Systemic antithrombotic effects of ADAMTS13.
The metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) cleaves highly adhesive large von Willebrand factor (VWF) multimers after their release from the endothelium. ADAMTS13 deficiency is linked to a life-threatening disorder, thrombotic thrombocytopenic purpura (TTP), characterized by platelet-rich thrombi in the microvasculature. Here, we show spontaneous thrombus formation in activated microvenules of Adamts13-/- mice by intravital microscopy. Strikingly, we found that ADAMTS13 down-regulates both platelet adhesion to exposed subendothelium and thrombus formation in injured arterioles. An inhibitory antibody to ADAMTS13 infused in wild-type mice prolonged adhesion of platelets to endothelium and induced thrombi formation with embolization in the activated microvenules. Absence of ADAMTS13 did not promote thrombi formation in alphaIIbbeta3 integrin-inhibited blood. Recombinant ADAMTS13 reduced platelet adhesion and aggregation in histamine-activated venules and promoted thrombus dissolution in injured arterioles. Our findings reveal that ADAMTS13 has a powerful natural antithrombotic activity and recombinant ADAMTS13 could be used as an antithrombotic agent.
Chauhan
Anil K
AK
CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Motto
David G
DG
Lamb
Colin B
CB
Bergmeier
Wolfgang
W
Dockal
Michael
M
Plaimauer
Barbara
B
Scheiflinger
Friedrich
F
Ginsburg
David
D
Wagner
Denisa D
DD
D000071120:ADAMTS13 Protein; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000941:Antigens / Q000378:metabolism; D001160:Arterioles / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000235:genetics; D011697:Purpura, Thrombotic Thrombocytopenic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014699:Venules / Q000378:metabolism / Q000473:pathology; D014841:von Willebrand Factor / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D005343:Fibrinolytic Agents; C029417:Von Willebrand antigen; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein