The use of low-molecular-weight heparins in cardiovascular disease.
Unfractionated heparin (UFH) has been used for decades as an effective and relatively inexpensive agent in the prevention of venous and arterial thromboembolic events. Low-molecular-weight heparin (LMWH) preparations are obtained by chemical or enzymatic depolymerization of unfractionated commercial grade heparin; their mean molecular weights range from below 4,000 to about 6,500 D (Table 1). Their mechanism of antithrombotic action is basically similar to that of UFH - binding to antithrombin to inhibit activated coagulation factors - but they have a different relative potency (to some extent also inter-individually) of anti-Xa versus anti-IIa activity. Shorter fragments which contain the essential pentasaccharide to bind to antithrombin but lack the required chain length to bind at the same time to thrombin, only inhibit activated Factor X. Fragments above 5,000 D which contain the pentasaccharide maintain their property to inhibit Factor Xa but with increasing chain length, they become stronger inhibitors of thrombin. LMWHs have little or no effect on global tests of blood coagulation such as the activated partial thromboplastin time when used in prophylactic or therapeutic dosages. A specific assay of anti-Xa activity is required to monitor biological activity but this is rarely needed. The main advantage of LMWHs for clinical practice derive from their pharmacokinetic properties. UFH binds to plasma proteins, endothelial cells and platelets. This saturable mechanism clears heparin rapidly from the circulation (the plasma half-life is non-linearly dose-related) and is held responsible for the large variation from person to person and from moment to moment in biological and clinical response. LMWHs bind far less to these elements and therefore have a 2 to 4-times longer plasma half-life, a markedly better bioavailability when injected subcutaneously and a more stable dose response. They also have a lower toxic effect in terms of heparin-induced thrombocytopenia which may be related to their lesser interaction with platelets.
Verhaeghe
R
R
Centre for Molecular and Vascular Biology, University of Leuven, Belgium.
D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D013923:Thromboembolism / Q000188:drug therapy / Q000517:prevention & control*
D006495:Heparin, Low-Molecular-Weight