We have compared the thrombolytic efficacy of a novel single-chain, recombinant
tissue-type plasminogen activator variant,
LY210825, containing the second kringle and
serine protease domains of native
tissue-type plasminogen activator, with
anisoylated plasminogen-streptokinase activator complex (
APSAC). Male hounds (16-22 kg) were anesthetized, the left circumflex coronary artery was isolated and an electromagnetic flow probe was placed around the artery proximal to the first main branch for the measurement of coronary blood flow. An occlusive
thrombus was formed after electrolytic injury of the intima of the coronary artery. After an occlusion period of 1 hr, either
LY210825 (n = 8) or
APSAC (n = 6) was administered as a single i.v. injection of 0.45 mg/kg. Blood was drawn (3.8%
citrate) for determination of plasma
fibrinogen,
plasminogen and
alpha-2 antiplasmin. Time to reperfusion was significantly faster with
LY210825 than with
APSAC, 20 +/- 2 vs. 54 +/- 8 min, respectively. The incidence of reocclusion was similar for both agents.
APSAC produced significant depletion of
alpha-2 antiplasmin,
plasminogen and circulating
fibrinogen, whereas
LY210825 caused only slight consumption of
plasminogen and only small decreases in
fibrinogen. After a single injection of
LY210825, thrombolytic concentrations of
plasminogen activator were available immediately, whereas there was a significant delay in lytic concentrations of active
streptokinase-
plasmin complex. Consequently,
LY210825 reperfused the coronary artery faster than did
APSAC. In addition,
LY210825 spared plasma
fibrinogen,
plasminogen and
alpha-2 antiplasmin and therefore, could potentially minimize the risk of
bleeding complications.