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  • American Society of Hematology  (4)
  • van Lummel, Menno  (4)
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  • American Society of Hematology  (4)
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  • 1
    Online Resource
    Online Resource
    Pathogenic anti-β2-glycoprotein I antibodies recognize domain I of β2-glycoprotein I only after a conformational change
    American Society of Hematology ; 2006
    In:  Blood Vol. 107, No. 5 ( 2006-03-01), p. 1916-1924
    Details
    In: Blood, American Society of Hematology, Vol. 107, No. 5 ( 2006-03-01), p. 1916-1924
    Abstract: Recently, we published the existence of 2 populations of anti-β2-glycoprotein I (β2-GPI) IgG antibodies. Type A antibodies recognize epitope G40-R43 in domain I of β2-GPI and are strongly associated with thrombosis. Type B antibodies recognize other parts of β2-GPI and are not associated with thrombosis. In this study we demonstrate that type A antibodies only recognize plasma-purified β2-GPI when coated onto a negatively charged surface and not when coated onto a neutrally charged surface. The affinity of type B antibodies toward plasma-purified β2-GPI was independent of the charge of the surface to which β2-GPI was coated. Type A antibodies did not recognize plasma-purified β2-GPI in solution, whereas they did recognize recombinant β2-GPI both in solution and coated onto a neutrally charged plate. When the carbohydrate chains were removed from plasma-purified β2-GPI, we found that type A antibodies did recognize the protein in solution. This supports the hypothesis that the difference in recognition of plasma-purified and recombinant β2-GPI is caused by the difference in glycosylation and that epitope G40-R43 of plasma-purified β2-GPI is covered by a carbohydrate chain. Type A anti-β2-GPI antibodies can only recognize this epitope when this carbohydrate chain is displaced as a result of a conformational change. This finding has major implications both for the detection of pathogenic anti-β2-GPI antibodies and the comprehension of the pathophysiology of the antiphospholipid syndrome.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2005-05-1943
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Correlation between antiphospholipid antibodies that recognize domain I of β2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5
    American Society of Hematology ; 2007
    In:  Blood Vol. 109, No. 4 ( 2007-02-15), p. 1490-1494
    Details
    In: Blood, American Society of Hematology, Vol. 109, No. 4 ( 2007-02-15), p. 1490-1494
    Abstract: The paradoxical correlation between thrombosis and the lupus anticoagulant (LAC) effect is an enigmatic feature of the antiphospholipid (aPL) syndrome. The Dutch authors previously reported that thrombosis-related anti–β2-glycoprotein I (β2GPI) antibodies recognize domain I and cause LAC. The American authors reported that aPLs disrupt an anticoagulant annexin A5 (AnxA5) crystal shield. We investigated whether antidomain I antibodies correlate with disruption of AnxA5-anticoagulant activity. We studied a well-characterized group of 33 patients including subgroups with β2GPI-dependent LAC that recognize domain I (n = 11), with β2GPI-independent LAC (n = 12), and lacking LAC (n = 10). The effects on AnxA5-anticoagulant activity were determined with an AnxA5 resistance assay that measures coagulation times with and without AnxA5. Patients with β2GPI-dependent LAC (group A, all with thrombosis) had significantly lower AnxA5-anticoagulant ratios than those with β2GPI-independent LAC (group B, thrombosis n = 4; 157.8% versus 235.6%, P 〈 .001) and those without LAC (group C, thrombosis n = 2; 157.8% versus 232.5%, P 〈 .001). There was no difference in the ratios between groups B and C (P = .92). Plasmas with β2GPI-dependent LAC that recognize domain I displayed significantly increased AnxA5 resistance, suggesting that specifically anti-β2GPI antibodies compete with AnxA5 for anionic phospholipids. These results are consistent with a model in which aPL antibodies may promote thrombosis by interfering with the anticoagulant activity of AnxA5.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2006-07-030148
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Pathological Anti-β2-Glycoprotein I Antibodies Disrupt the Anticoagulant Activity of Annexin A5: A Possible Explanation for the Lupus Anticoagulant Paradox.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 135-135
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 135-135
    Abstract: One of the most enigmatic features of the antiphospholipid (aPL) syndrome is the paradoxical correlation between thrombosis and the in vitro lupus anticoagulant (LAC) effect. It has recently been shown that only LAC that are due to β2-glycoprotein I (β2GPI) antibodies correlate with thrombosis. It has also been reported that aPL antibodies can disrupt the formation of an anticoagulant crystal shield that is formed by annexin A5 (AnxA5) over phospholipids bilayers. This disruption can be assayed by measuring resistance to AnxA5 anticoagulant activity. We therefore investigated whether the presence of these β2GPI-dependent LACs might correlate with the disruption of AnxA5 anticoagulant activity. We performed a double blind study with 30 patients divided into three groups; Group A: plasma of patients that show a β2GPI-dependent LAC; Group B: plasma of patients that show a β2GPI-independent LAC; Group C: plasma of SLE patients without a LAC. As previously demonstrated, we were able to discriminate between a β2GPI-dependent and a β2GPI-independent LAC by titrating cardiolipin into the plasma sample. A β2GPI-dependent LAC could be normalized by the addition of cardiolipin in contrast to a β2GPI-independent LAC which was prolonged by cardiolipin. To investigate the effects on AnxA5, we performed an APPT-based coagulation assay. In this assay we added AnxA5 to the plasma of patients and measured the prolongation in clotting time. We calculated the ratio of the clotting time divided by the clotting time with AnxA5 added to the plasma (=AnxA5 ratio). This assay represents the resistance against AnxA5 and gives an indication of its effect on the anticoagulant shield formed by AnxA5. Eleven patients displayed a β2GPI-dependent LAC (group A, all thrombosis), that gave an AnxA5 ratio of 151.3% (± SD 14.5). For 9 patients that displayed a β2GPI-independent LAC (group B, thrombosis n=3) we found a ratio of 225.4% (± SD 29.4). Ten patients did not have LAC (group C, thrombosis n=2) that gave a ratio of 219.2% (± SD 31.0). The annexin A5 ratio of group A was significantly lower than the ratio of group B (P=0.0002) and group C (P=0.0001). There was no difference in AnxA5 ratio between group B and group C (P=0.7802). β2GPI-dependent LAC correlate strongly with both thrombosis and AnxA5 resistance. The results therefore suggest that anti-β2GPI antibodies that cause LAC, in contrast to aPL antibodies with other specificities, are capable of disrupting the anticoagulant effect of AnxA5 on phospholipids. The disruption of the AnxA5 anticoagulant shield by LAC-causing anti-β2GPI antibodies may be a mechanism for thrombosis in APS and offers a potential explanation for the LAC paradox. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.135.135
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    Interaction of beta2-Glycoprotein I with Members of the Low Density Lipoprotein Receptor Family.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2646-2646
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2646-2646
    Abstract: The antiphospholipid syndrome (APS) is a non-inflammatory disease characterized by arterial and/or venous thrombosis and/or pregnancy morbidity in the presence of auto-antibodies that recognize beta2-glycoprotein I (beta2GPI) bound to cardiolipin. We have previously demonstrated that dimerization of beta2GPI by auto-antibodies induces platelet activation. This effect has been shown to be mediated by apoER2′. Here, we show that dimeric beta2GPI, and not plasma beta2GPI interacts with three different LDL-receptor family members; apolipoprotein E receptor 2′ (apoER2′), the low LDL-receptor related protein (LRP) and megalin. Interaction between dimeric beta2GPI and apoER2′ was best described with a one-site binding model (KD(app) 25 nM), whereas for LRP and megalin the interaction with dimeric beta2GPI was best described with a two-site binding model, representing a high- (3.1 nM) and a low-affinity site (192.1 and 241.2 nM, respectively). Binding kinetics of a dimeric beta2GPI mutant, that binds poorly to anionic phospholipids were similar to the binding kinetics of full length dimeric beta2GPI for all three LDL-receptor family members. Upon deletion of domain I or domain II of dimeric beta2GPI no changes in the binding kinetics were observed. Deletion of domain V however, significantly decreased the affinity for apoER2′, LRP and megalin. In conclusion, our data show that dimeric beta2GPI can interact with different LDL-receptor family members. This interaction is dependent on a recognition site in domain V of beta2GPI, which does not overlap with the phospholipid-binding site.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2646.2646
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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    Online Resource
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