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In vitro effect of an antithrombin in platelet activation by HIT antibodies

Purpose

Acute HIT usually precludes treatment with heparin. Clotting factor concentrates that contain heparin have also been regarded as contraindicated in these patients. Occurrence of HIT is currently shifting towards severely ill patients. These patients often require antithrombin (AT) substitution (e.g. for increased consumption in DIC). AT may contain heparin from the manufacturing process. In this study we assessed by means of an immunological assay whether heparin contaminations in AT can trigger platelet activation by HIT antibodies. As only 30% of heparins contain the AT binding pentasaccharide, determination of FXa activity is not sufficient to detect immunological relevant heparin concentrations.

Methods

After thawing and heat inactivation, HIT sera were tested in the 14C-serotonin release assay (14C-SRA) in the presence of heparin or two AT batches at different concentrations (undiluted, 1/2, 1/4, 1/8, 1/16, 1/32, 1/64, 1/128; one batch unspiked, one batch spiked with 1 IU heparin/ml) (Atenativ®; Octapharma AB, Stockholm, Sweden). A reaction in the presence of AT was considered positive if the 14C-SRA was > 20% with at least two of four platelet donors.

Results

Sera of 10 patients with documented clinical HIT were investigated. Using the unspiked AT batch only one of 10 HIT sera showed weak platelet activation in the 14C-SRA at a dilution of AT of 1:16 but not at less diluted AT. This indicates a false positive reaction rather than a real HIT-dependent platelet activation. With the spiked AT batch the sensitivity of the assay was determined to detect at least a concentration of 0.06 IU heparin/ml AT.

Conclusion

The antithrombin concentrate we tested does not contain ≥ 0.06 IU/ml heparin. Considering a worst-case scenario, treating a HIT patient with 1000 IU Atenativ® might theoretically result in a final heparin plasma concentration of maximally 0.2 × 10-3 IU/ml whole blood. It is unlikely that this amount of heparin will cause adverse effects in a HIT patient.

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Eichler, P., Lubenow, N., Raschke, R. et al. In vitro effect of an antithrombin in platelet activation by HIT antibodies. Crit Care 9, P341 (2005). https://doi.org/10.1186/cc3404

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Keywords

  • Heparin
  • Platelet Activation
  • Antithrombin
  • Pentasaccharide
  • False Positive Reaction