Program: Oral and Poster Abstracts
Session: 322. Disorders of Coagulation or Fibrinolysis: Poster II
Materials and Methods: RM 12,800 IU (2.02 mg) ampules were commercially obtained. Working solutions of buffered RM were prepared at 100 µg/ml. Tissue factor mediated generation of thrombin and its inhibition in normal human plasma (NHP) (n=50), platelet rich plasma (PRP) (n=50), plasma obtained from patients with DIC (n=25) and various PCCs such as Beriplex, Cofact, Feiba, Konyne, Octaplex, Preconativ, Profilnine, Prothromplex at 1 – 5 IU/ml were investigated. A fluorometric thrombokinetics method (Technoclone, Vienna, Austria) was used to determine thrombin generation and its modulation by RM. In addition such thrombin generation markers as prothrombin fragment (F1.2) and thrombin-antithrombin complex (TAT) were measured. The effect of RM on thrombin mediated fibrinokinetics was also measured using an optical method.
Results: RM produced a concentration dependent inhibition of thrombin generation in the plasma based systems. In NHP the IC50 was 0.29±0.06 µg/ml in contrast to PRP where the IC50 was 1.99±0.31 µg/ml. The inhibition of thrombin generation in various PCCs was also concentration and product dependent and only four factor concentrates were found to generate thrombin.. At concentrations of 1 IU/ml marked inhibition of thrombin generation was noted in Preconativ, Prothromplex and Beriplex. RM decreased the generation of F1.2 and TAT in a concentration dependent manner. However, at concentrations >2.5 IU/ml the thrombin generated in such PCCs as Prothromplex and Beriplex, markedly higher thrombin was generated overcoming the anticoagulant effect of RM. Proportionately higher levels of thrombin generation markers were formed and were dependant on PCC concentrations. RM also inhibited the thrombin induced formation of fibrin in both PRP and PPP systems in a differential manner. However, at higher concentration of thrombin the inhibitory effects of RM on fibrin formation were overcome.
Conclusions: These results suggest that in plasma based systems and in the PCCs at concentrations <1 IU/ml, RM is capable of inhibiting tissue factor mediated thrombin generation in addition to the direct inhibition of pre-formed thrombin. However, such PCCs as Beriplex and Prothromplex are capable of overcoming the thrombin generation inhibitory actions of RM in a concentration dependent fashion. Moreover, RM is also capable of modulating fibrin formation as evident by fibrinokinetic studies where increased thrombin levels may also overcome its effect on fibrin formation. These observations suggest that PCCs may have the potential to reverse the anticoagulant effect of RM and may be considered as a potential antidote for this agent.
Disclosures: Williams: Asahi Kasei Pharma America: Employment .
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