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J Thorac Cardiovasc Surg 1999;118:422-429
© 1999 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

CARDIOPULMONARY BYPASS AND ACTIVATION OF ANTITHROMBOTIC PLASMA PROTEIN C

This work was supported in part by grants from the Sigrid Jusélius Foundation, the Paulo Foundation, the Finnish Cultural Foundation, the Stein Endowment Fund, and the National Institutes of Health (R37HL52246 and R01HL 21544).

Address for reprints: Jari Petäjä, MD, PhD, Children’s Hospital, University of Helsinki, Stenbäckinkatu 11, FIN-00290 Helsinki, Finland (E-mail: jari.petaja{at}dlc.fi).

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective: We hypothesized that antithrombotic plasma-activated protein C plays a defensive antithrombotic role during coronary ischemia and postischemic reperfusion.
Methods and results: We evaluated protein C activation during cardiopulmonary bypass and coronary reperfusion in 20 patients undergoing coronary bypass surgery. During cardiopulmonary bypass and during the 10 minutes after aortic unclamping, the plasma levels of protein C (mean ± standard error of the mean) decreased from 123% ± 7% to 74% ± 5% of normal mean. In contrast, the levels of activated protein C in plasma increased from 122% ± 8% to 159% ± 21%, and the activated protein C/protein C ratio increased from 1.04 ± 0.08 to 2.29 ± 0.31 (P = .006, 2-tailed Wilcoxon signed rank test). Patients were stratified on the basis of the increase in activated protein C in the coronary sinus plasma at 10 minutes after reperfusion by means of the arbitrary value of 1.5 for the activated protein C/protein C ratio. Within 24 hours, the patients with low increases in activated protein C (ratio < 1.5, n = 8) had a significantly (P < .05) lower cardiac output and mean pulmonary artery pressure, as well as a higher systemic vascular resistance, than patients (n = 11) with high increases in activated protein C (ratio > 1.5). The rapid increase in activated protein C during the first 10 minutes after aortic unclamping indicated protein C activation in the reperfused vascular beds.
Conclusions: The antithrombotic protein C pathway was significantly activated during cardiopulmonary bypass mainly during the minutes after aortic unclamping in the ischemic vascular beds. Suboptimal protein C activation during ischemia may impair the postischemic recovery of human heart and circulation.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Acute thrombosis of coronary arteries is a central event in myocardial infarction, ^1-3 and microvessel thrombi may exacerbate the ischemic damage. ⁴ Activation of coagulation in the coronary vascular bed during cardiac operations may also impair myocardial postischemic recovery, and it may be related to perioperative myocardial infarction. ^5-7 Thus the regulation of coagulation and potential physiologic anticoagulant defensive mechanisms during myocardial ischemia are highly relevant for the pathophysiology of the coronary artery disease and for the operative management of the disease.

Protein C pathway is a major physiologic anticoagulant system whose defects result in significant thrombotic diathesis. ^8-12 Activated protein C (APC) may be an important anticoagulant in arterial circulation because, in animal studies, both physiologic activation of protein C in ischemic coronary circulation ¹³ and promising results of therapeutic use of APC in several models of arterial thrombosis have been reported. ^14-19 During human cardiac surgery and coronary ischemia, the protein C pathway has previously been evaluated in terms of its nonenzymatic components, including zymogen protein C, ^20,21 but informative data for APC levels in plasma are lacking.

In this study, we demonstrate a significant activation of protein C during cardiopulmonary bypass (CPB) and especially during myocardial reperfusion. Moreover, the increase in APC measured after 10 minutes of reperfusion is associated with more favorable cardiac function 24 hours after the operation. The data suggest an antithrombotic role for protein C activation during vascular ischemia.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients.
We studied 20 men undergoing CPB for elective coronary artery bypass grafting. The mean age was 61 years, ranging from 42 to 77 years. The present study was integrated with an intervention trial of nitecapone during CPB. ²² Seven of the patients belonged to the control group and 13 of the patients to the nitecapone group (see below).

Anesthesia and operation.
Patients were premedicated with lorazepam. Anesthesia was both induced and maintained with fentanyl citrate and midazolam. Enflurane or isoflurane was supplemented when needed. Pancuronium was used for muscle relaxation. A ventilator was used before CPB and after aortic unclamping.

The aorta and right atrium were cannulated for CPB. Left ventricular pressure was measured with a 4F pediatric thermodilution catheter (Arrow AI-07122, Arrow International, Inc, Reading, Pa) and single-use transducer (Deltran II, Utah Medical Products, Inc, Midvale, Utah). The catheter was placed into the left ventricle via the right superior pulmonary vein and the mitral valve. The coronary sinus was catheterized through the right atrium with a 14F coronary sinus cannula (Research Medical Inc, Sandy, Utah).

With the aid of conventional monitor devices and techniques, multiple hemodynamic variables (heart rate, stroke volume, mean arterial pressure [MAP], cardiac output [CO] and cardiac index [CO/body surface area], mean central venous pressure [CVP], pulmonary capillary wedge pressure [PCWP], mean pulmonary artery pressure [PAP], diastolic PAP, systemic vascular resistance [SVR], systemic vascular resistance index, pulmonary vascular resistance [PVR], and pulmonary vascular resistance index) were recorded at induction, immediately after CPB, on closure of the sternum, and 6 and 24 hours after the operation. In the calculations, the following formulas were used:

      SVR = 80 · (MAP – CVP)/CO

      PVR = 80 · (PAP – PCWP)/CO

The extracorporeal circuit was primed with 2000 mL of crystalloid solution containing 5000 IU of heparin. Before cannulation, the patients received a 300 IU/kg dose of heparin. Additional heparin was given when needed to maintain the activated clotting time over 400 seconds. CPB was conducted with nonpulsatile perfusion at a flow rate of 2.0 to 2.4 L/m². Mean arterial pressure was maintained at 40 to 80 mm Hg and hypothermia at 30°C to 32°C. The mean duration of CPB was 95 minutes (range, 47-146 minutes). After cessation of CPB, protamine (1 mg/100 IU of heparin) was administered. The duration of the extracorporeal perfusion after aortic unclamping was, on average, 30% of aortic crossclamping time.

The present study was integrated as a part of a nitecapone intervention trial. Nitecapone is a catechol derivative acting as a scavenger of superoxide, nitric oxide, hydrogen peroxide, and hydroxyl radicals, resulting in an antioxidant effect. In the control subjects, cardioplegia was induced with Plegisol solution (Orion-Pharma, Espoo, Finland) in a dose of 15 mL/kg body weight. An additional 2.0 mL/kg dose of the cardioplegic solution was infused every 15 minutes unless earlier necessitated by ventricular fibrillation. In the nitecapone group, a 50 µmol/L concentration of nitecapone (Orion-Pharma) was added to the cardioplegic solution.

Blood samples.
The timing of the blood samples was as follows: after induction of anesthesia but before the operation began (Pre), just before the onset of CPB (Before), just before aortic unclamping (0), and at 1, 5, and 10 minutes after aortic unclamping. After induction of anesthesia and just before aortic unclamping, a blood sample was drawn from the radial arterial cannula. At other time points, parallel blood samples were drawn from the aortic root and the coronary sinus. Nine volumes of blood were mixed with 1 volume of 0.109 mol/L trisodium citrate or, for APC and fibrinopeptide A (FPA) assays, with 1 volume of 0.2 mol/L EDTA + 0.3 mol/L benzamidine in 10 mmol/L HEPES, pH 7.4. Platelet poor plasma was separated by centrifugation (1900g for 15 minutes at 4°C) and the samples were stored at –70°C until assayed.

Laboratory methods.
The assays were run as duplicates. For all assays except for APC measurements, pooled normal human plasma from Precision Biologicals (Dartmouth, Nova Scotia, Canada) was used as a standard and the results are expressed as percentage relative to this plasma pool defined as 100%. For the APC assays, another, noncommercial plasma pool was used as a standard and taken as 100%. ²³

APC levels in plasma were determined by an enzyme capture assay as described previously. ²³ In brief, a monoclonal antibody against protein C was immobilized in microplates, after which the surface was blocked. Then, plasma samples containing APC and benzamidine, a reversible inhibitor of APC, were incubated in the wells for capture of APC and protein C antigen. Then unbound sample constituents and the benzamidine were removed by extensive washing. Finally, the amidolytic activity of the captured APC was measured with a chromogenic substrate S-2366 (Chromogenix AB, Mölndal, Sweden). The sensitivity of this assay is 5 pmol/L, corresponding to 13% of the normal mean plasma level. ²³ Total protein C based on its activity was measured by activating the bound protein C in the immunocaptured samples by Protac reagent (American Diagnostica, Greenwich, Conn) and by then measuring the amidolytic activity on the chromogenic substrate S-2366. ²³ Since APC was less than 1% of total protein C, the amidolytic activity observed after Protac reagent activation essentially equaled total protein C. Protein C antigen and total protein S antigen were assayed by Asserachrom Protein C and Asserachrom Protein S kits from Diagnostica Stago (Parsippany, NJ), respectively. Free protein S was determined by a sandwich enzyme-linked immunosorbent assay method with 2 monoclonal anti–free protein S antibodies as described earlier. ²⁴ C4b-binding protein was measured by an enzyme-linked immunosorbent assay. ²⁴

FPA levels were measured from the plasma samples anticoagulated with EDTA-benzamidine with the use of an Asserachrom FPA kit (American Diagnostics, Parsippany, NJ). Fibrinogen was removed from the samples by centrifuging sample aliquots in 0.5 mL spin vials fitted with 30,000 molecular weight cut off membranes (Gelman Sciences, Ann Arbor, Mich). ²⁵

Statistical methods.
Plasma concentrations of variables were calculated both corrected and uncorrected for hematocrit value. Within CPB and reperfusion, hemodilution did not have any significant effect on the results. Therefore the results are presented as uncorrected. When values during the operation were compared with those at induction, the 2-tailed Wilcoxon signed rank test was used because large differences in variances necessitated a nonparametric approach. When variances were not significantly different, continuous variables with normal distributions were also compared with the Student t test for unpaired samples. The Spearman rank correlation coefficient was used for calculation of correlations. Data are presented as mean ± standard error of mean (SEM).

Ethics.
The study was approved by the ethics committee of the University Central Hospital of Helsinki and by the Ministry of Health of Finland. Informed consent was obtained from each patient before entry into the study.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Protein C and APC data were initially analyzed separately for the patients who received nitecapone (n = 13) and for those who did not (n = 7). No significant differences between APC and protein C for the 2 groups were observed for any of the sampling times (data not shown). Similarly, no significant differences were observed between the nitecapone-treated or control patients in any of the measured hemodynamic variables from induction to the first postoperative day. Thus the patient groups were combined for all subsequent analyses presented below.

Plasma levels of protein C activity and antigen and of APC for the 20 subjects at various times before and during CPB are shown inFig 1, A to D. In 1 patient, samples after aortic unclamping were not obtained and all presented data involving post-unclamping samples are for 19 subjects. Hemodilution during CPB resulted in a 40% to 50% decrease in protein C levels(Fig 1, A and B). In contrast, APC plasma levels decreased by about 20% before CPB and remained stable despite the hemodilution during the operation. Remarkably, during reperfusion a rapid and pronounced increase in APC levels occurred that was linear with time(Fig 1, C). When the data were analyzed as the ratio between APC and protein C antigen level, which is not affected by hemodilution, the rate of APC increase was greatly enhanced on reperfusion(Fig 1, D). Even though we probably did not observe the true "APC peak" (APC was still rising at the 10-minute sample), 79% of the total measured increase in the APC/protein C ratio occurred after aortic unclamping and only 21% of the increase was measured during aortic crossclamping. A comparison of venous and arterial samples showed no gradient in the APC levels across the coronary vascular bed(Fig 1, C and D).

View larger version (34K): [in this window] [in a new window]   Fig. 1. Protein C and activated protein C (APC) plasma levels during CPB operations in 20 patients. A and B, Plasma protein C zymogen levels assayed with a functional or antigenic measurement, respectively. C, Plasma levels of APC. D, Calculated APC/protein C antigen ratios. The significance levels are for 2-tailed Wilcoxon signed rank test when compared with the preoperative sample. *P < .05, **P < .01; ***P < .001. In time of sampling, Pre indicates preoperative, Before indicates just before CPB, 0, just before aortic unclamping, and 1, 5, and 10 indicate minutes after aortic unclamping. Open symbols indicate arterial samples and closed symbols indicate samples from the coronary sinus. The error bars indicate standard error of the mean. X-clamp indicates aortic crossclamping time.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Fibrinopeptide A plasma levels in 20 patients. Open symbols indicate arterial samples and closed symbols indicate samples from the coronary sinus. Time of sampling is the same as forFig 1. The significance levels are for the 2-tailed Wilcoxon signed rank test when compared with the preoperative sample. *P < .05; **P < .01; ***P < .001. The difference between coupled samples from the coronary sinus and aorta was significant for the sample drawn 5 minutes after aortic unclamping (P = .02). The error bars indicate standard error of the mean. X-clamp indicates aortic crossclamping time.

The levels of free protein S, total protein S, and C4b-binding protein are shown inTable I. In accordance with the presumed acute phase reaction of the current patients with severe symptomatic coronary heart disease, the baseline levels of total C4b-binding protein were about twice normal (209% ± 14% of normal). Since protein S complexes with C4b-binding protein, ²⁴ it is logical that free protein S, which represents an active anticoagulant cofactor for APC, was also reduced in the preoperative sample (70% ± 4% of normal mean). The ratio of free to total protein S reflects availability of protein S as an APC cofactor. As seen inTable I, this ratio decreased from the preoperative 0.61 ± 0.03 to 0.50 ± 0.03 just before CPB and later normalized to 0.56 ± 0.05 toward the end of the observation period. However, when compared with alterations in the APC level(Fig 1), the slight albeit statistically significant drop in the free/total protein S ratio caused only a minor change in the availability of free protein S, an APC cofactor, during the operation and CPB.

View larger version (26K): [in this window] [in a new window]   Fig. 3. Mean pulmonary artery pressure (A), cardiac index (B), and systemic vascular index (SVRI) (C) in CPB patients with either poor APC generation response (PR, n = 8) or good APC generation response (GR, n = 11). PR and GR groups were defined as APC/protein C antigen ratio less than or greater than 1.5, respectively, in the plasma sample collected from the coronary sinus 10 minutes after reperfusion. In time of measurement Pre indicates preoperative, Post, immediately post-CPB, CS, during closure of the sternum, and 6 and 24 indicate 6 and 24 hours after operation, respectively. The comparisons between the PR and GR groups were done with the 2-tailed Student t test for independent samples. *P < .05. The error bars indicate standard error of the mean.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
The antithrombotic protein C pathway was activated during cardiac surgery and especially during reperfusion of ischemic cardiac and other vascular beds. Moreover, low APC levels measured in coronary venous blood after 10 minutes of reperfusion correlated with compromised myocardial and circulatory performance 24 hours later. It was not possible to define in which part of the circulation APC formation was most enhanced. However, in rabbits, intravenously infused thrombin is cleared mainly by lungs in a first-pass fashion, ²⁶ probably because of large quantities of endothelial thrombomodulin, the membrane protein required for protein C activation by thrombin. ²⁷ Another alternative is the hypoperfused splanchnic bed that may also be "reperfused" when the nonpulsatile flow by the pump is gradually turned into the pulsatile pattern after aortic unclamping. Notably, a systemic endotoxemia after aortic unclamping occurred within minutes after reperfusion of the heart, ^28,29 indicating that if APC was formed within the splanchnic circulation, it also could appear in arterial blood rapidly after aortic unclamping. Thus protein C activation after aortic unclamping may represent a general tissue response to reperfusion.

We were unable to show local activation of protein C across the coronary circulation as previously suggested by Snow and associates, ¹³ who used a porcine model of brief occlusion of the left anterior descending coronary artery. However, such local activation could not be excluded because the reperfused coronary vascular bed could be a site of both enhanced APC consumption and APC production. The transcoronary gradient of FPA showed locally enhanced activation of coagulation, which physiologically may result in consumption of physiologic anticoagulants including APC. Overall, however, increased levels of APC were present both systemically and locally in the coronary circulation on reperfusion of ischemic tissue.

In pigs, occlusion of a coronary artery caused a rapid increase in the APC level in the interventricular vein, and blocking this activation by anti–protein C monoclonal antibodies impaired the recovery of the ischemic myocardium. ¹³ Additionally, APC reduced arterial thrombus formation in a variety of animal models. ^14-19 Thus it is interesting that a low APC generation response in the present study was associated with compromised postoperative recovery of the myocardium and the hemodynamic state of the patient. Remarkably, 24 hours after the operation, cardiac output, central venous pressure, and pulmonary artery pressure correlated positively and systemic vascular resistance negatively with APC generation during the immediate reperfusion of the heart. Qualitatively, these findings in patients subjected to CPB are in good agreement with previous porcine data ¹³ and may be explained by microvascular thrombosis in the coronary or other vascular beds of the body.

APC and FPA levels correlated directly with each other, indicating the known significance of thrombin for activation of protein C. ^15,27 Thus one might ask whether the current hemodynamic effects attributed to APC could actually be mediated by thrombin or by some other thrombin effect independent of APC, for example, activation of fibrinolysis. In this regard the current data are inconclusive because only protein C activation was measured. However, a causal contribution from APC is suggested because another direct product of thrombin’s action, namely the FPA level during reperfusion, did not significantly correlate with cardiac output, cardiac index, systemic vascular resistance index, or central venous pressure (data not shown).

In summary, the antithrombotic protein C pathway was activated during reperfusion after CPB, and low APC formation measured after 10 minutes of reperfusion was associated with decreased myocardial function 24 hours after operation. Thus a rapid increase in APC levels during reperfusion of the heart and other ischemic vascular beds may be an important physiologic antithrombotic defense mechanism against ischemic tissue injury.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): José A. Fernández Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petäjä, J. Articles by Griffin, J. H. Search for Related Content PubMed PubMed Citation Articles by Petäjä, J. Articles by Griffin, J. H.