The Choay domain -: the structure responsible for the anticoagulant action of heparins

We describe the common structural basis for the anticoagulant action of the many different heparins available to the clinician. From different types of heparin we prepared fractions of virtually single molecular weight. We determined the molar concentration of material (HAM) containing the antithrombin (AT) binding pentasaccharide (A-domain), the specific catalytic activity in thrombin- and factor Xa inactivation and the capacity to inhibit thrombin generation (TG). We also calculated the molar concentration of A-domain with 12 sugar units at its non-reducing end, i.e. the structure that carries anti-thrombin activity (Choay- or C-domain). The anti-thrombin activity and the effects on TG are determined by the concentration of C-domain and independent of the source material or Mr. High Mr fractions (> 15.000) are less active, probably through interaction with non-AT plasma proteins. Anti factor Xa activity is not indicative of anticoagulant potency but is a sensitive indicator of Mr and therefore predicts favourable pharmacokinetic properties : long half-life in the circulation and high bioavailability.