Role of coagulation factors in cerebral venous sinus and cerebral microvascular thrombosis.
OBJECTIVE
The objective of this study was to define the relative contributions of three major pro- and anti-coagulation pathways (heparin-antithrombin, protein C, and tissue factor (TF)) in the thrombogenic responses that occur in large and small vessels of the brain.


METHODS
Cerebral venous sinus thrombosis was induced by topical application of FeCl3 on the superior sagittal sinus, while photoactivation of fluorescein was used to induce thrombus formation in cerebral microvessels. Heparin, activated protein C (APC), and antibodies to either APC or TF were used to assess thrombogenesis in wild-type mice. Mutant mice that overexpress the endothelial protein C receptor (EPCR-tg) or with TF deficiency in Tie2-expressing endothelial cells (LTFE) were also used.


RESULTS
Thrombus formation in the superior sagittal sinus of wild-type mice was attenuated by heparin and in EPCR-tg mice, while treatment with the APC antibodies enhanced thrombogenesis. Arteriolar thrombosis was largely unresponsive to the interventions studied. However, in cerebral venules, thrombosis was inhibited by heparin and in EPCR-tg mice. TF antibody treatment also inhibited venular thrombosis, with a similar attenuation noted in LTFE mice.


CONCLUSIONS
Thrombin promotes while the APC pathway blunts thrombus formation in an experimental model of cerebral venous sinus thrombosis. TF involvement is more evident in cerebral microvascular thrombogenesis, with endothelial cell-associated TF mediating this response in venules, but not arterioles.
Nagai
Mutsumi
M
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Yilmaz
Cigdem Erkuran
CE
Kirchhofer
Daniel
D
Esmon
Charles T
CT
Mackman
Nigel
N
Granger
D Neil
DN
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001779:Blood Coagulation Factors / Q000378:metabolism* / Q000627:therapeutic use*; D002712:Chlorides; D003392:Cranial Sinuses / Q000187:drug effects* / Q000378:metabolism; D003911:Dextrans; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D005290:Ferric Compounds; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D006493:Heparin / Q000378:metabolism / Q000627:therapeutic use; D020767:Intracranial Thrombosis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018715:Microscopy, Video / Q000379:methods; D011486:Protein C / Q000378:metabolism / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics
D015703:Antigens, CD; D001779:Blood Coagulation Factors; D002712:Chlorides; D003911:Dextrans; D000074283:Endothelial Protein C Receptor; D005290:Ferric Compounds; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; C015219:fluorescein isothiocyanate dextran; D006493:Heparin; D016650:Fluorescein-5-isothiocyanate; C024555:ferric chloride