Suppressed intrinsic fibrinolytic activity by monoclonal anti‐beta‐2 glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome

Takeuchi, Rie; Atsumi, Tatsuya; Ieko, Masahiro; Amasaki, Yoshiharu; Ichikawa, Kenji; Koike, Takao

doi:10.1046/j.1365-2141.2002.03928.x

Cited by 45 publications

(35 citation statements)

References 38 publications

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“…β2GP1 is identified as a major target antigen in patients with APS as well [37]. It has been suggested that β2GP1 and β2GP1-reactive antibodies may have direct interactions with the fibrinolytic system [38][39]. In our study, we found elevated anti-β2GP1 IgG antibodies in the plasma samples of type 1 diabetic patients.…”

Section: Discussionsupporting

confidence: 63%

Anti-prothrombin antibodies in type 1 diabetes mellitus

Bakar¹,

Ünlütürk²,

Başkal³

et al. 2013

Turk J Bioch

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Section: Discussionsupporting

confidence: 63%

Anti-prothrombin antibodies in type 1 diabetes mellitus

Bakar¹,

Ünlütürk²,

Başkal³

et al. 2013

Turk J Bioch

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“…Along this line, Takeuchi et al (38) showed that the EY2C9 IgM anti-␤ 2 GPI mAb (from an APS patient) suppressed intrinsic fibrinolysis in the presence of ␤ 2 GPI, apparently by enhancing the ␤ 2 GPI-mediated weak suppression of intrinsic fibrinolysis. Similar to intrinsic coagulation, intrinsic fibrinolysis is initiated by the contact activation of coagulation factor XII (FXII).…”

Section: Discussionmentioning

confidence: 92%

Identification of Anti-Plasmin Antibodies in the Antiphospholipid Syndrome That Inhibit Degradation of Fibrin

Yang

Hwang

Wang³

et al. 2004

The Journal of Immunology

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The combined presence of anti-phospholipid Ab (aPL) and thrombosis is recognized as the antiphospholipid syndrome (APS). The aPL represent a heterogeneous group of Ab that recognize various phospholipids (PL), PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found the presence of antithrombin Ab in some APS patients and that some of these anti-thrombin Ab could inhibit thrombin inactivation by antithrombin. Considering that thrombin is homologous to plasmin, which dissolves fibrin, we hypothesize that some APS patients may have Ab that react with plasmin, and that some anti-plasmin Ab may interfere with the plasmin-mediated lysis of fibrin clots. To test this hypothesis, we searched for anti-plasmin Ab in APS patients and then studied those found for their effects on the fibrinolytic pathway. The results revealed that seven of 25 (28%) APS patients have IgG anti-plasmin Ab (using the mean OD plus 3 SD of 20 normal controls as the cutoff) and that six of six patient-derived IgG anti–thrombin mAb bind to plasmin with relative Kd values ranging from 5.6 × 10−8 to 1 × 10−6 M. These Kd values probably represent affinities in the higher ranges known for human IgG autoantibodies against protein autoantigens. Of these mAb, one could reduce the plasmin-mediated lysis of fibrin clots. These findings suggest that plasmin may be an important driving Ag for some aPL B cells in APS patients, and that the induced anti-plasmin Ab may act either directly, by binding to plasmin and inhibiting its fibrinolytic activity, or indirectly, by cross-reacting with other homologous proteins in the coagulation cascade to promote thrombosis.

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“…It has also been suggested that h 2 GPI inhibits factor XII activation and that the inhibition is enhanced by anti-h 2 GPI [44]. Furthermore, suppression of intrinsic fibrinolytic activity of the euglobulin fraction from normal plasma by h 2 GPI, independent of factor XII, has been recently described and the effect is reversed by monoclonal anti-h 2 GPI antibodies in the presence of h 2 GPI [45]. Thus, h 2 GPI appears to not only interact with factors of the coagulation cascade, but also participate in the regulation of intrinsic fibrinolysis.…”

Section: Gpi and Coagulation Factorsmentioning

confidence: 93%

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

Miyakis

Robertson

Krilis

2004

Clinical Immunology

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The antiphospholipid syndrome is characterized by the presence in serum of autoantibodies against h2GPI. Although the role of h2GPI in the pathogenesis of antiphospholipid antibody syndrome (APS) is well recognized, its exact physiological functions still remain undisclosed. Several interactions of h2GPI with components of the coagulation cascade have been proposed, resulting in both procoagulant and anticoagulant effects. Additionally, h2GPI has been implicated in the mechanism of recurrent fetal loss entailed in APS. Recently, using a homologous recombination approach, reproduction of mice homozygous for deletion of the b2GPI gene has been feasible. h2GPI knockout mice offer a valuable tool for revealing the physiological role of the protein. These mice show decreased in vitro ability for thrombin generation. Furthermore, although mice lacking h2GPI are fertile, the success of early pregnancy is moderately compromised and functional h2GPI is believed necessary for optimal implantation and placental morphogenesis. AbstractThe antiphospholipid syndrome is characterized by the presence in serum of autoantibodies against h 2 GPI. Although the role of h 2 GPI in the pathogenesis of antiphospholipid antibody syndrome (APS) is well recognized, its exact physiological functions still remain undisclosed. Several interactions of h 2 GPI with components of the coagulation cascade have been proposed, resulting in both procoagulant and anticoagulant effects. Additionally, h 2 GPI has been implicated in the mechanism of recurrent fetal loss entailed in APS. Recently, using a homologous recombination approach, reproduction of mice homozygous for deletion of the b 2 GPI gene has been feasible. h 2 GPI knockout mice offer a valuable tool for revealing the physiological role of the protein. These mice show decreased in vitro ability for thrombin generation. Furthermore, although mice lacking h 2 GPI are fertile, the success of early pregnancy is moderately compromised and functional h 2 GPI is believed necessary for optimal implantation and placental morphogenesis. D

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Suppressed intrinsic fibrinolytic activity by monoclonal anti‐beta‐2 glycoprotein I autoantibodies: possible mechanism for thrombosis in patients with antiphospholipid syndrome

Cited by 45 publications

References 38 publications

Anti-prothrombin antibodies in type 1 diabetes mellitus

Anti-prothrombin antibodies in type 1 diabetes mellitus

Identification of Anti-Plasmin Antibodies in the Antiphospholipid Syndrome That Inhibit Degradation of Fibrin

Beta-2 glycoprotein I and its role in antiphospholipid syndrome—lessons from knockout mice

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