The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif--the C-domain.
BACKGROUND
Heparins in clinical use differ considerably as to mode of preparation, molecular weight distribution and pharmacodynamic properties.


OBJECTIVE
Find a common basis for their anticoagulant action.


METHODS
In 50 fractions of virtually single molecular weight (Mr), prepared from unfractionated heparin (UFH) and four low-molecular-weight heparins (LMWH), we determined: (i) the molar concentration of material (HAM) containing the antithrombin binding pentasaccharide (A-domain); (ii) the specific catalytic activity in thrombin and factor Xa inactivation; (iii) the capacity to inhibit thrombin generation (TG) and prolong the activated partial thromboplastin time (APTT). We also calculated the molar concentration of A-domain with 12 sugar units at its non-reducing end, i.e. the structure that carries antithrombin activity (C-domain).


RESULTS
The antithrombin activity and the effects on TG and APTT are primarily determined by the concentration of C-domain and independent of the source material (UFH or LMWH) or Mr. High Mr fractions (>15 000) are less active, probably through interaction with non-antithrombin plasma proteins. Anti-factor Xa activity is proportional to the concentration of A-domain, it is Ca2+- and Mr-dependent and does not determine the effect on TG and APTT.


CONCLUSIONS
For any type of heparin, the capacity to inhibit the coagulation process in plasma is primarily determined by the concentration of C-domain, i.e. the AT-binding pentasaccharide with 12 or more sugar units at its non-reducing end.
Al Dieri
R
R
Synapse BV, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, the Netherlands.
Wagenvoord
R
R
van Dedem
G W K
GW
Béguin
S
S
Hemker
H C
HC
D020816:Amino Acid Motifs; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008970:Molecular Weight; D010314:Partial Thromboplastin Time; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000096:biosynthesis
D000925:Anticoagulants; D006493:Heparin; D013917:Thrombin