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Isolated anecdotal reports of unfavorable clinical outcomes in HIT patients treated with danaparoid exist (Tandy-Poncet et al., 1995; Insler et al., 1997; Muhm et al., 1997). Cross-reactive antibodies were not always investigated, and their potential role vis-a-vis other clinical factors remains uncertain.

Magnani and Gallus (2006) found in a review of 1418 HIT patients treated with danaparoid that among 36 patients with apparent pre-treatment danaparoid cross-reactivity, 23 had clinical events (platelet count fall, thrombotic event) possibly indicating in vivo cross-reactivity. The remaining 13 patients were treated for a median of 11 days without a problem. A more recent update (Magnani, unpublished), which includes patients reported by Warkentin (1996b) and Newman et al. (1998), shows that of 58 patients treated with danaparoid despite a positive danaparoid pre-treatment cross-reactivity test, 31 (53%) were treated for up to 42 days with full recovery of platelet counts and no further thromboembolic events. In 14 (24.2%) of the remaining patients, the platelet count did not recover (half of these developed a thromboembolic event).

A further 22 patients developed apparent cross-reactivity seroconversion (i.e., negative pre-danaparoid cross-reactivity test became positive 2-14 days after

FIGURE 5 Serial platelet counts of representative HIT patients treated with danaparoid: Solid black bar shows duration of heparin administration, striped bar indicates danaparoid therapy, open bar shows warfarin therapy: (A) Typical profile of the 11 patients who were negative in both fluid-phase EIA and functional assay, (B) Typical profile of the eight patients who were positive in the fluid-phase, but negative in a functional assay, (C) Profile of patient A, one of the two patients who were positive in both types of assay. She recovered during a short course of danaparoid. (D) Profile of patient B, the other patient positive in both assays. The profile indicates the course of HIT following transfer to a major hospital. Despite treatment with many antithrombotic agents, he eventually died following major thrombosis. Abbreviations: HIT, heparin-induced thrombocytopenia; EIA, enzyme immunoassay. Source: From Newman et al., 1998.

FIGURE 5 Serial platelet counts of representative HIT patients treated with danaparoid: Solid black bar shows duration of heparin administration, striped bar indicates danaparoid therapy, open bar shows warfarin therapy: (A) Typical profile of the 11 patients who were negative in both fluid-phase EIA and functional assay, (B) Typical profile of the eight patients who were positive in the fluid-phase, but negative in a functional assay, (C) Profile of patient A, one of the two patients who were positive in both types of assay. She recovered during a short course of danaparoid. (D) Profile of patient B, the other patient positive in both assays. The profile indicates the course of HIT following transfer to a major hospital. Despite treatment with many antithrombotic agents, he eventually died following major thrombosis. Abbreviations: HIT, heparin-induced thrombocytopenia; EIA, enzyme immunoassay. Source: From Newman et al., 1998.

initiating danaparoid treatment); a thromboembolic event occurred in seven (two fatal). Thus, in total, 3.2% of the 1418 patients reviewed by Magnani and Gallus (2006) were reported to have had serologically confirmed clinical cross-reactivity with danaparoid (23 associated with pre-treatment cross-reactivity, 22 associated with cross-reactivity seroconversion). However, the development of platelet count reduction and/or a thromboembolic event during danaparoid treatment is not necessarily a marker of cross-reactivity, since 10 patients re-tested at the time of suspected clinical cross-reactivity remained seronegative (Magnani and Gallus, 2006).

There are several important considerations regarding danaparoid cross-reactivity. First, it is clear that a positive test for in vitro cross-reactivity does not necessarily mean that adverse effects related to danaparoid therapy will occur (at least half the patients will do well). Second, in vitro cross-reactivity itself might indicate more severe HIT, with the potential for greater risk of complications irrespective of which anticoagulant is given. Thus, it might not be possible to distinguish clinical cross-reactivity with the natural course of a severe episode of HIT (Warkentin, 1998; Newman et al., 1998; Baumgartel et al., 2000). Third, no standardized, validated testing method for cross-reactivity exists. Indeed, apparent in vitro cross-reactivity reported in some studies could even reflect the phenomenon of heparin-independent platelet activation caused by some HIT patient serum (see Chapter 10). Besides mimicking in vitro cross-reactivity (as some serum-induced platelet activation will occur whether or not danaparoid is added), this serological feature itself could portend a poor prognosis. Fourth, prospective and retrospective studies (Chong et al., 2001; Farner et al., 2001; Lubenow et al., 2006) showed favorable clinical outcomes when danaparoid was given without delay for performing in vitro cross-reactivity. This indicates that a high likelihood of satisfactory outcome can be obtained by using a strategy of prompt anticoagulation with danaparoid without performing in vitro cross-reactivity studies. Indeed, despite the issue of in vitro cross-reactivity with danaparoid, it is noteworthy that danaparoid-induced immune-mediated thrombocytopenia has never been reported. Based upon these considerations, in vitro cross-reactivity testing is not recommended prior to commencing therapy with danaparoid for suspected HIT (Warkentin and Greinacher, 2004). However, cross-reactivity testing may be appropriate in patients who develop new, progressive, or recurrent

TABLE 3 Countries in Which Danaparoid Is Approved for Clinical Usea

Country

DVT prophylaxis

Heparin-induced thrombocytopenia

Perioperative0

Poststroke

Prophylaxis

Treatment

North America Canada United States Europe Austria Belgium Czech Republic Denmark Finland France Germany Great Britain Greece Ireland Italy

Luxembourg The Netherlands Norway Portugal Sweden Switzerland Australasia and Africa Australia Japanf Korea

New Zealand South Africa

X Xc

0 0

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