Low-Molecular-Weight Heparins: An Overview of their Pharmacodynamics, Pharmacokinetics and Metabolism in Humans

Abstract

Low-molecular-weight heparins (LMWHs) comprise a group in the class of antithrombotic medications, a class headed by unfractionated heparin (UFH). The LMWHs, with mean molecular weights of 4.0-6.0 kD, differ in their individual manufacturing processes, the distribution of their fragment molecular weights, their in vitro potency (anti-Xa, antithrombin and anticoagulant activities) and, consequently, in their biodynamic patterns, recommended dose regimen, and efficacy/safety ratio. Their drug disposition profiles have been evaluated using two significant markers of their pharmacodynamic activity, namely anti-Xa and anti-IIa activities. Since they are mainly administered subcutaneously, then compared to UFH, they are almost completely absorbed (F > 90%) and, in contrast to UFH, those for which data are available in the literature exhibit linear pharmacokinetics with proportionality between anti-Xa (and anti-IIa in some cases) plasma concentration and dose, and stationary distribution volume and clearance processes when the dosage is increased. Their distribution volume is close to the blood volume, they are partially metabolized by desulphatation and depolymerization, but urinary excretion of anti-Xa activity for enoxaparin, dalteparin and nadroparin, all given at doses for prevention of venous thrombosis, is between 5 and 10% of the injected dose. However, these LMWHs differ in the extent of their non-renal clearance, resulting in different apparent elimination half-life values and relative apparent bioavailability. When considering certain at-risk situations, using doses for preventing thromboembolism, the LMWHs do not significantly cross the placenta of pregnant women and their excretion profiles are only slightly altered in severe (endogenous creatinine clearance less than 15 ml/min) renal disease patients when given at doses recommended for prevention of venous thromboembolism. Because of the differences among LMWHs, the clinical profile of a given LMWH cannot be extrapolated to another one or generalized to the whole LMWH family.

Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes

“…If so, full-blown humoral autoimmunity may appear with lupus nephritis as the inevitable consequence (38). Another explanation may be individual differences in the clearance capacity of heparin in vivo in mice (41,42), or that the dose of heparin needs to be increased.…”

Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function

“…Dosage reduction of up to 50% has been suggested for enoxaparin [1]. However, there is a lack of data for other LMWH because dosage suggestions may not be transferred from one LMWH to another due to differing pharmacokinetic parameters [13].…”

“…Primary objectives were peak anti-Xa levels and adjusted anti-Xa levels, adjustment being carried out for dose and body weight. Results: A total of 42 patients could be analyzed during a median of 10 days (interquartile range IQR 4-13, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In all groups, adjusted peak anti-Xa levels were not different on day 10 compared with day 1.…”

Low-molecular-weight heparin in pregnancy: peripartum bleeding complications

“…[1][2][3][4][5][6][7][8][9] Owing to their predictable dose-response, LMWH does not require routine laboratory monitoring or dose adjustments in the majority of nonpregnant patients, thus allowing for more convenient regimens. 10 As they do not cross the placenta and are safe in breastfeeding, LMWH has gained widespread use in pregnancy.…”