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Blood, 1 February 2006, Vol. 107, No. 3, pp. 955-964.
Prepublished online as a Blood First Edition Paper on October 4, 2005; DOI 10.1182/blood-2004-12-4856.
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Submitted December 21, 2004
Accepted September 19, 2005
Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS-13
Arnaud Bonnefoy, Kim Daenens, Hendrik B Feys, Rita De Vos, Petra Vandervoort, Jos Vermylen, Jack Lawler, and Marc F Hoylaerts*
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; INSERM, U 553; IFR 105, Institut d'Hematologie, Universite Paris VII Denis Diderot, Paris, France
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
Laboratory for Thrombosis Research, IRC, KULeuven Campus Kortrijk, University of Leuven, Leuven, Belgium
Laboratory of Morphology and Molecular Pathology, University of Leuven, Kortrijk, Belgium
Department of Pathology, Harvard Medical School, Boston, MA, USA
* Corresponding author; email: marc.hoylaerts{at}med.kuleuven.ac.be.
The function of thrombospondin-1 (TSP-1) in hemostasis was investigated in wild type (WT) and TSP-1-/- mice, via dynamic platelet interaction studies with A23187 stimulated mesenteric endothelium and with photochemically injured caecum subendothelium. Injected calcein labeled WT platelets tethered or firmly adhered to almost all A23187 stimulated blood vessels of WT mice, but TSP-1-/- platelets tethered to 45% and adhered to 25.8% of stimulated TSP-1-/- vessels only. Stimulation generated temporary endothelium-associated ultralarge von Willebrand factor (VWF) multimers, triggering platelet string formation in 48% of WT versus 20% of TSP-1-/- vessels. Injection of human TSP-1 or TTP patient-derived neutralizing anti-ADAMTS13 antibodies corrected the defective platelet recruitment in TSP-1-/- mice, while having a moderate effect in WT mice. Photochemical injury of intestinal blood vessels induced thrombotic occlusions with longer occlusion times in TSP-1-/- venules (1027±377s) and arterioles (858±289s) than in WT vessels (559±241s, P< 0.0003; 443±413s, P< 0.003), 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.
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