Chest

Chest

Volume 135, Issue 6, June 2009, Pages 1651-1664
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Postgraduate Education Corner
Contemporary Reviews in Critical Care Medicine
Heparin-Induced Thrombocytopenia: A Contemporary Clinical Approach to Diagnosis and Management

https://doi.org/10.1378/chest.08-2830Get rights and content

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia. HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Section snippets

Search Strategy

A thorough search of the English-language literature was performed using electronic bibliographic databases such as MEDLINE, EMBASE, and the Cochrane Database. For example, we applied the following terms for the search: “heparin”; “thrombocytopenia”; and “heparin-induced thrombocytopenia.” Additionally, we reviewed the references contained in the identified articles. A hand search for abstracts from international meetings and supplements of some major journals was also performed.

HIT: The Size and Scope of the Problem

Nonimmune heparin-associated thrombocytopenia occurs in 10 to 30% of patients receiving heparin.12 In contrast, HIT is less common, developing in 1 to 3% of all patients exposed to unfractionated heparin (UFH) and in 0 to 0.8% of patients receiving low-molecular-weight heparin (LMWH) who are exposed for ≥ 5 days, particularly in postoperative patients receiving antithrombotic prophylaxis.12, 13

Of note, antibodies against complexes of platelet factor 4 (PF4) with heparins (HIT antibodies) are

Pathogenesis of HIT

Free heparin is not immunogenic, but its conjugates with PF4 are very immunogenic. PF4 is a chemokine, a member of the CXC subfamily, produced by megakaryocytes. PF4 is stored in platelet α granules and released into circulation following weak platelet activation; it binds cell-surface glycosaminoglycans (eg, heparan sulfate on endothelial surfaces) and heparin.31 Plasma PF4 concentrations are normally very low but may be high in specific clinical circumstances, such as prosthetic hip or

Diagnosis and Clinical Presentation

HIT is often difficult to diagnose because of a wide range of background disorders, usually the very indications for heparin treatment, and also as a result of the coadministration of other drugs that can also potentially cause thrombocytopenia.49, 50 The diagnosis of HIT should be based both on clinical criteria (eg, thrombocytopenia and thrombosis) and laboratory data (eg, platelet count dynamics and detection of HIT antibodies).

Thrombocytopenia and Platelet Count Monitoring

Thrombocytopenia or a substantial decrease in the platelet count is a primary manifestation of HIT. In one study51 of 809 patients with clinically diagnosed HIT, the severity of the baseline thrombocytopenia was the best predictor of death, amputation, or thrombotic progression. According to recent guidelines52 published by the American College of Chest Physicians (ACCP), platelet count monitoring is recommended for heparin-treated patients with a high risk (eg, postoperative patients) or

Thrombosis

Thrombotic complications are the main contributors to the severity of HIT.55 The development of thrombosis is unpredictable and can occur throughout the period from the drop of the platelet count to the time of the initial platelet recovery stage, and even after discontinuation of heparin therapy. HIT-associated thrombosis may develop at almost any vascular location, although venous thrombosis, in the form of deep venous thrombosis (often extensive or bilateral), pulmonary embolism, upper limb

Laboratory Diagnosis of HIT

The following two main types of assays are commonly used in the diagnostic testing for HIT: platelet activation tests (eg, the serotonin release assay [SRA]); and antigen assays (eg, enzyme-linked immunosorbent assay [ELISA]). Platelet activation tests are based on the detection of donor platelet activation in the presence of the patient's plasma or serum and heparin. Platelet aggregometry performed with citrated platelet-rich plasma, is commonly used to detect platelet-activating HIT

Management of HIT

When HIT is suspected, heparin administration from all sources should be discontinued. Given that HIT is an immunologic reaction, it may develop following exposure to any dose of heparin. It has been reported75 that even exposure to very low amounts of heparin through heparin-coated catheters or heparin flushes to maintain IV lines may trigger HIT.

The discontinuation of heparin alone is not adequate treatment for HIT patients with or without thrombosis.47 In fact, thromboembolic events

Reexposure to Heparin

The HIT antibodies usually disappear approximately 100 days after the onset of HIT, and brief reexposure to heparin thereafter is unlikely to result in a recurrence of HIT. Nonetheless, it is usually recommended that heparin use be avoided in such patients. If heparin therapy is indicated, absence of the antibody should be documented by a sensitive test, and heparin should be used only for a short period. Recent data have suggested that heparin reexposure might also be effective in patients

Conclusion

HIT is a well-recognized serious adverse drug reaction that is associated with heparin use. Nonheparin anticoagulants that do not cause HIT are gradually replacing heparin in clinical practice. If this trend continues, the incidence of HIT will decrease with time and may ultimately disappear. Until then, HIT still occurs and remains a potentially life-threatening condition that requires prompt diagnosis and treatment management.

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    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

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    Copyright © 2009 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.