Pediatr Cardiol DOI 10.1007/s00246-014-0903-9
ORIGINAL ARTICLE
Dynamics of Factor XIII Levels After Open Heart Surgery for Congenital Heart Defects: Do Cyanotic and Acyanotic Patients Differ? Leo A. Bockeria • Natalia N. Samsonova • Ivan A. Yurlov • Ludmila G. Klimovich • Elena F. Kozar • Eva H. N. Olsen • Sergey B. Zaets
Received: 3 December 2013 / Accepted: 25 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Cardiopulmonary bypass (CPB) reduces coagulation factor levels through hemodilution and consumption. Differences in CPB-induced alterations of factor XIII (FXIII) levels in children with cyanotic and acyanotic congenital heart defects (CHDs) are not well characterized. FXIII activity (determined by Berichrom assay), prothrombin index, activated partial thromboplastin time, and fibrinogen were measured before open heart surgery with CPB and 5 days postoperatively for children older than 3 years with acyanotic (n = 30) and cyanotic (n = 30) CHDs. The preoperative FXIII levels did not differ significantly among the children of the compared groups. The cyanotic patients showed a significantly longer duration of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min; p = 0.026) and aortic cross-clamp (68.0 ± 27.1 vs 45.4 ± 31.4 min; p = 0.034). The drop in FXIII levels after termination of CPB was more profound for the children with cyanotic CHDs (87.1 ± 13.4 to 49.1 ± 13.2 vs 81.5 ± 12.6 to 58.6 ± 11.1 %, respectively; p = 0.018). The cyanotc patients also were restored to their baseline FXIII levels later than the children with acyanotic CHDs (at 48 vs 24 h). The post-CPB dynamics of the majority of the other coagulation parameters in the compared groups of patients were similar. The cyanotic patients experienced significantly
Presented in part at the 13th Congress of the International Society on Thrombosis and Haemostasis, Kyoto, Japan, 23–28 July 2011. L. A. Bockeria N. N. Samsonova I. A. Yurlov L. G. Klimovich E. F. Kozar Bakoulev Center for Cardiovascular Surgery, Moscow, Russia E. H. N. Olsen S. B. Zaets (&) Novo Nordisk, Inc., 800 Scudders Mill Road, Princeton, NJ 085536, USA e-mail: [email protected]
greater postoperative blood loss than the acyanotic patients (12.6 ± 4.9 vs 5.0 ± 2.1 mL/kg; p \ 0.001) and were transfused with larger volumes of red blood cells (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg; p = 0.007). The decrease in FXIII levels after CPB is more profound and lasts longer in children with cyanotic CHDs than in acyanotic patients. The rational strategy of postoperative FXIII replacement therapy for these categories of patients needs to be determined. Keywords Factor XIII Coagulation Cardiopulmonary bypass Congenital heart defects
Introduction Postoperative bleeding and the necessity of blood transfusions, which predispose to the development of multiorgan failure and septic complications, still remain an important issue after cardiac surgery with extracorporeal cardiopulmonary bypass (CPB). Bleeding after CPB might be associated with coagulation factor deficiency because it is known to reduce coagulation factor levels through hemodilution, consumption, or its influence on liver performance. Reduced factor XIII (FXIII) levels may play an important role in the pathogenesis of bleeding after CPB. FXIII is a transglutaminase involved in the final stage of blood coagulation. It is present in plasma as well as in platelets, monocytes, and macrophages. Plasma FXIII consists of two catalytic A subunits and two noncatalytic B subunits that serve as carrier molecules. Cellular FXIII consists of two A subunits only. Factor XIII circulates in plasma as an inactive precursor and is activated by thrombin. Activated FXIII stabilizes
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Pediatr Cardiol Table 1 Diagnosis of patients Diagnosis of patients
Table 2 Types of surgical procedures No. of patients
Diagnoses of patients
No. of operations
ASD
9
Acyanotic patients
ASD ? PAPVC
5
ASD closure
9
ASD ? pulmonary stenosis
1
5
Incomplete atrioventricular canal
2
VSD
8
ASD closure ? pulmonary vein redirection to the left atrium ASD closure ? pulmonary valvuloplasty
VSD ? aortic stenosis
1
Acyanotic patients
VSD ? tricuspid insufficiency
1
Congenital aortic insufficiency
3
Subtotal
30
Cyanotic patients Tetralogy of Fallot
20
Double-outlet right ventricle
5
Single ventricle
1
Tricuspid atresia
1
Pulmonary atresia
3
Subtotal
30
Total
60
ASD atrial septal defect, PAPVC partial anomalous pulmonary venous connection, VSD ventricular septal defect
1
ASD closure ? mitral valve plastic reconstruction
2
VSD closure
8
VSD closure ? resection of subaortic membrane
1
VSD closure ? tricuspid valve annuloplasty
1
Aortic valve replacement
3
Subtotal
30
Cyanotic patients Complete repair of tetralogy of Fallot
20
Complete repair of double-outlet right ventricle
3
Complete repair of pulmonary atresia
2
Reconstruction of the right ventricular outflow tract without VSD closure
1
Fontan operation
4
Subtotal
30
Total
60
ASD atrial septal defect, VSD ventricular septal defect
fibrin clots by cross-linking fibrin monomers, increases the mechanical strength of the clot, retards fibrinolysis, and enhances platelet adhesion to the injured tissue [22]. A significant drop in FXIII levels has been demonstrated after CPB used for coronary artery bypass grafting or for heart valve replacement in adults [3, 5, 6, 11, 12, 18, 24, 25]. Findings have shown that low postoperative plasma levels of FXIII in patients subjected to coronary artery bypass grafting are associated with increased bleeding [6, 11, 24, 25]. Data on the levels of FXIII in patients with congenital heart defects (CHDs) before and after CPB are limited and contradictory [1, 10, 20]. This study aimed to compare the dynamics of FXIII levels in patients with cyanotic and acyanotic CHDs subjected to open heart surgery with CPB and to investigate how it correlates with some other coagulation parameters.
Patients and Methods Patient Population This prospective observational study enrolled 60 pediatric patients with acyanotic (n = 30) or cyanotic (n = 30) CHDs subjected to open heart surgery at the Bakoulev Center for Cardiovascular Surgery (Moscow, Russia). The protocol was approved by the Research Council of the Bakoulev Center for Cardiovascular Surgery and the
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Ethical Review Committees of Novo Nordisk A/S. The parents or legal guardians of all the participating patients signed the Informed Consent Form. The informed consent for minors (Child Assent Form) also was signed by the children older than 6 years. The exclusion criteria ruled out diagnosed coagulation disorders, previous thrombotic events, and hepatic or renal failure. All the patients were older than 3 years. The most common diagnosis in the group of patients with acyanotic CHDs was atrial septal defect (Table 1). The most common diagnosis in the group of patients with cyanotic CHDs was tetralogy of Fallot. Various palliative interventions had been performed previously for 18 of the cyanotic patients including systemic-to-pulmonary shunt (n = 13), bidirectional cavopulmonary shunt (n = 4), and reconstruction of the right ventricular outflow tract without ventricular septal defect closure (n = 1). The types of surgical interventions performed in this study are shown in Table 2. All the operations were performed with CPB and hypothermia. The lowest rectal temperature during CPB was 28–34 °C (mean, 30.7 °C) for the cyanotic patients and 26–34 °C (mean, 31.5 °C) for the acyanotic patients. In the majority of the cases, the CPB circuit was primed with the whole blood or packed red blood cells (RBCs) and crystalloids. The total prime volume was 1,000 mL. The
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proportion of packed RBCs to crystalloids was 25–75 % in the acyanotic patients, and 15–85 % in the cyanotic patients with a hemoglobin level of 180 g/L or lower. In the cyanotic patients with a hemoglobin level higher than 180 g/L or a hematocrit level higher than 50 %, crystalloids or plasma together with crystalloids was used for priming. Cardioplegia was performed for all except four cyanotic patients, who were subjected to the Fontan operation with modification of the extracardiac conduit. Fluid transfused at completion of CPB corresponded to the institutional guidelines and mainly included packed RBCs (if necessary) and fresh frozen plasma. Packed RBC transfusion was mandatory if hemoglobin levels were below 80 g/L, optional for hemoglobin levels of 80–100 g/L, and not recommended if these levels were above 100 g/L. Fresh frozen plasma was to be transfused when the prothrombin index was below 60 %. Platelets could be given if the platelet count was lowered down to 100 109/mL or below. End Point Parameters The end point parameters included FXIII activity, prothrombin index (ratio between prothrombin time of control and patient plasma multiplied by 100 %), activated partial thromboplastin time (APTT), and fibrinogen. These parameters were measured repeatedly: before initiation of CPB, after discontinuation of CPB, and then 6, 12, 24, 48 and 120 h after CPB. The preoperative parameters used for the assessment of cyanosis were arterial blood oxygen saturation (SaO2) and hemoglobin concentration. The postoperative assessment also included the recording of blood loss (chest tube output) during the 24 h after admission to the intensive care unit (ICU) as well as the amount of blood product transfusion. The activity of the FXIII A subunit was determined by photometric FXIII activity assay (Berichrom FXIII; Dade Behring, Marburg, Germany) using the COBAS MIRA Plus analyzer (Roche, Basel, Switzerland). Measurements of the patient’s plasma samples were performed according to the manufacturer’s instructions. In this assay, plasma FXIII is activated by thrombin in the presence of aggregationinhibiting peptide to prevent fibrin-induced clot formation. Activated FXIII (FXIIIa) cross-links a specific peptide substrate, with subsequent release of the ammonia that in turn oxidizes NADH to nicotinamide adenine dinucleotide (NAD). The decrease in NADH is recorded by monitoring its absorbance at 340 nm. Statistical Analysis Data were analyzed using SPSS 9.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables are presented as
mean ± standard deviation. A two-sample Student’s t test was used to compare the baseline parameters in cyanotic and acyanotic patients. The parameters at multiple time points were compared by analysis of variance (ANOVA) followed by the t test. With the observational and exploratory character of the study taken into consideration, no correction for multiple tests was performed. The Pearson correlation coefficient was determined to assess the relationship between variables (FXIII levels at discontinuation of CPB and amount of blood loss/packed RBC transfusion). The statistical significance was set at a p value lower than 0.05.
Results The age of the patients did not differ in the compared groups (Table 3). Not surprisingly, the cyanotic patients had significantly lower preoperative arterial blood oxygen saturation and higher hemoglobin and hematocrit levels (Table 3). The preoperative FXIII plasma levels, platelet counts, prothrombin indexes, and APTTs did not differ significantly in the compared groups of patients. The cyanotic patients had significantly longer durations of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min, respectively; p = 0.026) and aortic cross-clamping (68.0 ± 27.1 vs 45.4 ± 31.4 min, respectively; p = 0.034). The rectal temperature during CPB did not differ between the cyanotic and acyanotic patients (p = 0.438). In both the acyanotic and cyanotic patients, the CPB resulted in hemodilution. The hematocrit levels lowered significantly down to 29.9 ± 3.6 and 31.7 ± 4.9 %, respectively (p \ 0.001 vs preoperative values). In the acyanotic patients, the hematocrit remained decreased for at least 24 h after surgery. In the cyanotic patients, it did not reach elevated preoperative levels during the follow-up period. Both the acyanotic and cyanotic patients experienced a significant drop in FXIII plasma levels immediately after CPB (Fig. 1). However, this depression was more profound in the patients with cyanotic CHDs. The cyanotic patients also experienced restored preoperative FXIII levels later than the acyanotic patients (48 vs 24 h after CPB, respectively). In both groups of patients, CPB also caused significant alterations of other coagulation parameters (prothrombin index, platelet number, APTT, and fibrinogen concentration) (Figs. 2, 3, 4, 5). The decrease in the number of platelets was more profound in the cyanotic patients. The time required for each parameter to return to preoperative levels ranged from 6 h (fibrinogen concentration) to 120 h (platelet number) but did not differ significantly in the compared groups of patients.
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Pediatr Cardiol Table 3 Preoperative clinical and laboratory parameters
Parameters
Acyanotic patients
Age (years) SaO2 (%) Hemoglobin (g/L) Data are presented as mean ± standard deviation (minimum–maximum) SaO2 arterial oxygen saturation, APTT activated partial thromboplastin time * p \ 0.05 vs acyanotic patients
Platelet count (109/mL)
8.8 ± 5.0 (3–15)
8.6 ± 3.8 (4–14)
0.915
82.4 ± 8.1 (62–89)*
\0.001
35.3 ± 4.1 (28–44) 329.7 ± 50.0 (190–435)
168.6 ± 13.9 (152–198)*
\0.001
46.1 ± 3.3 (41–52)*
\0.001
294.8 ± 51.8 (194–436)
0.326
Factor XIII activity (%)
81.5 ± 12.6 (50.9–110.5)
87.1 ± 13.4 (52.5–130.4)
0.512
Prothrombin index (%)
75.4 ± 12.3 (55.3–90.1)
73.5 ± 17.9 (42.8–99.3)
0.756
APTT (s) Fibrinogen (mg %)
32.8 ± 17.9 (18.3–88.4) 202.5 ± 96.3 (50–381)
Fig. 1 Dynamics of FXIII plasma levels after cardiopulmonary bypass (CPB). Cyanotic patients demonstrate a more profound and longer-lasting drop in FXIII plasma levels after CPB than acyanotic patients. Error bars represent standard deviation. *p \ 0.05 vs preCPB. #p \ 0.05 vs acyanotic patients
Greater postoperative blood loss was experienced by the cyanotic patients (12.6 ± 4.9 mL/kg) than by the acyanotic patients (5.0 ± 2.1 mL/kg) (p \ 0.001). Consequently, the cyanotic patients were transfused with larger volumes of packed RBCs (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg, p = 0.007). Both the cyanotic and acyanotic patients showed a significant inverse correlation between FXIII levels at discontinuation of CPB and postoperative blood loss (r = -0.491 and r = -0.463, respectively; p = 0.006 and p = 0.01, respectively) as well as the amount of transfused packed RBCs (r = -0.468 and r = -0.409, respectively; p = 0.009 and p = 0.025, respectively). The amount of transfused fresh frozen plasma was 13.5 ± 3.6 mL/kg for the cyanotic patients and 12.4 ± 2.4 mL/kg for the acyanotic patients and did not differ significantly between these compared groups (p = 0.22). Few platelet transfusions were administered (3 among the cyanotic and 1 among the acyanotic patients). Three of four cyanotic patients subjected to Fontan operations received
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p value
98.1 ± 1.0 (96–100) 119.5 ± 13.2 (104–156)
Hematocrit (%)
Cyanotic patients
38.5 ± 15.9 (20.2–71.4) 215.6 ± 77.4 (78–300)
0.425 0.722
Fig. 2 Dynamics of the prothrombin index after CPB. Both cyanotic and acyanotic patients demonstrate a decrease in prothrombin index after CPB that returns to baseline levels 12 h after intensive care unit (ICU) admission. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
albumin infusion because this type of surgical intervention usually is associated with massive pleural effusion.
Discussion Strategies to avoid bleeding after open heart surgery and to limit the necessity for blood transfusion in different categories of patients still are being thoroughly investigated. Coagulation factor deficiency caused by CPB is one of the mechanisms predisposing patients to bleeding complications. A postoperative decrease in FXIII levels in adult patients subjected to coronary artery bypass grafting or heart valve replacement/repair has been confirmed by multiple retrospective and prospective studies [3, 5, 6, 12, 18, 24, 25]. The drop in FXIII plasma levels after discontinuation of CPB bypass in the aforementioned category of patients
Pediatr Cardiol
Fig. 3 Dynamics of platelet number after CPB. Cyanotic patients demonstrate a larger decrease in platelet number after CPB than acyanotic patients. Both categories of patients restore their baseline platelet number 120 h after ICU admision. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB; #p \ 0.05 vs acyanotic patients
Fig. 4 Dynamics of activated partial thromboplastin time (APTT) after cardiopulmonary bypass (CPB). Both cyanotic and acyanotic patients demonstrate a prolongation of APTT prothrombin index after CPB that returns to baseline levels 12 h after ICU admision. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
reaches 28–61 % (Table 4). This drop is greater than would have been expected from CPB-related hemodilution alone. Consumption of FXIII also can contribute to the development of this phenomenon because the increased thrombin generation during CPB is well documented [8]. This wide range of postoperative FXIII plasma levels reported for patients with coronary artery disease or acquired valvular lesions may be caused by differences in perioperative treatment strategies or in the type of FXIII assays used. Blome et al. [3] demonstrated that the
Fig. 5 Dynamics of fibrinogen after CPB. Both cyanotic and acyanotic patients demonstrate a decrease in fibrinogen concentration after CPB that returns to baseline levels at 6 h after ICU admission. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
presence of aprotinin does not have an influence on the Berichrom FXIII assay. However, their study was an in vitro investigation with a sample limited in size. According to the majority of investigators, FXIII plasma levels do not return to baseline values at least during the first 24 h after CPB (Table 4). The reported mean values of absolute FXIII plasma levels in the early post-CPB period are relatively high and usually do not fall below 50 %. However, it remains disputable what FXIII plasma levels are sufficient during major surgical interventions (including cardiac surgery) to avoid excessive and prolonged bleeding or rebleeding [9, 12, 19, 24] Several studies have reported a strong inverse correlation between FXIII plasma levels after discontinuation of CPB and the amount of postoperative blood loss [6, 11, 24, 25], which also is supported by our findings. However, Blome et al. [3] did not confirm this phenomenon. Findings also have shown that the clot strength determined by thromboelastography correlates with post-CPB FXIII plasma levels [6]. The data concerning the impact of CPB on the FXIII plasma levels in pediatric patients with different types of CHD are very limited and contradictory. We found only one source in the available literature that reported a significant drop (*36 %) in FXIII plasma levels measured by immunoassay after open heart surgery performed for 10 patients younger than 6 years with both acyanotic and cyanotic CHDs. These data fully correlate with our findings that demonstrate a 35 % decrease in FXIII plasma levels at CPB discontinuation measured by Berichrom photometric assay in the entire patient population (acyanotic and cyanotic patients combined). We also showed that the drop in FXIII plasma levels was more profound in the cyanotic than in the acyanotic
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123 NR NR
14/HVR, CABG
19/CABG
34/CABG
98/elective CPB surgery
25a/CABG
57/CABG
CABG, HVR
28a/CHD
10/CHD
44/CHD
Brody et al. [5]
Shainoff et al. [24]
Chandler et al. [6]
Blome et al. [3]
Godje et al [12]
Ternstro¨m et al. [25]
Karkouti et al. [18]
Levin et al. [20]
Attard et al. [1]
Gertler et al. [10]
Blood products per institutional guidelines
RBC
Immunoassay Berichrom assay
Immunoassay
10
36
No
40
28
32
34
42
52
Yes
56–61b
At ICU arrival
Yes
NR
N/A
168 h after CPB
No
24 h after CPB
No
120 h after CPB
No
24 h after CPB
No
4 h after CPB
No
After CPB (protamine injection)
No
4 h after CPB
Return of factor XIII level to baseline at given time point
Drop in factor XIII level after CPB (%)
Not assessed
Not assessed
Not assessed
Not assessed
Yes
Yes
No
Yes
Not assessed
Not assessed
Correlation of post-CPB factor XIII level with postoperative blood loss
b
a
Numbers are given separately for HVR and CABG
No. of patients in placebo group is given for manuscripts evaluating treatment strategies
HVR heart valve replacement/repair, CABG coronary artery bypass grafting, RBC red blood cells, NR not reported, FFP fresh frozen plasma, CHD congenital heart defect, ICU intensive care unit
FFP
Antifibrinolyt
NR
NR
Blood products per protocol
Berichrom assay
Berichrom assay
Blood products per national guidelines Antifibrinolyt Antifibrinolyt
Berichrom assay
Berichrom assay
Immunoassay
Immunoassay
Immunoassay
Type of factor XIII assay
Antifibrinolyt
Crystalloids
Blood or crystalloids
Crystalloids
NR
Antifibrinolyt RBC
Gelatine
FFP
Platelets
Antifibrinolyt
NR
RBC
Concomitant medications and transfusions
Crystalloids
NR
NR
Crystalloids
No. of patientsa/type of surgery
Authors
CPB circuit priming
Table 4 Literature data on FXIII activity after cardiopulmonary bypass (CPB)
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patients (44 vs 28 %). Moreover, FXIII activity remained below baseline for a longer period after surgery in the cyanotic patients (48 vs 24 h), who experienced greater blood loss and received a larger volume of RBC transfusion than the acyanotic patients. The significant drop in FXIII levels of pediatric patients with CHDs subjected to CPB was not confirmed by other publications. Gertler et al. [10] reported a 10 % decrease in FXIII plasma levels measured by Berichrom assay after open heart surgery in 44 infants younger than 6 months, which did not reach statistical significance (Table 4). The FXIII levels had returned to baseline already when the infants arrived at the ICU. The authors failed to demonstrate any correlation between FXIII plasma levels, degree of cyanosis, amount of blood loss, and blood transfusion requirements. They believe that the routine addition of fresh frozen plasma to RBCs and crystalloid CPB circuit priming can prevent the drop in FXIII levels secondary to CPB-related hemodilution. It should be mentioned that only 27 % of the examined patient population had cyanotic CHDs, and the authors did not make direct a comparison of the end point parameters with that of the acyanotic patients. Such a comparison was made in the work of Levin et al. [20]. The number of pediatric patients 1 day to 8 years of age in their cyanotic and acyanotic placebo groups was 12 and 16, respectively. The cyanotic patients in this series were significantly older than the acyanotic patients. Similar to our study, the cyanotic patients had a longer CPB time and lost more blood postoperatively. However, the FXIII plasma levels measured by immunoassay did not change after CPB in any of the compared placebo groups. The authors did not report what type of CPB circuit priming was used in their study. The possible reasons for the inconsistency in results across the reported studies may include significant variations in the patients’ ages and differences in methods used for CPB circuit priming or measurement of FXIII plasma levels. We do not have sufficient data to explain fully the more profound and prolonged FXIII depletion recorded after CPB for the patients with cyanotic CHDs enrolled in our study. The most simplistic explanation could be that CPB bypass lasted significantly longer in the cyanotic patients. However, the postoperative dynamics of all the other coagulation parameters except the platelet count was similar for the cyanotic and acyanotic patients. We failed to show any preexisting coagulopathy reported for cyanotic patients by other authors [2, 4, 13–17, 21, 23, 26]. However, it should be mentioned that only a limited number of coagulation parameters was monitored. The baseline platelet number was lower for the cyanotic patients than for the acyanotic patients. However, this difference did not reach statistical significance. And more importantly, the
preoperative platelet count was within normal ranges in both of the compared groups. Consistent data from multiple sources on low FXIII activity in adults subjected to open heart surgery gave the rationale for the attempt to administer FXIII products in the early postoperative period and to investigate whether this therapeutic strategy can reduce blood loss and minimize blood product transfusion in this category of patients. The pilot study performed by Godje et al. [11] with 11 patients who underwent coronary surgery demonstrated that infusion of plasma-derived FXIII product (fibrogammin) in the amount of 2,500 units reduced drain volumes as well as the need for blood transfusion. However, the aforementioned findings were not supported by a prospective, randomized, double-blinded, placebo-controlled trial conducted several years later with the participation of the same institution as in the pilot study [12]. The patient population with coronary artery disease in this trial was larger and included 25 patients in each of the compared groups (group with placebo treatment and groups with 1,250 or 2,500 units of fibrogammin treatment provided after CPB discontinuation and dosing with protamine). In contrast to the pilot study, FXIII replacement therapy did not significantly decrease postoperative blood loss or the amount of transfused blood products. However, the secondary analysis demonstrated that the effectiveness of fibrogammin differs between patient subgroups with postoperative FXIII plasma levels below and above 70 %. The conclusion that FXIII replacement therapy is unable to eliminate blood transfusions after adult cardiac surgery was confirmed by another randomized, placebo-controlled multicenter study that included not only coronary patients but also subjects with heart valve disease [18]. This study included 409 patients undergoing coronary artery bypass grafting and/or heart valve replacement almost equally randomized to placebo or recombinant FXIII treatment groups (17.5 or 35 IU/kg, which corresponded to the dosage used in the study reported by Godje et al. [12] in 2006). The enrolled patients had a moderate risk for blood product transfusion that was strictly standardized. Treatment with recombinant FXIII did not have any effect on avoidance of blood product transfusion or the transfusion volume. In contrast to the aforementioned study by Godje et al. [12], the efficacy of treatment did not depend on preor postdose FXIII plasma levels. The authors hypothesized that FXIII could be more effective in a patient population with a higher transfusion risk. If this is true, patients with cyanotic CHDs, who have greater postoperative blood loss than acyanotic patients according to both the literature data [7, 20] and our findings, might be an appropriate target. Our study had several limitations. The CPB circuit priming was not exactly the same in the entire patient population. Besides, we did not have a standard
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postoperative transfusion protocol designed specifically for the current study. Finally, the dynamics of the FXIII levels after CPB were not compared with the dynamics of coagulation parameters except in terms of platelet number, prothrombin index, APTT, and fibrinogen concentration. Thus, additional investigations are necessary to understand why patients with cyanotic CHDs have a more profound and longer-lasting decrease in FXIII levels after CPB than acyanotic patients. Only prospective studies with a larger number of participants and a predefined transfusion protocol can determine whether patients with cyanotic CHDs undergoing CPB are a population that can benefit from routine monitoring of FXIII levels as well as from replacement therapy with FXIII products aimed at reducing both postoperative blood loss and the blood transfusion volume. Acknowledgments This study was funded by Novo Nordisk, Inc. and from the budget of the Bakoulev Center for Cardiovascular Surgery. Sergey B. Zaets and Eva H. N. Olsen are employees of Novo Nordisk, Inc.
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10. Gertler R, Martin K, Hapfelmeier A, Tassani-Prell P, Braun S, Wiesner G (2013) The perioperative course of factor XIII and associated chest tube drainage in newborn and infants undergoing cardiac surgery. Paediatr Anaesth 23:1035–1041 11. Godje O, Haushofer M, Lamm P, Reichart B (1998) The effect of factor XIII on bleeding in coronary surgery. Thorac Cardiovasc Surg 46:263–267 12. Godje O, Gallmeier U, Schelian M et al (2006) Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg 54:26–33 13. Goel M, Dk Shome, Singh ZN et al (2000) Hemostatic changes in children with cyanotic and acyanotic congenital heart disease. Indian Heart J 52:559–563 14. Goldschmidt B (1970) Effect of vitamin K on clotting factors in children with congenital cyanotic heart disease. Acta Pediatr Acad Sci Hung 11:135–139 15. Gralnick HR (1970) e-Aminocapronic acid in preoperative correction of hemostatic defect in cyanotic congenital heart disease. Lancet 1:1204–1205 16. Henriksson P, Varendh G, Lundstrom NR (1979) Haemostatic defects in cyanotic congenital heart disease. Br Heart J 41:23–27 17. Ihenacho NH, Breeze GR, Fletcher DJ, Stuart J (1973) Consumption coagulopathy in congenital heart disease. Lancet 1:231–234 18. Karkouti K, von Heymann C, Jespersen CM, Korte W, Levy JH, Ranucci M, Sellke FW, Song HK (2013) Efficacy and safety of recombinant factor XIII on reducing blood transfusions in cardiac surgery: a randomized, placebo-controlled, multicenter clinical trial. J Thorac Cardiovasc Surg 146:927–939 19. Korte WC, Szadkowski C, Ga¨hler A, Gabi K, Kownacki E, Eder M, Degiacomi P, Zoller N, Devay J, Lange J, Schnider T (2009) Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology 110:239–245 20. Levin E, Wu J, Devine DV et al (2000) Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid. Thromb Hemost 83:54–59 21. Maurer HM, McCue CM, Robertson LW, Haggins JC (1975) Correction of platelet dysfunction and bleeding in cyanotic congenital heart disease by simple red cell volume reduction. Am J Cardiol 35:831–835 22. Muszbek L, Adany R, Mikkola H (1996) Novel aspects of blood coagulation factor XIII: I. Structure, distribution, activation, and function. Crit Rev Lab Sci 33:357–421 23. Naiman JL (1970) Clotting and bleeding in cyanotic congenital heart disease. J Pediatr 76:333–335 24. Shainoff JR, Estafanous FG, Yared JP et al (1994) Low factor XIIIa levels are associated with increased blood loss after coronary artery bypass grafting. J Thorac Cardiovasc Surg 108:437–445 25. Ternstro¨m L, Radulovic V, Karlsson M, Baghaei F, Hyllner M, Bylock A, Hansson KM, Jeppsson A (2010) Plasma activity of individual coagulation factors, hemodilution and blood loss after cardiac surgery: a prospective observational study. Thromb Res 126:e128–e133 26. Wedemeyer AL, Edson JR, Krivit W (1972) Coagulation in cyanotic congenital heart disease. Am J Dis Child 124:656–660
ORIGINAL ARTICLE
Dynamics of Factor XIII Levels After Open Heart Surgery for Congenital Heart Defects: Do Cyanotic and Acyanotic Patients Differ? Leo A. Bockeria • Natalia N. Samsonova • Ivan A. Yurlov • Ludmila G. Klimovich • Elena F. Kozar • Eva H. N. Olsen • Sergey B. Zaets
Received: 3 December 2013 / Accepted: 25 March 2014 Ó Springer Science+Business Media New York 2014
Abstract Cardiopulmonary bypass (CPB) reduces coagulation factor levels through hemodilution and consumption. Differences in CPB-induced alterations of factor XIII (FXIII) levels in children with cyanotic and acyanotic congenital heart defects (CHDs) are not well characterized. FXIII activity (determined by Berichrom assay), prothrombin index, activated partial thromboplastin time, and fibrinogen were measured before open heart surgery with CPB and 5 days postoperatively for children older than 3 years with acyanotic (n = 30) and cyanotic (n = 30) CHDs. The preoperative FXIII levels did not differ significantly among the children of the compared groups. The cyanotic patients showed a significantly longer duration of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min; p = 0.026) and aortic cross-clamp (68.0 ± 27.1 vs 45.4 ± 31.4 min; p = 0.034). The drop in FXIII levels after termination of CPB was more profound for the children with cyanotic CHDs (87.1 ± 13.4 to 49.1 ± 13.2 vs 81.5 ± 12.6 to 58.6 ± 11.1 %, respectively; p = 0.018). The cyanotc patients also were restored to their baseline FXIII levels later than the children with acyanotic CHDs (at 48 vs 24 h). The post-CPB dynamics of the majority of the other coagulation parameters in the compared groups of patients were similar. The cyanotic patients experienced significantly
Presented in part at the 13th Congress of the International Society on Thrombosis and Haemostasis, Kyoto, Japan, 23–28 July 2011. L. A. Bockeria N. N. Samsonova I. A. Yurlov L. G. Klimovich E. F. Kozar Bakoulev Center for Cardiovascular Surgery, Moscow, Russia E. H. N. Olsen S. B. Zaets (&) Novo Nordisk, Inc., 800 Scudders Mill Road, Princeton, NJ 085536, USA e-mail: [email protected]
greater postoperative blood loss than the acyanotic patients (12.6 ± 4.9 vs 5.0 ± 2.1 mL/kg; p \ 0.001) and were transfused with larger volumes of red blood cells (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg; p = 0.007). The decrease in FXIII levels after CPB is more profound and lasts longer in children with cyanotic CHDs than in acyanotic patients. The rational strategy of postoperative FXIII replacement therapy for these categories of patients needs to be determined. Keywords Factor XIII Coagulation Cardiopulmonary bypass Congenital heart defects
Introduction Postoperative bleeding and the necessity of blood transfusions, which predispose to the development of multiorgan failure and septic complications, still remain an important issue after cardiac surgery with extracorporeal cardiopulmonary bypass (CPB). Bleeding after CPB might be associated with coagulation factor deficiency because it is known to reduce coagulation factor levels through hemodilution, consumption, or its influence on liver performance. Reduced factor XIII (FXIII) levels may play an important role in the pathogenesis of bleeding after CPB. FXIII is a transglutaminase involved in the final stage of blood coagulation. It is present in plasma as well as in platelets, monocytes, and macrophages. Plasma FXIII consists of two catalytic A subunits and two noncatalytic B subunits that serve as carrier molecules. Cellular FXIII consists of two A subunits only. Factor XIII circulates in plasma as an inactive precursor and is activated by thrombin. Activated FXIII stabilizes
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Pediatr Cardiol Table 1 Diagnosis of patients Diagnosis of patients
Table 2 Types of surgical procedures No. of patients
Diagnoses of patients
No. of operations
ASD
9
Acyanotic patients
ASD ? PAPVC
5
ASD closure
9
ASD ? pulmonary stenosis
1
5
Incomplete atrioventricular canal
2
VSD
8
ASD closure ? pulmonary vein redirection to the left atrium ASD closure ? pulmonary valvuloplasty
VSD ? aortic stenosis
1
Acyanotic patients
VSD ? tricuspid insufficiency
1
Congenital aortic insufficiency
3
Subtotal
30
Cyanotic patients Tetralogy of Fallot
20
Double-outlet right ventricle
5
Single ventricle
1
Tricuspid atresia
1
Pulmonary atresia
3
Subtotal
30
Total
60
ASD atrial septal defect, PAPVC partial anomalous pulmonary venous connection, VSD ventricular septal defect
1
ASD closure ? mitral valve plastic reconstruction
2
VSD closure
8
VSD closure ? resection of subaortic membrane
1
VSD closure ? tricuspid valve annuloplasty
1
Aortic valve replacement
3
Subtotal
30
Cyanotic patients Complete repair of tetralogy of Fallot
20
Complete repair of double-outlet right ventricle
3
Complete repair of pulmonary atresia
2
Reconstruction of the right ventricular outflow tract without VSD closure
1
Fontan operation
4
Subtotal
30
Total
60
ASD atrial septal defect, VSD ventricular septal defect
fibrin clots by cross-linking fibrin monomers, increases the mechanical strength of the clot, retards fibrinolysis, and enhances platelet adhesion to the injured tissue [22]. A significant drop in FXIII levels has been demonstrated after CPB used for coronary artery bypass grafting or for heart valve replacement in adults [3, 5, 6, 11, 12, 18, 24, 25]. Findings have shown that low postoperative plasma levels of FXIII in patients subjected to coronary artery bypass grafting are associated with increased bleeding [6, 11, 24, 25]. Data on the levels of FXIII in patients with congenital heart defects (CHDs) before and after CPB are limited and contradictory [1, 10, 20]. This study aimed to compare the dynamics of FXIII levels in patients with cyanotic and acyanotic CHDs subjected to open heart surgery with CPB and to investigate how it correlates with some other coagulation parameters.
Patients and Methods Patient Population This prospective observational study enrolled 60 pediatric patients with acyanotic (n = 30) or cyanotic (n = 30) CHDs subjected to open heart surgery at the Bakoulev Center for Cardiovascular Surgery (Moscow, Russia). The protocol was approved by the Research Council of the Bakoulev Center for Cardiovascular Surgery and the
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Ethical Review Committees of Novo Nordisk A/S. The parents or legal guardians of all the participating patients signed the Informed Consent Form. The informed consent for minors (Child Assent Form) also was signed by the children older than 6 years. The exclusion criteria ruled out diagnosed coagulation disorders, previous thrombotic events, and hepatic or renal failure. All the patients were older than 3 years. The most common diagnosis in the group of patients with acyanotic CHDs was atrial septal defect (Table 1). The most common diagnosis in the group of patients with cyanotic CHDs was tetralogy of Fallot. Various palliative interventions had been performed previously for 18 of the cyanotic patients including systemic-to-pulmonary shunt (n = 13), bidirectional cavopulmonary shunt (n = 4), and reconstruction of the right ventricular outflow tract without ventricular septal defect closure (n = 1). The types of surgical interventions performed in this study are shown in Table 2. All the operations were performed with CPB and hypothermia. The lowest rectal temperature during CPB was 28–34 °C (mean, 30.7 °C) for the cyanotic patients and 26–34 °C (mean, 31.5 °C) for the acyanotic patients. In the majority of the cases, the CPB circuit was primed with the whole blood or packed red blood cells (RBCs) and crystalloids. The total prime volume was 1,000 mL. The
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proportion of packed RBCs to crystalloids was 25–75 % in the acyanotic patients, and 15–85 % in the cyanotic patients with a hemoglobin level of 180 g/L or lower. In the cyanotic patients with a hemoglobin level higher than 180 g/L or a hematocrit level higher than 50 %, crystalloids or plasma together with crystalloids was used for priming. Cardioplegia was performed for all except four cyanotic patients, who were subjected to the Fontan operation with modification of the extracardiac conduit. Fluid transfused at completion of CPB corresponded to the institutional guidelines and mainly included packed RBCs (if necessary) and fresh frozen plasma. Packed RBC transfusion was mandatory if hemoglobin levels were below 80 g/L, optional for hemoglobin levels of 80–100 g/L, and not recommended if these levels were above 100 g/L. Fresh frozen plasma was to be transfused when the prothrombin index was below 60 %. Platelets could be given if the platelet count was lowered down to 100 109/mL or below. End Point Parameters The end point parameters included FXIII activity, prothrombin index (ratio between prothrombin time of control and patient plasma multiplied by 100 %), activated partial thromboplastin time (APTT), and fibrinogen. These parameters were measured repeatedly: before initiation of CPB, after discontinuation of CPB, and then 6, 12, 24, 48 and 120 h after CPB. The preoperative parameters used for the assessment of cyanosis were arterial blood oxygen saturation (SaO2) and hemoglobin concentration. The postoperative assessment also included the recording of blood loss (chest tube output) during the 24 h after admission to the intensive care unit (ICU) as well as the amount of blood product transfusion. The activity of the FXIII A subunit was determined by photometric FXIII activity assay (Berichrom FXIII; Dade Behring, Marburg, Germany) using the COBAS MIRA Plus analyzer (Roche, Basel, Switzerland). Measurements of the patient’s plasma samples were performed according to the manufacturer’s instructions. In this assay, plasma FXIII is activated by thrombin in the presence of aggregationinhibiting peptide to prevent fibrin-induced clot formation. Activated FXIII (FXIIIa) cross-links a specific peptide substrate, with subsequent release of the ammonia that in turn oxidizes NADH to nicotinamide adenine dinucleotide (NAD). The decrease in NADH is recorded by monitoring its absorbance at 340 nm. Statistical Analysis Data were analyzed using SPSS 9.0 for Windows (SPSS, Chicago, IL, USA). Continuous variables are presented as
mean ± standard deviation. A two-sample Student’s t test was used to compare the baseline parameters in cyanotic and acyanotic patients. The parameters at multiple time points were compared by analysis of variance (ANOVA) followed by the t test. With the observational and exploratory character of the study taken into consideration, no correction for multiple tests was performed. The Pearson correlation coefficient was determined to assess the relationship between variables (FXIII levels at discontinuation of CPB and amount of blood loss/packed RBC transfusion). The statistical significance was set at a p value lower than 0.05.
Results The age of the patients did not differ in the compared groups (Table 3). Not surprisingly, the cyanotic patients had significantly lower preoperative arterial blood oxygen saturation and higher hemoglobin and hematocrit levels (Table 3). The preoperative FXIII plasma levels, platelet counts, prothrombin indexes, and APTTs did not differ significantly in the compared groups of patients. The cyanotic patients had significantly longer durations of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min, respectively; p = 0.026) and aortic cross-clamping (68.0 ± 27.1 vs 45.4 ± 31.4 min, respectively; p = 0.034). The rectal temperature during CPB did not differ between the cyanotic and acyanotic patients (p = 0.438). In both the acyanotic and cyanotic patients, the CPB resulted in hemodilution. The hematocrit levels lowered significantly down to 29.9 ± 3.6 and 31.7 ± 4.9 %, respectively (p \ 0.001 vs preoperative values). In the acyanotic patients, the hematocrit remained decreased for at least 24 h after surgery. In the cyanotic patients, it did not reach elevated preoperative levels during the follow-up period. Both the acyanotic and cyanotic patients experienced a significant drop in FXIII plasma levels immediately after CPB (Fig. 1). However, this depression was more profound in the patients with cyanotic CHDs. The cyanotic patients also experienced restored preoperative FXIII levels later than the acyanotic patients (48 vs 24 h after CPB, respectively). In both groups of patients, CPB also caused significant alterations of other coagulation parameters (prothrombin index, platelet number, APTT, and fibrinogen concentration) (Figs. 2, 3, 4, 5). The decrease in the number of platelets was more profound in the cyanotic patients. The time required for each parameter to return to preoperative levels ranged from 6 h (fibrinogen concentration) to 120 h (platelet number) but did not differ significantly in the compared groups of patients.
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Pediatr Cardiol Table 3 Preoperative clinical and laboratory parameters
Parameters
Acyanotic patients
Age (years) SaO2 (%) Hemoglobin (g/L) Data are presented as mean ± standard deviation (minimum–maximum) SaO2 arterial oxygen saturation, APTT activated partial thromboplastin time * p \ 0.05 vs acyanotic patients
Platelet count (109/mL)
8.8 ± 5.0 (3–15)
8.6 ± 3.8 (4–14)
0.915
82.4 ± 8.1 (62–89)*
\0.001
35.3 ± 4.1 (28–44) 329.7 ± 50.0 (190–435)
168.6 ± 13.9 (152–198)*
\0.001
46.1 ± 3.3 (41–52)*
\0.001
294.8 ± 51.8 (194–436)
0.326
Factor XIII activity (%)
81.5 ± 12.6 (50.9–110.5)
87.1 ± 13.4 (52.5–130.4)
0.512
Prothrombin index (%)
75.4 ± 12.3 (55.3–90.1)
73.5 ± 17.9 (42.8–99.3)
0.756
APTT (s) Fibrinogen (mg %)
32.8 ± 17.9 (18.3–88.4) 202.5 ± 96.3 (50–381)
Fig. 1 Dynamics of FXIII plasma levels after cardiopulmonary bypass (CPB). Cyanotic patients demonstrate a more profound and longer-lasting drop in FXIII plasma levels after CPB than acyanotic patients. Error bars represent standard deviation. *p \ 0.05 vs preCPB. #p \ 0.05 vs acyanotic patients
Greater postoperative blood loss was experienced by the cyanotic patients (12.6 ± 4.9 mL/kg) than by the acyanotic patients (5.0 ± 2.1 mL/kg) (p \ 0.001). Consequently, the cyanotic patients were transfused with larger volumes of packed RBCs (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg, p = 0.007). Both the cyanotic and acyanotic patients showed a significant inverse correlation between FXIII levels at discontinuation of CPB and postoperative blood loss (r = -0.491 and r = -0.463, respectively; p = 0.006 and p = 0.01, respectively) as well as the amount of transfused packed RBCs (r = -0.468 and r = -0.409, respectively; p = 0.009 and p = 0.025, respectively). The amount of transfused fresh frozen plasma was 13.5 ± 3.6 mL/kg for the cyanotic patients and 12.4 ± 2.4 mL/kg for the acyanotic patients and did not differ significantly between these compared groups (p = 0.22). Few platelet transfusions were administered (3 among the cyanotic and 1 among the acyanotic patients). Three of four cyanotic patients subjected to Fontan operations received
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p value
98.1 ± 1.0 (96–100) 119.5 ± 13.2 (104–156)
Hematocrit (%)
Cyanotic patients
38.5 ± 15.9 (20.2–71.4) 215.6 ± 77.4 (78–300)
0.425 0.722
Fig. 2 Dynamics of the prothrombin index after CPB. Both cyanotic and acyanotic patients demonstrate a decrease in prothrombin index after CPB that returns to baseline levels 12 h after intensive care unit (ICU) admission. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
albumin infusion because this type of surgical intervention usually is associated with massive pleural effusion.
Discussion Strategies to avoid bleeding after open heart surgery and to limit the necessity for blood transfusion in different categories of patients still are being thoroughly investigated. Coagulation factor deficiency caused by CPB is one of the mechanisms predisposing patients to bleeding complications. A postoperative decrease in FXIII levels in adult patients subjected to coronary artery bypass grafting or heart valve replacement/repair has been confirmed by multiple retrospective and prospective studies [3, 5, 6, 12, 18, 24, 25]. The drop in FXIII plasma levels after discontinuation of CPB bypass in the aforementioned category of patients
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Fig. 3 Dynamics of platelet number after CPB. Cyanotic patients demonstrate a larger decrease in platelet number after CPB than acyanotic patients. Both categories of patients restore their baseline platelet number 120 h after ICU admision. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB; #p \ 0.05 vs acyanotic patients
Fig. 4 Dynamics of activated partial thromboplastin time (APTT) after cardiopulmonary bypass (CPB). Both cyanotic and acyanotic patients demonstrate a prolongation of APTT prothrombin index after CPB that returns to baseline levels 12 h after ICU admision. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
reaches 28–61 % (Table 4). This drop is greater than would have been expected from CPB-related hemodilution alone. Consumption of FXIII also can contribute to the development of this phenomenon because the increased thrombin generation during CPB is well documented [8]. This wide range of postoperative FXIII plasma levels reported for patients with coronary artery disease or acquired valvular lesions may be caused by differences in perioperative treatment strategies or in the type of FXIII assays used. Blome et al. [3] demonstrated that the
Fig. 5 Dynamics of fibrinogen after CPB. Both cyanotic and acyanotic patients demonstrate a decrease in fibrinogen concentration after CPB that returns to baseline levels at 6 h after ICU admission. Error bars represent standard deviation. *p \ 0.05 vs pre-CPB
presence of aprotinin does not have an influence on the Berichrom FXIII assay. However, their study was an in vitro investigation with a sample limited in size. According to the majority of investigators, FXIII plasma levels do not return to baseline values at least during the first 24 h after CPB (Table 4). The reported mean values of absolute FXIII plasma levels in the early post-CPB period are relatively high and usually do not fall below 50 %. However, it remains disputable what FXIII plasma levels are sufficient during major surgical interventions (including cardiac surgery) to avoid excessive and prolonged bleeding or rebleeding [9, 12, 19, 24] Several studies have reported a strong inverse correlation between FXIII plasma levels after discontinuation of CPB and the amount of postoperative blood loss [6, 11, 24, 25], which also is supported by our findings. However, Blome et al. [3] did not confirm this phenomenon. Findings also have shown that the clot strength determined by thromboelastography correlates with post-CPB FXIII plasma levels [6]. The data concerning the impact of CPB on the FXIII plasma levels in pediatric patients with different types of CHD are very limited and contradictory. We found only one source in the available literature that reported a significant drop (*36 %) in FXIII plasma levels measured by immunoassay after open heart surgery performed for 10 patients younger than 6 years with both acyanotic and cyanotic CHDs. These data fully correlate with our findings that demonstrate a 35 % decrease in FXIII plasma levels at CPB discontinuation measured by Berichrom photometric assay in the entire patient population (acyanotic and cyanotic patients combined). We also showed that the drop in FXIII plasma levels was more profound in the cyanotic than in the acyanotic
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123 NR NR
14/HVR, CABG
19/CABG
34/CABG
98/elective CPB surgery
25a/CABG
57/CABG
CABG, HVR
28a/CHD
10/CHD
44/CHD
Brody et al. [5]
Shainoff et al. [24]
Chandler et al. [6]
Blome et al. [3]
Godje et al [12]
Ternstro¨m et al. [25]
Karkouti et al. [18]
Levin et al. [20]
Attard et al. [1]
Gertler et al. [10]
Blood products per institutional guidelines
RBC
Immunoassay Berichrom assay
Immunoassay
10
36
No
40
28
32
34
42
52
Yes
56–61b
At ICU arrival
Yes
NR
N/A
168 h after CPB
No
24 h after CPB
No
120 h after CPB
No
24 h after CPB
No
4 h after CPB
No
After CPB (protamine injection)
No
4 h after CPB
Return of factor XIII level to baseline at given time point
Drop in factor XIII level after CPB (%)
Not assessed
Not assessed
Not assessed
Not assessed
Yes
Yes
No
Yes
Not assessed
Not assessed
Correlation of post-CPB factor XIII level with postoperative blood loss
b
a
Numbers are given separately for HVR and CABG
No. of patients in placebo group is given for manuscripts evaluating treatment strategies
HVR heart valve replacement/repair, CABG coronary artery bypass grafting, RBC red blood cells, NR not reported, FFP fresh frozen plasma, CHD congenital heart defect, ICU intensive care unit
FFP
Antifibrinolyt
NR
NR
Blood products per protocol
Berichrom assay
Berichrom assay
Blood products per national guidelines Antifibrinolyt Antifibrinolyt
Berichrom assay
Berichrom assay
Immunoassay
Immunoassay
Immunoassay
Type of factor XIII assay
Antifibrinolyt
Crystalloids
Blood or crystalloids
Crystalloids
NR
Antifibrinolyt RBC
Gelatine
FFP
Platelets
Antifibrinolyt
NR
RBC
Concomitant medications and transfusions
Crystalloids
NR
NR
Crystalloids
No. of patientsa/type of surgery
Authors
CPB circuit priming
Table 4 Literature data on FXIII activity after cardiopulmonary bypass (CPB)
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patients (44 vs 28 %). Moreover, FXIII activity remained below baseline for a longer period after surgery in the cyanotic patients (48 vs 24 h), who experienced greater blood loss and received a larger volume of RBC transfusion than the acyanotic patients. The significant drop in FXIII levels of pediatric patients with CHDs subjected to CPB was not confirmed by other publications. Gertler et al. [10] reported a 10 % decrease in FXIII plasma levels measured by Berichrom assay after open heart surgery in 44 infants younger than 6 months, which did not reach statistical significance (Table 4). The FXIII levels had returned to baseline already when the infants arrived at the ICU. The authors failed to demonstrate any correlation between FXIII plasma levels, degree of cyanosis, amount of blood loss, and blood transfusion requirements. They believe that the routine addition of fresh frozen plasma to RBCs and crystalloid CPB circuit priming can prevent the drop in FXIII levels secondary to CPB-related hemodilution. It should be mentioned that only 27 % of the examined patient population had cyanotic CHDs, and the authors did not make direct a comparison of the end point parameters with that of the acyanotic patients. Such a comparison was made in the work of Levin et al. [20]. The number of pediatric patients 1 day to 8 years of age in their cyanotic and acyanotic placebo groups was 12 and 16, respectively. The cyanotic patients in this series were significantly older than the acyanotic patients. Similar to our study, the cyanotic patients had a longer CPB time and lost more blood postoperatively. However, the FXIII plasma levels measured by immunoassay did not change after CPB in any of the compared placebo groups. The authors did not report what type of CPB circuit priming was used in their study. The possible reasons for the inconsistency in results across the reported studies may include significant variations in the patients’ ages and differences in methods used for CPB circuit priming or measurement of FXIII plasma levels. We do not have sufficient data to explain fully the more profound and prolonged FXIII depletion recorded after CPB for the patients with cyanotic CHDs enrolled in our study. The most simplistic explanation could be that CPB bypass lasted significantly longer in the cyanotic patients. However, the postoperative dynamics of all the other coagulation parameters except the platelet count was similar for the cyanotic and acyanotic patients. We failed to show any preexisting coagulopathy reported for cyanotic patients by other authors [2, 4, 13–17, 21, 23, 26]. However, it should be mentioned that only a limited number of coagulation parameters was monitored. The baseline platelet number was lower for the cyanotic patients than for the acyanotic patients. However, this difference did not reach statistical significance. And more importantly, the
preoperative platelet count was within normal ranges in both of the compared groups. Consistent data from multiple sources on low FXIII activity in adults subjected to open heart surgery gave the rationale for the attempt to administer FXIII products in the early postoperative period and to investigate whether this therapeutic strategy can reduce blood loss and minimize blood product transfusion in this category of patients. The pilot study performed by Godje et al. [11] with 11 patients who underwent coronary surgery demonstrated that infusion of plasma-derived FXIII product (fibrogammin) in the amount of 2,500 units reduced drain volumes as well as the need for blood transfusion. However, the aforementioned findings were not supported by a prospective, randomized, double-blinded, placebo-controlled trial conducted several years later with the participation of the same institution as in the pilot study [12]. The patient population with coronary artery disease in this trial was larger and included 25 patients in each of the compared groups (group with placebo treatment and groups with 1,250 or 2,500 units of fibrogammin treatment provided after CPB discontinuation and dosing with protamine). In contrast to the pilot study, FXIII replacement therapy did not significantly decrease postoperative blood loss or the amount of transfused blood products. However, the secondary analysis demonstrated that the effectiveness of fibrogammin differs between patient subgroups with postoperative FXIII plasma levels below and above 70 %. The conclusion that FXIII replacement therapy is unable to eliminate blood transfusions after adult cardiac surgery was confirmed by another randomized, placebo-controlled multicenter study that included not only coronary patients but also subjects with heart valve disease [18]. This study included 409 patients undergoing coronary artery bypass grafting and/or heart valve replacement almost equally randomized to placebo or recombinant FXIII treatment groups (17.5 or 35 IU/kg, which corresponded to the dosage used in the study reported by Godje et al. [12] in 2006). The enrolled patients had a moderate risk for blood product transfusion that was strictly standardized. Treatment with recombinant FXIII did not have any effect on avoidance of blood product transfusion or the transfusion volume. In contrast to the aforementioned study by Godje et al. [12], the efficacy of treatment did not depend on preor postdose FXIII plasma levels. The authors hypothesized that FXIII could be more effective in a patient population with a higher transfusion risk. If this is true, patients with cyanotic CHDs, who have greater postoperative blood loss than acyanotic patients according to both the literature data [7, 20] and our findings, might be an appropriate target. Our study had several limitations. The CPB circuit priming was not exactly the same in the entire patient population. Besides, we did not have a standard
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postoperative transfusion protocol designed specifically for the current study. Finally, the dynamics of the FXIII levels after CPB were not compared with the dynamics of coagulation parameters except in terms of platelet number, prothrombin index, APTT, and fibrinogen concentration. Thus, additional investigations are necessary to understand why patients with cyanotic CHDs have a more profound and longer-lasting decrease in FXIII levels after CPB than acyanotic patients. Only prospective studies with a larger number of participants and a predefined transfusion protocol can determine whether patients with cyanotic CHDs undergoing CPB are a population that can benefit from routine monitoring of FXIII levels as well as from replacement therapy with FXIII products aimed at reducing both postoperative blood loss and the blood transfusion volume. Acknowledgments This study was funded by Novo Nordisk, Inc. and from the budget of the Bakoulev Center for Cardiovascular Surgery. Sergey B. Zaets and Eva H. N. Olsen are employees of Novo Nordisk, Inc.
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