Editorial [Hot Topic: Understanding and Treatment of Diseases in the Haemostatic System (Guest Editor: M.P. Peppelenbosch Co-Editor: C.A. Spek)]

Upon vessel rupture, Tissue factor (TF) is the main initiator of the coagulation cascade, normally not present on cells that are in contact with the bloodstream, binds with high affinity to the zymogen factor VII. The subsequent generation of factor Xa, thrombin and fibrin deposition, finally results in the formation of a blood clot. For decades it has been thought that coagulation factors represent a group of relative passive mediators involved in the linear transduction of the coagulation cascade. Scientific progress in recent years has taught us, however, that these factors actively engage target cells to induce signal transduction and thus fulfil critical functions in a wide variety of pathophysiological phenomena. The most prominent example is the interaction between factor VIIa and tissue factor, which is critical for neo- angiogenesis, but also plays important roles in arteriosclerosis and inflammatory processes. Importantly, various laboratories have now provided convincing evidence that the effects of factor VIIa in pathophysiology require the activation of other vitamin K-dependent coagulation factors (especially factor X). In addition, also thrombin is now generally accepted as a vitamin K-dependent coagulation factor capable of inducing intracellular signal transduction. In turn, this signalling plays an important role in cardiovascular pathology as platelets from PAR4-deficient mice failed to change shape, mobilize calcium, secrete ATP or aggregate in response to thrombin. Many of the details of thrombin signal transduction have now been elucidated by in vitro investigations and especially feature prominent activation of Rho GTPases and activation of p38 and p42/p44 MAP kinases, in turn important for a variety of physiological events including angiogenesis, and thus do not merit special attention. Hence in the present issue we focus on more proximal events, models that bridge this preclinical work to data with relevance for disease and explore novel avenues for treating coagulation-related disease. The importance of coagulation-factor-dependent signal transduction in pathophysiology is clear. In addition, evidence is rapidly emerging demonstrating an important role for protein C in cardiovascular pathology (e.g. stroke and inflammation). Hence, for proper understanding pathology associated with the coagulation system knowledge of both evolutionary origin, RNA stabilization of cytokines, and action function of TF, Factor VIIa and factor X are essential and will be reviewed in this special issue of current genomics by various authors. Together a pattern emerges where, in general, vitamin K-dependent coagulation factors provoke intracellular signal transduction The role of the vitamin Kdependent coagulation factors in many cardiovascular pathophysiological processes (e.g. myocardial infarction, angiogenesis, and atherosclerosis) remains remarkably poorly investigated, and although subject to review in this issue will require a significant research effort in the future. Hence, we would like to end this editorial with an appeal to the appropriate authorities and funding agencies for continued support to enable building on body of work described in this special issue, resulting in improved patient care. The authors wish to acknowledge the support from the Dutch Heart foundation (grants 99.188 and 99.197) for the studies presented in this special issue of current genomics.