Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces.
The protein C/protein S system is known to regulate thrombin generation in vivo by cleaving factors Va and VIIIa. We have examined the activity of activated protein C in several tissue factor-initiated models of coagulation. We used 4 models: monocytes as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as the tissue factor source with platelets as the thrombin-generating surface; endothelial cells as both the tissue factor source and the thrombin-generating surface; and relipidated tissue factor with lipid vesicles providing the surface for thrombin generation. With the lipid surface, activated protein C dose-dependently reduced thrombin generation. Similarly, when endothelial cells provided the only surface for thrombin generation, activated protein C dose-dependently decreased thrombin generation significantly. By contrast, whenever platelets were present, activated protein C only minimally affected the amount of thrombin generated. When endothelial cells were the tissue factor source with platelets providing the surface for thrombin generation, activated protein C did increase the time until the burst of thrombin generation but had minimal effects on the total amount of thrombin generated. Activated protein C had essentially no effect on thrombin generation when monocytes were the tissue factor source with platelets providing the surface for thrombin generation. From the studies reported here, we conclude that in vivo, despite the important role of the protein C system in regulating thrombosis, activated protein C does not serve as a primary regulator of platelet-dependent thrombin generation.
Oliver
Julie A
JA
Duke University and the Durham VA Medical Hospital, Durham, NC, USA.
Monroe
Dougald M
DM
Church
Frank C
FC
Roberts
Harold R
HR
Hoffman
Maureane
M
D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D015943:Factor Va / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin
D008081:Liposomes; D011486:Protein C; D015943:Factor Va; D013925:Thromboplastin; D013917:Thrombin