at high risk of thrombosis

In reply: ‘Non-criteria’ antiphospholipid antibodies and thrombosis (February 2018)

Profiles of criteria and non-criteria anti-phospholipid autoantibodies are associated with clinical phenotypes of the antiphospholipid syndrome

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