title: von Willebrand Factor-Rich Platelet Thrombi in the Liver Cause Sinusoidal Obstruction Syndrome following Oxaliplatin-Based Chemotherapy.
abstract: Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin-based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation.
authors.affiliation: Department of Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Nishigori
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Koyama
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hayakawa
authors.affiliation: Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan.
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyayama
authors.affiliation: Department of Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Saiho
authors.initials: S
authors.lastname: Ko
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
authors.affiliation: Department of Surgery, Nara Medical University, Kashihara, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D000068258:Bevacizumab / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006504:Hepatic Veno-Occlusive Disease / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D013163:Splenomegaly / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001323:Autoantibodies; D009944:Organoplatinum Compounds; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014841:von Willebrand Factor; D000077150:Oxaliplatin; D000068258:Bevacizumab; D001219:Aspartate Aminotransferases