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NewsletterLiterature Review Heparin-induced thrombocytopenia Lubenow N, Kempf R, Eichner A, et al. Chest
2002; 122:37-42
Background: Heparin-induced thrombocytopenia (HIT) is a significant complication associated with the use of unfractionated heparin (UFH) and may be defined as a decrease in platelet count during or shortly after exposure to heparin. Two types of HIT are recognized (1). Type I HIT, also called "non-immune heparin-associated thrombocytopenia", is due to a direct interaction between heparin and platelets. In about 10% of the patients started on heparin therapy, the platelet count decreases within the first 2 days, but usually stays above 100,000/mm3and returns to normal over the next few days. Type I HIT is not associated with thromboembolic complications and usually requires no specific treatment. On the other hand, type II HIT is defined by a decrease in platelet count, usually < 100,000/mm3, in association with an antiheparin antibody. When specific IgG or IgM antibodies bind to a complex of platelet factor 4 and heparin on platelet and endothelial surfaces, platelets are activated and aggregate to form "white clots", and lead to thrombin activation. Thromboembolic complications may ensue. Antiheparin antibodies may develop in up to 8% of the patients on heparin, whereas 1-5% of the patients on heparin will develop clinically significant type II HIT. When platelet count decreases after heparin therapy is initiated, distinguishing between the two types of HIT has therapeutic implications. However, laboratory confirmation of the antiheparin antibody often takes days, making the distinction a challenging task. In this study, the authors examined the temporal pattern of thrombocytopenia in patients with laboratory-confirmed type II HIT. Methods: The authors retrospectively examined the registry of patients who had been enrolled in a multicenter study of lepirudin (2) and had laboratory confirmation of a platelet count < 100,000/mm3 and an antiheparin antibody. Although a 50% decrease in platelet count during heparin treatment may be more predictive of the presence of type II HIT than an absolute count < 100,000/mm3, platelet count preceding the drop were often not available for the patients of this study and an absolute count < 100,000/mm3 was used as the cutoff value instead. The authors examined the timing of the onset of HIT as a function of (1) whether the patient had had a prior exposure to heparin, (2) the time interval between the previous exposure and the current treatment with heparin, and (3) the route of heparin administration (intravenous (IV) vs. subcutaneous (SC)). Results: One hundred nineteen patients with 125 treatment episodes were assessed. Thrombocytopenia < 100,000/ml occurred on day 10.8 ± 5.1 (mean ± SD). The platelet count decrease showed a biphasic distribution, with the patients who were heparin-naive or had not been exposed to heparin within the previous 3 months developing thrombocytopenia < 100,000/mm3 on day 11.9 ± 4.6 and 11.5 ± 5.5, respectively, and the patients who had been exposed to heparin within the previous 3 months developing thrombocytopenia on day 4.9 ± 4.4. The likelihood of developing thrombocytopenia < 100,000/mm3 by day 5 was 12 % for heparin naive patients, ~ 25 % for patients with heparin exposure > 3 months ago, and > 80% for those with heparin exposure within the previous 3 months. The route of heparin administration had no significant effect on the timing of onset of thrombocytopenia. The mean nadir platelet count was about 30,000/mm3. Discussion/Comments: Curiously, the immune response that leads to type II HIT is not anamnestic. Antiheparin antibodies are transient: the platelet factor 4 heparin enzyme-linked immunosorbent assay remains positive for about 3 months, whereas the platelet serotonin release assay is positive for an average of 50 days (3). Reflecting this lack of anamnestic response, the authors found that the onset of thrombocytopenia < 100,000/mm3 was earlier in those patients who had been exposed to heparin within the previous 3 months, compared to those who had been exposed more than 3 months previously or were heparin-naive. The current study is consistent with an earlier study (3) that demonstrated a rapid onset of thrombocytopenia in patients treated with heparin within the previous 100 days. Even patients who have a laboratory-confirmed diagnosis of HIT do not necessarily develop a new episode of HIT, if reexposure occurs after the disappearance of heparin-dependent antibodies (3). Applying the results of this study, thrombocytopenia due to type II HIT is not likely in the first 5 days of heparin treatment in heparin-naive patients or patients who have not been exposed to heparin in the previous 3 months. Daily platelet count may be of little yield in these patients before day 5 of heparin. However, deciding whether a patient is indeed heparin-naive is not simple. Heparin exposure may occur from hemodialysis, IV catheter flushes, and even heparin-coated central venous catheters (4). It should also be noted that even in heparin-naive patients of this study, one out of 8 HIT diagnoses occurred before day 5. This study does not obviate the need for platelet count monitoring even in the first few days of heparin therapy. If type II HIT is diagnosed, heparin needs to be discontinued immediately. But therapy of HIT is more than just stopping heparin. An alternative anticoagulant should be administered not only for the original indication of anticoagulation, but also because of the high risk of thromboembolism due to antiheparin antibodies. Danaparoid (a mixture of sulfated heparinoids) that inhibits the factor Xa (5), or the direct thrombin inhibitors lepirudin (2) or argatroban (6) may be used to anticoagulate patients with HIT. Low molecular weight heparin crossreacts with antiheparin antibodies in about 90 % of the cases and is not recommended in HIT. Likewise, warfarin is not recommended during the acute phase of HIT, because warfarin may mediate protein C depletion and thus worsen ongoing thrombosis problem. Although the antiheparin antibody response is transient and not anamnestic, all patients with a laboratory confirmed diagnosis of type II HIT should have heparin listed as an allergy and should not be treated with heparin, at least not until the antibodies disappear and, even then, only for compelling indications and as briefly as possible.
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