<0.0001 0.2907

<0.0001 0.2327

<0.0001 0.0252

2 table; surgical (42/1999) and medical (25/

aStudies were pooled across patient type to produce a simple 2) 3811), Fisher's exact test (2-sided) p-value.

bMale/surgical and male/medical not considered due to lack of events.

Abbreviations: HIT, heparin-induced thrombocytopenia; UFH, unfractionated heparin; LMWH, low molecular weight heparin.

Source: From Warkentin et al., 2006a.

intravascular catheters (Doty et al., 1986; Heeger and Backstrom, 1986; Kappa et al., 1987; Rama et al., 1991; Brushwood, 1992; Parney and Steinke, 2000).

In most of the reports of patients developing HIT during LMWH treatment, recent prior exposure to UFH was not excluded. Indeed, incidental exposure to UFH by intraoperative invasive catheters could lead to formation of HIT antibodies that are inappropriately attributed to later postoperative LMWH prophylaxis (Shumate, 1995). However, if true, it would suggest that the apparent difference in immunogenicity between UFH and LMWH could be even greater than initially reported.

To address this issue, a randomized, double-blind clinical trial was performed to test the hypothesis that incidental exposure to UFH by intraoperative invasive lines, rather than postoperative LMWH antithrombotic prophylaxis, was the predominant explanation for postoperative HIT antibody formation (Warkentin et al., 1998b). Patients were randomized to receive either UFH or normal saline flushes during surgery. However, the data obtained essentially ruled out the hypothesis: the frequency of HIT antibodies was not higher in the patients who were randomized to receive UFH flushes (2.2% vs. 2.7%; p = 0.73). Rather, the results suggested that postoperative LMWH prophylaxis administered to both groups was the predominant factor in causing HIT antibody formation. However, HIT antibody formation occurred in two patients who received UFH flushes, but who subsequently were given warfarin anticoagulation. Because intraoperative UFH flushes occasionally result in formation of high levels of HIT antibodies that can lead to life-threatening, acute HIT if therapeutic-dose UFH is administered a few weeks later (Ling and Warkentin, 1998), and because there is no clinical benefit to flushing intravascular catheters with UFH (Warkentin et al., 1998b), it seems reasonable to recommend that normal saline flushes be considered for routine flushing of intravascular catheters used during surgery.

A double-blind placebo-controlled trial of UFH for maintaining peripheral vein catheter patency in neonates also evaluated the incidence of anti-PF4/heparin antibodies and clinical HIT. None of the 108 neonates who were allocated to receive heparin developed HIT or HIT antibodies (Klenner et al., 2003).

It is possible that heparin flushes for venous access devices in cancer patients can cause anti-PF4/heparin antibody formation. In a serosurveillance study, Mayo and colleagues (1999) found that about one-third of 49 such patients tested formed low levels of antibodies (detected by EIA) at least once. However, only one patient developed a positive SRA, and no patient developed thrombocytopenia. These data are in keeping with our own experience that HIT is very uncommon in this patient population.

In recent years, many centers have substituted saline for heparin to intermittently "flush" peripheral venous catheters. This is because saline flushing of such devices "locked" between use have similar patency rates as when heparin flushes are used (Randolph et al., 1998a). In contrast, heparin may help prolong the patency of intra-arterial, central venous, and pulmonary artery catheters (Randolph et al., 1998b), and consequently exposure to heparin by these routes remains common.

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