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Becker, R.C. et al.

Becker, Alexander, Li, Robertson, Kunitada, Spencer, Yang, Harrington,

Vascular endothelial tissue factor pathway inhibitor kinetics in culture following exposure to DX-9065a--a selective and direct factor Xa inhibitor.

BACKGROUND: Tissue factor (TF), a membrane-bound glycoprotein that initiates blood coagulation by allosteric activation of factor (f) VII, is regulated predominantly by tissue factor pathway inhibitor (TFPI). Because vascular endothelial cells synthesize and constitutively secrete TFPI and fXa may directly influence its cellular clearance, we sought to determine the effects of DX-9065a, a direct and selective fXa inhibitor, on TFPI kinetics in culture. METHODS/RESULTS: Human umbilical vein endothelial cells were grown to confluence and incubated with unfractionated heparin (1.0 U/mL), enoxaparin (1.5 U/mL), or DX-9065a at low (10 ng/ml), moderate (30 ng/ml), or high (90 ng/ml) concentrations. Compared to control, increases in TFPI were seen with both unfractionated heparin (182% higher, p < 0.001) and enoxaparin (194% higher, p < 0.001). Low concentration DX-9065a did not increase TFPI levels above control (0.8% higher, p = 0.91). In contrast, moderate and high concentrations produced 124% higher (p < 0.001) and 198% higher (p < 0.001) TFPI concentrations than control, respectively. CONCLUSIONS: DX-9065a increases vascular endothelial cell TFPI concentrations in human tissue culture. Although the mechanism has yet to be established, decreased fXa availability may limit fXa-TFPI complex formation and its subsequent cellular uptake. Whether increased surface TFPI contributes to the overall anticoagulant profile of DX-9065a will require further investigation.[1]

References

Vascular endothelial tissue factor pathway inhibitor kinetics in culture following exposure to DX-9065a--a selective and direct factor Xa inhibitor. Becker, R.C., Alexander, J.H., Li, Y., Robertson, T., Kunitada, S., Spencer, F.A., Yang, H., Harrington, R.A. J. Thromb. Thrombolysis (2004) [Pubmed]

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