The molecular biology and biochemistry of tissue factor

The cloning of tissue factor (TF) cDNAs has recently been carried out which has allowed the characterization of this cellular receptor for factor VII. The predicted primary structure indicates that it is a multidomain protein comprised of a hydrophilic extracellular domain, a membrane spanning structure and a cytoplasmic region. Post-translational modifications include four potential N-linked glycosylation sites of which three are occupied. There is evidence that the intracellular cysteine residue is thioester-linked to palmitic acid, and that this could enhance the anchoring of the receptor to the membrane. The four remaining cysteine residues are located in the putative extracellular domain and appear to form two intramolecular disulphide bonds. There is no significant homology between TF and any other published protein sequence in current databases. There is evidence that TF is the primary initiator of the coagulation cascade. Early models of coagulation tended to assign TF to a subordinate role, but now it is widely accepted that the extrinsic pathway is critical as TF/FVIIa activates both FX and FIX. It has been reported that zymogen FVII has catalytic activity and this would indicate that the simple complexing of FVII and TF is sufficient to initiate coagulation without an infinite regression of proteolytic events. Many cell types synthesize TF constitutively but, significantly, endothelial cells do not normally express TF on their surfaces, consistent with a quiescent haemostatic system. Recently a number of agonists known to be thrombogenic in vivo have been shown to induce de novo synthesis of TF by endothelial cells. TF thus operates at two levels: exposure of the subendothelium to blood results in the binding of FVII to TF and consequently to clot formation, and induction of TF synthesis by a variety of agonists results in the intact endothelium becoming procoagulant. In concert with TF expressed by monocytes and macrophages this endothelial cell procoagulant activity may play a role in the pathogenesis of thrombotic disease.