Biomedical subjects

M J Simmelink

Publications and source records attributed to M J Simmelink.

4 recordsLinked to original sources

PubMed2001

Complexes of anti-prothrombin antibodies and prothrombin cause lupus anticoagulant activity by competing with the binding of clotting factors for catalytic phospholipid surfaces.

We investigated the mechanism by which anti-prothrombin antibodies cause lupus anticoagulant (LAC) activity. Addition of affinity-purified anti-prothrombin antibodies from LAC-positive plasma samples (alpha-FII-LAC+) to normal plasma induced LAC activity. Upon increasing the phospholipid concentration, LAC activity was neutralized. Addition of purified alpha-FII-LAC+ to normal plasma strongly inhibited factor Xa formation. No inhibition was measured when alpha-FII-LAC+ were added to prothrombin-deficient plasma or when purified anti-prothrombin antibodies from LAC-negative plasma samples (alpha-FII-LAC-) were added. When a combination of prothrombin and alpha-FII-LAC+ was added to the purified clotting complex, a strong inhibition of factor Xa and IIa formation was seen. The alpha-FII-LAC+ alone or a combination of prothrombin and alpha-FII-LAC- did not show inhibition. Ellipsometry studies showed that, in the presence of alpha-FII-LAC+, the affinity of prothrombin for a phospholipid surface increased dramatically, whereas a much lower increase was observed with alpha-FII-LAC-. Our results show that complexes of prothrombin and anti-prothrombin antibodies with LAC activity inhibit both prothrombinase and tenase. The antibodies increase the affinity of prothrombin for the phospholipid surface, thereby competing with clotting factors for the available catalytic phospholipid surface, a mechanism similar to that of anti-beta2-glycoprotein I antibodies.

Antiphospholipid Syndrome↗

PubMed2000

Structure-function studies on beta 2-glycoprotein I.

Human beta 2-glycoprotein I is a heavily glycosylated plasma protein which has been implicated in the binding of antiphospholipid antibodies to negatively charged phospholipids; a process considered as an important risk factor for the development of thrombosis. We have solved the crystal structure of beta 2-glycoprotein I. In this review we will discuss what the three-dimensional structure teaches us about the role of beta 2-glycoprotein I in the pathogenesis of the antiphospholipid syndrome.

Glycoproteins↗

PubMed1999

Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids based on its crystal structure.

Human beta(2)-glycoprotein I is a heavily glycosylated five-domain plasma membrane-adhesion protein, which has been implicated in blood coagulation and clearance of apoptotic bodies from the circulation. It is also the key antigen in the autoimmune disease anti-phospholipid syndrome. The crystal structure of beta(2)-glycoprotein I isolated from human plasma reveals an elongated fish-hook-like arrangement of the globular short consensus repeat domains. Half of the C-terminal fifth domain deviates strongly from the standard fold, as observed in domains one to four. This aberrant half forms a specific phospholipid-binding site. A large patch of 14 positively charged residues provides electrostatic interactions with anionic phospholipid headgroups and an exposed membrane-insertion loop yields specificity for lipid layers. The observed spatial arrangement of the five domains suggests a functional partitioning of protein adhesion and membrane adhesion over the N- and C-terminal domains, respectively, separated by glycosylated bridging domains. Coordinates are in the Protein Data Bank (accession No. 1QUB).

Antibodies, Antiphospholipid↗

PubMed1998

Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant.

Antiphospholipid antibodies are a heterogeneous group of antibodies, comprising antibodies with different antigen specificity. Prothrombin is one of the antigens which can be detected by antiphospholipid antibodies and therefore anti-prothrombin antibodies belong to the antiphospholipid antibody family. The presence of antiphospholipid antibodies correlates strongly with thromboembolic complications; however a mechanism by which these autoantibodies induce a thrombotic complication in vivo is not understood. The classic assays for the detection of antiphospholipid antibodies (LAC and anticardiolipin ELISAs) aim to measure all the antiphospholipid antibodies present in the samples without making a distinction between the different subspecificities of the antibodies present in one single sample. Moreover, most of the in-vitro studies performed were carried out with total IgGs, which contain a mixture of antibodies. The absence of an accurate characterization of the plasma samples and the lack of specificity of the IgGs used in in-vitro tests makes it difficult to determine the contribution of antiprothrombin antibodies to the thrombotic complications. Here we review and critically analyse the literature regarding the clinical relevance of the presence of antiprothrombin antibodies and the possible participation of these antibodies in the pathogenesis of the thrombotic complications.

Animals↗