title: Hemostatic activation in a chemically induced rat model of severe hemolysis and thrombosis.
abstract: BACKGROUND
  In hemolytic diseases such as sickle cell disease and beta-thalassemia, the mechanisms of thrombosis are poorly understood, however erythrocyte/endothelium interactions are thought to play an important role. Appropriate animal models would increase our understanding of the pathophysiology of thrombosis and aid in the development of new therapeutic strategies. We previously reported that rats exposed to 2-butoxyethanol (2-BE) develop hemolysis and enhanced adherence of erythrocytes to the extracellular matrix, possibly secondary to the recruitment of cellular adhesion molecules at the erythrocyte/endothelium interface.
  
  
  METHODS
  We exposed rats to 250 mg/kg/day of 2-BE for 4 days, and collected blood for coagulation markers on each day.
  
  
  RESULTS
  As previously observed, erythrocytes dropped precipitously (8.0 to 1.8x10(6)/microl in 48 h), and diffuse microvascular thrombosis developed in the heart, lungs, liver, bones and eyes. Prothrombin times, activated partial thromboplastin times, fibrinogen, and antithrombin-III were unchanged between treated and control rats, indicating that hemostasis is largely unperturbed. However the thrombin-antithrombin III levels in the 2-BE treated rats for all days were 3-7 times greater than the control rats. The plasma intercellular adhesion molecule-1 (ICAM-1) levels of 2-BE treated animals were approximately twice that of the controls on days 2 and 3 and 1.5 times the controls on day 4 (P<0.05).
  
  
  CONCLUSIONS
  Our findings are consistent with the observations of increased erythrocyte aggregation, increased erythrocyte/endothelium interaction, and increased plasma ICAM-1 levels observed in sickle cell disease and beta-thalassemia patients. This model may be useful for studying therapeutic agents that disrupt erythrocyte/endothelium interactions.
authors.affiliation: Hemostasis and Thrombosis Center, Department of Medicine, Duke University Medical Center, Duke University Health System, Box 3422 Durham, NC 27710, USA. Lewis064@mc.duke.edu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Anil
authors.initials: A
authors.lastname: Potti
authors.forename: Heather A
authors.initials: HA
authors.lastname: Hoke
authors.forename: Keith F
authors.initials: KF
authors.lastname: Klemp
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Ward
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Peddada
authors.forename: Jogin
authors.initials: J
authors.lastname: Wu
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Ortel
mesh_terms: D000743:Anemia, Hemolytic / Q000097:blood / Q000139:chemically induced / Q000150:complications; D000755:Anemia, Sickle Cell / Q000503:physiopathology; D000818:Animals; D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D002450:Cell Communication; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D004903:Erythrocyte Aggregation; D005026:Ethylene Glycols; D005260:Female; D006461:Hemolysis / Q000502:physiology*; D006487:Hemostasis / Q000187:drug effects / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D051381:Rats; D011916:Rats, Inbred F344; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D017086:beta-Thalassemia / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D005026:Ethylene Glycols; C046193:antithrombin III-protease complex; D018799:Intercellular Adhesion Molecule-1; D000990:Antithrombin III; D010447:Peptide Hydrolases; C017096:n-butoxyethanol