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Hamilton, ON, Canada
Dr. Warkentin is Professor, Departments of Pathology and Molecular Medicine, and Medicine, McMaster University, Hamilton, ON, Canada. He is also Associate Head, Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, and is a hematologist at the Hamilton Health Sciences (Hamilton General Site). Dr. Eikelboom is Associate Professor, Department of Medicine, McMaster University, Hamilton, ON, Canada, and is a hematologist at the Hamilton Health Sciences (Hamilton General Site).
Correspondence to: Theodore E. Warkentin, MD, Room 1–180A, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences (Hamilton General Site), 237 Barton St E, Hamilton, ON L8L2X2, Canada; e-mail: twarken{at}mcmaster.ca
Heparin-induced thrombocytopenia (HIT) is an important adverse effect of heparin therapy that is caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Among the reasons for its importance are its paradoxical association with thrombosis (the very complication that heparin was intended to prevent) and its relatively common occurrence.1 There are at least four factors that influence the risk of HIT, as follows (Table 1 )2345: duration of heparin therapy; type of heparin used; type of patient population; and patient sex.
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The authors remarked that the "low" frequency of HIT they observed (0.2% overall) seemed to be at odds with the literature, which quotes frequencies of HIT as high as 1 to 5%, particularly in the setting of post-orthopedic surgery thromboprophylaxis.78 What is the reason for this discrepancy? As the authors surmise, the duration of heparin exposure is probably the major factor. The studies that reported HIT frequencies to be as high as 5% were performed in post-orthopedic surgery patients who received UFH thromboprophylaxis for 10 to 14 days. Since platelet-activating anti-PF4/heparin antibodies become detectable beginning about 5 days after starting heparin therapy, and reach peak levels about 1 week later, the continuation of heparin therapy beyond a week is far more likely to trigger HIT than a briefer exposure (Table 1). Indeed, for post-orthopedic surgery thromboprophylaxis in the Detroit study,6 the mean duration of heparin use was only about 3 days, with < 10% of the patients receiving > 4 days of heparin therapy. The reason for such brief UFH thromboprophylaxis was attributed to the strategy of using UFH as a "bridge" therapy to warfarin anticoagulation.
This overall HIT frequency of 0.2% is as good an estimate as any for a contemporary "real-world" assessment of HIT occurrence among diverse clinical settings of UFH use. There is a tendency to extrapolate the quoted figure of 5% for HIT frequency together with estimates of the number of UFH-exposed patients in the United States (about 12,000,000 patients per year), and thereby to conclude that HIT could be developing in 600,000 patients per year.9 If that number were correct, we would expect there to be 600 cases of HIT per year at our medical community in Hamilton, ON, Canada (based on Canada having one tenth of the population of the United States, and our medical community delivering care to about one one hundredth the population of Canada). In reality, "only" about 26 to 30 cases (depending on the serologic criteria used) of HIT were diagnosed in Hamilton in 2004 (although the number of patients investigated for HIT was substantially greater).10 However, by applying the 0.2% figure, rather than the 5% figure so often quoted in the literature, the estimated number of cases in Hamilton would fall from 600 (x 0.2/5) to 24, which approximately matches the number of cases actually diagnosed.
But, while positing a more realistic figure for the number of occurrences of HIT, the Detroit study6 also draws attention to the following striking finding: that about half of their patients (24 of 49 patients; 49%) were identified in the post-cardiac surgery population (ie, those who had undergone coronary artery bypass and/or valve replacement). The frequency of HIT in these patients was found to be 2.1% (24 of 1,163 patients), which is a value that is similar to that reported in the literature.451112 Interestingly, postoperative heparin therapy had been administered to only 14 of these 24 patients (58.3%). Perhaps some of the remaining patients had early postoperative thrombocytopenia (in which the diagnosis of HIT is questionable vis-à-vis the universal phenomenon of perioperative hemodilution5). Or, perhaps a few patients had the dramatic syndrome of "delayed-onset HIT," in which HIT begins 
5 days after cardiac surgery, even in the absence of further heparin therapy (reflecting the presence of unusually high levels of antibodies that can activate platelets independently of the need for pharmacologic heparin therapy).11314 Associated thrombosis developed in 7 of the 24 patients (29.1%).
Post-cardiac surgery patients have very high frequencies of anti-PF4/heparin antibody formation, with about 15 to 20% of patients having antibodies with platelet-activating properties1215; so, beginning or continuing heparin therapy about 5 days after cardiac surgery may pose an even higher risk of the development of HIT than was observed in the Detroit study.6 Even when routine UFH thromboprophylaxis is not administered after cardiac surgery, there are numerous circumstances (eg, mechanical valve insertion, prolonged perioperative atrial fibrillation, or clinically evident venous or arterial thrombosis) that could trigger the use of heparin, thus increasing the patient’s risk of HIT.
Smythe and colleagues6 deserve congratulations for helping point out who is still getting HIT. The persistently high risk of HIT in the post-cardiac surgery patient draws attention to the need to develop effective thromboprophylaxis and thrombosis treatment strategies that minimize the risk of developing this potentially life-threatening and limb-threatening complication.
Footnotes
Dr. Warkentin has done consultant work for and/or has given lectures on behalf of GlaxoSmithKline, Organon Inc, the Medicines Company, and Berlex Laboratories, all of which manufacture antithrombotic drugs that have been used in the treatment of patients with HIT. Dr. Eikelboom has done consultant work for and/or has given lectures on behalf of GlaxoSmithKline, which is a manufacturer of antithrombotic drugs that have been used in the treatment of patients with HIT.
References
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