Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor.
Acute thrombotic arterial occlusion is the leading cause of morbidity and mortality in the Western world. Von Willebrand factor is thought to be the only indispensable adhesive substrate to promote thrombus formation in high shear environments. We found that thrombospondin-1, a glycoprotein enriched in arteriosclerotic plaques, might function as an alternative substrate for thrombus formation. Platelets adhered to thrombospondin-1 in a shear dependent manner with an optimum shear as found in stenosed arteries. Adhesion is extremely firm, with no detachment of platelets up to a shear rate of 4000 s(-1). Experiments using platelets from a patient completely lacking von Willebrand factor showed that von Willebrand factor is not involved in platelet binding to thrombospondin-1. Platelet adhesion to thrombospondin-1 is not mediated via beta3-integrins or GPIa. CD36 partially mediates the adhesion of pre-activated platelets. We identified GPIb as high shear adhesion-receptor for thrombospondin-1. Soluble GPIb, as well as antibodies against the GPIb, blocked platelet adhesion almost completely. The new discovered thrombospondin-1-GPIb adhesion axis under arterial shear conditions might be important, not only during thrombus formation but also for pathological processes where other cells bind to the endothelium or subendothelium, including arteriosclerosis, inflammation and tumor metastasis, and a promising therapeutic target.
Jurk
Kerstin
K
Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University-Hospital Münster, Mendelstr. 11, 48149 Münster, Germany.
Clemetson
Kenneth J
KJ
de Groot
Philip G
PG
Brodde
Martin F
MF
Steiner
Michael
M
Savion
Naphtali
N
Varon
David
D
Sixma
Jan J
JJ
Van Aken
Hugo
H
Kehrel
Beate E
BE
D006801:Humans; D008954:Models, Biological; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D013314:Stress, Mechanical; D019700:Thrombospondin 1 / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
D019038:Platelet Glycoprotein GPIb-IX Complex; D019700:Thrombospondin 1; D014841:von Willebrand Factor