Inflammation and Coagulation: Linked Processes Potentially Regulated Through a Common Pathway Mediated by Protein C

Unraveling the biochemical basis of the complex process of blood coagulation has been the focus of intense investigation for more than 30 years. During this period of time, considerable progress has been made in elucidating the structure and assembly of the coagulation complexes (for a review, see ref. 1). From our perspective, the framework of the biochemical basis of the assembly of the coagulation complexes provided the basis for examining the potential cross talk between inflammatory injury and coagulation. The importance of the linkage between inflammation and coagulation is manifest most dramatically in gram negative septic shock. During this process, leukocytes, platelets and monocytes are activated, cytokines are liberated, fibrinogen is consumed and massive vascular damage ensues. In this process, tissue factor is formed de novo and protein C is activated (for a review, see ref. 2). While each of these events definitely occur in the shock process, the influence of each event on other events and their relative contribution to the vascular damage and death are only beginning to emerge. The development of quantitative binding and kinetic assays has led to a second important advance — the appreciation of the roles of endothelial cells, neutrophils, monocyte/macrophage and platelets in these processes (1). In particular, cellular activation now appears to be central to the control of blood coagulation. It is cellular activation that probably constitutes a major link between inflammation, coagulation and vascular damage. This chapter will review our concepts of how these diverse processes may be linked. Our interests have focused on inflammation-coagulation interactions in three areas: 1) E. coli induced shock and disseminated intravascular coagulation (DIC); 2) venous thrombosis; and 3) reperfusion injury. The basic approach that has been taken is to combine basic information with clinical observations to design specific physiological experiments to test the relative importance of particular regulatory molecules on each of the above processes.