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Ann Thorac Surg 2006;81:886-891
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Phosphorylcholine Coating May Limit Thrombin Formation During High-Risk Cardiac Surgery: A Randomized Controlled Trial

Federico Pappalardo, MD a , * , Patrizia Della Valle, PhD b , Giuseppe Crescenzi, MD a , Chiara Corno, PhD, MS a , Annalisa Franco, MD a , Lucia Torracca, MD c , Ottavio Alfieri, MD c , Laura Galli, PhD b , c , d , Alberto Zangrillo, MD a , Armando D'Angelo, MD b

a Department of Cardiovascular Anesthesia and Intensive Care, IRCCS San Raffaele Hospital, Milan, Italy
b Coagulation Service and Thrombosis Research Unit, IRCCS San Raffaele Hospital, Milan, Italy
c Department of Cardiac Surgery, IRCCS San Raffaele Hospital, Milan, Italy
d Epidemiology Unit, IRCCS San Raffaele Hospital, Milan, Italy

Accepted for publication September 1, 2005.

* Address correspondence to Dr Pappalardo, Department of Cardiovascular Anesthesia and Intensive Care, IRCCS San Raffaele Hospital, Via Olgettina, 60, Milan 20132, Italy (Email: pappalardo.federico{at}hsr.it).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: During cardiopulmonary bypass, blood contact with the large nonendothelial surfaces of the extracorporeal circuit induces activation and consumption of platelets and plasma coagulation factors. Phosphorylcholine (Pc) coating of oxygenators has been designed to improve surface biocompatibility. We evaluated the effects of a Pc-coated oxygenator on blood coagulation in patients undergoing high-risk open heart surgery and receiving tranexamic acid.

METHODS: Thirty-nine patients undergoing reoperative valvular or combined procedures were randomized to the use of an oxygenator treated with Pc coating (Pc group) or of a standard oxygenator (control group). Platelet count, soluble CD40 ligand, fibrinogen, antithrombin, D-Dimer, prothrombin fragment 1.2 (F1.2), and free plasma hemoglobin levels were measured at baseline, at aortic unclamping, and at arrival in the intensive care unit.

RESULTS: Postoperative bleeding, need for blood products, and clinical outcomes were similar in the two groups. At unclamping, F1.2, a marker of in vivo thrombin formation, increased to a greater extent in control patients than in Pc patients (p = 0.02), and in the latter group of patients was positively correlated with aortic cross-clamp times (r = 0.70). Relative to baseline values, the percent decrease in platelet count, fibrinogen, and antithrombin levels was not significantly different in Pc patients and in control patients after adjustment for multiple comparisons, but the percent decrease in platelet counts was negatively correlated with F1.2 levels in the entire series of patients (r = -0.62, p < 0.0001). All the evaluated parameters were similar in the two groups of patients at arrival in the intensive care unit.

CONCLUSIONS: For patients undergoing high-risk open heart surgery and receiving tranexamic acid, a phosphorylcholine-coated oxygenator may reduce intraoperative thrombin formation and the associated consumption of platelets, fibrinogen, and antithrombin.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiac surgery involving cardiopulmonary bypass (CPB) induces marked abnormalities of primary and secondary hemostasis. These phenomena are caused by the contact of blood with the large nonendothelial surfaces of the extracorporeal circuit, the release of tissue factor due to the surgical trauma, the reinfusion of tissue factor and activated coagulation factors with mediastinal shed blood, the shear-forces generated by cardiotomy suction, and the mechanical alteration of corpuscular blood elements due to mechanical propelling devices: as a result, plasma coagulation factors and platelets are activated, with secondary fibrinolysis contributing to their consumption. Clinical consequences of these phenomena are thromboembolism, inflammation, hemorrhage, need for transfusion and, eventually, organ damage and death.

Efforts have been undertaken to reduce these complications: removal of some of the processes that activate platelets and coagulation factors (shed blood separation); reduction of the shear-forces; and surface coating. Among the most recent coating treatments, phosphorylcholine (Pc) has been shown beneficial [1–5], by preventing from protein adsorption to the surface [6] and thereby limiting platelets adhesion.

The purpose of this study was to evaluate the effects of Pc-coating of oxygenators on selected factors of blood coagulation in patients undergoing high-risk open heart surgery and receiving intraoperative tranexamic acid infusion.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Protocol
The study protocol was approved by the institutional Ethical Committee, and informed consent was obtained. Forty-four consecutive patients belonging to the highest (IV) category for bleeding risk according to the stratification by Hardy and colleagues [7] (reoperative valvular or combined procedures) were randomly assigned by a computer-generated list to one of two groups: (1) control group, use of a standard oxygenator (Avant D903; Dideco, Mirandola, Italy); or (2) Pc group, use of an oxygenator with phosphorylcholine (Pc) coating (Avant D903 with Ph.i.s.i.o. treatment; Dideco). The Pc-coated and standard oxygenators differed only for the coating treatment, geometrical and material features being identical. Patients were not included if operated on urgency-emergency priority or with a minimally invasive approach. No patient received warfarin or antiplatelet drugs within 7 days before surgery; patients on intravenous heparin had it stopped at least 6 hours preoperatively. Patients were not considered eligible if the preoperative platelet count was less than 80,000 x 109/L; if they had preoperative prothrombin time or partial thromboplastin time ratios greater than 1.2; or if they had a history of hematologic, hepatic, or renal diseases. Enrolled patients were excluded from the analysis if requiring an intra-aortic balloon pump or showing clear evidence of a surgical source of bleeding.

Patient Management
Before institution of CPB, patients received intravenous porcine heparin (300 IU/kg of body weight), and during CPB, additional doses (5,000 IU) if required, to maintain the activated clotting time (ACT II; Medtronic) greater than 480 s. After termination of CPB and surgical hemostasis, heparin was neutralized with protamine sulphate (1:1 ratio).

All patients received an intraoperative infusion of tranexamic acid (1 g in 20 minutes before skin incision, followed by a continuous infusion of 400 mg/h until completion of surgery) according to our institutional protocol [8]. Postoperative blood loss was collected in a graduated reservoir connected to a closed evacuation system (Argyle, Aqua-Seal; Sherwood Medical, Tullamore, Ireland).

Intraoperative and postoperative criteria for allogenic transfusions were standardized. Packed red blood cells were transfused during CPB if hemoglobin concentration was less than 6.5 g/dL or hematocrit less than 20%, and after CPB and during all the hospital stay if hemoglobin less than 9 g/dL or hematocrit less than 27%. In the presence of active bleeding after protamine administration, fresh frozen plasma was infused with PT ratios of 1.5 times or more of the baseline values, and platelet concentrates were transfused with platelet counts less than 50 000 · 109 /L. Attending physicians were masked for the type of oxygenator used.

Cardiopulmonary Bypass Circuit
Extracorporeal circulation was instituted in all patients by draining blood by gravity into an open venous reservoir (Avant Reservoir; Dideco), and by driving it by means of a roller peristaltic pump (Caps; Stöckert Instruments, Munich, Germany) through a heat exchanger integrated with a hollow fiber membrane oxygenator (Avant D903 or Avant D903 Ph.i.s.i.o.; Dideco) and through an arterial filter (D734 MICRO 40; Dideco) back into the patient at a mean flow rate of 2.4 L · min-1 · m-2. The circuit was primed with 1500 mL Ringer's lactate solution, 100 mL mannitol 18%, and 5,000 IU porcine heparin. Intermittent cold (4°C) blood cardioplegia was infused by means of a heat exchanger (D720 Helios C; Dideco) and two roller pumps, according to Buckberg's protocol [9]. Mild-to-moderate hypothermia (mean internal temperature, 31.4°C) was employed.

Shed mediastinal blood suction and left heart venting were actively performed with two separated roller pumps. Additionally, blood was aspirated from the operative field with a vacuum suction device (D745; Dideco), processed in a cell saving device (Compact-A; Dideco), and then reinfused after closure of the chest.

Laboratory Assays
Blood samples were collected from a radial arterial catheter by means of a two-syringe technique. Ten milliters of blood were withdrawn with the first syringe and discarded, and 5 mL obtained in the second syringe. Sample time points were as follows: (A) at induction of anesthesia (baseline); (B) after removal of the aortic cross-clamp (unclamp); (C) at intensive care unit arrival (ICU arrival). Determinations were performed on samples collected in 0.129 M sodium citrate (9:1 v/v) and centrifuged within 1 hour for 20 minutes at 2,000g at room temperature. Aliquots of platelet-poor plasma (0.5 mL) were snap-frozen and stored at -80°C until assay. Fibrinogen (STA Fibrinogen; Roche Diagnostic, Mannheim, Germany), antithrombin (STA Antithrombin III), and D-dimer levels (STA Liatest D-DI) were measured with a fully automated coagulometer (STA; Diagnostica Stago, Asnier sur Seine, France). Prothrombin fragment 1+2 (F1.2) and soluble CD40 ligand (sCD40L) were measured by commercially available enzyme-linked immunosorbent assays (Enzygnost F1+2; Dade Behring, Marburg, Germany; and Quantakine; R&D Systems, Minneapolis, Minnesota).

Free plasma hemoglobin was measured by spectrophotometry (UVICON 923; Bio-tek Instruments, Winooski, Vermont) with phosphate buffer by the second derivative method.

Statistical Analysis
Patients' characteristics and preoperative data were entered into a specifically designed database. Normality of the distribution of continuous variables was evaluated with the Kolmogorov-Smirnov test. Data are reported as mean ± SD or median with interquartile range (25th to 75th percentile). Comparisons in continuous variables between patients randomly assigned to the different oxygenators were performed by analysis of variance after log transformation of nonnormally distributed variables. The {chi}2 test (with Yates' correction for continuity) and Fisher's exact test were used for comparisons of discrete variables.

The changes in hematochemical variables from baseline were evaluated by two-way analysis of variance for repeated measures after log-transformation of nonnormally distributed variables (sCD40L), including the type of oxygenator as factor. In presence of significant response variables, the unequal variances version of the Student's t test was used for between-group comparisons at specific time points. Given the major confounding effect of hemodilution, proportional to baseline values, over the expectedly minor oxygenator-related changes, between-group differences in hematocrit, platelet counts, fibrinogen, and antithrombin levels were also analyzed as percent change over baseline values (unequal variances version of Student's t test). Analysis of correlation was used to examine the association at unclamping of F1.2 levels with aortic cross-clamp times and with percent changes in platelet counts, fibrinogen, and antithrombin. The Bonferroni correction was used to adjust p values for multiple comparisons.

Statistical analyses were conducted with Systat 7.0 for Windows (SPSS, Chicago, Illinois). Statistical significance was considered for p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Preoperative Data, Operative Conditions, and Clinical Outcomes
Forty-four patients were enrolled into the study. Five patients were excluded (2 in the control group and 3 in the Pc group) owing to postoperative intra-aortic balloon pump insertion (n = 2) or evident surgical bleeding (n = 3). Demographic characteristics and perioperative data of the remaining patients, similar in the two groups, are reported in Table 1. The cardiotomy suction was used in all patients; the volumes processed in the cell-saving device were similar in the Pc and control groups (794 ± 358 mL versus 905 ± 222 mL, p = 0.30).


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  		Table 1. Demographic Characteristics and Perioperative Data of Patients in Phosphorylcholine-Coated Oxygenator Group (Pc) and Standard Oxygenator Group (Control)
 
During the postoperative course, 2 units of packed red blood cells were transfused to 1 patient in the Pc group and 4 patients in the control group; 1 patient in the control group also received 4 units of fresh frozen plasma and 7 platelet concentrates (Table 2). One patient in the control group experienced an event of oxygenator high pressure drop and required platelet concentrate transfusion in the postoperative course. No patient underwent surgical reexploration for bleeding. Postoperative bleeding was similar in the two groups (p = 0.41). Other postoperative clinical and laboratory data, similar in the two groups of patients, are shown in Table 2.


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  		Table 2. Use of Blood Products in Operating Room (OR) and in Intensive Care Unit (ICU), Postoperative Clinical Course, and Laboratory Markers in Phosphorylcholine-Coated Oxygenator Group (Pc) and Standard Oxygenator Group (Control)
 
Laboratory Assays
The changes in hematochemical variables are shown in Table 3. In both groups of patients, significant changes over baseline were observed for all the variables except for sCD40L and D-Dimer levels (p ≤ 0.001). The between-group difference in F1.2 levels was close to statistical significance and there was a significant interaction of time with the type of oxygenator (Table 3). The F1.2 levels increased to a greater extent at unclamping in patients of the control group than of the Pc group (p = 0.02, adjusted for multiple comparisons), but were similar in the two groups at ICU arrival (p = 0.22; Fig 1, left panel). The F1.2 levels at unclamping were significantly correlated with aortic cross-clamp times in Pc patients only (r = 0.70, p = 0.001, adjusted for multiple comparisons; Fig 1, right panels). Percent changes from baseline in hematocrit, platelet counts, fibrinogen, and antithrombin levels at unclamping are shown in Table 4. While the changes in hematocrit were virtually identical in the two groups at unclamping, platelet counts, fibrinogen, and antithrombin levels declined to a greater extent in control patients than in Pc patients, albeit not reaching statistical significance after adjustment for multiple comparisons. In the entire series of patients and irrespective of the type of oxygenator, there was a strong correlation at unclamping between the percent changes in platelet counts and F1.2 levels (r = -0.62, p = 0.0001 after adjustment for multiple comparisons).


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  		Table 3. Hematochemical Variables at Time Points Baseline, Unclamp (Aortic Cross-Clamp Release), and ICU Arrival in Phosphorylcholine-Coated Oxygenator Group (Pc) and Standard Oxygenator Group (Control)
 

Figure 1
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  		Fig 1. (Left panel) Prothrombin fragment 1.2 (F1.2) levels at baseline, unclamp (aortic cross-clamp release), and intensive care unit (ICU) arrival in the phosphorylcholine-coated oxygenator group (closed circles) and in the standard oxygenator group (open circles). The correlation between F1.2 levels at unclamp and the aortic cross-clamp time is separately shown for (upper right panel) the standard oxygenator group and (lower right panel) the phosphorylcholine-coated oxygenator group.

 

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  		Table 4. Percent Change Over Baseline Values at Unclamping in Hematocrit, Platelet Counts, Fibrinogen, and Antithrombin Levels in the Phosphorylcholine-Coated Oxygenator Group (Pc) and in the Standard Oxygenator Group (Control)
 
At ICU arrival, all variables examined were similar in the two groups of patients.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Because the abnormalities of hemostasis secondary to contact of blood with the extracorporeal circuit play a significant role in postoperative morbidity and mortality after cardiac operations, attempts have been made to improve surface biocompatibility. An early approach to surface treatment was covalent or ionic binding of heparin to the material. In a large randomized study, the use of heparin-coated circuits was associated with a lower rate of patients having a severely impaired clinical outcome [10]; experimental data, however, indicate that heparin-coated circuits do not avoid recruitment of platelets and consumption of coagulation factors, and lead to the release of heparin from the surface into the circulation [11].

Phosphorylcholine coating is an innovative approach to extracorporeal surface treatment. Phosphorylcholine is the major lipid head group component found in the outer surface of biologic cell membranes. By biomembrane mimicry, Pc-coating of materials is aimed at reducing contact activation [12]. The Pc-coating of CPB circuits has been previously evaluated by analyzing its effect on platelet counts and on some specific markers of activation of platelets (for example, beta-thomboglobulin, platelet factor 4, thromboxane B2), coagulation (for example, thrombin-antithrombin complex, F1.2), and fibrinolysis (plasmin-antiplasmin complex) [1–4]. Compared with uncoated circuits and irrespective of associated shed blood separation [1, 2], patients operated on with Pc-coated circuits had lower or no intraoperative increase in beta-thromboglobulin [2–4], platelet factor 4 [4], and thromboxane B2 levels [3], and reduced intraoperative F1.2 [3] and plasmin-antiplasmin complex levels [1]. Most of these studies have been conducted on patients undergoing coronary artery bypass grafting surgery [1, 2, 4].

To evaluate whether the beneficial effects of Pc-coating on primary and secondary hemostasis are also detected under conditions of extreme activation of blood clotting (suction, large contact with air, large cardiotomy, adhesions) and quenching of fibrinolysis, we determined the changes in selected platelet and coagulation variables in 39 patients undergoing open heart procedures with tranexamic acid for combined or reoperative surgery randomly assigned to phosphorylcholine-coated or standard oxygenators.

By inhibiting fibrinolysis, tranexamic acid infusion markedly dampens the increase in D-dimer levels observed during CPB surgery without affecting the reduction in platelet counts and in fibrinogen and antithrombin levels [8–13]. In line with these findings, D-dimer levels were unchanged in both groups of patients. At variance, in vivo thrombin generation, a mechanism reflected by F1.2 levels and not anticipated to be significantly influenced by inhibition of fibrinolysis, was apparently influenced by the Pc-coated oxygenator. The repeated measures analysis of variance failed to detect a significant between-group difference when all time periods were considered. There was however a statistically significant interaction term, and after the Bonferroni adjustment for multiple comparisons, F1.2 levels were significantly lower at unclamping in Pc patients than in control patients. In addition, with the Pc-coated, but not with the standard oxygenator, F1.2 levels at unclamping were positively correlated with aortic cross-clamp times, indicating a major role of the oxygenator in triggering thrombin generation.

Increased thrombin generation is expected to be accompanied by an increased consumption of platelets, fibrinogen and antithrombin. Although the decline in these variables was consistently greater at unclamping in control patients than in Pc patients, no statistically significant between-group difference was observed after adjustment for multiple comparisons. There was, however, a strong, negative correlation at unclamping between the percent change in platelet counts and F1.2 levels (r = -0.62), suggesting a role for intraoperatory thrombin generation in the disappearance of platelets from the circulation.

The effect of the coating on F1.2 disappears in the ICU sample; however, protamine has a direct effect on the generation of thrombin, and therefore the measurement of F1.2 at the ICU sampling is affected by many factors.

We also evaluated changes in the plasma levels of a marker of platelet activation, the soluble CD40 ligand (CD40L). The CD40 receptor is constitutively expressed by vascular endothelial cells and its complementary ligand CD40L is expressed at the surface of activated platelets. Binding of the platelet ligand to the endothelial CD40 receptor may initiate inflammation of the vessel wall [14]. Soluble CD40L is shed from the platelet surface, most probably because of the action of proteases [15]. Soluble CD40L levels did not show significant changes in the two groups of patients, possibly as the result of the inhibition of plasmin activity by tranexamic acid. Tranexamic acid has been shown to block plasmin-dependent platelet activation during CPB [16], and plasmin may also play a role in the shedding of soluble CD40L from the surface of activated platelets.

As previously reported [1, 2, 4], free plasma hemoglobin levels, reflecting overall intraoperative hemolysis, were not significantly different in the two groups of patients. At arrival in ICU, consistent with the findings of other authors [1–4], all the variables evaluated were similar in the two groups of patients.

Some limitations of the study have to be acknowledged. First, we evaluated just an oxygenator and not a tip-to-tip coated circuit as done by other authors [1–4]. The oxygenator constitutes the greater portion of the surface exposed to contact with blood, however, and if anything, the results should have been even more favorable with a tip-to-tip coated circuit. Second, as the study involved different surgeons and a percentage of reoperative procedures, the results should be interpreted in the light of any potential effects of these variables. Third, and more important, the relatively low number of patients enrolled does not allow for our observations to be translated into a clinical benefit in terms of bleeding complications, which were similar in the two groups of patients.

In conclusion, our study shows that also in high-risk patients receiving tranexamic acid during CPB surgery, Pc-coating may reduce in vivo thrombin generation, and probably the associated consumption of platelets as compared with standard oxygenators. Although these findings add to the mechanistic basis for the favorable effects on bleeding [5,17] and postoperative complications [17] of Pc-coated circuits, larger studies are required to prove a clinical benefit.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We are indebted to all staff perfusionists and to all the nurses for their support in data collection and for the care provided to these patients. The Avant D903 Ph.i.s.i.o. oxygenators were provided by Dideco, Mirandola, Italy.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Albes JM, Stohr IM, Kaluza M, et al. Physiological coagulation can be maintained in extracorporeal circulation by means of shed blood separation and coating J Thorac Cardiovasc Surg 2003;126:1504-1512.[Abstract/Free Full Text]
  2. De Somer F, Van Belleghem Y, Caes F, et al. Tissue factor as the main activator of the coagulation system during cardiopulmonary bypass J Thorac Cardiovasc Surg 2002;123:951-958.[Abstract/Free Full Text]
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  8. Casati V, Gerli C, Franco A, et al. Tranexamic acid in off-pump coronary surgerya preliminary, randomized, double-blind, placebo-controlled study. Ann Thorac Surg 2001;72:470-475.[Abstract/Free Full Text]
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  10. Ranucci M, Mazzucco A, Pessotto R, et al. Heparin-coated circuits for high-risk patientsa multicenter, prospective, randomized trial. Ann Thorac Surg 1999;67:994-1000.[Abstract/Free Full Text]
  11. van der Kamp KW, van Oeveren W. Contact, coagulation and platelet interaction with heparin treated equipment during heart surgery Int J Artif Organs 1993;16:836-842.[Medline]
  12. Campbell EJ, O'Byrne V, Stratford PW, et al. Biocompatible surfaces using methacryloylphosphorylcholine laurylmethacrylate copolymer ASAIO J 1994;40:M853-M857.
  13. Casati V, Della Valle P, Benussi S, et al. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgerycomparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 2004;128:83-91.[Abstract/Free Full Text]
  14. Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells Nature 1998;391:591-594.[Medline]
  15. Henn V, Steinbach S, Buchner K, Presek P, Kroczek RA. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40 Blood 2001;98:1047-1054.[Abstract/Free Full Text]
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