Thrombosis research
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Bleeds in hemophilia are treated either on demand or prophylactically by intravenous replacement therapy with FVIII or FIX. However, there is a call for subcutaneous and less frequent drug administration, and this need may be met by administration of a suitable antibody. Pioneering studies in vitro] and in a rabbit hemophilia model suggest that blockage of tissue factor pathway inhibitor (TFPI) provides a potential alternative approach to current therapy of hemophilia patients. ⋯ Blockage of TFPI with various antagonists has been shown to effectively enhance FX activation by TF/FVIIa and improve clot formation in hemophilia blood and plasma. The monoclonal antibody, mAb 2021, is one such antagonist directed towards the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI which is now being tested in preclinical and clinical trials. Using mAb 2021, we have confirmed the original findings, and further characterized the pro-haemostatic effect of this specific anti-KPI-2 mAb in preclinical studies.
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Thrombosis research · Apr 2012
Comparative StudyIn vitro study of the anticoagulant effects of edoxaban and its effect on thrombin generation in comparison to fondaparinux.
Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in Phase III development for prevention and treatment of thromboembolic disorders. Fondaparinux is an approved indirect FXa inhibitor. This study compared the effects of edoxaban and fondaparinux on thrombin generation (TG) using the calibrated automated thrombogram (CAT). Secondary objectives included evaluation of edoxaban and inhibition of coagulation parameters (prothrombin time [PT], activated partial thromboplastin time [aPTT]), anti-FXa activity and clotting times. ⋯ TG evaluation by the CAT method, coagulation tests, and anti-FXa and clotting assays demonstrated concentration-dependent effects of edoxaban. The PT and aPTT prolongation are reagent dependent; correction of PT ratio by international normalized ratio does not reduce variability in response. The greater effect of edoxaban vs. fondaparinux may be related to the broader activity of direct FXa inhibitors compared with indirect FXa inhibitors.
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Thrombosis research · Apr 2012
Co-localization of Protein Z, Protein Z-Dependent protease inhibitor and coagulation factor X in human colon cancer tissue: implications for coagulation regulation on tumor cells.
Several hemostatic system components, including factor X (FX), contribute to cancer progression. The Protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex directly inhibits factor Xa proteolytic activity. The aim of this study was to determine the antigenic distribution of ZPI and PZ, in relation to FX, as well as indicators of blood coagulation activation (F1+2 and fibrin) in human colon cancer tissue. ⋯ The localization of PZ/ZPI and FX in colon cancer cells indicates that PZ/ZPI may contribute to anticoagulant events at the tumor site. Strong co-localization of PZ/ZPI and FX in cancer cells, and the presence of the mRNAs encoding the proteins, suggests their role in the tumor's biology. However, the presence of F1+2 and fibrin at the colon cancer site also suggests that the regulation of FXa by the PZ/ZPI complex at this site is incomplete.