Cross Reactivity of HIT Antibodies with Danaparoid

As danaparoid consists of a mixture of GAGs (mainly heparan sulfate), it is not surprising that a small percentage of antibodies from HIT patients cross-react with the drug. The mean overall reported frequency of in vitro danaparoid cross-reactivity rate in over 2200 plasma samples from HIT patients is 7.6% (Magnani and Gallus, 2006). If aggregation studies using citrated platelet-rich plasma are performed (Makhoul et al., 1986; Kikta et al., 1993; Ramakrishna et al., 1995; Vun et al., 1996), the cross-reactivity is less compared with the more sensitive washed platelet activation assays (Warkentin, 1996b; Koster et al., 2000) or a fluid-phase enzyme immunoassay (EIA) (Newman et al., 1998; Warkentin et al., 2006) (see Chapter 10). Because activation assays are dependent on the donor platelets used for testing, highly reactive donor platelets under standardized conditions have been used for the platelet aggregation test to investigate the cross-reactivity of HIT antibodies for danaparoid and LMWH. Using this modification, cross-reactivity rates of 7% with danaparoid and 83-89% with LMWH (Vun et al., 1996) were found. However, with the sensitive fluid-phase EIA, a higher cross-reactivity rate of 50% with danaparoid and 88% with LMWH (Newman et al., 1998) was observed (Fig. 4). Importantly, even when in vitro reactivity with danaparoid is observed, it is generally weak and quantitatively much less than seen with LMWH.

The in vitro cross-reactivity of the HIT antibodies with danaparoid does not appear to be usually clinically significant. Newman et al. (1998) investigated the clinical significance of in vitro cross-reactivity in 21 patients treated with danapar-oid. The eight patients who tested positive for cross-reactivity by the fluid-phase EIA, but negative by the [14C]serotonin-release washed platelet assay, recovered with resolution of their thrombocytopenia and thrombosis, in a fashion similar to the 11 patients who did not manifest in vitro danaparoid cross-reactivity in either assay. Two patients tested positive in both assays: in one patient, both thrombocy-topenia and pulmonary embolism resolved during danaparoid treatment. However, in the other patient, thrombocytopenia and extensive thrombosis persisted despite danaparoid therapy, although it was unclear whether this unusual patient course represented a specific danaparoid treatment failure (the patient's subsequent clinical course was characterized by consistent failure of all antithrombotic therapies used) (Fig. 5).

Warkentin (1996b) also evaluated the clinical significance of in vitro cross-reactivity with danaparoid in 29 HIT patients treated with danaparoid. This investigator found no difference in clinical outcomes, or in the time to platelet count recovery, between the two patient groups.

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