Blood inhibitory capacity toward exogenous plasmin.
Stabilized, active plasmin is a novel thrombolytic for direct delivery to clots. Although it is known that protease inhibitors in plasma inhibit plasmin, the amount of plasmin that can be added to plasma/blood before free plasmin is observed is not clear. Determination of free plasmin activity in plasma using chromogenic substrates represents a challenge due to false-positive signals from plasmin entrapped by alpha2-macroglobulin. Size-exclusion chromatography was used to separate the plasmin-alpha2-macroglobulin complex from uninhibited, free plasmin. In this in-vitro study, exogenous plasmin is effectively inhibited up to 2.4 micromol/l after 5-min incubation with plasma at 37 degrees C. Initially, plasmin was consumed predominantly by alpha2-antiplasmin up to 1.2 micromol/l plasmin. Following exhaustion of alpha2-antiplasmin, plasmin was further consumed by alpha2-macroglobulin up to 2.4 micromol/l plasmin added to human plasma. Whole human blood was found to have an increased inhibitory capacity over that of plasma; free plasmin activity could be measured only above 3.8 micromol/l added plasmin. In conclusion, several mechanisms exist that control plasmin activity in human blood; in addition to alpha2-antiplasmin and alpha2-macroglobulin, blood cells contribute to the inhibition of exogenously administered plasmin. These in-vitro results indicate that doses of plasmin up to approximately 12 mg/kg in humans can be completely inactivated by blood.
Banbula
Agnieszka
A
Talecris Biotherapeutics, Research Triangle Park, North Carolina 27709, USA.
Zimmerman
Thomas P
TP
Novokhatny
Valery V
VV
D001773:Blood Cells / Q000378:metabolism*; D005341:Fibrinolysin / Q000032:analysis* / Q000037:antagonists & inhibitors*; D006801:Humans; D010949:Plasma / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000494:pharmacology
D000979:alpha-2-Antiplasmin; D000511:alpha-Macroglobulins; D005341:Fibrinolysin