Pharmacy & Therapeutics - November 2008 - (Page 642)

COVER STORY Heparin-Induced Thrombocytopenia Overview and Treatment Daniel A. Zinkovsky, PharmD, and Marilena S. Antonopoulos, PharmD, FASCP INTRODUCTION A variety of drugs and disorders can cause thrombocytopenia in patients. Heparin-induced thrombocytopenia (HIT) is considered the most common form of drug-induced thrombocytopenia as well as one of the common causes of thrombocytopenia in hospitalized patients.1,2 Next to bleeding, HIT is the most significant adverse effect associated with heparin therapy. Two clinical forms of HIT are generally recognized. Type I (heparin-associated thrombocytopenia) occurs in up to 30% of patients receiving heparin. It is a non–immune-mediated reaction often presenting early to exposure (within one to two days) with an asymptomatic, mild-to-moderate transient decline in the platelet count (rarely below 100,000/mcL) with few complications. Resolution is often spontaneous without discontinuation of therapy (Table 1).2 Type II (heparin-induced thrombocytopenia) is the more severe immune-mediated reaction and is the focus of this article. PATHOPHYSIOLOGY AND ETIOLOGY Heparin alone is not the major antigen target for the body’s antibody response. Heparin is a negatively charged sulfated glycosaminoglycan with high binding affinity for platelet factor-4 (PF4). PF4 is a positively charged, heparin-neutralizing protein contained in platelet alpha granules and a member of the CXC subfamily of chemokines. It is expressed on the surface of some endothelial cells and the platelet cell surface following activation. When heparin is administered, it binds to PF4, initiating a conformational change that exposes antigenic epitopes, independent of the heparin-binding domain on PF4. The epitopes are recognized by the immune system and promote the formation of anti-heparin PF4 antibodies (HIT antibodies), most frequently immunoglobulin G (IgG).3 The large, stable heparin–PF4 complex allows the IgG antibodies to cross-link and occupy FcγIIa receptors, found on the cell surface of platelets, thereby activating the platelets and causing further expression of PF4 in a positive feedback loop mechanism (Figure 1).4 Platelet activation also causes the release of prothrombotic microparticles, platelet consumption, and thrombocytopenia. Activated platelet aggregation and their removal from circulation are believed to be responsible for thrombocytopenia and thrombosis.3,5 The multimolecular antibody complex can also contribute to thrombosis in other ways via interaction with monocytes, producing tissue factor and endothelial injury.6,7 More than 12 million patients and almost one-third of all hospitalized patients receive heparin each year.8 HIT antibodies develop in up to 50% of patients following exposure to heparin and can continue to circulate for three months or more in approximately 40% of patients.9,10 A widespread myth is that a positive result for HIT antibodies means that a patient has HIT. Actually, heparin–PF4 antibodies are relatively common following heparin exposure and can be nonpathogenic. 11 Clinical HIT can lead to a severely prothrombotic state, occurring in 1% to 5% of patients receiving heparin and accounting for 600,000 cases of HIT annually. Half of these patients, (approximately 300,000) experience complications associated with thrombosis, and 90,000 die.3 Generally, the frequency of HIT is dependent on four risk factors:12 • duration of heparin use (the risk begins at day 5 and peaks between days 10 and 14) • type of heparin (bovine unfractionated heparin [UFH] > porcine UFH > low-molecular-weight heparin [LMWH]) • type of patient population (surgical > medical > obstetrical) • patient’s sex (females > males) Dr. Antonopoulos is Assistant Professor of Pharmacy Practice at the Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, in Brooklyn, New York; Adjunct Assistant Professor at NYU’s Langone Medical Center in New York, New York; and a Clinical Pharmacy Specialist in Internal Medicine at the New York Harbor Healthcare System, Department of Veterans Affairs in New York. At the time of this writing, Dr. Zinkovsky was a student at the Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University. Disclosure: The authors have no financial or commercial relationships to report in regard to this article. Table 1 Comparison of Heparin-Induced Thrombocytopenia (HIT I and HIT II) Type I Frequency Timing of onset Typical nadir platelet count Antibody mediated Thromboembolic sequelae Hemorrhagic sequelae Management 10% to 20% 1 to 4 days 100,000/mcL No None None Observe Type II 2% to 30% 5 to 10 days 30,000–55,000/mcL Yes 30%–80% Rarely Cessation of heparin, alternative anticoagulation, additional therapy Accepted for publication August 23, 2008. From Brieger DB, Mak KH, Kohke-Marchant K, et al. J Am Coll Cardiol 1998; 31:1449. Reproduced with permission of Elsevier.19 642 P&T® • November 2008 • Vol. 33 No. 11

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Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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