title: Intimatan (dermatan 4,6-O-disulfate) prevents rethrombosis after successful thrombolysis in the canine model of deep vessel wall injury.
abstract: BACKGROUND
  Intimatan (dermatan 4,6-O-disulfate), a heparin cofactor II (HCII) agonist, inhibits both the fluid phase and thrombus bound thrombin. The efficacy of Intimatan as an adjunctive anticoagulant during thrombolysis was evaluated in the canine model of arterial injury.
  
  
  METHODS
  After forming an occlusive thrombus in the right carotid artery (RCA), twenty-one dogs were administered recombinant tissue plasminogen activator (rt-PA) intra-arterially to achieve thrombolysis in the presence of either 0.9% NaCl or Intimatan (9 mg/kg bolus+300 mug/kg/min i.v. infusion). Next, the left carotid arteries (LCA) of the same animals were injured in the presence of either Intimatan or 0.9% NaCl.
  
  
  RESULTS
  The incidence of RCA rethrombosis between the Intimatan and control groups was 2/9 and 8/12, respectively. The quality of RCA blood flow, i.e., patency score (Scale of 0-3, i.e., no flow to high flow, respectively), was 2.3+/-0.4 (Intimatan) versus 0.9+/-0.4 (0.9% NaCl). The incidence of primary thrombosis was determined among the groups as 0/9 (Intimatan) versus 7/12 (0.9% NaCl); the patency score was 2.8+/-0.1 (Intimatan) versus 0.9+/-0.4 (0.9% NaCl). Intimatan resulted in a >90% ex vivo inhibition of gamma-thrombin-induced platelet aggregation whereas 0.9% NaCl had no inhibitory effect. Clot-bound thrombin activity was reduced significantly by Intimatan. Intimatan induced <2-fold change in aPTT and bleeding time (BT) when corrected for the 0.9% NaCl group.
  
  
  CONCLUSIONS
  Intimatan significantly reduces the incidence of both primary and secondary arterial thrombosis while maintaining a high-grade vessel patency score with only moderate increases in BT and aPTT.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632, USA.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hong
authors.forename: Cornelius L
authors.initials: CL
authors.lastname: Van Gorp
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cardin
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001158:Arteries / Q000293:injuries / Q000473:pathology; D001760:Bleeding Time; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D003871:Dermatan Sulfate / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D015844:Heparin Cofactor II / Q000819:agonists; D008297:Male; D008956:Models, Chemical; D010974:Platelet Aggregation; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D011994:Recombinant Proteins; C416431:intimatan; D003871:Dermatan Sulfate; D015844:Heparin Cofactor II; D013917:Thrombin; D010959:Tissue Plasminogen Activator