Fundamental

Most of what is published in the Journal of Thrombosis and Haemostasis builds on the philosophical notion that complex systems are the sum of their simpler parts. This approach was eloquently put into words by the French philosopher Ren e Descartes in his book ‘Discours de la m ethode’ that was published in Leiden in 1637: ‘. . . de diviser chacune des difficult es que j’examinerais, en autant de parcelles qu’il se pourroit, et qu’il seroit requis pour les mieux r esoudre’ (. . . to divide each of the difficulties under examination into as many parts as possible, and as might be necessary for its adequate solution). In the context of the February issue of the Journal of Thrombosis and Haemostasis this notion of reductionism implies that in order to fully understand the results of the large epidemiological study by Frey and co-workers on the risk of bleeding in elderly patients one needs to devise studies that separately examine all the elements thought to play a determining role in the ageing process and the hemostatic system. Not only will this reductionist approach yield improved understanding of bleeding, it might also pave the way to improved treatment. The level of detail that can be ultimately reached is nicely illustrated by the article from Madsen and co-workers on the allosteric networks that are activated in factor (F) VIIa upon binding of tissue factor. In this article the authors use simulations of molecular dynamics in order to delineate the structural changes that are most likely to occur in the catalytic domain of FVIIa as soon as it is bound by tissue factor. They provide further evidence that, in addition to its role in aligning FVIIa with its substrate FIX/X, tissue factor induces long-range allosteric pathways that lead to stabilization of the active site catalytic triad and encouragement of the N-terminal insertion event, two hallmarks of the zymogen/enzyme transition. This means that we now better understand how binding of tissue factor to one side of FVIIa propagates conformational changes towards the active site, a site that is far removed from where tissue factor actually binds. Detailed understanding of what comprises a fully catalytically active FVIIa may ultimately lead to improved hemostatic agents that can be used in elderly patients who bleed. The appearance of two such seemingly different papers that essentially target a similar subject in the same issue underlines the desire of the Journal of Thrombosis and Haemostasis to publish on all aspects of the hemostatic system and its diseases, at all levels. However, in order to maintain a healthy mix between clinical and epidemiological studies on one side of the spectrum, and detailed mechanistic studies on the other, the journal is fully dependent on what is submitted. At present the number of manuscripts on clinical studies submitted weekly outranks the number of fundamental studies by a factor of two or three. This relatively low submission rate of fundamental papers is also clearly reflected in the monthly content of the journal in which clinical studies predominate. In an earlier editorial we pointed out that part of the reason for the relatively low number of fundamental papers might be that almost without exception, fundamental studies are dependent on significant outside funding and an elaborate infrastructure in order to be state of the art. This dependence on funding and infrastructure is also true for large epidemiological studies, but it is not uncommon that, over the years, such studies produce tens or hundreds of articles, a number that cannot easily be matched by a detailed fundamental study. In addition, the analyses for many of the clinical studies that are submitted make use of data collected in a healthcare setting. Such studies are more reliant on the enthusiasm of medical doctors than on outside funding. The reference list of the article by Madsen and co-workers contains two fundamental papers that were published in this journal among many papers that were published in specialized biochemistry journals. In our attempt to maintain this blend of fundamental and clinical studies we would like to encourage the readership of the journal to submit their ‘deep’ biochemistry work to the Journal of Thrombosis and Haemostasis, where it will receive a warm welcome.