Heparin compromises streptokinase-induced arterial patency in rabbits.
BACKGROUND
Little is known with regard to efficacy of heparin as an adjunct to fibrinolytics under conditions of severe vascular damage. In this study, we compared the effects of unfractionated heparin (UH), low-molecular weight heparin (LMWH), and recombinant desulfohirudin (HIR) in combination with streptokinase (SK) in such settings.


METHODS
We used an established rabbit model, in which thrombosis, critical stenosis, and vascular wall damage were introduced to a segment of the abdominal aorta and the effects of the respective therapies were assessed by time to patency (TTP in minutes), cumulative patency (CP (%)), lysis of original clot (CL (%)), and net clot accretion (NCA (%)). Treatments were administered over 90 min at the following doses: SK: 33,000 U/kg, UH: 125-250 U/kg, LMWH: 1.25-2.5 mg/kg, HIR: 0.25-0.55 mg/kg.


RESULTS
Unexpectedly, UH and LMWH had a paradoxical and detrimental effect on SK-mediated recanalization as measured by both TTP and CP. Thus, administration of SK vs. SK+UH or SK+LMWH resulted in TTP values of 43+/-8 min vs. 70+/-11 min (p<0.05) and 67+/-12 min. (p<0.08), respectively. For CP, the corresponding values were 21+/-7%, 0.5+/-0.3% and 9+/-8%. This delay in vessel recanalization occurred despite excessive systemic anticoagulation (activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) ratios >6 and >34, respectively). Of interest, both heparinoids completely inhibited SK-induced fibrinogen consumption (FC). In contrast, recombinant desulfohirudin (HIR) shortened SK-induced TTP (4.97+/-0.81 min) without preserving fibrinogen.


CONCLUSIONS
Our findings suggest that caution needs to be exercised, when using the combination of SK and heparinoids for the treatment of arterial thrombosis under conditions of severe vascular damage and stenosis.
Vlasin
M
M
Henderson Research Centre and McMaster University, Hamilton, Ontario, Canada.
Rak
J
J
Weitz
J I
JI
Peng
L
L
Gumulec
J
J
Johnston
M
M
Klement
P
P
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects; D001024:Aortic Valve Stenosis / Q000150:complications; D004195:Disease Models, Animal; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D005342:Fibrinolysis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006629:Hirudins / Q000494:pharmacology; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013300:Streptokinase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013927:Thrombosis / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors; D014654:Vascular Patency / Q000187:drug effects*
D006495:Heparin, Low-Molecular-Weight; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; D013300:Streptokinase