How to handle low-molecular-weight heparins in patients with decreased renal function: an open issue

Abstract

Chronic renal failure is a leading cause of morbidity and mortality in Western countries [1]. The prevalence of patients with end stage renal disease (ESRD) is growing constantly, and ever more frequently require physicians of several specialties to manage these patients with reduced renal function. An example of this event is the prevention and treatment of venous thromboembolism (VTE), acute deep vein thrombosis (DVT) or pulmonary embolism (PE) with heparins. Heparins are the most effective treatment for the thromboembolic disorders, but their management requires careful usage in patients with reduced glomerular filtration rate (GFR). Heparin is an indirect thrombin inhibitor that forms complexes with antithrombin (AT, formerly known as AT III), and converts this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa [2, 3]. The binding of heparin to the heparin binding site on AT produces a conformational change in AT that accelerates the inactivating process by 1,000to 4,000-fold [4]. The type of unfractionated (UF) heparin in current clinical use is polydispersed unmodified heparin, with molecular weights ranging from 3,000 to 30,000 Da and a mean molecular weight of approximately 15,000. Low molecular weight (LMW) derivatives of commercial heparin have been obtained. They have a molecular weight range from 2,000 to 9,000 Da, and a mean molecular weight of 4,000–5,000 [5]. Like UF heparins, LMW heparins inactivate factor Xa, but have a lesser effect on thrombin, because most of the molecules do not contain enough saccharide units to bind to form the quaternary complex in which thrombin and AT are bound simultaneously [5]. As a result, LMW heparins do not prolong the aPTT. LMW heparins are at least as effective as unfractionated heparin for the treatment and prevention of venous thromboembolism [5]. LMW heparins also have a number of advantages over UF heparins [6]. They have greater bioavailability when given by subcutaneous injection, and their anticoagulant effect is longer than UF heparins because of reduced binding to macrophages and endothelial cells, permitting once or twice daily administration. The anticoagulant response (anti-Xa activity) to LMW heparin is highly correlated with body weight, permitting administration of a fixed dose. Nevertheless, the dose may have to be adjusted for patients who are extremely obese or have renal failure [2]. LMW heparins are much less likely to induce immune-mediated thrombocytopenia than UF heparins (0 vs. 2.7% in one study) [7] and they do not increase osteoclast number and activity as much as UF heparins, thus producing less bone loss [8, 9]. All these features make LMW heparin suitable for safe administration in the outpatient setting and particularly in renal patients. Two Cochrane reviews have explored the benefits of LMW heparin over UF heparin, and conclude that in patients with acute VTE, fixed-dose subcutaneous LMW heparin is more effective than adjusted-dose of UF heparin for reducing the incidence of symptomatic recurrent VTE, major hemorrhage, and all-cause mortality [10]. Moreover, home management using LMW heparin is cost effective, G. S. Netti L. Gesualdo (&) Department of Biomedical Sciences, Section of Nephrology, University of Foggia, Viale Luigi Pinto, 1, 71100 Foggia, Italy e-mail: l.gesualdo@unifg.it