Domain V of β2-Glycoprotein I Binds Factor XI/XIa and Is Cleaved at Lys317-Thr318

Shi, Tao; Giannakopoulos, Bill; Iverson, G M; Cockerill, Keith A.; Linnik, Matthew D.; Krilis, Steven A.

doi:10.1074/jbc.m410291200

Cited by 29 publications

(18 citation statements)

References 47 publications

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“…They also demonstrated that factor XIa proteolytically cleaved β2GPI at Lys317 -Thr318 of domain V. Thus, factor XIa cleavage of β2GPI in vivo during thrombus formation may accelerate factor XI activation by decreasing the inhibitory effect of β2GPI. 241 In another report, the same group showed that, when both β2GPI and anti-β2GPI were incubated with factor XI, anti-β2GPI potentiated the ability of β2GPI to inhibit the activation of factor XI, and, thus, anti-β2GPI could be considered as a factor that inhibits coagulation. 242…”

Section: The Role Of Apl and Their Respective Antigens In Activatimentioning

confidence: 96%

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

Vlachoyiannopoulos

Samarkos

Sikara

et al. 2007

Critical Reviews in Clinical Laboratory Sciences

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Antiphospholipid antibodies (aPL) constitute a heterogeneous group of autoantibodies that share the ability to bind phospholipids (PL) alone, protein-PL complexes, or PL-binding proteins. They have been detected in isolation, in association with autoimmune diseases such as systemic lupus erythematosus (SLE), and during the course of different infections. aPL have been associated with an array of clinical manifestations in virtually every organ, although deep vein and arterial thrombosis as well as pregnancy morbidity are predominant. The co-occurrence of these clinical findings with aPL constitutes the so-called antiphospholipid syndrome (APS). aPL can be detected by immunological methods [e.g., anticardiolipin antibodies (aCL)] or by functional methods that exploit the effect of aPL on blood coagulation [lupus anticoagulant (LA)]. Since aPL are heterogeneous, numerous immunological and coagulation assays have been developed. These assays have not been fully standardized, and, therefore, problems such as high interlaboratory variation are relatively frequent. Recently, recommendations have been published regarding LA and aCL testing. Not all aPL are pathogenic. However, when they are not associated with infections, they have a role in the pathogenesis of APS. Clinical and experimental data have shown that aPL exert their pathogenic activity by interfering with the function of coagulation factors, such as thrombin and factors X, XI and XII, and with the function of anticoagulant proteins of the protein C system. In addition, aPL interaction with platelets and endothelial cells induces a pro-adhesive activated phenotype.

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Section: The Role Of Apl and Their Respective Antigens In Activatimentioning

confidence: 96%

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

Vlachoyiannopoulos

Samarkos

Sikara

et al. 2007

Critical Reviews in Clinical Laboratory Sciences

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“…Because of the high affinity of ␤ 2 GPI for anionic phospholipids, it was thought that ␤ 2 GPI, by inhibition of the contact phase activation of coagulation, could play a role in maintaining the hemostatic balance. [15][16][17] Furthermore, it has been suggested that ␤ 2 GPI is involved in platelet prothrombinase activity and ADP-mediated platelet aggregation. 18,19 ␤ 2 GPI binds liposomes and microparticles via an interaction with phosphatidylserine, and it also is involved in the clearance of these negatively charged cellular fragments in mice.…”

mentioning

confidence: 99%

β2-Glycoprotein I: a novel component of innate immunity

Ağar

Groot

Mörgelin

et al. 2011

Blood

102

123

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Sepsis is a systemic host response to invasive infection by bacteria. Despite treatment with antibiotics, current mortality rates are in the range of 20%-25%, which makes sepsis the most important cause of death in intensive care. Gram-negative bacteria are a prominent cause of sepsis. Lipopolysaccharide (LPS), one of the major constituents of the outer membrane of Gram-negative bacteria, plays a major role in activating the host's immune response by binding to mono-cytes and other cells. Several proteins are involved in neutralization and clearance of LPS from the bloodstream. Here, we provide evidence that 2-glycoprotein I (2 GPI) is a scavenger of LPS. In vitro, 2 GPI inhibited LPS-induced expression of tissue factor and IL-6 from monocytes and endothelial cells. Binding of 2 GPI to LPS caused a conformational change in 2 GPI that led to binding of the 2 GPI-LPS complex to monocytes and ultimately clearance of this complex. Furthermore, plasma levels of 2 GPI were inversely correlated with temperature rise and the response of inflammatory markers after a bolus injection of LPS in healthy individuals. Together, these observations provide evidence that 2 GPI is involved in the neutralization and clearance of LPS and identify 2 GPI as a component of innate immunity. (Blood. 2011;117(25):6939-6947)

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“…Cleavage can occur at Lys 317 -Thr 318 (11) by plasmin (12) and factor XIa (FXIa) (13). Domain V can bind to thrombin (14), anionic phospholipids (9), FXI (13), heparin (15), apolipoprotein E receptor 2 (16), and GPIb␣ (17,18).…”

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confidence: 99%

Beta₂‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β₂‐glycoprotein I autoantibodies

Rahgozar¹,

Giannakopoulos²,

Yan³

et al. 2008

Arthritis & Rheumatism

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Objective. Beta 2 -glycoprotein I (␤ 2 GPI) is an important autoantigen in the antiphospholipid syndrome (APS). In vitro studies suggest that it may have multifaceted physiologic functions, since it displays both anticoagulant and procoagulant properties. We have previously reported that ␤ 2 GPI can directly bind thrombin, a key serine protease in the coagulation pathway. The present study was undertaken to examine the influence of ␤ 2 GPI on thrombin inactivation by the serpin heparin cofactor II (HCII). The effect of anti-␤ 2 GPI antibodies was also examined.Methods. HCII inactivation of thrombin was assessed using chromogenic and various platelet functional assays. The influence of intact and proteolytically cleaved ␤ 2 GPI and anti-␤ 2 GPI antibodies was determined in these systems.Results. ␤ 2 GPI protected thrombin against inactivation by HCII/heparin. Cleavage of ␤ 2 GPI at Lys 317 -Thr 318 abrogated its protective effect. Patient polyclonal IgG and murine monoclonal anti-␤ 2 GPI antibodies potentiated the procoagulant influence of ␤ 2 GPI in this system.Conclusion. These novel findings suggest that ␤ 2 GPI may regulate thrombin inactivation by HCII/ heparin. The observation that anti-␤ 2 GPI antibodies potentiate the protective effect of ␤ 2 GPI on thrombin in this system, thereby promoting a procoagulant response, may potentially delineate one of the pathophysiologic mechanisms contributing to the prothrombotic tendency in patients with APS.

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Domain V of β2-Glycoprotein I Binds Factor XI/XIa and Is Cleaved at Lys317-Thr318

Abstract: The fifth domain (DV) of

Cited by 29 publications

References 47 publications

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

β2-Glycoprotein I: a novel component of innate immunity

Beta₂‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β₂‐glycoprotein I autoantibodies

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Domain V of β2-Glycoprotein I Binds Factor XI/XIa and Is Cleaved at Lys317-Thr318

Abstract: The fifth domain (DV) of

Cited by 29 publications

References 47 publications

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

Antiphospholipid Antibodies: Laboratory and Pathogenetic Aspects

β2-Glycoprotein I: a novel component of innate immunity

Beta2‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β2‐glycoprotein I autoantibodies

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Beta₂‐glycoprotein I protects thrombin from inhibition by heparin cofactor II: Potentiation of this effect in the presence of anti–β₂‐glycoprotein I autoantibodies