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© 1999 American Heart Association, Inc.
Original Contributions |
Two-Chain Factor VIIa Generated in the Pericardium During Surgery With Cardiopulmonary Bypass
Relationship to Increased Thrombin Generation and Heparin Concentration
From the Imperial College School of Medicine, Charing Cross Hospital (H.P., D.A.L.), and the Royal Brompton Hospital (S.J.D., M.T.M., J.R.P., J.F.B.), London, United Kingdom.
Correspondence to David A. Lane, PhD, Department of Haematology, Charing Cross Hospital, Imperial College School of Medicine, Hammersmith, London W6 8RP, United Kingdom. E-mail d.lane{at}ic.ac.uk
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Abstract |
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Abstract—Several recent studies have proposed that coagulation is triggered during cardiopulmonary bypass surgery by extrinsic pathway activation involving factor VIIa generation, but the methodology was indirect. Therefore, 12 patients were studied during routine cardiac and cardiopulmonary bypass surgery. Samples were taken before, during, and after bypass from the perfusate, from the aorta (retrograde cardiac drainage), pericardium, and collected suction fluid originating from the whole operative field. These samples were analyzed by enzyme-linked immunosorbent assay for 2-chain factor VIIa, by prothrombin F1+2 assay, by thrombin-antithrombin (TAT) assay, and for heparin concentration. Factor VIIa, F1+2, and TAT levels in samples from the pericardium were greatly elevated (mean, 0.92 to 1.01, 227 to 334, and 399 to 526 µg/L, respectively; preoperative mean, 0.33, 32.3, and 1.90 µg/L, respectively; P<0.05 for all), whereas levels in suction fluid were less consistently high. Factor VIIa and both F1+2 and thrombin-antithrombin levels in samples from the aorta, pericardium, and suction fluid were significantly correlated (r=0.57, P<0.001, n=111; and r=0.51, P<0.001, n=105, respectively), and all were inversely correlated with heparin levels (r>-0.35, P<0.001, n>92). There was no evidence of factor VIIa generation in the circuit during bypass surgery, and both F1+2 and thrombin-antithrombin levels rose only
2-fold, probably because heparin levels were higher than
they were in the pericardium (P<0.05). We concluded
that appreciable activation of factor VII occurs on the pericardium and
that this is associated with increased thrombin generation. Ineffective
local heparinization may be partly responsible. These results suggest
that pericardium-induced activation of factor VII should be the target
of anticoagulant strategies during cardiopulmonary bypass
surgery.
Key Words: cardiopulmonary bypass • coagulation • heparin • pericardium
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Introduction |
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During cardiopulmonary bypass surgery, there is a substantial trigger to the blood coagulation system, resulting in thrombin generation, even in the presence of high concentrations of the anticoagulant heparin.1 2 3 The origins of the trigger have been uncertain and subject to speculation. Evidence of concurrent surface activation of prekallikrein and high-molecular-weight kininogen seemed to suggest that the contact (intrinsic) system of coagulation was the main stimulus.4 It was reasoned that the foreign surfaces in bypass equipment might form a critical focus for components of the intrinsic system to assemble and on which to be activated; such components are known to be activated slowly by glass and other surfaces. However, as the methodology for detection of early activation events in coagulation improved, evidence was presented that appeared to be incompatible with a primary role of the intrinsic system. Using enzyme-linked immunosorbent assays (ELISAs), several investigators showed that factor XIIa is unlikely to contribute to the activation of factor IX, factor X, or prothrombin.5 6 7 Furthermore, a patient deficient in factor XII was shown to generate levels of thrombin during bypass surgery comparable to those generated by patients with normal levels of factor XII.8 An alternative source of activation (ie, triggering of the extrinsic system) was suggested, but specific methodology was unavailable to provide direct experimental support for the proposal. Meanwhile, examination of blood in the pericardial cavity during bypass surgery provided evidence of the role of the wound in thrombin generation and implicated suctioned blood used for retransfusion as a source of activation during bypass.9 10 More recently, increased tissue factor antigen on the surface of mononuclear cells from the pericardial cavity has been reported.11 Enhanced generation was accompanied by elevated factor VIIa levels and increased prothrombin fragment F1+2 levels.
Collectively, these results point to a powerful stimulus to coagulation driven by extrinsic system activation involving tissue factor and factor VIIa. Recently, though, Parret and Hunt12 suggested that during bypass surgery, upregulation of monocyte CD11b may occur and that this could initiate coagulation at a point downstream of the extrinsic system in the coagulation pathway. If the extrinsic system is a powerful stimulator, it could have implications for anticoagulant therapy during bypass surgery. It is therefore of value to consider some potential limitations of the studies performed to date. At the center of the argument that tissue factor is a major trigger is the generation of factor VIIa, an obligatory partner for coagulation triggering.13 14 In the single study reported that measured changes in factor VIIa levels,11 a functional assay utilizing recombinant truncated tissue factor15 was used. Because heparin affects the performance of the functional factor VIIa assay, it was necessary to remove this polysaccharide before assaying, a procedure that may have resulted in the lower levels of factor VIIa found than are generally reported with the assay.
Factor VIIa may be measured in plasma by a number of methods differing in principle. The above-mentioned functional assay is specific for factor VIIa provided that no factor VII is activated during the clotting reaction that is its end point (tissue factor–independent activation of factor VII by factor Xa is possible16 ). An alternative approach was recently devised17 in which samples are assayed by specific ELISA and there are no induced clotting reactions that could cause amplification of any factor VIIa present. The capture antibody used in this assay was raised against a synthetic peptide based on the sequence adjacent to the cleavage activation site on factor VII. Importantly, when normal plasma is assayed using this immunological technique, the levels of unbound factor VIIa are systematically different from those found in the functional assay.17 Because of the importance of establishing the role of factor VIIa in coagulation activation during bypass surgery and because of the methodological uncertainties, we determined the levels of factor VIIa during bypass surgery using this ELISA and explored the relations among factor VIIa, markers of thrombin generation, and the level of heparin achieved during bypass surgery.
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Methods |
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Patients were randomly selected as part of a larger study of routine coronary artery revascularization including only first-time elective surgeries for coronary artery bypass grafts for ischemic heart disease. Ethical approval was given by the Ethics Committee of Royal Brompton Hospital. There were 12 patients (10 men and 2 women) with a mean weight of 83 kg and a mean age of 65 years. No patients had had previous cardiac surgery. All were operated on by the same surgeon.
Cardiopulmonary bypass was established with a 2-stage venous cannular and aortic return. Body temperature was lowered to a core temperature of 32°C. Cardiac arrest was induced by antegrade cold-blood cardioplegia at a volume of 150 mL/M2 over 3 minutes and maintained by cold-blood cardioplegia via retrograde perfusion of 75 mL/M2 over 3 minutes every 20 minutes, maintaining the coronary sinus pressure at <40 mg Hg. A microporous membrane oxygenator was used in all cases.
The mean time for cardiopulmonary bypass was 107 minutes. Before establishment of the extracorporeal circulation, heparin was administered intravenously to attain a mean administered dose of 510 IU/kg; details of the actual heparin levels achieved are presented in Results. Heparin was neutralized with protamine at the end of bypass. None of the patients received aprotinin.
Blood samples were taken from each patient through a separate, dedicated in-dwelling central venous line in the superior vena cava, directly from the pericardial cavity, from the outflow of coronary perfusion into the aorta, and from the pooled blood recollected by suction from the whole operative field into a cardiotomy reservoir.
Blood was collected into 105 mmol/L sodium citrate anticoagulant
(Becton Dickinson). The ratio of blood to anticoagulant was 9:1
(vol/vol). Platelet-poor plasma was obtained by
centrifugation at room temperature for 10 minutes at
2000g, snap-frozen, and stored at -70°C until assayed.
Plasma samples were then assayed for immunologically determined factor
VIIa, F1+2, and thrombin-antithrombin (TAT).
Samples were taken from each patient at 12 time points (samples 1 to
12); samples from the pericardium, suction fluid, and aorta (retrograde
cardiac drainage) were taken at 4 of these points during surgery
(samples 5 to 8). For details of the sampling points, see Table 1
. Blood taken after administration of
crystalloid was diluted by this infusion; therefore, increases in
levels of activation markers are underestimated with respect to samples
taken before surgery. Correction for dilution was not, however,
performed because hematocrits were not determined for every sample
collected. The increases in levels of markers should therefore be
considered as the minimum increases attained.
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Factor VIIa levels were determined by ELISA, which is described in
detail elsewhere.17 In brief, a synthetic peptide was
prepared, based on the sequence N terminus to the cleavage activation
site of factor VIIa, Arg152-Ile153. The 11-residue peptide also
contained an N-terminal Cys residue to facilitate coupling of the
peptide to a carrier protein by heterobifunctional conjugation. This
conjugate was used to immunize rabbits with a standard protocol, and
hyperimmune antisera were applied to a column containing
immobilized synthetic peptide. Specific antibody isolated
from this affinity chromatography step was found to
recognize factor VIIa but not factor VII (>3000-fold specificity). The
isolated antibody was used as a capture antibody in the ELISA. In the
original study, the assay was standardized with a single batch of
factor VIIa (batch C437831), a clinical-grade preparation purchased
from NovoNordisk. Subsequent examination of additional batches of
recombinant factor VIIa from this (including the material used for the
international standard for factor VIIa) and other manufacturers
indicated that this particular batch (C437831) had 10-fold higher
immunoreactivity in the ELISA and that its coagulant assay activity was
comparable to that of the other products. In this study, a highly
purified, well-characterized batch of factor VIIa from NovoNordisk
(batch 960207/1531) (supplied by Dr Maria Johannessen, NovoNordisk) was
used to standardize the ELISA. A consequence of this is that the levels
of plasma factor VIIa in this report are 10-fold higher than those
reported earlier. The reason for the different immunological
cross-reactivity of these different factor VIIa batches has not been
fully resolved. Two potential explanations have been considered. First,
batch C437831, the clinical-grade material, was supplied freeze-dried,
whereas batch 960207/1531 was frozen. Freeze-drying of the
latter batch resulted in a small (3-fold) increase in
cross-reactivity. Although they do not account totally for the
discrepancy, these preliminary observations suggest that the epitope
recognized by the capture antibody in the ELISA might become more
exposed on denaturation. Second is the possibility of degradation of
the epitope on factor VIIa that is recognized by the capture antibody.
This could occur if proteolysis of the newly generated C-terminal
Arg152 residue of factor VIIa occurs (a suggestion first made by Dr J.
Morrissey during the XVIth Congress of the International Society on
Thrombosis and Hemostasis, Florence, Italy, 1997).
Unfortunately, a quantitative evaluation of the C-terminal Arg cannot
be performed on batch C437831 because only trace amounts now remain. It
remains possible that this clinical-grade batch contains a different
content of C-terminal Arg152.
A related issue is the stability of the epitope when factor VIIa is added to plasma. Some reproducibility and stability data on the factor VIIa epitope detected by the ELISA were presented in the original report.17 These studies have now been expanded to show that in vitro epitope degradation in citrated plasma does not confound use of the assay.
This 10-fold difference in plasma factor VIIa levels estimated by the
ELISA arising from use of different standards is of interest in terms
of the plasma levels of factor VIIa obtained when the truncated,
soluble tissue factor clotting assay is used. It was previously
reported that the ELISA reports 100-fold lower values of plasma
factor VIIa than the functional assay; when the new factor VIIa
standard is used, that difference is reduced to 10-fold. This
remaining 10-fold difference in plasma levels determined by the 2
assays may be caused by in vivo, as opposed to in vitro, epitope
degradation. In vivo, factor VIIa may be more susceptible to the action
of carboxypeptidases in blood because of the Ca2+
dependency of their action. Differences in elimination profiles of
recombinant factor VIIa concentrates given to treat bleeding in
patients with coagulation factor deficiency and monitored by the factor
VIIa ELISA and the functional assay (with truncated tissue factor)
provide support for this (D.A. Lane, unpublished observations,
1998).
A final methodological consideration that can be mentioned relates use of the new factor VIIa standard used here to the presence of inhibitors of factor VIIa in plasma. Activation of factor VII to factor VIIa by tissue factor in plasma has been shown to be quantitative under optimum conditions. This suggests that complex formation involving factor VIIa and proteinase inhibitors does not significantly impede detection of factor VIIa immunoreactivity in plasma (D.A. Lane, unpublished observations, 1998).
The ELISA used for F1+2 is described in detail elsewhere,3 and that for TAT was purchased from Behringwerke. Heparin levels were determined with a commercial kinetic assay based on inhibition of factor Xa (Stachrome, Diagnostica Stago) using a Cobas Mira analyzer.
Means results are presented in the text (SEs are
presented in the Table
). Data were log-transformed before
analysis with either the unpaired or paired (where appropriate)
Student's t test. Correlation analysis was also
performed on log-transformed data.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Heparin levels in the patients (n=12) were 4.43 IU/mL after the initial heparin dose, 4.03 IU/mL at the beginning of bypass, and 2.57 IU/mL at the end of bypass. Lower levels were found in blood sampled from the pericardium (mean, samples 5 through 8: 2.86, 2.07, 2.01, and 1.90 IU/mL, respectively), and these levels were significantly lower (P<0.05) than levels in samples taken from the central line at corresponding times (4.03, 3.96, 3.72, and 3.53 IU/mL, respectively; see Table
and
Figure). Similarly, mean levels of
heparin in suction fluid at the same time points (3.43, 3.47, 3.52, and
3.41 IU/mL) were lower than corresponding levels in samples from the
central line, but these were significantly different only at sampling
points 5 and 7 (see Table). Retrograde coronary drainage
samples from the aorta were, in contrast, mostly statistically
indistinguishable from those taken from the central line, except at
sampling point 8 (2.84 IU/mL), which was significantly lower than the
level of the corresponding sample taken from the central line.
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), suction fluid (
), pericardium (
), and aorta (
) in
12 patients undergoing routine and cardiopulmonary bypass
surgery. For key to sampling points, see Methods and Table 1
Factor VIIa levels in samples from the central line decreased
significantly (rather than increased) during bypass from 0.33 to 0.17
µg/L (Table and Figure); the decreases were significant after heparin
infusion (between sampling points 4 and 11). Mean factor VIIa levels
were uniformly much higher in samples taken from the pericardium
(samples 5 through 8, 1.01, 0.92, 0.98, and 0.97 µg/L, respectively)
than in samples from the central line at all points
(P<0.05). Although mean levels were also higher in all
samples of suction fluid, differences were significant only at points 5
and 6 (P<0.05). Samples taken from the aorta at points 5
through 8 did not show large changes compared with samples from the
central line and were, surprisingly, constant throughout at 0.21
µg/L. The results at points 7 and 8 were significantly lower than the
initial central line result at point 1.
The mean level of F1+2 from the central
line increased significantly from its presurgical level of 32.3 µg/L
to 48.0 µg/L after heparin infusion and before the start of bypass
(compare sampling points 1 and 4) and rose progressively during bypass
from 37.6 to 70.2 µg/L at its end (samples 5 through 10; Table and
Figure). This modest (2-fold) rise was eclipsed by the more dramatic
and significant elevations found at points 5 through 8 in samples from
the pericardium (334, 256, 248, and 227 µg/L, respectively). The
suction fluid also had significant elevations above those of the
perfusate at sampling points 5, 7, and 8, whereas levels in the
aorta were more modest and not elevated significantly.
The marker of thrombin inhibition, TAT, was elevated above the
presurgical level of 1.90 µg/L immediately after the start of
anesthesia (sampling point 2) to 30.5 µg/L, and no
further rise was observed during bypass (between sampling points 4 and
10; Table and Figure). Once again, levels of TAT in samples from the
pericardium were all greatly and significantly elevated above levels in
corresponding samples from the central line (526, 515, 425, and 399
µg/L, respectively). Levels in suction fluid at sampling points 6 and
8 were also elevated, and the level in a single aortic sample (point 7)
was significantly less than the level in the central line sample taken
at the same time.
It was of interest to determine the relations between factor VIIa, F1+2, TAT, and heparin levels in samples taken from the operative field, where there was definite evidence of coagulation activation. For the following analysis, samples from pericardium, suction fluid, and aorta are considered together. First, as expected, levels of the 2 activation markers (F1+2 and TAT, reflecting thrombin generation and inhibition, respectively) were well correlated (r=0.63, P<0.001, n=98). Interestingly, levels of both F1+2 and TAT correlated well with those of factor VIIa (r=0.57, P<0.001, n=111; and r=0.51, P<0.001, n=105, respectively). All 3 activation markers (factor VIIa, F1+2, and TAT) were inversely correlated with heparin levels determined in aliquots of the same samples (r=-0.35, P<0.001, n=102; r=-0.46, P<0.001, n=92; and r=-0.53, P<0.001, n=109, respectively).
In contrast to these consistently correlating results, when samples taken from the central line were examined for relations between activation markers and heparin, no significant correlations were found.
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Discussion |
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A number of recent reports have highlighted the role of the extrinsic tissue factor/factor VIIa pathway of blood coagulation in the hypercoagulable response induced in cardiopulmonary bypass,5 7 8 11 18 19 a response that is difficult to suppress even with very high doses of heparin.1 2 3 Triggering of the coagulation system by the extrinsic pathway is thought to require 2 distinct components that interact to form an activation complex. The first of these components is tissue factor, a cell surface protein not found in appreciable quantities on the vascular endothelium or the surface of circulating mononuclear cells under normal physiological conditions.20 However, there is ample experimental evidence that tissue factor is abundant in structures underlying normal vessels and in atherosclerotic plaques.21 Furthermore, it is documented that mononuclear cells and even endothelial cells can become activated (possibly by cytokine stimulation) and express tissue factor.22 23 24 25 In short, it is reasonable to propose that tissue factor will be exposed and/or expressed as a consequence of tissue damage caused by sternotomy and vessel manipulation during heart surgery. Blood pooling in the pericardium may have been exposed to tissue factor, may contain cells activated to express tissue factor during surgery, and may even become exposed to tissue factor if this is present on the pericardium. Until recently, expression of tissue factor within the pericardial cavity during cardiopulmonary bypass had not been investigated experimentally. However, Chung et al11 showed that blood mononuclear cells taken from the pericardium express twice the level of tissue factor compared with cells taken simultaneously from the perfusate.
The second requirement for an activation complex is the presence of factor VIIa. The tissue factor–factor VIIa complex generates thrombin via factors IXa and Xa.26 Evidence of increased amounts and activity of an activation complex would be provided by increased factor VIIa levels. Until recently, the only assay available for detecting plasma factor VIIa levels was a functional assay using truncated recombinant tissue factor.15 27 As noted above, performance of this assay is influenced by heparin, and removal of the high heparin levels that occur during bypass is a potential source of confounding results. Accordingly, we used a recently developed assay to investigate factor VIIa in the pericardium and perfusate. The assay detects immunologically the cleavage activation site in factor VII, recognizing the new C terminus generated during activation. The recognition, or capture, antibody does not recognize single-chain factor VII on immunoblotting, and any detection of factor VII by the ELISA can be attributed to trace contamination by factor VIIa.
When blood from the pericardium was analyzed by ELISA,
all samples had elevated levels of factor VIIa, together with
corresponding elevations in markers of direct and indirect thrombin
generation (F1+2 and TAT; see Table and Figure).
These results strongly support suggestions that the extrinsic system is
involved in coagulation triggering in cardiopulmonary
bypass5 6 8 and directly confirm that 2-chain
factor VIIa is generated on the
pericardium.11
Interestingly, pericardial blood had lower levels of heparin than corresponding perfusate samples, and the levels of heparin in samples from the operative field correlated inversely with those of activation markers, including factor VIIa. This suggests that poor local anticoagulation is at least partially responsible for factor VIIa and thrombin generation. Heparin has been reported to be an effective inhibitor of coagulation activation when factor VIIa has not been activated28 29 ; however, it is not so efficient once factor VIIa is activated. These observations, together with our current findings, raise the possibility that excessive pericardial blood coagulation activation could be suppressed if anticoagulant control were improved.
Blood collected as suction fluid and stored for retransfusion also had elevated activation marker levels, although these levels were lower than those in samples from the pericardium. Elevations may have been diminished by dilution of blood in the operative field that was not exposed to tissue factor. These results confirm the suggestions and findings of others that the general practice of retransfusion is a potential source of activated hemostatic components.10 Only a few key activation markers reflecting thrombin generation and inhibition were studied here, but given the known ubiquitous action of thrombin, it seems probable that its many substrates (fibrinogen, factor V, factor VII, and platelets) may all become activated.
In the current study, activation of coagulation in the blood circulating in patients was low. Indeed, factor VIIa levels actually fell, and F1+2 levels rose slightly but significantly. It appears that in this series of patients, activation by the bypass circuit was less than we and others have reported in previous series.2 3 5 8 A possible explanation for this is the very high level of heparin maintained in the perfusate during bypass. Heparin levels are not usually measured specifically but assessed by their effects on activated coagulation time; therefore, detailed comparisons between different studies is not possible. In the current series, there was limited thrombin generation in the circuit, so it was not necessary to invoke circuit-dependent mechanisms of coagulation activation in addition to the pericardium source. This finding of minimal circuit thrombin generation does not exclude additional mechanisms of triggered activation in the circulation (such as those arising from monocyte or contact pathway activation) that have occurred in other patient series (in which definite evidence of more extensive activation has been reported). A possible contributory explanation for more extensive activation of coagulation in the circuit in other studies might be lower heparin levels than found here.
The results of this study confirming extensive pericardium factor VIIa and thrombin generation, together with those of other recent studies, have potential practical consequences. First, it has been pointed out by others9 10 that retransfusion of activated blood should be viewed as a possible hazard. The results of the current study suggest that very high levels of heparin in the perfusate may be effective in minimizing the effects of transfused activated coagulation factors. Second, knowledge of a major source of activation may enable anticoagulation strategies to be modified. Particularly, it would seem sensible to target the pericardium to achieve more effective suppression of coagulation, because the levels of heparin at this site were found here to be systematically lower than in the circuit. Clearly, if knowledge of the molecular basis of the tissue factor–factor VIIa interaction30 31 is translated into novel therapeutic and specific anticoagulant agents, triggered coagulation on the pericardium during cardiac surgery would be an interesting and potentially profitable situation for their evaluation.
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Acknowledgments |
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This work was supported by grants from the Wellcome Trust and the British Heart Foundation (PG 94127 and 95128).
Received January 15, 1998; accepted June 18, 1998.
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