Alternatively spliced isoforms of tissue factor pathway inhibitor

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 TFPIa, TFPIß, and TFPId in humans and TFPIa, TFPIß, and TFPI? 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 TFPIa message when compared to that of TFPIß. Consistent with this finding, several lines of evidence suggest that TFPIa is the predominant protein isoform in humans. In contrast, recent work from our laboratory demonstrates that TFPIß is the major protein isoform produced in adult mice, suggesting that TFPI isoform production is translationally regulated. © 2010 Elsevier Ltd. All rights reserved

Biology of tissue factor pathway inhibitor

Recent studies of the anticoagulant activities of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPIa and TFPIß, have provided new insight into the biochemical and physiological meagulant activities. An alternative splicing event in the 59 untranslated region allows for translational regulation of TFPIß expression. TFPIa has 3 Kunitz-type inhibitor domains (K1, K2, K3) and a basic C terminus, whereas TFPIß has the K1 and K2 domains attached to a glycosylphosphatidyl inositol-anchored C terminus. TFPIa is the only isoform present in platelets, whereas endothelial cells produce both isoforms, secreting TFPIa and expressing TFPIb on the cell surface. TFPIa and TFPIß inhibit both TF-factor VIIa-dependent factor Xa (FXa) generation and free FXa. ProteinSenhances FXa inhibition by TFPIa. TFPIa produces isoform-specific inhibition of prothrombinase during the initiation of coagulation, an anticoagulant activity that requires an exosite interaction between its basic C terminus and an acidic region in the factor Va B domain. Platelet TFPIa may be optimally localized to dampen initial thrombin generation. Similarly, endothelial TFPIß may be optimally localized to inhibit processes that occur when endothelial TF is present, such as during the inflammatory response. © 2014 by The American Society of Hematology