Pharmacology of Anticoagulants Used in the Treatment of Venous Thromboembolism

J Thromb Thrombolysis (2016) 41:15–31 DOI 10.1007/s11239-015-1314-3 Pharmacology of anticoagulants used in the treatment of venous thromboembolism 1 2 3 4 Edith A. Nutescu • Allison Burnett • John Fanikos • Sarah Spinler • Ann Wittkowsky5 Published online: 16 January 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Anticoagulant drugs are the foundation of Introduction therapy for patients with VTE. While effective therapeutic agents, anticoagulants can also result in hemorrhage and Anticoagulant drugs are the mainstay of therapy for other side effects. Thus, anticoagulant therapy selection patients with venous thromboembolism (VTE). Specific should be guided by the risks, benefits and pharmacologic treatment decisions are guided by balancing the risks and characteristics of each agent for each patient. Safe use of benefits of various anticoagulants. The treatment of VTE anticoagulants requires not only an in-depth knowledge of can be divided into 3 phases: acute (first 5–10 days), long- their pharmacologic properties but also a comprehensive term (first 3 months), and extended (beyond 3 months) [1]. approach to patient management and education. This paper The acute treatment phase of VTE consists of administer- will summarize the key pharmacologic properties of the ing a rapid-onset parenteral anticoagulant [unfractionated anticoagulant agents used in the treatment of patients with heparin (UFH), low molecular weight heparin (LMWH), VTE. fondaparinux] or direct oral anticoagulant (DOAC; apixaban, rivaroxaban). Long-term and extended phase antico- Keywords Pharmacology Á Mechanism of action Á agulation for VTE is usually accomplished using oral Anticoagulants Á Warfarin Á Heparins Á Direct oral anticoagulant agents such as warfarin, or one of the anticoagulants (DOAC) DOACs (apixaban, dabigatran, edoxaban and rivaroxaban) [1, 2]. The optimal selection and management of anticoagulant drugs for the treatment of VTE requires not only an in-depth knowledge of the efficacy, safety and clinical outcomes data but also of the pharmacology for each agent. & Edith A. Nutescu This paper will summarize the key pharmacologic prop- [email protected] erties of the anticoagulant agents used in the treatment of VTE. 1 Department of Pharmacy Systems Outcomes and Policy and Center for Pharmacoepidemiology & Pharmacoeconomic Unfractionated heparin Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA UFHs are naturally-occurring glycosaminoglycans derived 2 Inpatient Antithrombosis Services, University of New Mexico Hospital, University of New Mexico College of from porcine intestinal or bovine lung mucosal tissues [3– Pharmacy, Albuquerque, NM, USA 6]. Commercial UFH is composed of a heterogeneous 3 Brigham and Women’s Hospital, Massachusetts College of group of highly sulfated polysaccharide chains varying in Pharmacy, Boston, MA, USA molecular weight from 3000 to 30,000 daltons (mean 4 Philadelphia College of Pharmacy and Science, Philadelphia, 15,000 daltons) or approximately 45 saccharide units [3–7]. PA, USA They are considered indirect anticoagulants because their 5 University of Washington School of Pharmacy, Seattle, WA, activity requires the presence of antithrombin (AT), an USA endogenous anticoagulant glycoprotein produced by the 123 16 E. A. Nutescu et al. Fig. 1 Mechanism of action of heparin, low molecular weight heparin, and pentasaccharide (fondaparinux) liver. Approximately one-third of heparin chains contain an protease enzymes including myosin TPase, RNA-depen- active pentasaccharide sequence capable of binding to AT dent DNA polymerase, elastase, and renin [7]. (Fig. 1). This heparin-AT complex inhibits thrombin (fac- After entering the blood stream UFH binds to plasma tor IIa) and factors Xa, IXa, XIa, and XIIa. In order to proteins which contribute to its low bioavailability and inhibit thrombin activity, an UFH chain has to bind to both variable anticoagulant response [3–7]. As UFH is poorly AT and thrombin simultaneously to form a ternary com- absorbed orally, intravenous (IV) infusion or subcutaneous plex (UFH-AT-thrombin complex). In contrast, in order to (SC) injection are the preferred routes of administration inhibit Factor-Xa activity, UFH only needs to form a binary [8]. IV administration (with a bolus dose) rapidly achieves complex by binding to AT. Thus, in order to catalyze therapeutic plasma concentrations and is the preferred thrombin inhibition, UFH chains need to be longer than 18 method of administration when rapid anticoagulation is saccharide units, whereas chains that are shorter than 18 required. When given SC, the bioavailability of UFH ran- saccharide units can still catalyze Factor-Xa inhibition. In ges from 30 to 70 %, depending on the dose given. both cases however, binding to AT occurs at the active Therefore, higher doses ([30,000 units/day) of UFH must pentasaccharide sequence level. UFH exhibits equal inhi- be given if the SC route of administration is used to deliver bitory activity against factor-Xa and thrombin, binding therapeutic doses of the agent. The onset of anticoagulation these in a 1:1 ratio. Once UFH binds and activates AT, it is delayed by 1–2 h if UFH is given by SC injection can readily dissociate and bind to additional AT, providing whereas the onset is immediate (seconds to minutes) if a continuous anticoagulant effect. UFH has no fibrinolytic given IV. The half-life of UFH is dose dependent and activity and therefore does not dissolve an existing ranges from 30 to 90 min but may be significantly longer, thrombus, but does prevent its propagation and growth. up to 150 min, with high doses. UFH blocks thrombin-induced activation of factors V and UFH’s elimination from the systemic circulation is VII, enhances tissue factor pathway inhibitor (TFPI) dose-related and occurs through two independent mecha- release by vascular endothelial cells reducing the proco- nisms [3, 4]. In the initial phase, enzymatic degradation agulant activity of the tissue factor-VIIa complex and at occurs via a rapid, saturable zero-order process. The sec- higher concentrations catalyzes thrombin inhibition ond phase is a slower, non-saturable, renal-mediated first- through heparin cofactor II (HCII) [3, 4, 7]. UFH is also order process. Lower UFH doses are primarily cleared via known to inhibit tumor growth as well as a variety of enzymatic processes, whereas higher doses are primarily 123 Pharmacology of anticoagulants used in the treatment of venous thromboembolism 17 renally eliminated. At therapeutic doses, UFH is cleared thromboembolic disease. Weight-based dosing nomograms primarily in the initial phase with the higher molecular have been associated with significantly higher initial hep- weight chains being cleared more rapidly than lower arin doses, shorter time to therapeutic aPTTs and no weight counterparts. As clearance becomes dependent on increase in bleeding events. Heparin dosing nomograms renal function, increased or prolonged UFH dosing pro- will differ from hospital to hospital due to differences in vides a disproportionate increase in both the intensity and thromboplastin reagents and inter-laboratory standardiza- the duration of the anticoagulant effect. Patients with active tions in aPTT measurements [9, 10]. thrombosis may require higher UFH doses due to a more The major complications of UFH therapy include rapid elimination or variations in the plasma concentrations bleeding (major bleeding, 0 to 5 %; fatal bleeding, 0 to of heparin-binding proteins. 3 %), heparin-induced thrombocytopenia (1–5 %), and Due to interpatient variability in dose response and osteoporosis (2–3 %) [11, 12]. Hypersensitivity reactions, changes in patient response over time, UFH requires alopecia and hyperkalemia have also been reported but are monitoring and dosing adjustments. Since plasma UFH more rare side effects [13, 14]. Hemorrhagic episodes are levels can’t be measured directly, the anticoagulant associated with the intensity and stability of anticoagula- response to IV UFH administration is monitored using the tion, route of administration, and concomitant use of anti- activated partial thromboplastin time (aPTT) [3]. The aPTT platelet or fibrinolytic therapy [11, 12, 15–17]. Patient- is a measure of the time (in seconds) it takes for thrombus specific risk factors are the most important consideration formation (from the activation of factor XII within the when determining the bleeding risk and include age, gen- intrinsic pathway to the last step of fibrin formation in the der, history of previous bleeding, renal function, body common pathway). The aPTT may be influenced by lab- weight, risk of falls or trauma, recent surgery and alcohol oratory reagent sensitivity, monitoring equipment, vari- consumption [13]. ability in plasma proteins and circulating clotting factors. The treatment of severe UFH related bleeding includes Traditionally, the therapeutic aPTT range was defined as reversal of anticoagulant effect with protamine sulfate, 1.5–2.5 times the control aPTT value. However, due to transfusion therapy, and supportive care [18, 19]. Pro- changes in reagents and instrumentation over time, as well tamine sulfate is a cationic protein that binds to UFH, as variations in the reagents and instruments across labo- forming a stable salt and terminating its anticoagulant ratories, each institution should establish their own thera- action. Protamine dosing is dependent on timing of the last peutic range for UFH. The institution-specific

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