ACTION AND CLINICAL PHARMACOLOGY

　　Mechanism of Action

　　FRAGMIN is a low molecular weight heparin with antithrombotic properties.

　　Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa. It is composed of strongly acidic sulphated polysaccharide chains with a weight average molecular weight of 6000 Daltons and about 90% of the material within the range 2000-9000. Dalteparin sodium is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site that is essential for high affinity binding to the plasma protein antithrombin (AT III).

　　Pharmacodynamics

　　FRAGMIN acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin. However, it preferentially potentiates inhibition of Factor Xa, resulting in only slight increases of clotting time, i.e., activated partial thromboplastin time (APTT).

　　Effects of unfractionated heparin are monitored by assessing APTT and anti-factor Xa (anti-Xa) activity. For FRAGMIN, however, only high doses lead to noticeable increases in the APTT; therefore, measurement of APTT can be used only as an indicator of overdosage. In the case of FRAGMIN, anti-Xa activity of plasma is used both as an estimate of clotting activity, and as a basis to determine dosage. FRAGMIN potency is described in international anti-Xa units (IU).

　　The specific activity of FRAGMIN on factor Xa (by measurement of anti-factor Xa IU/mg) is 130, and its specific activity on factor IIa (by measurement of anti-factor IIa IU/mg) is 58. The ratio of anti-Xa/anti-IIa activity for FRAGMIN is 2.2 (for unfractionated heparin the anti-Xa/anti-IIa is equal to 1).

　　Dalteparin sodium has a smaller effect on platelet function and platelet adhesion than heparin, and thus has only a small effect on primary hemostasis. Heparin treatment depletes the pool of platelet factor 4, while dalteparin sodium has much less of an effect.