Improving the laboratory diagnosis of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is an increasingly recognized complication of therapy with unfractionated or low molecular weight heparin. Certain patients who receive heparin, especially those undergoing cardiac or orthopedic surgical procedures, produce antibodies to the heparin–platelet factor 4 (heparin/PF4) complex (1). Immune complexes consisting of immunoglobulin (Ig) G– heparin/PF4 bind to platelet Fc receptors, resulting in intense platelet activation, formation of platelet microparticles, thrombocytopenia, and a profound hypercoagulable state (2). The diagnosis of heparin-induced thrombocytopenia is based on clinical criteria combined with a positive laboratory test that detects heparin-dependent antibodies. The clinical criteria include exposure to unfractionated or low molecular weight heparin; thrombocytopenia or a 50% decrease in the baseline platelet count; exclusion of other causes of thrombocytopenia (e.g., other medications, infection, disseminated intravascular coagulation); the presence or absence of thrombosis; atypical features in a minority of cases (e.g., skin lesions, systemic reactions to heparin); and recovery of thrombocytopenia after cessation of heparin exposure (1). Assessment of clinical criteria is usually straightforward, and a quantitative method of assessing clinical variables has been presented (3). The difficulty in diagnosing heparin-induced thrombocytopenia lies in the laboratory test. A diverse range of assays is available to measure either functional or antigenic properties of the heparin/PF4 complex, the immunologic target of pathologic antibodies in heparin-induced thrombocytopenia; however, each assay has advantages and disadvantages (4). For example, functional assays measure platelet activation (e.g., C-serotonin release) or aggregation, a relevant endpoint, but they are tedious to perform and have lengthy turnaround times, and are offered by few laboratories. The more widely available antigenic assays, which detect antibodies to the heparin/PF4 complex, can be performed rapidly, but may also detect clinically unimportant antibodies (4). Thus, one approach to the laboratory diagnosis of heparin-induced thrombocytopenia favors the use of an antigenic assay as an initial test, with a functional assay performed in patients with low pretest probability and a positive antigenic assay, or in those with weakly positive antigenic assay results (4). In this issue of the Journal, Alberio and colleagues describe a clinically useful advance in the diagnosis of heparin-induced thrombocytopenia (5). They combined the clinical criteria of Greinacher et al. (3) with a quantitative immunoassay for the heparin/PF4 complex, a concept that has been applied successfully to the exclusion diagnosis of pulmonary embolism (clinical pretest criteria combined with a quantitative D-dimer test) (6). The assay used by Alberio et al. was originally described by Meyer et al. (7)—a particle gel immunoassay that yields results within 20 minutes. Alberio et al., however, modified this assay by reporting results quantitatively (dilution titer), which allows patients who have a weakly positive result to be distinguished from those with a strongly positive result. Their data analysis identified a dilution titer 4 as being useful in discriminating between patients with clinically important disease (those with positive functional assay results, thrombosis, or both) and patients with heparin-induced thrombocytopenia of lesser clinical importance. The concept of quantitating an assay for heparin-induced thrombocytopenia has also been studied by Refaai et al. (8) who evaluated the utility of reporting titers of a widely used enzyme-linked immunosorbent assay (ELISA) for heparin/PF4. However, this study focused on evaluating the predictive value of a negative test result. It is conceivable that a similar quantitative strategy could be employed with the ELISA method as was employed by Alberio et al. Why is the study by Alberio et al. important? Current treatment recommendations include discontinuing all forms of heparin exposure and instituting alternative anticoagulant therapy with argatroban or lepirudin, even in patients without obvious thrombosis (9). This strategy is recommended because if discontinuation of heparin is the only treatment used for patients with heparin-induced thrombocytopenia, the risk of thrombosis over time is greater than 50% (10,11). Thus, physicians must make a clinical decision about whether to initiate expensive alternative anticoagulant therapy without rapid confirmation of the diagnosis with a reliable test. The availability of a reliable test for heparin-induced thrombocytopenia would allow confident exclusion of the diagnosis in many patients, avoiding the need for alternative therapy. Am J Med. 2003;114:609 – 610. From the Division of Hematology, University of Utah Health Sciences Center, Salt Lake City, Utah. Requests for reprints should be addressed to George M. Rodgers, MD, PhD, Division of Hematology, University of Utah Health Sciences Center, 50 North Medical Center Drive, Room 4C416, Salt Lake City, Utah 84132, or george.rodgers@hsc.utah.edu.