Therapeutic effect of a low molecular weight dermatan sulphate (Desmin 370) in rat venous thrombosis--evidence for an anticoagulant-independent mechanism.
We evaluated the capacity of a low molecular weight dermatan sulphate (D370) to prevent thrombus formation and to induce a reduction of a stabilized thrombus in a rat venous thrombosis model. Injection of D370, 10 min before induction of venous stasis (prevention model), prevented thrombus formation in a dose-dependent way (ED50: 2.3 mg/kg). When given to rats 6 h after induction of venous stasis (therapeutic model), D370 caused a time- and dose-dependent reduction in thrombus size (60% to 70% reduction 2 h after injection of 10 mg/kg). At comparable antithrombotic dosages (i.e. minimum dose giving complete inhibition of thrombus formation), heparin (0.5 mg/kg) only caused 40% reduction of a preformed thrombus while hirudin (1 mg/kg) was virtually ineffective (less than 10% reduction in weight). All three compounds inhibited 125I-fibrin(ogen) deposition on 6-h aged thrombi by more than 85%, suggesting that D370 and, to a lesser extent, heparin reduce thrombus size via mechanisms other than inhibition of thrombus accretion. The involvement of a fibrinolysis-mediated mechanism in the D370-induced effect is suggested by the following. EACA (1 g/kg), when given to thrombus-bearing control animals, did not influence thrombus weight. However, when administered before D370 treatment, it prevented the expected reduction in thrombus weight by more than 80%, without influencing the effect of D370 on 125I-fibrin(ogen) accumulation onto preexisting thrombi. D370 injection caused neither an enhancement of fibrinolytic activity nor a reduction of PAI in plasma. In vitro, D370 (200 microns/ml) was unable to potentiate the spontaneous or PA-induced lysis of 125I-fibrinogen labelled blood, plasma, or purified fibrin clots.(ABSTRACT TRUNCATED AT 250 WORDS)
Barbanti
M
M
Alfa Wassermann, Bologna, Italy.
Calanni
F
F
Milani
M R
MR
Marchi
E
E
Semeraro
N
N
Colucci
M
M
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003871:Dermatan Sulfate / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006487:Hemostasis / Q000187:drug effects; D008297:Male; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D013924:Thrombophlebitis / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control
D003871:Dermatan Sulfate