The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis.
GPIbalpha binding to von Willebrand factor (VWF) exposed at a site of vascular injury is thought to be the first step in the formation of a hemostatic plug. However, our previous studies in VWF-deficient mice demonstrated delayed but not absent arterial thrombus formation, suggesting that, under these conditions, GPIbalpha may bind other ligands or that a receptor other than GPIbalpha can mediate platelet adhesion. Here, we studied thrombus formation in transgenic mice expressing GPIbalpha in which the extracellular domain was replaced by that of the human IL-4 receptor (IL4Ralpha/GPIbalpha-tg mice). Platelet adhesion to ferric chloride-treated mesenteric arterioles in IL4Ralpha/GPIbalpha-tg mice was virtually absent in contrast to avid adhesion in WT mice. As a consequence, arterial thrombus formation was inhibited completely in the mutant mice. Our studies further show that, when infused into WT recipient mice, IL4Ralpha/GPIbalpha-tg platelets or WT platelets lacking the 45-kDa N-terminal domain of GPIbalpha failed to incorporate into growing arterial thrombi, even if the platelets were activated before infusion. Surprisingly, platelets lacking beta3 integrins, which are unable to form thrombi on their own, incorporated efficiently into WT thrombi. Our studies provide in vivo evidence that GPIbalpha absolutely is required for recruitment of platelets to both exposed subendothelium and thrombi under arterial flow conditions. Thus, GPIbalpha contributes to arterial thrombosis by important adhesion mechanisms independent of the binding to VWF.
Bergmeier
Wolfgang
W
CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. bergmeier@cbrinstitute.org
Piffath
Crystal L
CL
Goerge
Tobias
T
Cifuni
Stephen M
SM
Ruggeri
Zaverio M
ZM
Ware
Jerry
J
Wagner
Denisa D
DD
D000818:Animals; D001160:Arterioles / Q000473:pathology / Q000503:physiopathology; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010973:Platelet Adhesiveness / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000209:etiology; D014841:von Willebrand Factor / Q000502:physiology*
D053662:Interleukin-4 Receptor alpha Subunit; D008024:Ligands; D019038:Platelet Glycoprotein GPIb-IX Complex; D011994:Recombinant Proteins; D014841:von Willebrand Factor