The distinction between thrombocytopenia that begins early (within 4 days) or late (5 or more days after beginning heparin treatment) is a simple clinical feature that is useful to distinguish nonimmune HAT, which begins early, from (immune) HIT, which begins late. For this assessment, the first day of heparin use is considered day 0. There is an important exception to this rule of timing for HIT: a rapid fall in platelet count on starting heparin therapy can represent acute HIT, but only if a patient already has circulating HIT antibodies, usually the result of a recent heparin exposure. HIT antibodies are transient, which could explain why the risk for rapid-onset HIT is restricted to a period of about 100 days following exposure to heparin (Warkentin and Kelton, 2001) (see Chapter 2).
Typically, nonimmune HAT begins 1 -2 days after starting heparin administration and resolves during continued heparin therapy (Johnson et al., 1984; Chong and Berndt, 1989; Warkentin and Kelton, 1994; Warkentin et al., 1995; Greinacher, 1995). The platelet count fall is usually mild, with a nadir between 75 and 150 X 109/L. This early platelet count fall may be the result of a direct activating effect of heparin on platelets (Chong and Ismail, 1989; Chong and Castaldi, 1986) or of comorbid clinical factors.
TABLE 1 Explanations for Variable Frequency of HIT Among Prospective Studies
Patient population studied (frequency of HIT antibody formation differs among patient populations, possibly because of differences in platelet activation and PF4 release) Type of heparin used: immunogenicity (bovine UFH > porcine UFH > porcine LMWH ~ fondaparinux) and in vivo cross-reactivity (UFH > LMWH >> fondaparinux); also, possibility of lot-to-lot variability in immunogenicity/cross-reactivity among heparins Variable duration of heparin treatment (HIT typically begins between days 5 and 10) Gender: female > male (exception: HIT is rare during pregnancy) Dose of heparin used (dose-dependent thrombocytopenia) Technical explanations
Variable definition of thrombocytopenia used Differing baseline platelet counts permitted for study entry Requirement to repeat platelet count testing to confirm thrombocytopenia Variable intensity of platelet count surveillance Variable intensity of surveillance for thrombotic events Failure to exclude nonimmune heparin-associated thrombocytopenia Lack of use of in vitro test for HIT antibodies Use of insensitive or nonspecific HIT antibody assays Inclusion of patients with "early" thrombocytopenia
Failure to exclude patients whose platelet count recovered during continued heparin treatment Failure to exclude patients with other explanations for thrombocytopenia
Abbreviations: HIT, heparin-induced thrombocytopenia; LMWH, low molecular weight heparin; PF4, platelet factor 4; UFH, unfractionated heparin.
Early nonimmune HAT occurs in up to 30% of patients receiving heparin (Bell et al., 1976; Nelson et al., 1978; Warkentin et al., 1995). Systematic serological investigation of patients with early thrombocytopenia was performed in one study comparing UFH with LMWH for postoperative antithrombotic prophylaxis in patients who underwent hip replacement surgery (Warkentin et al., 1995). With 150 x 109/L as a platelet count threshold, early thrombocytopenia was observed in 189/665 (28%) patients; however, HIT antibodies were not detected in any of the 98 patients tested, and platelet count recovery to more than 150 x 109/L within 3 days occurred despite continuing the heparin (Warkentin et al., 1995). No difference in the frequency of early thrombocytopenia was observed between patients who received UFH (28%) and those who received LMWH (29%). This suggests that unrelated clinical factors, such as perioperative hemodilution with fluid and blood products, were primarily responsible. In contrast, the onset of late thrombocytopenia (i.e., between days 5 and 10 of heparin treatment) was strongly associated with the formation of heparin-dependent platelet-activating antibodies and occurred significantly more frequently in the patients who received UFH (discussed subsequently).
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