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.
CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Anil K
AK
Chauhan
David G
DG
Motto
Colin B
CB
Lamb
Wolfgang
W
Bergmeier
Michael
M
Dockal
Barbara
B
Plaimauer
Friedrich
F
Scheiflinger
David
D
Ginsburg
Denisa D
DD
Wagner
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