The effects of heparin and dermatan sulphate on t-PA-induced thrombolysis and blood loss in rabbits

Abstract

The clinical use of heparin in combination with tissue plasminogen activator (t-PA) is based upon the rationale that heparin acceleration of thrombin inhibition by antithrombin III (ATHI) should prevent thrombus growth, allowing for more rapid thrombolysis by t-PA. However, studies both in vitro and in vivo suggest that t-PA+heparin is not synergistic, presumably because t-PA and heparin compete for the same fibrin binding sites. Recenty, we found that dermatan sulphate, which accelerates thrombin inhibition by heparin cofactor II (HCH), prevented fibrin accretion and subsequent thrombus growth more effectively than heparin. Thus, we compared the abilities of heparin and dermatan sulphate to enhance t-PA-induced thrombolysis. Thrombolysis was assessed in 125I-fibrin labelled thrombi in the jugular veins of rabbits. There was no thrombolysis during 4h in saline-treated animals. When rabbits were infused with t-PA (30000 IU/kg/h), thrombolysis was 39±4%, p<0.01. 80-fold more heparin (on the basis of anti-thrombin U/kg) was required to enhance t-PA-induced thrombolysis than dermatan sulphate. The dose of [t-PA+heparin] which enhanced thrombolysis, increased bleeding 30-fold, assessed as blood loss from 5 cuts made in the rabbits' ears. The dose of [t-PA+dermatan sulphate] which enhanced thrombolysis did not increase bleeding. We conclude that both dermatan sulphate and heparin enhance t-PA induced thrombolysis, but the dose of heparin required to achieve this effect also enhances bleeding.