Expression of a structurally constrained von Willebrand factor variant triggers acute thrombotic thrombocytopenic purpura in mice.
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that presents with thrombocytopenia, disseminated thrombosis, hemolytic anemia, and organ dysfunction. The etiology of TTP has revealed that patients share a deficiency in plasma protease a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), the enzyme responsible for cleaving ultra-large von Willebrand factor (VWF) multimers into nonthrombogenic fragments. Therefore, existing TTP mouse models were developed by targeted disruption of the ADAMTS13 gene. ADAMTS13(-/-) mice are mostly asymptomatic in the absence of a trigger, as redundant proteases appear to take on VWF processing. As an alternative approach to creating one such model, we devised a strategy based on the expression of a cleavage-resistant VWF mutant in mice. The creation of a disulfide bond within the A2 domain of VWF was found to render VWF multimers resistant to proteolysis by plasma proteases under flow. Furthermore, mice expressing the murine VWF/p.S1494C-p.A1534C mutant present with symptoms characteristics of acute TTP such as thrombocytopenia, red cell shredding, accumulation of VWF-rich thrombi in the microvasculature, and advanced TTP symptoms such as renal dysfunction and splenomegaly. Because this model appears to faithfully emulate the pathophysiology of TTP, it should prove most useful in the study of microangiopathic diseases and their treatment.
Kyoto University, Career-Path Unit for Young Life Scientists, Kyoto, Japan;
Yoko
Y
Morioka
Inserm Unité 770, Université Paris-Sud, Unité Mixte de Recherche-S 770, Le Kremlin-Bicêtre, France; and.
Caterina
C
Casari
Inserm Unité 770, Université Paris-Sud, Unité Mixte de Recherche-S 770, Le Kremlin-Bicêtre, France; and.
Nikolett
N
Wohner
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
Sungyun
S
Cho
Kyoto University, Career-Path Unit for Young Life Scientists, Kyoto, Japan;
Sachiko
S
Kurata
Kyoto University, Career-Path Unit for Young Life Scientists, Kyoto, Japan;
Ayumi
A
Kitano
Inserm Unité 770, Université Paris-Sud, Unité Mixte de Recherche-S 770, Le Kremlin-Bicêtre, France; and.
Olivier D
OD
Christophe
Inserm Unité 770, Université Paris-Sud, Unité Mixte de Recherche-S 770, Le Kremlin-Bicêtre, France; and.
Peter J
PJ
Lenting
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA.
Renhao
R
Li
Inserm Unité 770, Université Paris-Sud, Unité Mixte de Recherche-S 770, Le Kremlin-Bicêtre, France; and.
Cécile V
CV
Denis
Kyoto University, Career-Path Unit for Young Life Scientists, Kyoto, Japan;
Nicolas
N
Prévost
D000595:Amino Acid Sequence; D000818:Animals; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014841:von Willebrand Factor / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D004220:Disulfides; D014841:von Willebrand Factor; D010447:Peptide Hydrolases