Biology of tissue factor pathway inhibitor

Recent studies of the anticoagulant activities of the tissue factor (TF) pathway inhibitor (TFPI) isoforms, TFPI alpha and TFPI beta, have provided new insight into the biochemical and physiological mechanisms that underlie bleeding and clotting disorders. TFPI alpha and TFPI beta have tissue-specific expression patterns and anticoagulant activities. An alternative splicing event in the 59 untranslated region allows for translational regulation of TFPI beta expression. TFPI alpha has 3 Kunitz-type inhibitor domains (K1, K2, K3) and a basic C terminus, whereas TFPI beta has the K1 and K2 domains attached to a glycosylphosphatidyl inositol-anchored C terminus. TFPI alpha is the only isoform present in platelets, whereas endothelial cells produce both isoforms, secreting TFPI alpha and expressing TFPI beta on the cell surface. TFPI alpha and TFPI beta inhibit both TF-factor VIIa-dependent factor Xa (FXa) generation and free FXa. Protein S enhances FXa inhibition by TFPI alpha. TFPI alpha 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 TFPI alpha may be optimally localized to dampen initial thrombin generation. Similarly, endothelial TFPI beta may be optimally localized to inhibit processes that occur when endothelial TF is present, such as during the inflammatory response.