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Ann Thorac Surg 2007;83:21-23
© 2007 The Society of Thoracic Surgeons
a Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada
b Department of Medicine, McMaster University, Hamilton, Ontario, Canada
* Address correspondence to Dr Warkentin, Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences (General Site), Room 1-180A, 237 Barton St E, Hamilton, Ontario, L8L 2X2 Canada (Email: twarken{at}mcmaster.ca).
Immune heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies of immunoglobulin G class that recognize multi-molecular complexes of platelet factor 4 (a member of the C-X-C subfamily of chemokines) bound to heparin or certain other polyanions. Clinically, HIT is characterized by thrombocytopenia or thrombosis, or both, that bear a temporal relationship to heparin exposure and resulting immunization. Typically there is a minimum interval of 5 days from the immunizing exposure to heparin, and the subsequent clinical sequela(e) of HIT, whether this is a platelet count fall or thrombosis, or both.
Heparin-induced thrombocytopenia is relatively common in patients receiving postoperative antithrombotic prophylaxis with unfractionated heparin. Indeed, HIT was found in approximately 5% of patients receiving unfractionated heparin thromboprophylaxis in two orthopedic surgery studies [1, 2]. Typically, in HIT the platelet count begins to fall 5 to 10 days after starting heparin (ie, a time when the platelet count is expected to be rising after the initial period of early postoperative thrombocytopenia) [3, 4]. By defining thrombocytopenia as a relative (proportional) fall in platelet count of 50% or more that begins on or after day 5 of heparin therapy, and by testing for the pathogenic heparin-dependent platelet-activating antibodies, it is relatively easy to distinguish HIT from mimicking thrombocytopenic disorders [3, 4]. This is because postoperative complications causing thrombocytopenia are uncommon this long after surgery [3]. However the situation is more complex when evaluating disorders in which there is a high frequency of major and persisting thrombocytopenia. One of these situations is the patient who is critically ill.
Recently two European studies of patients receiving unfractionated heparin for anticoagulation associated with use of a ventricular assist device (VAD) have reported particularly high frequencies of HIT. Schenk and coworkers [5] observed HIT in 12 (10.6%) of 115 VAD patients. Ten (83.3%) of these 12 patients had one or more thrombotic events develop, with all but one being transient or irreversible cerebral ischemic events. In a subsequent larger study by Koster and colleagues [6], as reported in this issue of The Annals of Thoracic Surgery, HIT occurred in 28 (7.8%) of 358 patients, with 4 (14.3%) of these 28 patients having thrombosis develop (ie, all ischemic strokes). This predisposition to cerebral ischemia and infarction in a VAD population that develops HIT is of interest, because the type of thrombosis that occurs in a given HIT patient usually reflects other underlying risk factors. For example, HIT results in a particularly high risk of venous thromboembolism in a postorthopedic surgery patient [3, 4], a high risk of arterial thrombosis in a post-coronary artery bypass surgery population (reflecting associated arteriopathy) [7], and is often complicated by symptomatic upper-limb deep-vein thrombosis in a patient with concurrent or recent use of central venous catheters [8].
However, is the frequency of HIT really 8% to 10% in patients with VAD receiving heparin? If so, this would represent the highest risk patient population for this adverse drug reaction yet described. However, it is not clear that all of these patients with putative HIT really have this diagnosis. Patients requiring VAD often have circulatory shock and other potential causes of thrombocytopenia, potentially leading to a false diagnosis of HIT. The question thus arises: in a VAD patient, when is HIT really HIT?
Systematic serological studies of postoperative orthopedic or cardiac surgical patients [2–4, 9, 10] or intensive care unit patients [11, 12] have shown that only a small subset of patients who form anti-PF4/heparin antibodies actually have clinically-evident HIT develop. In this iceberg model of HIT (Fig 1), certain serological features predict greater risk of HIT, namely immunoglobulin class (immunoglobulin G rather than immunoglobulin A or immunoglobulin M) [9, 10, 13], platelet-activating properties of the antibodies (assessed by platelet activation assay using "washed" platelets, including the serotonin-release assay [SRA] and the heparin-induced platelet activation assay [2, 4, 9, 10]), and the magnitude of a positive test result (higher percent serotonin release in the SRA; shorter lag time in the heparin-induced platelet activation assay; higher units of optical density in the enzyme-immunoassay [EIA]) [9, 10, 14]. Nevertheless, there are some patients who have all of these serological features, including the presence of strong platelet-activating antibodies, but who do not have HIT develop [9, 10], perhaps because these patients have platelets that are relatively nonreactive to HIT antibodies (eg, low Fc receptor numbers [15]; low platelet-associated PF4 levels [16]).
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Given all these considerations, what could explain a high apparent frequency of HIT in patients requiring a VAD? We will consider two contrasting viewpoints, that the excess of HIT cases is spurious, and that it is real.
It is easy to argue that these data represent an overestimate of the true frequency of HIT in VAD patients. The explanation is straightforward: both thrombocytopenia and nonpathologic anti-PF4/polyanion antibody formation are common events in VAD patients, and their coincidence in any given patient may well represent just that, a coincidence. In other words, circulatory shock explains the thrombocytopenia and formation of nonpathologic (nonfunctional) antibodies accounts for the positive antibody test. For example, consider the patient shown in Fig 2A (ie, the early platelet count fall, absence of thrombosis, and the nonplatelet-activating [SRA-negative] anti-PF4/heparin antibodies [detectable by EIA and particle gel immunoassay]) argue strongly against HIT. However, a liberal clinicopathologic definition of HIT may consider such a patient as having HIT (incorrectly, in our view).
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However, a real conundrum is posed by a patient’s clinical course depicted in Figure 2C. Here, thrombocytopenia begins soon after initiating heparin therapy, and coexists with multiorgan system failure due to circulatory shock. The platelet count remains low, without a further fall, after 5 days of heparin therapy (when immunization against PF4/heparin complexes occurs), and the patient does not experience a thrombotic event. What if this patient has a weakly positive SRA (eg, 20% to 50% serotonin release)? In this case we suggest that this clinical scenario most likely does not indicate HIT.
So how did these two VAD studies define HIT? Unfortunately neither study provided sufficient clinical information (particularly the temporal features of platelet count decline in relation to heparin administration) to determine whether the thrombocytopenia began (or was exacerbated) 5 or more days after beginning heparin. Both studies did assess whether there were functional (platelet-activating) antibodies, using the heparin-induced platelet activation test [19, 20]. Indeed, in the study by Schenk and coworkers [5], there was a marked difference in the risk of thrombotic events if the EIA-positive patients also had a positive heparin-induced platelet activation test, calling into question the utility of the EIA test in this setting.
So is there really a higher frequency of clinically-important HIT in patients with VAD? There is no doubt that these patients frequently have both multifactorial thrombocytopenia and anti-PF4/polyanion antibodies. However, based on the lack of specificity of available diagnostic tests, we would argue that most patients with these characteristics do not have HIT; their "HIT antibodies" are not clinically relevant and their thrombocytopenia can be attributed to their underlying disease. Diagnostic specificity of the platelet activation assays is greatest if the threshold for regarding a test as positive is set sufficiently high (eg, >80% serotonin release). A greater appreciation of the complexities of diagnosing HIT in patients with VAD is relevant to other critically-ill patient populations, in which the diagnostic challenge is to distinguish HIT from the common concurrence of thrombocytopenia in a patient with clinically irrelevant anti-PF4/polyanion antibodies.
Perhaps this discussion has become too academic and insufficiently practical. After all, HIT is an important complication in VAD patients (whether its true frequency is 2% or 10%). However, given the frequent consideration of HIT in such patients, considerable health care resources are being consumed in the evaluation of thrombocytopenia, irrespective of what the ultimate diagnosis is in any given patient. The time is ripe to develop and to evaluate appropriate management strategies for this problem.
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  N. Barzaghi, A. Locatelli, and M. Ranucci Ventricular Assist Device Implantation and the Risk for Heparin-Induced Thrombocytopenia Ann. Thorac. Surg., January 1, 2008; 85(1): 360 - 361. [Full Text] [PDF]
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T. E. Warkentin, M. A. Crowther, and A. Koster Reply Ann. Thorac. Surg., January 1, 2008; 85(1): 361 - 361. [Full Text] [PDF]
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A. Koster Reply Ann. Thorac. Surg., October 1, 2007; 84(4): 1423 - 1424. [Full Text] [PDF]
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A. Lappa, P. Picozzi, E. D'Avino, S. Riondino, A. Menichetti, and F. Musumeci HIT in VAD Patients: Considerations Ann. Thorac. Surg., October 1, 2007; 84(4): 1422 - 1423. [Full Text] [PDF]
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