Anticlotting Mechanisms 2: Pharmacology and Clinical Implications
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Anticlotting mechanisms 2: pharmacology and clinical implications 1A02 J Adanma Ezihe-Ejiofor FRCA, FWACS, MBBS Nevil Hutchinson FRCA Key points Anticlotting mechanisms can be pathologically mixture of sulphated glycosaminoglycan (muco- up-regulated leading to excessive bleeding or polysaccharide) molecules with molecular Drugs that exert their effect via anticlotting mechanisms either down-regulated resulting in thrombotic events. weights ranging from 3 to 50 kDa. It has the act on the anticoagulant system Clinicians may then need to intervene with highest negative charge density of any known Downloaded from or act on the fibrinolytic system. pharmacological agents that either enhance or biological molecule. Agents that augment attenuate a particular response. The molecules in UFH contain between 10 antithrombin activity are a Anaesthetists will increasingly encounter and 100 saccharide units. The AT binding site major group of anticoagulants. They comprise heparins and patients already on such drugs or may have to is a unique pentasaccharide sequence. Only non-heparin anticoagulants give drugs intraoperatively to either prevent ex- about 30% of the molecules in UFH have this http://ceaccp.oxfordjournals.org/ (pentasaccharide anticoagulants cessive bleeding or clotting. AT binding site, and this fraction is responsible and danaparoid). This review focuses on how drugs can exert for most of its anticoagulant activity. The reduced protein and cell their effect by acting on anticlotting mechanisms. binding of low-molecular-weight heparin (LMWH) compared These drugs can be broadly classified into with unfractionated heparin those that act on the anticoagulant system and Actions accounts for most of its clinical those acting on the fibrinolytic system. advantages. The level of circulating endogenous heparin is low, so heparin does not play a significant role Coagulation monitoring is not The anticoagulant system routinely required in patients on in anticlotting mechanisms in vivo. by Philip Anderson on April 23, 2014 LMWH and non-heparin Drugs that act on the antithrombin– The main anticoagulant value of heparin is anticoagulants. glycosaminoglycan pathway derived when it is administered as an exogen- Drugs acting on the fibrinolytic ous therapeutic agent. system comprise Antithrombin (AT) is the main physiological antifibrinolytics given to treat or anticoagulant enzyme. It predominantly inhibits † Exogenous heparin will augment the activ- prevent excessive haemorrhage ity of AT by a factor of at least 1000-fold. and thrombolytics thrombin (FIIa) but also limits the activity of (streptokinase and recombinant FXa and to a lesser extent FIXa. The role of The coagulation enzymes most effectively tissue plasminogen activators). AT as an effective anticoagulant depends on its inhibited by the heparin–AT complex are interaction with glycosaminoglycan substances thrombin (FIIa) and FXa. that act as cofactors and augment its activity. For thrombin inactivation, both heparin and AT This knowledge has been usefully applied in J Adanma Ezihe-Ejiofor FRCA, FWACS, must bind directly to each other as well as to the manufacture of a group of anticoagulants MBBS thrombin, thereby forming a complex in which ST6 Anaesthetics that act by augmenting AT activity. all three components are linked. Brighton and Sussex University Hospitals Drugs that augment AT activity can be NHS Trust divided into: Brighton UK † heparin anticoagulants. This includes Nevil Hutchinson FRCA unfractionated heparin (UFH) and low- Consultant Anaesthetist molecular-weight heparins (LMWHs). Brighton and Sussex University Hospitals † Non-heparin anticoagulants. This group is NHS Trust continuously evolving but presently it com- In contrast, for FXa inactivation, heparin Brighton UK prises the pentasaccharide anticoagulants needs to bind only to AT. Department of Anaesthetics and danaparoid. Royal Sussex County Hospital Brighton BN2 5BE UK Heparin Tel: þ44 (0)12 73696955 UFH is a naturally occurring anticoagulant that Fax: þ44 (0)12 73609060 is produced and stored in the granules of mast E-mail: [email protected] (for correspondence) cells and basophils. UFH is a heterogeneous doi:10.1093/bjaceaccp/mks062 Advance Access publication 11 January, 2013 93 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 13 Number 3 2013 & The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected] Anticlotting mechanisms † Heparin can also catalyse thrombin inhibition by augmenting duration and dose of UFH. There is a greater risk with high the activity of heparin cofactor II. This however requires doses and if treatment exceeds 3 months. much higher heparin doses than those needed to augment AT † Heparin interacts with the glycocalyx coating of the endothe- activity. This mechanism may play a significant role in lium. It can have a protective effect in ischaemia–reperfusion patients with AT deficiency that can manifest clinically as but possibly a detrimental effect on normal endothelium.2 heparin resistance. Owing to its short half-life, the anticoagulant effect of UFH can † Heparin stimulates the release of tissue factor pathway usually be reversed by stopping the drug. When given by infusion, inhibitor (TFPI). TFPI is the main inhibitor of the tissue the convention still remains to stop the infusion 4–6 h before factor pathway of coagulation (formerly the extrinsic surgery. If more rapid reversal is required, then protamine can be pathway). given at a dose of 1 mg (100 IU of heparin)21. † A recent report suggests that heparin may also augment the The elimination of UFH is through macrophages and endothe- activity of protein Z-dependent protease inhibitor (ZPI).1 ZPI lial cell receptors with very little renal clearance. It is therefore is a circulating plasma enzyme that inhibits FXa. The cofactor considered safer than LMWH in patients with severe renal Downloaded from for ZPI in vivo is a glycoprotein called protein Z. impairment. † Heparin binds to von Willebrand factor (vWF), thereby inhi- biting vWF-mediated platelet adhesiveness. Low-molecular-weight heparin † It inhibits thrombin-mediated platelet aggregation and LMWH is produced by subjecting UFH to cleavage procedures activation. yielding smaller molecules that contain between 10 and 20 sac- http://ceaccp.oxfordjournals.org/ When administered by the i.v. route the onset of action of UFH is charide units and have an average molecular weight of 4–5 kDa immediate with a plasma half-life of about 1 h (0.5–2 h). There is (range 1–10 kDa). a delayed onset of about 1 h when UFH is given by the subcutane- Heparin molecules with fewer than 18 saccharide units cannot ous route. The bioavailability of UFH by the subcutaneous route is bind simultaneously to AT and thrombin. For this reason, most var- poor especially when low doses are used. This poor bioavailability iants of LMWH have a much reduced ability to catalyse the inacti- is further compounded by the tendency of UFH to bind to varied vation of thrombin. plasma proteins, macrophages, and endothelial cells. This non- UFH is considered to have an anti-FXa:anti-FIIa ratio of 1:1. specific binding also affects the clearance of UFH. As a result of In contrast, LMWHs have anti-FXa:anti-FIIa ratios ranging from its unpredictable pharmacokinetics, there is wide variation in 2:1 to 4:1 depending on their molecular size distribution.3 by Philip Anderson on April 23, 2014 patient response to a given dose of UFH that necessitates thera- peutic monitoring. Actions The activated partial thromboplastin time (APTT) is used to † LMWHs exert their main effect by augmenting AT-mediated monitor UFH activity and monitors the inhibitory effects of inactivation of FXa and so act as indirect FXa inhibitors. heparin on thrombin, FXa and FIXa. † LMWHs also stimulate the release of TFPI from the vascula- ture. This is thought to contribute to the extended antithrom- botic action of LMWH. So, despite a half-life of 4–6 h a Adverse effects once daily dose of LMWH is adequate for † Rapid administration of large doses can cause temporary che- thromboprophylaxis. lation of free calcium ions that is reflected by a short-lived dip in blood pressure. The smaller molecules in LMWH lack the tendency of UFH to † An immediate mild thrombocytopenia that is non-immune bind to various proteins and cells. The resulting improved bioavail- and thought to result from enhanced platelet aggregation. ability accounts for most of the clinical advantages of LMWH † IgG-mediated heparin-induced thrombocytopenia (HIT) when compared with UFH (Table 1). which usually occurs 5–15 days after initiating therapy. The bioavailability of LMWH after subcutaneous injection Heparin molecules with more than 11 saccharide units can approaches 100% even with low doses. bind to the positively charged platelet factor 4 (PF-4), which Coagulation monitoring is not usually required. However, in is released from platelet a-granules. This causes a conform- special patient groups such as severe obesity .120 kg (BMI . ational change and creates antigen sites on PF-4 to which IgG 50), pregnancy, or severe renal impairment, it is considered binds. The bound IgG then activates platelets via their FcgIIa prudent to monitor the effect of LMWH therapy.3 receptors causing venous, arterial thrombosis or both. The most widely available test for monitoring LMWH is † Hyperkalaemia as a result of heparin-induced aldosterone anti-FXa