Increased thrombogenesis and embolus formation in mice lacking glycoprotein V.
The glycoprotein (GP) Ib-V-IX complex plays a critical role in initiating platelet adhesion to von Willebrand factor (vWF) at the site of vascular injury. The complex also forms a high-affinity binding site for thrombin. Using an intravital microscopy mouse model, it was previously established that vWF plays a critical role in mediating platelet adhesion and thrombus formation following mesenteric arteriolar injury induced by ferric chloride. Further characterization of this model showed that these thrombotic events were also thrombin dependent. Using this vWF- and thrombin-dependent model, this study shows that GP V gene deficiency significantly accelerates both platelet adhesion and thrombus formation in mice following arteriolar injury. The time required for vessel occlusion in GP V-deficient (GP V(-/-)) mice was significantly shorter than that in wild-type mice. Interestingly, large emboli were also produced in GP V(-/-) mice, but not in wild-type mice, causing frequent downstream occlusion. However, when the 2 genotypes were compared in the in vitro perfusion chamber where thrombin was inhibited by heparin, no significant differences were found in either initial single-platelet adhesion or thrombus volume. These results demonstrate that GP V(-/-) mice have accelerated thrombus growth in response to vascular injury and suggest that this is caused by enhanced thrombin-induced platelet activation rather than enhanced binding of GPIb-V-IX to vWF. Absence of GP V also compromises thrombus stability.
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Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Ramakrishnan
V
V
Ruggeri
Z M
ZM
Papalia
J M
JM
Phillips
D R
DR
Wagner
D D
DD
D000818:Animals; D001606:Bernard-Soulier Syndrome; D004617:Embolism / Q000235:genetics*; D018056:Hemorheology; D006493:Heparin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010973:Platelet Adhesiveness; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D013927:Thrombosis / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism / Q000494:pharmacology
D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D006493:Heparin; D013917:Thrombin