title: A recombinant fragment of von Willebrand factor reduces fibrin-rich microthrombi formation in mice with endotoxemia.
abstract: BACKGROUND
  Disseminated fibrin deposition in the microvasculature such as in disseminated intravascular coagulation (DIC) arises from uninhibited activated coagulation secondary to sustained systemic inflammation. Currently there is no treatment for DIC. Treating the underlying trigger and supportive care are the current recommendations to manage DIC. This study aims at using recombinant von Willebrand factor (VWF) A2 domain polypeptide to inhibit VWF-mediated platelet adhesion to fibrin and prevent DIC.
  
  
  METHODS
  We use flow chamber assay to test the capacity of purified A2 protein to inhibit platelet adhesion to immobilized fibrin(ogen) and platelet-fibrin clot formation. We use a murine model of lipopolysaccharide-induced DIC to examine the effect of A2 protein on DIC.
  
  
  RESULTS
  The A2 protein blocked flow-dependent platelet adhesion to fibrin, delayed fibrin polymerization, and inhibited platelet-fibrin clot formation in vitro. The infusion of the purified A2 protein to the endotoxin-treated mice prevented fibrin-rich microthrombi formation in brain, lung, kidney, and liver. It also attenuated levels of inflammatory mediators, and markedly reduced mortality rates at 96hours.
  
  
  CONCLUSIONS
  The A2 protein inhibited platelet interaction with fibrin(ogen). Furthermore, A2 prevented disseminated fibrin-rich microthrombi and decrease mortality in a lipopolysaccharide-induced DIC murine model. A2 could provide a novel therapeutic approach in critically ill patients with uninhibited activated coagulation and disseminated fibrin deposition such as DIC.
authors.affiliation: Section of Critical Care Medicine, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX 77030; Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States.
authors.forename: Trung C
authors.initials: TC
authors.lastname: Nguyen
authors.affiliation: Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States.
authors.forename: Francisca
authors.initials: F
authors.lastname: Gushiken
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Juliana I
authors.initials: JI
authors.lastname: Correa
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Dong
authors.affiliation: Department of Pathology, Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Dasgupta
authors.affiliation: Department of Pathology, Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States.
authors.forename: Perumal
authors.initials: P
authors.lastname: Thiagarajan
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX 77030, United States. Electronic address: miguelc@bcm.edu.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cruz
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D019446:Endotoxemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000097:blood / Q000627:therapeutic use*; D010973:Platelet Adhesiveness / Q000187:drug effects; D011485:Protein Binding; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D014841:von Willebrand Factor / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C440499:lipopolysaccharide, Escherichia coli O111 B4; D014841:von Willebrand Factor; D005337:Fibrin
keywords: and fibrin; disseminated intravascular coagulation (DIC); endotoxemia; microvascular thrombosis; platelet adhesion