Usually, serological investigation for HIT antibodies is performed on patients who develop thrombocytopenia during heparin treatment. Since 1995, however, many studies have systematically assessed heparin-dependent antibody seroconversion using sensitive assays (EIA, SRA, or both), irrespective of whether or not thrombo-cytopenia occurred. Some interesting insights into the pathogenesis of HIT have emerged from these reports.
As shown in Table 8, three main types of patient population have been investigated: medical patients receiving therapeutic-dose UFH; orthopedic patients receiving UFH or LMWH; and cardiac surgical patients receiving UFH or LMWH. There appear to be distinct frequencies of HIT antibody formation, as well as varying risks of "breakthrough" of HIT, among these different populations (see Fig. 3). Several observations emerge from these studies:
1. The prevalence of seroconversion depends on the diagnostic assay used. The PF4-heparin EIA is more sensitive than the SRA for the detection of anti-PF4/heparin antibodies (Bauer et al., 1997; Pouplard et al., 1999; Warkentin et al., 2000, 2005a; Warkentin and Sheppard, 2006a); however, this increase in sensitivity does not necessarily translate into greater predictive value for clinical HIT (see Chapter 10).
2. With use of PF4/polyanion EIA, the frequency of seroconversion following cardiac surgery ranges to as high as about 75% (Visentin et al., 1996; Bauer et al., 1997; Warkentin et al., 2000; Warkentin and Sheppard, 2006a). A high frequency of seroconversion (13-20%) was also observed using the SRA. Despite the highest frequency of HIT seroconversion reported in this patient population, the likelihood of developing HIT appears to be less than in orthopedic patients also treated with postoperative UFH.
3. Seroconversion occurs frequently without thrombocytopenia or thrombosis. Indeed, most patients who form HIT antibodies do not develop HIT. The proportion who develop HIT, however, is highest among the patients who have a positive SRA. This suggests that HIT antibodies "strong" enough to activate platelets are more likely to be clinically significant. Patient-dependent factors also must be important, however, because the probability of a positive SRA indicating clinical HIT ranges from about <10% (cardiac surgery) to approximately 50% (orthopedic surgery patients receiving UFH).
4. Regardless of which diagnostic assay is used, new seroconversion occurs more frequently after exposure to UFH than LMWH (Warkentin et al., 1995, 2000, 2003, 2005a; Amiral et al., 1996; Lindhoff-Last et al., 2002; Ahmad et al., 2003a) (Fig. 3).
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