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Author Conference Year # HIT HITT Confirmation Dose Duration Recovery15 Pits0 VTE Amp Death Hem

Boshkov et al. ASH 2004 1g 1 N/R 0.15mg/kg 3 mo N/A 0 0 0 0 0

Grabowski and Bussel ASH 2006 2s 2 N/R N/R 4.5-8 mo N/R 0 0 0 0 0

Piovella et al. ASH 2006 20 3 17 N/R 2.5-7.5 mg 4-25 days N/R 1 0 0 0 1

aNumber of patients with a history of HIT.

bTime to platelet count recovery, determined only from those patients treated with fondaparinux while thrombocytopenic.

"Number of patients with persistent or recurrent thrombocytopenia while on fondaparinux.

dDose of fondaparinux adjusted due to renal failure.

eDeaths were not perceived by investigators to result from fondaparinux.

'Bradner JE, Yeh RW, Hallisey RK, Kuter DJ. Fondaparinux in the treatment of heparin-induced thrombocytopenia (unpublished observations). 9Pediatric patient.

Abbreviations: Amp, limb amputation; EIA, (PF4-dependent) enzyme-immunoassay; Hem, major hemorrhage; HIPA, heparin-induced platelet activation test (washed platelet assay); HIT, isolated HIT (i.e., HIT without thrombosis); HIT-T, HIT-associated thrombosis; PAT(Dir), platelet aggregation test (direct, i.e., using the patient's own platelets); N/R, not reported by investigators; VTE, venous thromboembolism.

UFH (100% of donor platelet samples aggregated), LMWH (76%), danaparoid (8%) or pentasaccharide (0%). Thus, platelet aggregation was induced in all samples in the presence of UFH but was not induced in the presence of fondaparinux.

These observations were confirmed shortly thereafter by another group in France using enzyme-linked immunoassay (EIA) (Amiral et al., 1997). Plasmas from 49 patients with HIT (confirmed by platelet aggregometry) were compared with respect to their ability to induce the binding of antibodies to immobilized PF4 in the presence of increasing concentrations of fondaparinux or UFH. Although antibodies were fixed by a broad range of concentrations of UFH, no antibody binding was detected in the presence of fondaparinux.

A subsequent prospective study tested the cross-reactivity of fondaparinux with sera obtained from 39 patients with laboratory-confirmed HIT and 15 unaffected controls (Savi et al., 2005). Three functional (platelet activation) tests for cross-reactivity were performed by independent laboratories: the serotonin-release assay, the heparin-induced platelet activation assay (both the aforementioned are washed platelet assays) and conventional platelet aggregometry (using platelet-rich plasma). Although cross-reactivity between HIT plasma and UFH was observed in 75 of 94 assays (79.8%), only three of 91 assays (3.3%) conducted in the presence of fondaparinux were reported as positive. The authors concluded that fondaparinux was essentially non-reactive with HIT sera.

Two recent studies have investigated the potential for formation of PF4/ fondaparinux complexes. Rauova et al. (2006) investigated the biophysical structure and polysaccharide determinants of ultra-large PF4 complexes (ULC). Using high performance liquid chromatography (HPLC) size exclusion chromatography and electron microscopy, the authors observed that ULC formation was formed preferentially by UFH and less well by LMWH. In contrast, fondaparinux was incapable of forming ULC. However, using atomic force microscopy (AFM) and photon correlation spectroscopy, Greinacher et al. (2006) provided evidence that fondapar-inux can induce some formation of PF4 clusters, although this effect was much less marked than for UFH and LMWH.

These studies support the concept that fondaparinux exhibits no (or negligible) in vitro cross-reactivity with HIT antibodies, although the AFM studies suggest that it might provoke an immune response against PF4-dependent antigens. Indeed, in the PENTAMAKS and PENTATHLON orthopedic thrombopro-phylaxis RCTs, anti-PF4/heparin antibodies were generated at similar frequencies in both the fondaparinux and enoxaparin study arms, although none of the 2700 patients studied developed clinical HIT (Warkentin et al., 2005). Interestingly, the antibodies that were generated recognized PF4 in the presence of UFH and LMWH, but not in the presence of fondaparinux, even when the blood samples were obtained from patients who had formed antibodies while receiving fondapar-inux (Fig. 2). In a smaller study, Pouplard et al. (2006) also observed a low frequency of anti-PF4/heparin antibody formation among post-orthopedic surgery patients undergoing fondaparinux thromboprophylaxis. One interpretation of these data is that anti-PF4/heparin antibodies formed in patients treated with fondapar-inux likely would not cause clinical HIT even in the presence of fondaparinux, given the negligible degree of in vitro cross-reactivity. It should be further noted that neither of the above studies proves immunogenicity of fondaparinux, as a background frequency of "spontaneous" antibody formation after orthopedic surgery has not been ruled out (Warkentin et al., 2005, 2006). To date, there is only a single published case of possible fondaparinux-induced HIT (Warkentin et al., 2007).

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