Think of HIT When Thrombosis Follows Heparin

corticosteroids and the risk of acute myocardial infarction in COPD. Eur Respir J 2005; 25:634 – 639 17 Lo¨fdahl CG, Postma D, Pride N, et al. Does inhaled budesonide protect against cardio-ischemic events in mild-moderate COPD: a post-hoc evaluation of the EUROSCOP study [abstract]. Eur Respir J Suppl 2005; 26:2333

Think of HIT When Thrombosis Follows Heparin vein thrombosis (DVT) and pulmonary D eep embolism (PE) are the most common thrombotic complications of heparin-induced thrombocytopenia (HIT).1 Appropriately, review articles discussing HIT diagnosis and management typically indicate that the possibility of HIT should be considered when a manifestation of venous thromboembolism (VTE) either during or soon after antithrombotic therapy or prophylaxis with heparin develops in a patient.2,3 However, the converse is not necessarily true. Reviews of VTE management sometimes do not mention that a diagnosis of HIT should be considered during a diagnostic evaluation of VTE.4,5 In part, this “disconnect” arises because there is little information quantifying the risk of HIT in a patient in whom VTE develops during or soon after receiving unfractionated heparin (UFH) or low-molecularweight heparin (LMWH). In this issue of CHEST, Levine and colleagues (see page 681)6 report a metaanalysis addressing this issue. They have analyzed those studies in which the frequency of HIT during VTE therapy or prophylaxis was evaluated, and in which information on the frequency of VTE occurrence or recurrence, and whether HIT-associated or not, was available. They found that HIT was present in about 1 in 8 patients (12.8%) in whom VTE developed following UFH therapy or prophylaxis, but in ⬍ 1 in 100 patients (0.7%) who received LMWH. This striking difference in the risk of HIT-associated VTE between the two heparin types (odds ratio, 21.0; p ⬍ 0.001) is consistent with the increased frequency of HIT with UFH therapy compared with LMWH therapy.7 The key message is that HIT is a relatively common concomitant when VTE complicates UFH treatment. Given that HIT-associated VTE can pose serious sequelae (eg, venous limb gangrene) and requires therapy with anticoagulant agents other than UFH and LMWH, this is clinically important. Could Levine and colleagues have underestimated the risk of HIT when VTE follows heparin therapy? This could be the case if the studies they analyzed used routine screening for VTE, thus identifying www.chestjournal.org

both symptomatic and asymptomatic thrombi, and if HIT had occurred disproportionately more often among patients with symptomatic thrombosis. There is evidence to support this possibility. For example, one study8 considered by Levine and colleagues6 reported both distal DVT and proximal DVT (pDVT). These events were identified by a routine end-of-study contrast venogram, which detected symptomatic thrombi as well as asymptomatic thrombi. If an analysis is performed that considers only pDVT, venous limb ischemia, and/or PE (thrombotic events likely to have been symptomatic), then the analysis might show an even greater frequency of HIT-associated VTE. In fact, this is the case. In the study in question,8 of the 332 patients who received UFH, pDVT, venous limb ischemia, and/or PE developed in 20 patients (6.0%; pDVT alone, 17 patients; distal DVT plus PE, 1 patient; PE without venographic DVT, 2 patients). Notably, 9 of these 20 patients (45.0%) had HIT. In contrast, of the 333 patients who received LMWH, pDVT, venous limb ischemia, and/or PE developed in 17 patients (5.1%; pDVT alone, 15 patients; venous limb ischemia, 1 patient; PE without DVT, 1 patient).8,9 Only 1 of these 17 patients (5.9%) had HIT. Thus, the risks of VTE being associated with HIT after UFH and LMWH therapy based on this surrogate marker for symptomatic VTE (45.0% and 5.9%, respectively) were greater than the corresponding values reported by Levine and colleagues (17.5% and 0.6%, respectively).6 The implication is that the probability of HIT suggested by Levine and colleagues6 among heparin-treated patients might have been even higher had the data been available to them indicating the frequency of symptomatic VTE. After all, only symptomatic thrombi are detected in the “real world” in which routine imaging studies for VTE are rarely employed. Similar to the main findings of Levine and colleagues,6 symptomatic VTE complicating heparin thromboprophylaxis was more likely to represent HIT when it occurred in association with UFH prophylaxis rather than LMWH prophylaxis (odds ratio, 13.1; 95% confidence interval, 1.37 to 608.7; p ⫽ 0.0102). Symptoms or signs of VTE develop in many patients with HIT shortly before, or coincident with, the initial phase of the platelet count decline representing the presence of HIT.1,10 In these cases, it may not be realistic to diagnose HIT until after the platelet count fall has been well-established, which may not occur until after a therapeutic dose of UFH or LMWH has been administered to treat the symptomatic thrombosis that only later is determined to represent HIT. Is there any way to avoid this situation? One possibility is to use fondaparinux, CHEST / 130 / 3 / SEPTEMBER, 2006

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which is an indirect factor Xa inhibitor that is modeled after the antithrombin-binding pentasaccharide region of heparin. This anticoagulant, which has been approved for the treatment of DVT and PE in the United States and elsewhere, does not crossreact with HIT antibodies in vitro11 or in vivo,12 and thus is an ideal agent for managing VTE in the context of recent therapy with UFH, and where the possibility of HIT cannot be readily excluded, especially when platelet count declines are absent or are minor. However, fondaparinux is not an approved anticoagulant agent for the treatment of HIT (or HIT-associated thrombosis). Thus, when the presence of thrombocytopenia strongly suggests the diagnosis of HIT, other alternative nonheparin anticoagulants (eg, danaparoid [outside the United States], lepirudin, or argatroban) for which there is greater experience in treating HIT may be preferred. Levine and colleagues6 deserve congratulations for quantifying the risk of HIT when VTE occurrence (or recurrence) complicates therapy or prophylaxis with heparin. Indeed, think of HIT when thrombosis follows heparin therapy. Theodore E. Warkentin, MD Hamilton, ON, Canada Dr. Warkentin is Professor, Department of Pathology and Molecular Medicine, and Department of Medicine, McMaster University. He is also Associate Head of Transfusion Medicine, Hamilton Regional Laboratory Medicine Program, and Hematologist, Hamilton Health Sciences (Hamilton General Site). 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. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). 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, L8L 2X2, Canada; e-mail: [email protected] DOI: 10.1378/chest.130.3.631

References 1 Warkentin TE, Kelton JG. A 14-year study of heparininduced thrombocytopenia. Am J Med 1996; 101:502–507 2 Rice L. Heparin-induced thrombocytopenia: myths and misconceptions (that will cause trouble for you and your patient). Arch Intern Med 2004; 164:1961–1964 3 Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121:535–555 4 Motsch J, Walther A, Bock M, et al. Update in the prevention and treatment of deep vein thrombosis and pulmonary embolism. Curr Opin Anaesthesiol 2006; 19:52–58 5 Merli G. Diagnostic assessment of deep vein thrombosis and pulmonary embolism. Am J Med 2005; 118(suppl):3S–12S 6 Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest 2006; 130:681– 687 632

7 Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated heparin and low-molecularweight heparin thromboprophylaxis: a meta-analysis. Blood 2005; 106:2710 –2715 8 Warkentin TE, Roberts RS, Hirsh J, et al. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med 2003; 163:2518 –2524 9 Warkentin TE, Roberts RS, Hirsh J, et al. Heparin-induced skin lesions and other unusual sequelae of the heparininduced thrombocytopenia syndrome: a nested cohort study. Chest 2005; 127:1857–1861 10 Greinacher A, Farner B, Kroll H, et al. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis: a retrospective analysis of 408 patients. Thromb Haemost 2005; 94:132–135 11 Warkentin TE, Cook RJ, Marder VJ, et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106:3791–3796 12 Kuo KH, Kovacs MJ. Fondaparinux: a potential new therapy for HIT. Hematology 2005; 10:271–275

Can You Get More Than You Paid For With Lung Cancer Screening? insky et al suggest in their article appearing in P this issue of CHEST (see page 688) that chest 1

radiographs (CXRs) performed as a screening test for lung cancer may also provide important prognostic information about premature death from respiratory and cardiovascular disease. These investigators took advantage of the huge database obtained as part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (⬎ 70,000 subjects had CXRs performed annually for 3 years in this trial) to calculate the hazard ratios for all-cause mortality, respiratory mortality, and cardiovascular mortality based on CXR interpretations of abnormalities that were not suspicious for cancer. Approximately 35% of all CXRs were found to have findings that were abnormal but not suspicious for cancer, with granulomas, scarring/pulmonary fibrosis, and cardiac abnormalities being frequently described. Significantly increased hazard ratios for cardiovascular mortality were found for cardiac abnormalities and pleural fluid; COPD/emphysema and scarring/pulmonary fibrosis were associated with significant increases in respiratory mortality. The results are intriguing, but the reader should be cautious about using CXRs, or extrapolating these results to CT scans, for more ambitious screening for three reasons. First, the implicit rationale behind this analysis is that radiographic screening for lung cancer will prove effective. Although this has not been shown Editorials