LONG-TERM PERSISTENCE OF LOW-MOLECULAR-WEIGHT MATERIAL WITH ANTI-FACTOR-XA ACTIVITY CONTRIBUTES TO ANTICOAGULANT AND ANTITHROMBOTIC EFFECTSAFTER SUBCUTANEOUS INJECTION OF CY-216 IN THE RABBIT

This study was done to document further the mechanism of the antithrom botic effect of CY 216 after subcutaneous injection in the rabbit. We first measured the circulating anti-factor Xa and anti-thrombin activi ties expressed in either international Unit or Standard Independent Un it and from these activities we calculated the above critical length m aterial (ACLM) and below critical length material (BCLM) levels. The c learance of the BCLM was half that of the ACLM. Then we determined the inhibitory effect of CY 216 on thrombin generation (TG) in platelet-p oor plasma (PPP) and in whole blood. TG was both inhibited and delayed in whole blood, while it was only inhibited in PPP. The IC50 on TG in PPP and in whole blood were 1.80 +/- 0.16 and 4.33 +/- 1.01 mu g.ml(- 1) respectively. After the injection, the inhibition of TG was signifi cant as long as BCLM was detectable. The duration of the antithromboti c effect was essentially correlated to the ACLM level in the Wessler-t hromboplastin model and to the BCLM level in the Wessler-serum model. Taken together, these results demonstrate that both ACLM and BCLM comp onents of CY 216 are involved in its anticoagulant effect ex vivo as w ell as in its antithrombotic activity in vivo, and that the relative c ontribution of BCLM increases with the time after administration.