Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13.
The function of thrombospondin-1 (TSP-1) in hemostasis was investigated in wild-type (WT) and Tsp1-/- mice, via dynamic platelet interaction studies with A23187-stimulated mesenteric endothelium and with photochemically injured cecum subendothelium. Injected calcein-labeled WT platelets tethered or firmly adhered to almost all A23187-stimulated blood vessels of WT mice, but Tsp1-/- platelets tethered to 45% and adhered to 25.8% of stimulated Tsp1-/- vessels only. Stimulation generated temporary endothelium-associated ultralarge von Willebrand factor (VWF) multimers, triggering platelet string formation in 48% of WT versus 20% of Tsp1-/- vessels. Injection of human TSP-1 or thrombotic thrombocytopenic purpura (TTP) patient-derived neutralizing anti-ADAMTS13 antibodies corrected the defective platelet recruitment in Tsp1-/- mice, while having a moderate effect in WT mice. Photochemical injury of intestinal blood vessels induced thrombotic occlusions with longer occlusion times in Tsp1-/- venules (1027 +/- 377 seconds) and arterioles (858 +/- 289 seconds) than in WT vessels (559 +/- 241 seconds, P < .001; 443 +/- 413 seconds, P < .003) due to defective thrombus adherence, resulting in embolization of complete thrombi, a defect restored by both human TSP-1 and anti-ADAMTS13 antibodies. We conclude that in a shear field, soluble or local platelet-released TSP-1 can protect unfolded endothelium-bound and subendothelial VWF from degradation by plasma ADAMTS13, thus securing platelet tethering and thrombus adherence to inflamed and injured endothelium, respectively.
Bonnefoy
Arnaud
A
Center for Molecular and Vascular Biology, Laboratory of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium.
Daenens
Kim
K
Feys
Hendrik B
HB
De Vos
Rita
R
Vandervoort
Petra
P
Vermylen
Jos
J
Lawler
Jack
J
Hoylaerts
Marc F
MF
D000071120:ADAMTS13 Protein; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D000001:Calcimycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness / Q000187:drug effects; D013152:Splanchnic Circulation; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D019700:Thrombospondin 1 / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*
D007476:Ionophores; D019700:Thrombospondin 1; D014841:von Willebrand Factor; D000001:Calcimycin; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein