Intimatan (dermatan 4,6-O-disulfate) prevents rethrombosis after successful thrombolysis in the canine model of deep vessel wall injury.
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.
Hong
Ting-Ting
TT
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.
Van Gorp
Cornelius L
CL
Cardin
Alan D
AD
Lucchesi
Benedict R
BR
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
D000925:Anticoagulants; D011994:Recombinant Proteins; C416431:intimatan; D003871:Dermatan Sulfate; D015844:Heparin Cofactor II; D013917:Thrombin; D010959:Tissue Plasminogen Activator