Circulating levels of β2-glycoprotein I in thrombotic disorders and in inflammation

Lin, Feng Yen; Murphy, Ross T.; White, Barry; Kelly, Jacinta; Feighery, C.; Doyle, Robin; Pittock, Sean J.; Moroney, Joan T.; Smith, Owen; Livingstone, Wendy; Keenan, Catherine M.; Jackson, J. F.

doi:10.1191/0961203306lu2270oa

Cited by 36 publications

(28 citation statements)

References 57 publications

(82 reference statements)

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“…16 As elderly people suffer more regularly from pathologic conditions, the rise in beta2GPI levels might be a result of increased production or decreased clearance. In this respect, it is interesting to note that VWF also increases with age.…”

Section: Discussionmentioning

confidence: 99%

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men

Laat

Groot

Derksen

et al. 2009

Blood

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von Willebrand factor (VWF) serves as adhesive surface for platelets to adhere to the vessel wall. We have recently found that beta2-glycoprotein I is able to inhibit platelet binding to VWF, indicating a role in the pathophysiology of arterial thrombosis. In the present study, we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. We have measured beta2-glycoprotein I and VWF antigen levels in 539 men with a first myocardial infarction and in 611 control subjects. Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population, we found a dosedependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men 60 years and older. In this age group, we found an odds ratio of 0.41 (95% confidence interval, 0.22-0.74) for high beta2-glycoprotein I levels compared with low levels. High plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of VWF. To conclude, high circulating levels of beta2-glycoprotein I appeared to be associated with a reduced risk of myocardial infarction in elderly men. In vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction. (Blood. 2009;114:3656-3661)

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Section: Discussionmentioning

confidence: 99%

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men

Laat

Groot

Derksen

et al. 2009

Blood

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“…A distinctive feature of A1-A1 compared to A1 is that A1-A1 preferentially interacts with b2GPI bound to antib2GPI antibodies. 30,31 Because b2GPI is present in the blood at high concentration, 4 mM, 32 it is important that a potential drug binds predominantly to pathological b2GPI/antibody complexes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Kolyada

Porter

Beglova

2014

Blood

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• A1-A1 inhibits thrombotic properties of anti-b2GPI antibodies in mice.• A1-A1 does not affect thrombus size in the absence of anti-b2GPI antibodies.Antiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy losses. b2-glycoprotein I (b2GPI) is the major antigen for clinically relevant antibodies in APS. We engineered a molecule, A1-A1, which interferes with 2 prothrombotic mechanisms in APS: the binding of b2GPI to negatively charged cellular surfaces and ApoE receptor 2. We studied how A1-A1 affects arterial thrombosis in vivo in lupus-prone (NZW 3 BXSB)F 1 male mice. For the first time, we demonstrated that A1-A1 efficiently reduces thrombus size in vivo in the presence of chronic autoimmune antib2GPI antibodies. We have shown that A1-A1 interferes with thrombotic properties of b2GPI/antibody complexes and does not affect normal thrombus formation in the absence of anti-b2GPI antibodies. A1-A1 inhibits prothrombotic properties of b2GPI/antibody complexes in wild-type mice after acute infusion with anti-b2GPI antibodies, as well as in mice expressing persistent autoimmune anti-b2GPI antibodies. A1-A1 reduced thrombus size in a mouse model of APS in the presence of lupus features, suggesting that A1-A1 might effectively interfere with thrombosis not only in primary APS but also in APS secondary to lupus. Our results suggest that A1-A1 could be a prototype for an antithrombotic drug in APS. (Blood. 2014;123(7):1090-1097) IntroductionAntiphospholipid syndrome (APS) is an autoimmune disorder with increased risk for thrombosis and pregnancy loss. [1][2][3] It is diagnosed based on the combination of clinical features and laboratory tests for circulating autoantibodies. Thrombotic events in APS nearly equally occur in veins and arteries, and about 30% of patients with thrombosis are men. [4][5][6][7] Thrombosis in APS correlates with the presence of antibodies to b2-glycoprotein I (b2GPI). [8][9][10][11] The physiological function of b2GPI is not well defined 12 and its deficiency in humans or mice does not result in apparent abnormalities. [13][14][15][16] b2GPI acquires prothrombotic properties only after association with antibodies. 10,12 Treatment with anti-b2GPI antibodies or recombinant dimers of b2GPI mimicking b2GPI/antibody complexes results in increased thrombus size in animal models of thrombosis and cellular activation in vitro. 2,3,[17][18][19][20] It was demonstrated both in vitro and in vivo that exposure of endothelial cells, monocytes, and platelets to b2GPI/anti-b2GPI antibody complexes shifts the cellular phenotype to prothrombotic and proinflammatory (reviewed in Giannakopoulos and Krilis,2 Tripodi et al, 3 and Harper et al 20 ). Anionic phospholipids, Toll-like receptors 2 and 4 (TLR2 and TLR4), annexin A2, and ApoER2 are cell-surface molecules involved in binding and activation of endothelial cells and monocytes by b2GPI/antibody complexes. [21][22][23][24][25][26] The binding of b2GPI to anionic phospholipids and the assembly of b2GPI/antibody c...

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“…34 β2GPI, also known as apolipoprotein H, 35 is a multifunctional 53 kDa glycosylated plasma protein 36 with physiological values of 20-300 mg/L. 37 The protein consists of 326 amino acids folded into five domains, where the fifth domain is positively charged, with a lysine-rich region 281 CKNKEKKC, 288 a hydrophobic loop 313 LAFW, 316 and extended C-terminal domain, that enable binding to negatively charged phospholipids. [38][39][40] After binding to phospholipids, β2GPI changes its conformation from circular to open fish-hook, exposing a cryptic epitope which is recognized by antibodies against β2GPI (anti-β2GPI) directed against domain I.…”

Section: Introductionmentioning

confidence: 99%

Binding of plasma proteins to titanium dioxide nanotubes with different diameters

Kulkarni

Flašker

Lokar

et al. 2015

IJN

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Titanium and titanium alloys are considered to be one of the most applicable materials in medical devices because of their suitable properties, most importantly high corrosion resistance and the specific combination of strength with biocompatibility. In order to improve the biocompatibility of titanium surfaces, the current report initially focuses on specifying the topography of titanium dioxide (TiO 2 ) nanotubes (NTs) by electrochemical anodization. The zeta potential (ζ-potential) of NTs showed a negative value and confirmed the agreement between the measured and theoretically predicted dependence of ζ-potential on salt concentration, whereby the absolute value of ζ-potential diminished with increasing salt concentrations. We investigated binding of various plasma proteins with different sizes and charges using the bicinchoninic acid assay and immunofluorescence microscopy. Results showed effective and comparatively higher protein binding to NTs with 100 nm diameters (compared to 50 or 15 nm). We also showed a dose-dependent effect of serum amyloid A protein binding to NTs. These results and theoretical calculations of total available surface area for binding of proteins indicate that the largest surface area (also considering the NT lengths) is available for 100 nm NTs, with decreasing surface area for 50 and 15 nm NTs. These current investigations will have an impact on increasing the binding ability of biomedical devices in the body leading to increased durability of biomedical devices.

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Circulating levels of β2-glycoprotein I in thrombotic disorders and in inflammation

Cited by 36 publications

References 57 publications

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men

Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

Binding of plasma proteins to titanium dioxide nanotubes with different diameters

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