Alternatively spliced isoforms of tissue factor pathway inhibitor

Abstract 

Tissue factor pathway inhibitor (TFPI) is the major regulator of tissue factor (TF)-induced coagulation. It down regulates coagulation by binding to the TF/fVIIa complex in a fXa dependent manner. It is predominantly produced by microvascular endothelial cells, though it is also found in platelets, monocytes, smooth muscle cells, and plasma. Its physiological importance is demonstrated by the embryonic lethality observed in TFPI knockout mice and by the increase in thrombotic burden that occurs when heterozygous TFPI mice are bred with mice carrying genetic risk factors for thrombotic disease, such as factor V Leiden. Multiple TFPI isoforms, termed TFPIα, TFPIβ, and TFPIδ in humans and TFPIα, TFPIβ, and TFPIγ in mice, have been described, which differ in their domain structure and method for cell surface attachment. A significant functional difference between these isoforms has yet to be described in vivo. Both human and mouse tissues produce, on average, approximately 10 times more TFPIα message when compared to that of TFPIβ. Consistent with this finding, several lines of evidence suggest that TFPIα is the predominant protein isoform in humans. In contrast, recent work from our laboratory demonstrates that TFPIβ is the major protein isoform produced in adult mice, suggesting that TFPI isoform production is translationally regulated.

Abbreviations: TF, Tissue factor, TFPI, Tissue factor pathway inhibitor, K1, first Kunitz domain, K2, second Kunitz domain, K3, third Kunitz domain, GPI, glycosylphosphatidylinositol

Keywords: Tissue factor pathway inhibitor, Blood coagulation, Alternative splicing, Translational regulation