Laboratory Testing

As in adults, no data exist to justify routine screening for HIT antibodies during heparin use in children. Testing for HIT antibodies should be used to exclude or confirm clinically suspected HIT. During UFH therapy, platelet counts should be monitored regularly (see Chapter 3), particularly between days 5 and 14 of heparin use [when >90% of HIT begins (see Chapter 2)].

For laboratory testing, functional and antigen tests are available (see Chapter 10). Commercial antigen assays (ElAs) are often used and are especially appropriate for neonates and infants because small blood volumes are needed (<100 pL vs. >1 mL for most platelet activation assays). However, the appropriate cutoff level that defines a positive EIA result suitable for children is debated. In a retrospective study, Schmugge and coworkers (2002) investigated cutoff levels for children using a commercial EIA (Asserachrom, Stago). Among 612 children, HIT was suspected in 14 because of thrombocytopenia and thrombosis. Positive test results (using the adult cutoff) were seen in six of the 14 patients. In the remaining eight children with suspected HIT, test results ranged from 26% to 80% of the adult cutoff level, i.e., levels that were higher than among controls (with wide overlap).

A retrospective analysis performed by Risch and colleagues (2003) of the same 612 pediatric ICU patients initially reported by Schmugge et al. (2002) addressed whether there was an association between anti-PF4/heparin antibody levels and thrombosis. Ten patients who developed thrombosis without thrombocytopenia constituted the study group and were compared with 19 matched controls with neither thrombosis nor thrombocytopenia. All 29 subjects had lower antibody levels than the adult cutoff level. However, median assay results were significantly higher in the thrombosis patients than in controls (51% vs. 23% of the manufacturer's cutoff; p = 0.004). The authors concluded that there might be an association between anti-PF4/heparin antibody levels and thrombosis, even in the absence of thrombo-cytopenia or a positive test result (by conventional criteria).

However, in our randomized, double-blind trial (Klenner et al., 2003b), none of the infants developed anti-PF4/heparin antibodies using the adult cutoff [UFH group: mean optical density (OD), 0.020; maximum, 0.328; saline group: mean OD, 0.019, maximum, 0.239; PF4/polyvinyl sulfonate EIA (GTI, Inc., Wausheka, WI)]. Minor increase in OD (>0.100) occurred in six patients (three in each group) (Fig. 2). Therefore, these minor increases in OD are unlikely to be related to UFH use and could represent a nonspecific increase in antibody levels in ill patients (acute phase reaction). Among the subjects receiving placebo, all OD values were below 0.400 (the accepted adult cutoff value), suggesting that this level is also appropriate for neonates.

The limitations of antigen assays observed in adults likely also apply to children. In some cases, the antigen assay could be false-negative if HIT antibodies recognize a non-PF4-dependent antigen (Greinacher et al., 1994) (see Chapters 5 and 6). Thus, a functional test for HIT antibodies should be performed when HIT

FIGURE 2 Six neonates with rising absorbance levels in PF4-dependent ElA. Six of 213 neonates participating in a randomized, double-blind trial comparing heparin with normal saline for maintenance of peripheral venous catheter patency developed a rise in absorbance of more than 0.100 OD units by PF4/polyvinyl sulfonate EIA (GTI, Inc., Waukesha, WI). All OD values were less than the positive adult cutoff (0.400 OD units). No differences were observed between patients receiving heparin (solid lines) compared to patients receiving saline (dotted lines). As the maximum OD in saline controls was 0.239, the 0.400 cutoff seems appropriate also for pediatric patients. Abbreviations: EIA, enzyme-immunoassay; PF4, platelet factor 4; OD, optical density. Source: Klenner et al., 2003b.

FIGURE 2 Six neonates with rising absorbance levels in PF4-dependent ElA. Six of 213 neonates participating in a randomized, double-blind trial comparing heparin with normal saline for maintenance of peripheral venous catheter patency developed a rise in absorbance of more than 0.100 OD units by PF4/polyvinyl sulfonate EIA (GTI, Inc., Waukesha, WI). All OD values were less than the positive adult cutoff (0.400 OD units). No differences were observed between patients receiving heparin (solid lines) compared to patients receiving saline (dotted lines). As the maximum OD in saline controls was 0.239, the 0.400 cutoff seems appropriate also for pediatric patients. Abbreviations: EIA, enzyme-immunoassay; PF4, platelet factor 4; OD, optical density. Source: Klenner et al., 2003b.

remains strongly suspected despite a negative EIA. However, when the pretest probability of HIT is low, a negative antigen test usually excludes HIT.

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