The heparins: all a nephrologist should know

Nephrol Dial Transplant (2005) 20: 2036–2042 doi:10.1093/ndt/gfi004 Advance Access publication 19 July 2005 Editorial Review The heparins: all a nephrologist should know Gerd R. Hetzel1 and Christoph Sucker2 1 Department of Nephrology and 2Department of Hemostasis and Transfusion Medicine, Heinrich Heine University Medical Center, Duesseldorf, Germany Introduction For decades, the use of unfractionated heparin (UFH) has been the basic principle of anticoagulation in patients at risk of or with established thromboembolic disorders. Nowadays, low molecular weight heparins (LMWHs) are increasingly used in this setting, because they are as effective but more convenient than UFH. The advantages of LMWHs include a longer elimination half-life, a lower incidence of heparin-induced thrombocytopenia type II (HIT-II), a lower risk of osteopenia and a more predictable anticoagulant effect that reduces the need for routine laboratory monitoring. Major clinical trials have demonstrated superior therapeutic efficacy in patients with acute coronary syndrome or venous thromboembolism compared with UFH [1–3]. However, most trials excluded subjects at risk for unpredictable pharmacokinetics such as the severely obese, the very elderly and patients suffering from chronic kidney disease stage IV and V. In renal failure, the elimination half-life of all LMWHs is significantly prolonged. Thus, severe and even fatal bleeding complications have been reported after unadjusted dosing [4–8]. Although the use of these agents is not strictly contraindicated in patients with advanced renal failure, there are currently no data indicating superior efficacy and safety compared with UFH. It is therefore essential to know the relevant data concerning the pharmacology and pharmacokinetics of different heparins in order to render an individual decision in patients at risk of bleeding. In the following, we summarize the main information for the nephrologist to know. Chemical structure and mechanism of action UFH is a mixture of polyanionic branched glycosaminoglycans with a wide range of mol. wts between 6000 Correspondence and offprint requests to: PD Dr med. Gerd Rüdiger Hetzel, Department of Nephrology, University Medical Center, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Email: and 30 000 Da (mean mol. wt 15 000 Da,
45 monosaccharide chains). It is isolated from porcine intestinal mucosa or bovine lung. In humans, heparin is found in mast cells and basophilic granulocytes. Additionally, heparin-like anticoagulants are expressed on the surface of endothelial cells and modulate the haemostatic process by interacting with components of haemostasis such as antithrombin (AT) and von Willebrand factor. Administered in pharmacological doses, 30% of UFH binds to AT with high affinity, thus leading to a conformational change, which converts AT from a slow to a very rapidly (1000 times) acting inhibitor of thrombin. Apart from thrombin, AT interacts with coagulation factor Xa, and other components of plasmic haemostasis such as factors IXa, XIa and XIIa, plasmin, kallikrein and trypsin. The key chemical sequence for binding heparin to AT is a pentasaccharide composed of three sulfated glucosamins and two uronic acids. By inactivating thrombin, UFH inhibits not only fibrin formation but also thrombininduced platelet activation. In contrast, anticoagulant effects of thrombin, particularly inactivation of coagulation factors Va and VIIIa by thrombin– thrombomodulin-induced activation of protein C, are also inhibited by UFH. The inactivation of thrombin by the heparin–AT complex needs a heparin molecule composed of at least 18 monosaccharides. In contrast, smaller molecules containing the above-mentioned pentasaccharide sequence are sufficient to inhibit factor Xa. This explains why LMWHs (mean mol. wt 3000–9000 Da), which are prepared from UFH through chemical or enzymatic depolymerization, exhibit a stronger inhibition of factor Xa compared with thrombin (Figure 1). The relationship between thrombin and factor Xa inactivation differs among different LMWHs (Table 1). In this context, the recently introduced synthetic pentasaccharide fondaparinux that actually represents a very short LMWH selectively inhibits factor Xa but does not inactivate thrombin. The use of this agent for anticoagulation of a haemodialysis patient with HIT-II has recently been reported [9]. ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: The heparins 2037 Factor Xa Pentasaccharide UFH Antithrombin Thrombin Pentasaccharide LMWH Factor Xa Antithrombin Fig. 1. Mechanism of action: UFH vs LMWH. Table 1. The heparins: chemistry and specific action on factor-Xa UFH Enoxaparin Nadroparin Reviparin Dalteparin Tinzaparin Certoparin Danaparoid Fondaparinux Mol. Wt (Da) Method of preparation from UFH Activity ratio anti-Xa/anti-IIa 6000–30 000 3500–5500 3600–5000 4500–5000 5600–6400 5600–7500 6000–6700
5500 1728 b-Eliminative cleavage—alkali Deaminative cleavage—nitrous acid Deaminative cleavage—nitrous acid Deaminative cleavage – nitrous acid Enzymatic cleavage—heparinase Deaminative cleavage—isoamyl nitrate (Isolation from porcine intestinal mucosa) (Synthetic pentasaccharide) 1.0 4.1 3.5 3.5 2.4 1.9 2.4 >20 1 Danaparoid is a low molecular weight heparinoid, which is isolated from porcine intestinal mucosa. During the production of this agent, UFH and its fragments are eliminated, leaving a mixture of heparan sulfate (84%), dermatan sulfate (12%) and chondroitin sulfate A and C (4%) as active components. There is a high selectivity regarding factor Xa inactivation (Table 1) and a low affinity for platelet factor 4 (PF4), allowing its use in patients with established HIT-II, which is discussed later. The AT–heparin complex binds covalently to thrombin, factor Xa and other coagulation factors, thereby irreversibly inhibiting their procoagulant activity. Thereafter, heparins dissociate from the complex and may be reutilized, while the protease–AT– complex is cleared through the reticuloendothelial system. Due to their polyanionic structure, heparins bind not only to AT but also to a myriad of different proteins and cell membranes. These so-called unspecific interactions are much stronger in UFH compared with LMWH and danaparoid due to longer polysaccharide chains. After binding to endothelial cells, synthesis of heparan sulfate is amplified, which augments the anticoagulatory effect possibly in combination with the release of tissue factor pathway inhibitor [10]. In vivo, a rise in plasma free fatty acids after activation of lipoprotein lipase can be demonstrated in patients exposed to heparins. In very high concentrations, heparins may paradoxically induce platelet aggregation. Furthermore, they bind unspecifically to a multitude of plasma proteins and platelet-associated proteins such as PF4, thrombospondin, complement factors and b-thrombog (...truncated)