Cytokines and hemostasis.
OBJECTIVE
Cytokines are low molecular weight polypeptides that act as pleiotropic mediators of inflammation and may contribute significantly to regulation of hemostatic balance in both physiologic and pathologic conditions. The purpose of this review is to underline the most significant progresses recently achieved in this rapidly growing area.


METHODS
The authors have been involved both at home and abroad in experimental and clinical research in this field for years and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles published in journals covered by the Science Citation Index and Medline.


RESULTS
Tissue factor, a transmembrane glycoprotein that serves as a surface receptor for coagulation factor VIIa, plays a key role in the initiation of coagulation processes. Very little, if any, tissue factor activity is detectable in normal conditions on the cell surface of monocytes and endothelial cells. However, upon proper stimulation by a number of agents such activity may be expressed in these cells, which can then contribute significantly to clotting activation. Pro-inflammatory cytokines (IL-1, IL-6 and TNF) are effective inducers of tissue factor upregulation and may trigger endothelial cells to change their antithrombotic properties into a procoagulant, clot-promoting state. Indeed, much experimental and clinical evidence has been accumulated to suggest that cytokines play a key role in the pathophysiology of hemostatic abnormalities in different disease states. These include, inter alia, the coagulopathy observed during septicemia, the veno-occlusive disease of the liver after bone marrow transplantation, the prothrombotic state associated with atherosclerotic vessels, the occurrence of deep venous thrombosis after major abdominal surgery and the thrombotic tendency of patients with cancer. Several new antithrombotic strategies based on these new concepts have been attempted in experimental models of thrombosis and also in man. Examples of new possible antithrombotic agents are the tissue factor pathway inhibitor, Fab fragments of monoclonal antibodies directed against factor VII or factor VIIa, mutant forms of biologically inactive tissue factor and inhibition of cytokines involved in the regulation of tissue factor expression. Many of these studies have produced positive or interesting results, although more must be learned before the appropriate drug and the adequate dose are defined in the different clinical situations.


CONCLUSIONS
Pro-inflammatory cytokines (IL-1, IL-6 and TNF) play a key role in tissue factor expression on monocytes and on endothelial cells and contribute significantly to regulation of hemostatic balance in physiologic and pathologic conditions. This effect is of great interest from both speculative and practical viewpoints.
Grignani
G
G
Department of Internal Medicine and Medical Therapy, Institute for Medical Care "Città di Pavia", Viale Parco Vecchio, 27, 27100 Pavia, Italy. grignani@unipv.it
Maiolo
A
A
D000818:Animals; D001778:Blood Coagulation Disorders / Q000097:blood; D016207:Cytokines / Q000494:pharmacology* / Q000502:physiology; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000378:metabolism; D006801:Humans; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D005343:Fibrinolytic Agents; D006490:Hemostatics; D013925:Thromboplastin