Visualizing the von Willebrand factor/glycoprotein Ib-IX axis with a platelet-type von Willebrand disease mutation

• Published in: Blood Vol. 114; no. 27; pp. 5541 - 5546
• Main Authors: Guerrero, Jose A., Kyei, Mark, Russell, Susan, Liu, Junling, Gartner, T. Kent, Storrie, Brian, Ware, Jerry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2009; American Society of Hematology
• Series: Thrombosis and Hemostasis
• Subjects: Animals; Blood Platelets - metabolism; Blood Platelets - pathology; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Carotid Artery Injuries - complications; Female; Fibrinogen - metabolism; Flow Cytometry; Humans; Male; Megakaryocytes - metabolism; Megakaryocytes - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Mutation; Platelet Glycoprotein GPIb-IX Complex - genetics; Platelet Glycoprotein GPIb-IX Complex - metabolism; Platelet Membrane Glycoprotein IIb - metabolism; Thrombosis - etiology; Thrombosis and Hemostasis; von Willebrand Diseases - blood; von Willebrand Diseases - genetics; von Willebrand Diseases - metabolism; von Willebrand Factor - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-03-210823

Platelet-type von Willebrand disease (PT-VWD) is a bleeding disorder of the platelet glycoprotein Ib-IX/von Willebrand factor (VWF) axis caused by mutations in the glycoprotein Ib-IX receptor that lead to an increased affinity with VWF. In this report, platelets from a mouse expressing a mutation associated with PT-VWD have been visualized using state-of-the art image collection and processing. Confocal analysis revealed that VWF bound to the surface of single platelets and bridging micro-aggregates of platelets. Surface-bound VWF appears as a large, linear structure on the surface of 50% of the PT-VWD platelets. In vivo thrombus formation after chemical injury to the carotid artery revealed a severe impairment to occlusion as a consequence of the PT-VWD mutation. In vitro stimulation of PT-VWD platelets with adenosine diphosphate or thrombin demonstrates a significant block in their ability to bind fibrinogen. The impairment of in vivo thrombus formation and in vitro fibrinogen binding are more significant than might be expected from the observed platelet binding to VWF polymers over a small portion of the plasma membrane. Visualization of the receptor/ligand interaction and characterization of a severe antithrombotic phenotype provide a new understanding on the molecular basis of bleeding associated with the PT-VWD phenotype.