Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein

Tissue factor (TF) is an essential enzyme activator that forms a catalytic complex with FVIIa and initiates coagulation by activating FIX and FX, ultimately resulting in thrombin formation(1). TF is found in adventitia of blood vessels(2) and the lipid core of atherosclerotic plaques(3). In unstable coronary syndromes, plaque rupture initiates coagulation by exposing TF to blood(4,5). Biologically active TF has been detected in vessel walls and circulating blood(6). Elevated intravascular TF has been reported in diverse pro-thrombotic syndromes such as myocardial infarction, sepsis, anti-phospholipid syndrome and sickle-cell disease(7-10). It is unclear how TF circulates, although it may be present in pro-coagulant microparticles(11,12). We now report identification of a form of human TF generated by alternative splicing. Our studies indicate that alternatively spliced human tissue factor (asHTF) contains most of the extracellular domain of TF but lacks a transmembrane domain and terminates with a unique peptide sequence. asHTF is soluble, circulates in blood, exhibits pro-coagulant activity when exposed to phospholipids, and is incorporated into thrombi. We propose that binding of asHTF to the edge of thrombi contributes to thrombus growth by creating a surface that both initiates and propagates coagulation.