GREINACHER, A and ALBAN, S and DUMMEL, V and FRANZ, G and MUELLERECKHARDT, C (1995) CHARACTERIZATION OF THE STRUCTURAL REQUIREMENTS FOR A CARBOHYDRATE-BASED ANTICOAGULANT WITH A REDUCED RISK OF INDUCING THE IMMUNOLOGICAL TYPE OF HEPARIN-ASSOCIATED THROMBOCYTOPENIA. THROMBOSIS AND HAEMOSTASIS, 74 (3). pp. 886-892. ISSN 0340-6245,
Full text not available from this repository.Abstract
HAT is the most frequent drug induced immune-thrombocytopenia. We recently identified multimolecular PF4/heparin complexes as the major antigen. In order to evaluate the structural requirements for formation of the antigenic complex. we chemically synthesized 13 glucan sulfates and used 5 heparin fractions (2.4-4.8 kD) and a synthesized pentasaccharide, representing the antithrombin III binding sequence of heparin, to further characterize the HAT antigen. In the presence of glucan sulfates and heparin, HAT antibodies caused platelet activation typically at low but not at high concentrations, as measured by C-14-5HT release. The concentration range giving the activation pattern depended on the degree of sulfation (DS) and molecular weight (MW) of the glucan sulfates but not on the type of glycosidic linkage of a polysaccharide. With linear glucan sulfates with a chain length of 35 monosaccharides, the critical DS to form the HAT antigen ranged between 0.60 and 1.20. Glycosidic branched glucan sulfates were able to form the HAT antigen at a lower DS and a lower MW than linear glucan sulfates. Platelet activation by HAT-antibodies in the presence of linear curdlan sulfate fractions was dependent on their MW. At a low concentration (0.01 mu M) medium-size fractions (60 kD) caused platelet activation but neither small (12 kD) nor large fractions (>150 kD) did. Ar higher concentrations (2 mu M) the opposite reaction pattern was observed. In the case of heparin, the optimal chain length for forming the HAT antigen is a hexadecasaccharide (4.8 kD). Antigen generation decreased with larger and smaller fractions. For 50% platelet activation by HAT antibodies increasing concentrations of heparin were necessary using heparins with decreasing MW: 0.02 +/- 0.015 mu M (4.8 kD), 0.09 +/- 0.016 mu M (3.0 kD), 0.8 +/- 0.21 mu M (2.4 kD). In the presence of the pentasaccharide. HAT antibodies did not cause platelet activation at any concentration tested, nor bound to PF4-pentasaccharide complexes in a PF4 based ELISA system. We conclude that generation of the HAT antigen is dependent on the ratio of MW and DS of a glucan sulfate. We conclude from this study that a carbohydrate based anticoagulant with a reduced risk of forming the HAT antigen should be linear with a DS <0.6 or a MW <2.4 kD. These data might be important for the design of new drugs for parenteral anticoagulation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PLATELET FACTOR 4; OLIGOSACCHARIDES; ANTIBODIES; ORG-10172; BINDING; ORGARAN; MAIPA; |
| Depositing User: | Dr. Gernot Deinzer |
| Last Modified: | 19 Oct 2022 08:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/52370 |
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