Tissue Factor and Nitric Oxide: a Controversial Relationship!

Tissue factor (TF) is the primary physiological initiator of blood coagulation. TF has a high-affinity for factor (F) VII resulting in the formation of (TF:FVII:FVIIa) bimolecular complex which, in the presence of Ca(2+), increases the enzymatic activity of FVIIa towards its natural substrates, FIX and FX, generating their active forms FIXa and FXa, respectively. This eventually leads to thrombin generation and a fibrin clot formation. Up-regulation of TF in injured blood vessels and atherosclerotic plaque can lead to undesirable vascular thrombosis. Nitric oxide (NO) is a free radical synthesized from L-arginine and molecular oxygen by nitric oxide synthases (NOS). NO participates in diverse physiological and pathophysiological process as an intra or extracellular messenger. A relationship between TF and NO has been proposed. Thus, models of TF regulation by NO has been studied in different cells and experimental animal models, but the results have been conflicting. The premise that NO donors can prevent TF expression in vivo has provided the foundation for a broad field of pharmacotherapeutics in vascular medicine. A new class of drugs combining a statin (inhibitors of coenzyme A reductase) with an NO-donating moiety has been described. The resulting drug, nitrostatin, has been suggested to increase the antithrombotic effects of native statin. However, it is questionable if NO release from these drugs had any significant role on TF inhibition. In summary, care must be taken in drawing conclusions about the relationship between NO and TF. Interpretation of NO studies must take several factors into consideration, including NO bioavailability, its half-life and inactivation, as well as the cell type and experimental model used.