期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 10, 期 3, 页码 430-436出版社
WILEY
DOI: 10.1111/j.1538-7836.2012.04618.x
关键词
enoxaparin; heparin-induced thrombocytopenia; oligosaccharides; platelet factor 4; serotonin release assay; surface plasmon resonance
资金
- Institut de Recherche sur la Thrombose et l'Hemostase (IRTH)
- Sanofi
. Background: The minimal structural requirements of low-molecular-weight heparins that determine the risk of developing heparin-induced thrombocytopenia (HIT) are not fully defined.Objectives: The ability of enoxaparin-derived oligosaccharides (OS) to induce platelet activation and exposure of platelet-factor 4 (PF4) epitopes recognized by antibodies developed in HIT was studied by surface plasmon resonance (SPR) and serotonin release assay.Results: Decasaccharides with = 11 sulfate groups induced platelet activation in the presence of plasma from patients with confirmed HIT. Serotonin release of > 80% without full inhibition at 100 mu g mL-1 was achieved with decasaccharides containing 14 or 15 sulfate groups, 2 dodecasaccharides and 2 tetradecasaccharides. An SPR method was developed using purified PF4 immobilized on carboxymethylated dextran. Antibodies from all HIT samples bound to PF4/heparin in SPR assays with resonance units (RU) ratio of 109173 with HIT plasma vs. 8893 with control plasma. RU ratios > 100 were measured when PF4 was pre-incubated with OS with = 10 saccharide units and one octasaccharide containing 10 sulfate groups. RU ratios > 140, similar to those measured when PF4 was pre-incubated with unfractionated heparin or enoxaparin, were obtained with purified dodeca- and tetradecasaccharides. RU values strongly correlated with the number of sulfate groups in the decasaccharides tested (r = 0.93, P = 0.02).Conclusions: LMWHs with fragments > 10 saccharides and a large number of sulfate groups are more likely to be associated with a higher risk of HIT. These structure-activity relationships were independent of the ability of the OS to bind antithrombin.
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