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Mechanisms of thrombin generation during surgery and cardiopulmonary bypass
[see comments]
MD Boisclair, DA Lane, H Philippou, MP Esnouf, S Sheikh, B Hunt and KJ Smith
Department of Haematology, Charing Cross and Westminster Medical School,
London, UK.
Although in vitro studies have been invaluable in revealing the complex
biochemistry of the blood coagulation system, the mechanisms involved
during the in vivo response to hypercoagulable stimuli are still unclear.
We have used plasma-based enzyme-linked immunosorbent assays (ELISAs) to
study the mechanisms by which the coagulation system is activated in vivo
during human cardiopulmonary bypass (CPB) surgery (n = 8). A novel
immunoassay for factor XIIa was used to detect activation of the contact
system, factor IX activation peptide (FIXAP) was used as a marker for
activation of factor IX, and prothrombin fragment F1 + 2 (F1 + 2) was used
as a marker for thrombin generation. The ELISA for FIXAP is described for
the first time herein. F1 + 2 levels increased early in response to
surgical intervention: from a baseline of 38.7 +/- 9.7 ng/mL (mean +/-SE),
levels increased rapidly during surgery and bypass to a maximum of 448.5
+/- 92.0 ng/mL. A modest yet significant increase in factor XIIa levels
from 3.47 +/- 0.54 ng/mL to 4.33 +/- 0.85 ng/mL was evident during surgery
before bypass, but no further significant increase was detected on
establishing extracorporeal circulation. FIXAP levels demonstrated a small
and late increase during surgery from 4.98 +/- 0.55 ng/mL to a maximum of
10.20 +/- 1.23 ng/mL, the increase beginning at the time of near maximal F1
+ 2 levels. There was no association between activation of the contact
system (factor XIIa levels) and the generation of thrombin (F1 + 2 levels).
However, a strong association (r = .705) was apparent between the
generation of thrombin (F1 + 2 levels) and activation of factor IX (FIXAP
levels), despite the delay between the activation of prothrombin and factor
IX. The data do not support the established view that contact activation
resulting from exposure of blood to foreign surfaces is the major
procoagulant stimulus in CPB. Instead, the results suggest that the main
trigger to coagulation during CPB surgery was provided via the tissue
factor-factor VIIa mechanism in response to the cutting of blood vessels,
which directly activated factor X and then prothrombin. The late activation
of factor IX, which presumably also contributed to maximal prothrombin
activation, could have arisen due to direct tissue factor-factor VIIa
action, or by secondary feedback action of thrombin on the intrinsic
system.
Volume 82,
Issue 11,
pp. 3350-3357,
12/01/1993
Copyright © 1993 by The American Society of Hematology
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