Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate

Von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate

Fibrin is actively involved in platelet reactions essential for thrombus growth, in which von Willebrand factor (VWF) might be an important mediator. The aim of this study was to localize VWF domains that bind to fibrin and to determine their relevance in platelet adhesion. VWF binds specifically to...

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Bibliographic Details
Published in:Blood Vol. 103; no. 5; pp. 1741 - 1746
Main Authors: Keuren, JeffreyF.W., Baruch, Dominique, Legendre, Paulette, Denis, Cécile V., Lenting, Peter J., Girma, Jean-Pierre, Lindhout, Theo
Format: Journal Article
Language:English
Published: Washington, DC Elsevier Inc 01-03-2004
The Americain Society of Hematology
Subjects:
Animals
Binding Sites
Binding, Competitive
Biological and medical sciences
Blood coagulation. Blood cells
Cell Adhesion
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Fibrin - chemistry
Fundamental and applied biological sciences. Psychology
General aspects, investigation methods, hemostasis, fibrinolysis
Humans
Kinetics
Mice
Mice, Inbred C57BL
Molecular and cellular biology
Platelet Adhesiveness
Platelet Aggregation
Platelet Glycoprotein GPIb-IX Complex - chemistry
Platelet Glycoprotein GPIIb-IIIa Complex - metabolism
Protein Binding
Protein Structure, Tertiary
Stress, Mechanical
Time Factors
von Willebrand Factor - chemistry
Animal model
Hemostatic
Thrombus
Rodentia
Polymer
Adhesion
Fibrin
Vertebrata
Platelet
Mammalia
Mouse
Hemostasis
Shear stress
Willebrand factor
Molecular domain
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Summary:Fibrin is actively involved in platelet reactions essential for thrombus growth, in which von Willebrand factor (VWF) might be an important mediator. The aim of this study was to localize VWF domains that bind to fibrin and to determine their relevance in platelet adhesion. VWF binds specifically to fibrin with an apparent Kd of 2.2 μg/mL. Competition in the presence of 2 complementary fragments, SpIII (residues 1-1365) and SpII (residues 1366-2050), indicated that the high affinity binding site for fibrin is located in the C-terminal part, thus distinct from the A domains. Comparison of 2 deleted rVWF (ΔD4B-rVWF, ΔC1C2-rVWF) suggested that the C1C2 domains contained a fibrin binding site. This site is distinct from RGD, as shown by binding of D1746G-rVWF to fibrin. Perfusion studies at high shear rate demonstrated that C1C2 domains were required for optimal platelet adhesion to fibrin. With the use of a VWF-deficient mouse model, it was found that plasma VWF is critical for platelet tethering and adhesion to fibrin. These results suggest a dual role of fibrin-bound VWF in thrombus formation: first, fibrin-bound VWF is critical in the recruitment of platelets by way of glycoprotein (GP) Ib, and, second, it contributes to stationary platelet adhesion by way of binding to activated αIIbβ3.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2003-07-2267