Other Drugs that Reduce Thrombin Generation in HIT

Other drugs with antithrombotic activity described anecdotally as treatment for HIT include bivalirudin (see Chapter 16), dermatan sulfate (Agnelli et al., 1994; Taliani et al., 1999; Imberti et al., 2003), and the antithrombin-binding pentasaccharide, fondaparinux (see Chapter 17). The last agent is a particularly attractive option for thromboprophylaxis or thrombosis treatment in a patient with a history of HIT, as the risk of inducing HIT with this agent is believed to be negligible (Warkentin et al., 2005). However, the use of fondaparinux for management of a patient with acute HIT is debated (Table 6). The available evidence is too limited to draw definite conclusions about its efficacy and safety in this patient population.

TABLE 6 Fondaparinux as a Potential Treatment for HIT: Pros and Cons Pro Con

Fondaparinux does not promote platelet activation by HIT antibodies (negligible in vitro cross-reactivity by platelet activation assays) (Savi et al., 2005) Fondaparinux does not promote binding of HIT antibodies in vitro to PF4 (negligible in vitro cross-reactivity by EIA) To date, only one case of HIT reported with fondaparinux, despite many thousands of patients treated since approval (Warkentin et al., 2007) Several case reports suggest that fondaparinux may be a treatment option for HIT Effective anticoagulant despite lack of anti-thrombin (anti-IIa) activity, based on studies of several non-HIT patient groups Once-daily sc injection (ty2 ~ 17 h)—this provides the option for outpatient administration, which is not readily practical for lepirudin and argatroban

No anticoagulant monitoring is necessary

Both prophylactic- and therapeutic-dose regimens exist

Costs of therapeutic-dose fondaparinux less than that of DTI or danaparoid therapy

Fondaparinux in therapeutic concentrations does not inhibit platelet activation by HIT antibodies (cf. danaparoid3)

Fondaparinux treatment is associated with formation of anti-PF4/heparin antibodies (Warkentin et al., 2005) Duration of fondaparinux treatment often limited to <1 wk in approval trials (thus limiting ability to detect immune HIT)

Many of the case reports do not include convincing clinical and serologic evidence for acute HIT

Perhaps anti-IIa activity is important in HIT management (note: DTIs have anti-IIa activity; and danaparoid has some anti-IIa activity) Steady-state levels take several days to achieve, whereas maximal therapeutic drug effect in HIT is required initially when thrombin generation is maximal; also, absorption of sc injection may be suboptimal in certain patient populations Fondaparinux can accumulate due to its long ty2, especially in patients with renal dysfunction Lack of established dosing regimen for management of acute HIT (with or without thrombosis) Lack of approval status for HIT may cause medicolegal difficulties; informed consent for use in treatment of HIT may be required aIn some patients, danaparoid in therapeutic concentrations inhibits HIT antibody-induced platelet activation (Chong et al., 1989).

Abbreviations: DTI, direct thrombin inhibitor; EIA, enzyme-immunoassay; HIT, heparin-induced thrombocytopenia; PF4, platelet factor 4; sc, subcutaneous; ty2, drug half-life.

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