HIT-T 12/332 (3.6%) 1/333 (0.3%) <0.001 1/100 (1.0%)

HIT 16/332 (4.8%) 2/333 (0.6%) <0.001 1/100 (1.0%)

+ SRA 19/192 (9.9%) 5/170 (2.9%) 0.010 20/100 (20.0%)

+ EIA-IgG 29/192 (15.1%) 11/170 (6.5%) 0.011 50/100 (50.0%)

+ EIA-GTI 56/188 (29.8%) 26/169 (15.4%) 0.0015 76/98 (77.6%)

FIGURE 3 Iceberg model of HIT. The top panel depicts a generic "iceberg", illustrating the interrelationship of clinical HIT with formation of anti-PF4/heparin antibodies detected by the platelet SRA, an EIA-IgG, and a commercial EIA (from GTI, Inc.) that detects antibodies of all three major immunoglobulin classes (IgG, IgA, and IgM) against PF4/polyanion (EIA-GTI). The lower panel illustrates the event rates for clinical HIT (HIT), including the subgroup with HIT-T, in relation to the frequencies of antibody formation, in three clinical settings: UFH or LMWH thromboprophy-laxis during orthopedic surgery (data from an RCT) and UFH thromboprophylaxis postcardiac surgery (prospective cohort study). + indicates positive test. Abbreviations: EIA-IgG, enzyme-immunoassay that detects IgG antibodies against PF4/heparin complexes; HIT, heparin-induced thrombocytopenia; HIT-T, HIT-associated thrombosis; LMWH, low molecular weight heparin; SRA, serotonin release assay; UFH, unfractionated heparin. Source: Warkentin et al., 1995, 2000, 2003, 2005a; Warkentin and Sheppard, 2006a.

prophylaxis with UFH (Trossaert et al., 1998; Pouplard et al., 1999, 2002, 2005; Warkentin et al., 2000; Warkentin and Sheppard, 2006a) (see Fig. 3). Pooling the data, the frequency of HIT appears to be about 2%. This frequency is consistent with a number of retrospective studies (Glock et al., 1988; Walls et al., 1992a,b; Singer et al., 1993) that reported a frequency of HIT of up to 5%, but overall, also noted a frequency of about 2% (Table 9). Furthermore, HIT was associated with a risk of thrombosis of 38-81%, and with an overall mortality of 18 -43% in these studies. In contrast to the orthopedic patient population, the predominant throm-botic event appears to be arterial.

Only one group has examined the influence of postoperative antithrombotic prophylaxis with UFH or LMWH on the frequency of HIT antibody formation and HIT following heart surgery (Pouplard et al., 1999, 2002, 2005). In their multi-year observational studies involving nonrandomized comparisons between UFH and LMWH, a significant difference in risk of HIT was observed: UFH = 11/437 (2.5%) versus LMWH = 8/1874 (0.4%); p < 0.0001. However, differences in patient composition prevent firm conclusions.

TABLE 9 Frequency of HIT and Thrombosis in Retrospective Studies of HIT in Cardiovascular Surgery Patients
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