Circulation, Vol 90, 2432-2438, Copyright © 1994 by American Heart Association
BJ Meyer, JJ Badimon, A Mailhac, A Fernandez-Ortiz, JH Chesebro, V Fuster and L Badimon
BACKGROUND--Residual mural thrombus on severely damaged arterial wall is
very thrombogenic. We tested the hypothesis that direct thrombin inhibition
will block thrombus growth on fresh thrombus better than indirect thrombin
inhibition, cyclooxygenase inhibition, or both. METHODS AND RESULTS--A
fresh mural thrombus was formed by directly perfusing fresh porcine blood
for 5 minutes over severely damaged arterial wall at a high shear rate in a
well-characterized ex vivo perfusion system. The average platelet (P) and
fibrinogen (F) deposition (D) achieved in 5 minutes were 382 +/- 32 x 10(6)
platelets/cm2 and 296 +/- 36 x 10(12) fibrinogen molecules/cm2,
respectively. Thrombus growth on the fresh mural thrombus was quantitated
by directly perfusing blood from pigs with 111In-labeled platelets and
125I-labeled fibrinogen for an additional 5 minutes over the preformed
mural thrombus. Treatment included recombinant hirudin (1 mg/kg per hour
IV) as a probe for thrombin, aspirin (5 mg/kg IV) as a platelet inhibitor
of cyclooxygenase, heparin (moderate, 100 IU/kg per hour IV; high-dose, 250
IU/kg per hour IV) as an indirect thrombin inhibitor, and heparin (100
IU/kg per hour) plus aspirin (5 mg/kg IV). Thrombus growth as measured by
labeled PD (x 10(6)/cm2) and FD (x 10(12) molecules/cm2) was mildly but not
significantly reduced by aspirin (1034 +/- 92 and 436 +/- 78, respectively)
compared with baseline (1113 +/- 67 and 545 +/- 52, respectively).
Inhibition of thrombus growth with heparin was dose dependent. A regression
analysis showed an inverse correlation of PD and FD with mean plasma
heparin concentrations (r = -.81, P = .0001 and r = -.49, P = .0007,
respectively). Recombinant hirudin led to a profound inhibition of thrombus
growth (PD, 30 +/- 12; FD, 109 +/- 21), which was significant compared with
all groups, even the highest dosage of heparin (250 IU/kg per hour).
CONCLUSIONS--Specific thrombin inhibition markedly inhibits platelet and
fibrinogen deposition onto fresh mural thrombus at a high shear rate.
Aspirin alone or in combination with heparin has little effect on evolving
thrombosis. Heparin dose dependently reduces thrombus growth, but even the
highest dosage is less effective than hirudin. Thrombin appears to be the
primary activator of platelets by fresh thrombus.
ARTICLES
Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy
Cardiovascular Biology Research Laboratory, Massachusetts General Hospital, Boston.
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