Tissue factor - a therapeutic target for thrombotic disorders.
Exposure of blood to tissue factor (TF) sets off the coagulation cascade. TF is a transmembrane protein that serves as an essential cofactor for activated coagulation factor VII (FVIIa). TF may be exposed locally by vascular injury (such as balloon angioplasty) or by spontaneous rupture of an atherosclerotic plaque. Expression of TF may also be induced on monocytes and endothelial cells in conditions like sepsis and cancer, causing a more generalised activation of clotting. TF may thus play a central role in thrombosis in a number of settings, and attention has turned to blocking TF as a means to prevent thrombosis. Inhibiting the inducible expression of TF by monocytes can be achieved by 'deactivating' cytokines, such as interleukin (IL)-4, -10 and -13, or by certain prostanoids; by drugs that modify signal transduction, such as pentoxifylline, retinoic acid or vitamin D(3), or by antisense oligonucleotides. Such approaches are for the most part at a preclinical stage. The function of TF can be blocked by antibodies that prevent the binding of FVIIa to TF; by active site-inhibited FVIIa, which competes with native FVIIa for binding; by antibodies or small molecules that block the function of the TF/FVIIa complex; and by molecules, such as TF pathway inhibitor or nematode anticoagulant peptide C2, which inhibit the active site of FVIIa in the TF/FVIIa complex after first binding to activated factor X. The latter two agents have entered Phase II clinical trials. Perhaps most intriguing is the use of anti-TF agents locally, which holds the promise of stopping thrombosis at a specific site of injury without the bleeding risk associated with systemic anticoagulation.
Houston
Donald S
DS
Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, R3E 0V9, Canada. houston@cc.umanitoba.ca
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000097:blood / Q000150:complications; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D015195:Drug Design; D004730:Endothelium, Vascular / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015942:Factor VIIa / Q000037:antagonists & inhibitors / Q000502:physiology; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006023:Glycoproteins / Q000502:physiology; D015801:Helminth Proteins / Q000494:pharmacology / Q000627:therapeutic use; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008074:Lipoproteins / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000097:blood / Q000150:complications; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011453:Prostaglandins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D019851:Thrombophilia / Q000188:drug therapy / Q000503:physiopathology; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D000911:Antibodies, Monoclonal; D016207:Cytokines; D005343:Fibrinolytic Agents; D006023:Glycoproteins; D015801:Helminth Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D046912:Multiprotein Complexes; D016376:Oligonucleotides, Antisense; D011453:Prostaglandins; C051928:lipoprotein-associated coagulation inhibitor; C021240:tissue-factor-pathway inhibitor 2; D013925:Thromboplastin; D015942:Factor VIIa