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: Naoto Nishigori, Masanori Matsumoto, Fumikazu Koyama, Masaki Hayakawa, Kinta Hatakeyayama, Saiho Ko, Yoshihiro Fujimura, Yoshiyuki Nakajima
• Journal: PloS one (PLoS One) Vol. 10 Issue 11 Pg. e0143136 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26580395 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Autoantibodies
• Organoplatinum Compounds
• Platelet Glycoprotein GPIIb-IIIa Complex
• von Willebrand Factor
• Oxaliplatin
• Bevacizumab
• Aspartate Aminotransferases

Topics

• Adult
• Aged
• Angiogenesis Inhibitors (therapeutic use)
• Antineoplastic Agents (administration & dosage, adverse effects)
• Aspartate Aminotransferases (blood)
• Autoantibodies (blood)
• Bevacizumab (therapeutic use)
• Blood Platelets (drug effects, metabolism, pathology)
• Colorectal Neoplasms (blood, drug therapy, pathology)
• Disease Progression
• Endothelial Cells (drug effects, metabolism, pathology)
• Female
• Hepatic Veno-Occlusive Disease (blood, etiology, pathology, prevention & control)
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Organoplatinum Compounds (administration & dosage, adverse effects)
• Oxaliplatin
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Splenomegaly (blood, etiology, pathology, prevention & control)
• Thrombosis (blood, etiology, pathology, prevention & control)
• von Willebrand Factor (metabolism)