Heparin-induced Thrombocytopenia: A Guide for Pharmacists

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy and is characterized by two types.¹ HIT I is a benign, mild thrombocytopenia, which usually occurs within 2 days after heparin administration. Because the platelet count normalizes even with continued heparin therapy, it is not associated with increased thrombotic risk. HIT II is characterized by antibody mediated, a potentially fatal disorder which requires alternative type of anticoagulation other than heparin.

Pathophysiology

Prothrombotic clinical manifestations occur due to antibody formation to platelet factor 4 (PF4) and heparin. The reaction is mainly IgG and IgM mediated.² The antibody binding with heparin-PF4 complex forms Circulating Immune Complex (CIC). The CIC activates platelets by binding to Fc receptor.³ This process promotes hypercoagulability state.

Clinical presentation and diagnosis

HIT is suspected when a patient receiving heparin has a decreased platelet count, especially more than 50% from the baseline count.⁴ Symptoms often involve skin lesions at the injection site, fever, and chill after heparin administration. HIT complications include deep vein thrombosis (DVT), pulmonary embolism (PE), and thrombotic stroke.⁵ Among HIT patients, around 10% experience amputation.⁶ If HIT is suspected, the 4T scoring system on CHEST guideline is utilized to estimate the probability that a patient has HIT (6-8: high probability, 4-5: intermediate probability, ≤3 low probability). ⁷ This tool is especially useful because it is common to experience delay in lab results, and clinical management needs to be made immediately. Rate of thrombosis increases about 5% daily, prior to treatment.⁸

Commonly used lab assays are antigen assays, and functional assays.⁷ The most commonly used antigen assay is the enzyme-linked immunosorbent assays (ELISA), which test for PF4/heparin or PF4/polyvinyl sulfonate reactive antibodies. They provide robust sensitivity, however with moderate specificity. A functional assay, such as Serotonin Release Assay (SRA), and Heparin Induced Platelet Activation (HIPA), provides excellent sensitivity and specificity. As a result SRA and HIPA are widely accepted as reference assays.

Unfractionated Heparin (UFH) vs Low Molecular Weight Heparin (LMWH)

A meta-analysis of randomized controlled trials (RCT) have shown that incidence of HIT between UFH and LMWH on treatment for DVT, and PE does not significantly differ.⁹ However, a different meta-analysis of RCTs on post-orthopedic surgery concluded that the risk of HIT with LMWH is significantly lower than with UFH.¹⁰

Treatment

Heparin needs to be discontinued, and an alternative anticoagulation therapy needs to be initiated once HIT is diagnosed. The CHEST guideline recommends use of either argatroban, danaparoid, lepirudin, bivalirudin, or fondaparinux. Argatroban, lepirudin, and bivalirudin are dosed based on aPTT level while danaparoid, and fondaparinux are dosed based on anti-Xa level. For argatroban, target aPTT (reference range: 30-40 seconds¹¹) would be 1.5-3.0 times patient baseline. aPTT level is recommended to be monitored every four hours during dose titration. It is initiated at 2mcg/kg/min continuous IV infusion and adjusted to achieve initial baseline value. Maximum dose is 100mcg/kg/min¹²

Danaparoid is not available in the US market. Bivalirudin is only approved for patients undergoing percutaneous coronary intervention. Fondaparinux does not have FDA indication for HIT, but may be considered.

References

• Salter B, Weiner M, Trinh M. Heparin-Induced Thrombocytopenia: A Comprehensive Clinical Review. Journal of the American College of Cardiology.:2519-2532
• Suh J, Aster RH, Visentin GP. Antibodies From Patients with Heparin-Induced Thrombocytopenia/Thrombosis Recognize Different Epitopes on Heparin: Platelet Factor 4. Blood Journal, American Society of Hematology. 1991;91:916-922.
• Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83:575-582.
• Warkentin T, Roberts R, Hirsh J, Kelton J. An Improved Definition of Immune Heparin-Induced. Arch Intern Med. 2003;163:2518-2524. www.bing.com/cr?IG=C00E33AEB9644763A051175E8A23740B&CID=3016A82CA77B63DC04D4A34CA6D46251&rd=1&h=KAtynVdVZ-zxBI8Qrwz7eeSw_wQT4iN9x3D13w2p-Tg&v=1&r=https%3a%2f%2farchinte.jamanetwork.com%2fjournals%2fINTEMED%2farticlepdf%2f216311%2fioi21062.pdf&p=DevEx,5067.1. Accessed April 13, 2018.
• Boskhov LK, Warkentin TE, Hayward CPM, et al. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. Br J Haematol. 1993;84:322-328.
• Jang I-K, Hursting MJ. Thrombocytopenia when heparins promote thrombosis: review of heparin-induced. Circulation. 2005;111;2671-2683.
• Antithrombotic Therapy and Prevention of Thrombosis 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
• Lubenow N , Eichler P , Lietz T , Greinacher A ; Hit Investigators Group. Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT- . J Thromb Haemost. 2005 ; 3 ( 11 ): 2428 - 2436 .
• Warkentin TE, Greinacher A. So, does low-molecular-weight heparin cause less heparin-induced thrombocytopenia than unfractionated heparin or not? Chest. 2007;132:1108-1110.
• Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106:2710-2715
• Paganda KD, Paganda TJ, et al. 2010 Mosby’s manual of diagnostic and laboratory tests. 4^th ed.
• Product Information: argatroban IV injection, argatroban IV injection. Encysive Pharmaceuticals Inc, Houston, TX, 2008.