von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins.
von Willebrand factor (VWF) protects factor VIII (FVIII) from proteolysis and mediates the initial contact of platelets with the injured vessel wall, thus playing an important role in hemostasis and thrombosis. VWF is crucial for the formation of occlusive thrombi at arterial shear rates. However, with only a few conflicting studies published, the role of VWF in venous thrombosis is still unclear. Using gene-targeted mice, we show that in ferric chloride-injured veins platelet adhesion to subendothelium is decreased and thrombus growth is impaired in VWF(-/-) mice when compared with wild type (WT). We also observed increased embolization in the VWF(-/-) mice, which was due to lower FVIII levels in these mice as recombinant factor VIII (r-FVIII) restored thrombus stability. Despite normalization of blood clotting time and thrombus stability after r-FVIII infusion, the VWF(-/-) venules did not occlude. Transgenic platelets lacking the VWF receptor GPIbalpha extracellular domain showed decreased adhesion to injured veins. But, after a delay, all the injured venules occluded in these transgenic mice. Thus, VWF likely uses other adhesion receptors besides GPIbalpha in thrombus growth under venous shear conditions. Our studies document crucial roles for VWF and FVIII in experimental thrombosis under venous flow conditions in vivo.
Chauhan
Anil K
AK
CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA-02115, USA.
Kisucka
Janka
J
Lamb
Colin B
CB
Bergmeier
Wolfgang
W
Wagner
Denisa D
DD
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014680:Veins / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D014841:von Willebrand Factor; D005169:Factor VIII