Establishment of a rat model of thrombosis induced by intravenous injection of anti-phosphatidylserine–prothrombin complex antibody

Yamada, Mai; Kawakami, Tamihiro; Takashima, Kohei; Nishioka, Yusuke; Nishibata, Yuka; Masuda, Sakiko; Yoshida, Shigeru; Tomaru, Utano; Ishizu, Akihiro

doi:10.1093/rheumatology/kew477

Cited by 7 publications

(7 citation statements)

References 18 publications

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“…[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%

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: 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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“…The histone-priming model has been used to study the role of anti-PS/PT antibodies in APS [ 35 ]. Recent studies have shown that high titers of anti-PS/PT antibodies are a useful predictor of APS severity, while histones are likely important players in endothelial priming during inflammatory types of thrombosis [ 60 , 61 ].…”

Section: Microvascular Aps Modelsmentioning

confidence: 99%

Understanding the Pathophysiology of Thrombotic APS through Animal Models

Gandhi

Estes

Rysenga

et al. 2021

IJMS

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Antiphospholipid syndrome (APS) is a leading acquired cause of thrombotic events, with a notable tendency to promote thrombosis in vascular beds of all sizes, including both arterial and venous circuits. While pathogenic antiphospholipid antibodies circulate at relatively stable levels in blood, thrombosis tends to manifest as discrete and acute events, suggesting the requirement for a “second hit.” While this two-hit model is generally accepted, much remains to be learned about exactly how antiphospholipid antibodies predispose to thrombosis in vivo and exactly how this predisposition interacts with the second hit. To this end, investigators have turned to animal models. Numerous approaches for modeling APS in animals have been described to date, each with potential advantages and disadvantages. This review will attempt to describe the most common APS models employed so far while discussing some pros and cons of each. Mechanisms of thrombotic APS that have thus far been explored in animal models will also be briefly addressed.

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“…To bind aPS/PT Abs in the serum with vascular endothelium, endothelial cells have to express PS on the surface. In the preceding study, cell-free histones (≥12.5 µg/ml) induced apoptosis of cultured rat vascular endothelial cells [12]. To determine the concentration of histones necessary for the cell surface expression of PS on vascular endothelium in the skin, inbred wild-type rats were given a subcutaneous injection of histones at varied concentrations, and then the skin was subjected to immunostaining using an aPS/PT monoclonal Ab (Fig.…”

Section: Binding Of Aps/pt Ab With Vascular Endotheliummentioning

confidence: 99%

“…Because PS is expressed on the surface of apoptotic or damaged vascular endothelial cells, a speci c treatment is required before the administration of aPS/PT Abs. Recent studies have demonstrated that cell-free histones induce apoptosis of vascular endothelial cells in mice [11] and rats [12]. In this study, a subcutaneous injection of cell-free histones was employed as priming to express PS on the surface of vascular endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

404 Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis

Kawakami

Tamura

Dong

et al. 2021

Journal of Investigative Dermatology

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Objective. It was previously demonstrated that cutaneous vasculitis, including IgA vasculitis and cutaneous arteritis (CA), is associated with the presence of IgM antibodies (Abs) against the phosphatidylserine/prothrombin complex (PS/PT). Recently, novel enzyme-linked immunosorbent assay kits for the detection of IgG and IgM anti-PS/PT (aPS/PT) Abs have become commercially available.Methods. The prevalence of serum IgG and IgM aPS/PT Abs in both cutaneous and systemic vasculitis was determined using these kits. In addition, to examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones (250 µg/ml, 300 µl/site) 2 hours in advance.Results. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and CA compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no signi cant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection-developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. Conclusion.IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis.

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Establishment of a rat model of thrombosis induced by intravenous injection of anti-phosphatidylserine–prothrombin complex antibody

Cited by 7 publications

References 18 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

Understanding the Pathophysiology of Thrombotic APS through Animal Models

404 Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis

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