β2-Glycoprotein I Modulates the Anticoagulant Activity of Activated Protein C on the Phospholipid Surface

Mori, Terumi; Takeya, Hiroyuki; Nishioka, Junji; Gabazza, Esteban C.; Suzuki, Koji

doi:10.1055/s-0038-1650220

Cited by 88 publications

(48 citation statements)

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“…52 However, ␤ 2 -glycoprotein I may be a more efficient inhibitor of the anticoagulant reaction in which activated protein C cleaves factor V or factor Va on a phospholipid membrane. 53 The ␤ 2 -glycoprotein I bound to phospholipid is the primary antigen of lupus-type anticoagulants. 54 When an antibody links 2 ␤ 2 -glycoprotein I molecules, the membranebinding affinity is increased, and ␤ 2 -glycoprotein becomes a more potent in vitro anticoagulant.…”

Section: Discussionmentioning

confidence: 99%

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Shi

Gilbert

2003

Blood

161

151

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Lactadherin, a glycoprotein of the milk-fat globule membrane, contains tandem C domains with homology to discoidin-type lectins and to membrane-binding domains of blood-clotting factors V and VIII. We asked whether the structural homology confers the capacity to compete for the membrane-binding sites of factor VIII and factor V and to function as an anticoagulant. Our results indicate that lactadherin competes efficiently with factor VIII and factor V for binding sites on synthetic phosphatidylserine-containing membranes with half-maximal displacement at lactadherin concentrations of 1 to 4 nM. Binding competition correlated to functional inhibition of factor VIIIa-factor IXa (factor Xase) enzyme complex. In contrast to annexin V, lactadherin was an efficient inhibitor of the prothrombinase and the factor Xase complexes regardless of the degree of membrane curvature and the phosphatidylserine content. Lactadherin also inhibited the factor VIIa-tissue factor complex efficiently whereas annexin V was less effective. Because the inhibitory concentration of lactadherin was proportional to the phospholipid concentration, and because lactadherin was not an efficient inhibitor in the absence of phospholipid, the major inhibitory effect of lactadherin relates to blocking phospholipid sites rather than forming inhibitory protein-protein complexes. Lactadherin was also an effective inhibitor of a modified whole blood prothrombin time assay in which clotting was initiated by dilute tissue factor; 60 nM lactadherin prolonged the prothrombin time 150% IntroductionLactadherin is a 47 000-Da molecular weight (MW) glycoprotein of milk-fat globules. It has also been known as PAS-6/7, indicating the 2 glycosylation variants, 1 bovine-associated mucoprotein, BA-46, P47, and MFG-E8. 2 Lactadherin has a domain structure of EGF1-EGF2-C1-C2 in which EGF indicates epidermal growth factor homology domains, and the C domains share homology with the discoidin family, including the lipid-binding C domains of blood coagulation factor VIII and factor V. 2 The second EGF domain displays an Arg-Gly-Asp motif, 3 which binds to the ␣ v ␤ 3 and ␣ v ␤ 5 integrins. 1,[4][5][6] The second C domain binds to phospholipids. 6 In milk-fat globules, lactadherin lines the surface of the phospholipid bilayer that surrounds the central triglyceride droplet, apparently stabilizing the bilayer. 7 Lactadherin decreases the symptoms of rotavirus infection in infants, possibly by binding to rotavirus particles via carbohydrate moieties. 8 In tissue sections, lactadherin is found localized on the apical portion of secretory epithelium in the breast. 7 Abundant expression by breast carcinoma tissue makes lactadherin a potential target for antigen-guided radiation therapy. 9 Lactadherin is also found on the apical surface of epithelia in the biliary tree, the pancreas, and sweat glands 7 and is synthesized by aortic medial smooth muscle cells. 10 Function in these tissues remains unknown. Lactadherin has been identified as a zona pellucida-binding protein on the a...

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Section: Discussionmentioning

confidence: 99%

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Shi

Gilbert

2003

Blood

161

151

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“…On the other hand, Mori and co-workers (17) showed that ␤2GPI can inhibit the anticoagulant activity of activated protein C. Thus, currently it is not clear whether ␤2GPI in vivo has anticoagulant or procoagulant properties. It has recently been demonstrated the ␤2GPI-dependent activation of human umbilical vein endothelial cells by IgG autoantibodies from patients with APS, as measured by increased expression of adhesion molecules (18).…”

Section: Generation Of ␤2gpi-nullmentioning

confidence: 99%

Impaired Thrombin Generation in β2-Glycoprotein I Null Mice

Sheng¹,

Reddel²,

Herzog³

et al. 2001

Journal of Biological Chemistry

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Autoimmune antibodies to ␤ 2 -glycoprotein I (␤2GPI) have been proposed to be clinically relevant because of their strong association with thrombosis, miscarriage, and thrombocytopenia. By using a homologous recombination approach, ␤2GPI-null mice were generated to begin to understand the physiologic and pathologic role of this prominent plasma protein in mammals. When ␤2GPI heterozygotes on a 129/Sv/C57BL/6 mixed genetic background were intercrossed, only 8.9% of the resulting 336 offspring possessed both disrupted alleles. These data suggest that ␤2GPI plays a beneficial role in implantation and/or fetal development in at least some mouse strains. Although those ␤2GPI-null mice that were born appeared to be relatively normal anatomically and histologically, subsequent analysis revealed that they possessed an impaired in vitro ability to generate thrombin relative to wild type mice. Thus, ␤2GPI also appears to play an important role in thrombinmediated coagulation.

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“…Beta 2 -glycoprotein I has anticoagulant properties since it can inhibit ADPmediated platelet aggregation (22) and the activation of FXI by thrombin and FXIIa (23). On the other hand, ␤ 2 GPI impairs activated protein C, suggesting that it may also serve a procoagulant function (24). Furthermore, ␤ 2 GPI clipped at Lys 317 -Thr 318 by plasmin can bind to Glu-plasminogen and inhibit its activation by tissue plasminogen activator (19).…”

mentioning

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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β2-Glycoprotein I Modulates the Anticoagulant Activity of Activated Protein C on the Phospholipid Surface

Cited by 88 publications

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Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Impaired Thrombin Generation in β2-Glycoprotein I Null Mice

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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β2-Glycoprotein I Modulates the Anticoagulant Activity of Activated Protein C on the Phospholipid Surface

Cited by 88 publications

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Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites

Impaired Thrombin Generation in β2-Glycoprotein I Null Mice

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