Abstract
Introduction:Both thrombomodulin and activated protein C play an important role in the regulation of hemostasis. Recombinant versions of both the thrombomodulin (rTM) and activated protein C (rAPC) have been developed for clinical applications. Marked differences in their biochemical and pharmacological profiles exist. Such differences in their effects may be due to target sites and other interactions and may have therapeutic and safety implications.Aim:The aim of this study is to investigate the biochemical and pharmacological differences between a clinically developed rTM (ART-123, Asahi Kasei Pharma, Tokyo, Japan) and a plasma derived APC (Haematologic Technologies, Burlington, VT, USA).Materials and Methods:The anticoagulant profile of both agents was investigated in native whole blood using the ACT, TEG and global anticoagulant profile using PT and APTT assays at a concentration range of 0-10 ug/ml. The global anticoagulant profile in plasma based systems in terms of PT and APTT was also investigated. The effect of both of these agents was studied in the antiprotease (Xa and IIa) inhibitory assays and thrombin generation inhibition methods. A modified TEG system was used to study the modulation of tissue plasminogen activator mediated fibrinolysis by these agents.Results:In the ACT assays APC produced a much stronger anticoagulant effect in a concentration range of 0-10 ug/ml with a doubling time at 3 ug/ml, whereas rTM produced marginal effects on this parameter. The TEG profile of APC exhibited much stronger anticoagulant effects in comparison to rTM. At 3 ug/mL, APC produces much longer prolongation of the R and K time parameters in comparison to rTM. APC also facilitated tPA-mediated fibrinolysis in contrast to rTM. In the anti-IIa assays, rTM produced concentration dependent inhibition of thrombin and no inhibition of factor Xa. APC did not have any effect on either Factor Xa or IIa. In the thrombin generation assays, APC produced a stronger inhibition of thrombin generation (IC50=0.4 ug/mL) whereas rTM was relatively weaker (IC50 = 1.2 ug/mL). In the APTT assay APC produced a much stronger anticoagulant effect whereas rTM produced relatively weaker effects. Both agents did not produce any modification of agonist induced platelet aggregation. In terms of anticoagulant potency the APC exhibited 70 + 6 USP U/mg whereas the rTM was much weaker < 10 USP U/mg.Conclusions:These studies demonstrate that APC is a much stronger anticoagulant in comparison to rTM. In addition both agents produced different modulation of fibrinolytic and hemostatic processes. These observations suggest that in clinical indications such as DIC, these agents may have differential safety/efficacy implications. DisclosuresTanaka:Asahi Kasei Pharma America Corporation: Employment. Tsuruta:Asahi Kasei Pharma America Corporation: Employment.
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