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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2423-2431
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Blood coagulation at the site of microvascular injury: effects of
low-dose aspirin
Anetta Undas,
Kathleen Brummel,
Jacek Musial,
Kenneth G. Mann, and
Andrew Szczeklik
From the Department of Medicine, Jagellonian University
School of Medicine, Cracow, Poland; and Department of Biochemistry,
University of Vermont, Burlington.
The sequence of coagulant reactions in vivo following vascular
injury is poorly characterized. Using quantitative immunoassays, the
time courses were evaluated for activation of prothrombin, factor (F)V,
FXIII, fibrinogen (Fbg) cleavage, and FVa inactivation in bleeding-time
blood collected at 30-second intervals from 12 healthy subjects both
before and after aspirin ingestion. Prothrombin decreased at a maximum
rate of 14.2 ± 0.6 nM per second to 10% of initial values at the
end of bleeding. Significant amounts of  -thrombin B chain appeared
rapidly at 90 seconds of bleeding and increased at a maximum rate of
0.224 ± 0.03 nM per second to a peak value of 38 nM. Kinetics of
prethrombin 2 generation was almost identical. Prothrombinase
concentration reached a peak value of 22 pM at 150 seconds and then
decreased to 9 pM at the end of bleeding. Prothrombin fragment 1.2 (F1.2) was produced explosively (0.673 ± 0.05 nM per second),
whereas thrombin-antithrombin III (TAT) complexes were generated at a
much slower rate (0.11 ± 0.008 nM per second;
P = .002). FVa light chain was detectable 30 seconds
later than the heavy chain (150 seconds) and was produced at a slightly
slower rate (0.027 ± 0.001 nM per second) when compared with the
heavy chain (0.032 ± 0.002 nM per second; P = .041). The 30 000 fragment (residues 307-506) of FVa heavy chain produced by
activated protein C appeared as early as at 90 seconds and increased
with time. Fbg was removed from the blood shed with a high rate of
0.047 ± 0.02 µM/s and became undetectable at approximately 180 seconds of bleeding. The velocity of FXIII activation correlated with
thrombin B-chain formation. A 7-day aspirin administration (75 mg/d)
resulted in significant reductions in maximum rates of (1) prothrombin
removal (by 29%; P = .008); generation of -thrombin B-chain (by 27.2%; P = .022), and prethrombin 2 (by
26%; P = .014); formation of F1.2 (by 31.4%;
P = .009) and TAT (by 30.3%; P = 0.013);
(2) release of FVa heavy chain (by 25%; P = .003) and FVa light chain (by 29.6%; P = .007); (3) Fbg depletion
from solution (by 30.5%; P = .002); and (4) FXIII
activation (by 28.6%; P = .003). Total amounts of the
proteins studied, collected at every interval, also significantly
decreased following aspirin ingestion. These results indicate that
low-dose aspirin impairs thrombin generation and reactions catalyzed by
this enzyme at the site of the injury.
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