PB0301 - Impaired vWF-ADAMTS13 axis promotes mucosal microvascular thrombus formation and subsequent exacerbation in ulcerative colitis

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

KT

Kyota Tatsuta

medical doctor
Department of Medical Physiology, Hamamatsu University School of Medicine
Hammatsu, Shizuoka, Japan

Co-Author(s)

NH

Naoki Honkura

Associate professor
Department of Medical Physiology, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
NM

Nanami Morooka

Assistant professor
Department of Medical Physiology, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
MS

Mayu Sakata

Assistant professor
Department of Surgery, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
KK

Kiyotaka Kurachi

Associate Professor
Department of Surgery, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
HT

Hiroya Takeuchi

Professor
Department of Surgery, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
Koichi Kokame, PhD

Director
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center
Suita, Osaka, Japan
TU

Tetsumei Urano

Professor
Department of Medical Physiology, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan
Yuko Suzuki, MD, PhD

Professor
Department of Medical Physiology, Hamamatsu University School of Medicine
Hamamatsu, Shizuoka, Japan

Background: Ulcerative colitis (UC) is characterized by chronic inflammation of the gastrointestinal tract and increases the risk for venous thromboembolism. An endothelial injury marker, von Willebrand factor (vWF), increased in the blood of UC patients and correlated with disease activity. Several studies have reported the formation of thrombi in mucosal microvascular of inflamed colitis. However, their formation process and the significance in UC pathogenesis remain unclear.

Aims: To investigated the role of the vWF-ADAMTS13 axis in UC pathogenesis and its potential as a therapeutic target, using patients' plasma and UC animal model.

Methods: UC patients’ plasma and inflamed lesion tissue were analyzed and compared with control subjects (IRB: 21-208). For animal experiments, dextran sulfate sodium (DSS) was administrated to induce colitis in wild-type (WT) and ADAMTS13 deficiency (ADAMTS-KO) mice and evaluated disease progression, mucus layer disruption, leukocyte recruitment, and thrombus formation in mucosal vessels, using intravital multiphoton-excitation microscopy.

Results: The decreased plasma ADAMTS13 activity in UC patients significantly correlated with UC disease severity markers. Immunohistochemical staining showed a significant increase in vWF accumulation in the inflamed UC colon compared to normal colon. ADAMTS13-KO significantly aggravated colitis symptoms after 4 days of DSS administration compared to WT. Intravital colon imaging revealed early mucus layer disruption, increased leukocyte recruitment, and pronounced microvascular thrombi by DSS administration, which were more potent in ADAMTS13-KO than WT. Furthermore, ADAMTS13-KO formed microvascular thrombi before leukocyte recruitment, facilitating UC disease activity exacerbation. Administration of rhADAMTS13 significantly reduced the microvascular thrombi and leukocyte recruitment in both mice types, reducing colitis severity. These results suggested that the increased microthrombi associated with impaired ADAMTS13 function could be an exacerbating factor for colitis.

Conclusion(s): This study underscores the critical role of the vWF-ADAMTS13 axis in early UC pathogenesis. The therapeutic potential of rhADAMTS13 administration highlights this axis as a novel target for UC treatment strategies.