J Thromb Thrombolysis (2011) 32:372–377 DOI 10.1007/s11239-011-0606-5
Cardiac catheterization: haemostatic changes in pediatric versus adult patients Gerd Hoerl • Erwin Tafeit • Bettina Leschnik • Thomas Wagner • Wolfgang Muntean • Guenther Juergens Martin Koestenberger • Gerhard Cvirn
•
Published online: 11 June 2011 Ó Springer Science+Business Media, LLC 2011
Abstract Thrombophilic or haemorrhagic complications are possible adverse events following cardiac catheterization particularly in pediatric patients. It was therefore the aim of our study to compare the cardiac catheterization-related haemostatic changes in children with that in adults. The total of 50 patients was subdivided into Gr I (1–6 years), Gr II (7–18 years), and Gr III (19–58 years). Parameters of coagulation activation, plasma levels of various clotting factors and heparinase-modified thrombelastometry parameters were determined prior and immediately after cardiac catheterization. The haemostatic system of pediatric patients was markedly more affected by the procedure than that of adults. Levels of thrombin/antithrombin complex and prothrombin fragment 1?2 in the post-catheter plasma samples were significantly increased in Grs I and II, not in Gr III. The catheter-related decrease in fibrinogen and F II levels was higher in Gr I than in Grs II and III. F VII levels were significantly decreased in Grs I and II, not in Gr III. The catheter-related prolongation of Coagulation times was highest in Gr I, followed by Gr II and finally Gr III. A significant catheter-related decrease of maximum clot firmness was observed solely in Gr I. Our results show that cardiac catheterisation perturbs the haemostatic system of adults, and,
G. Hoerl E. Tafeit G. Juergens G. Cvirn (&) Institute of Physiological Chemistry, Medical University of Graz, Harrachgasse 21/II, 8010 Graz, Austria e-mail:
[email protected] B. Leschnik W. Muntean M. Koestenberger Department of Pediatrics, Medical University of Graz, Graz, Austria T. Wagner Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, Graz, Austria
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even more pronounced, that of pediatric patients. Thus, our results indicate that children might be at a higher risk for either thrombotic complications or post-operative bleeding events than adults. Keywords Cardiac catheterization Haemostatic profiling Heparinase-modified thrombelastometry Pediatric and adult patients Abbreviations APTT Activated partial thromboplastin time CT Coagulation time CHD Congenital heart disease F 1?2 Prothrombin fragment 1?2 HEPTEM Heparinase-modified thrombelastometry MCF Maximum clot firmness TAT Thrombin/antithrombin complex TT Thrombin time
Introduction Cardiac catheterization has been shown to be associated with coagulation activation [1–4]. Consequently, thrombophilic or haemorrhagic complications in both pediatric and adult patients are possible adverse events following cardiac catheterization [5–7]. We anticipated that catheterization-related haemostatic changes in children might differ from that occurring in adults since there are important physiological differences in the respective haemostatic systems [8, 9]. For example, plasma concentrations of many procoagulant proteins are decreased throughout childhood [10, 11]. Moreover, information regarding the proper use of anticoagulants in
Catheterization and haemostatic profiling
children undergoing cardiac catheterization is scarce [12] and anticoagulants are used off-label. Thus, the aim of our study was to compare the cardiac catheterization-related haemostatic changes in children with that in adults. The following haemostatic parameters were investigated before and immediately after the surgical procedure: the markers of coagulation activation thrombin/ antithrombin complex (TAT) and prothrombin fragment 1?2 (F 1?2), as well as plasma levels of fibrinogen and the coagulation factors (F) II, V, VII, and X. Routinely, prothrombin time (PT), activated partial thromboplastin time (APTT) or thrombin time (TT) are measured to estimate the patient’s coagulation status. However, these standard coagulation times can not reasonably be determined in the post-catheter plasma samples due to heparinization [13]. Therefore, we applied heparinase-modified thrombelastometry (HEPTEM) for haemostatic profiling. HEPTEM has been shown to be a suitable method to detect possible hyper- or hypocoaguable states in heparinized patients [14]. In the HEPTEM assay, plasma samples become activated via the intrinsic pathway in the presence of a heparin processing enzyme (heparinase) [15]. HEPTEM not only provides information about coagulation times (CTs). Presumably, this method also allows determination of the influence of the cardiac catheterization procedure on the clot forming capacity. For example, the parameter maximum clot firmness (MCF) sensitively reflects changes in plasma fibrinogen levels [16, 17]. To our knowledge, cardiac catheterization-related haemostatic changes in children and adults have not been comparatively evaluated. Results from our study might help to assess the relative risk of children for postcatheter bleeding or thrombotic complications.
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unfractionated heparin bolus therapy (100 IU/kg bodyweight). The patients were subdivided somewhat arbitrary into the following three groups by age: infants, toddlers and young children from the age of 1 to 6 years (Gr I), school children and adolescents from the age of 7 to 18 years (Gr II), and adults from the age of 19 to 30 years (Gr III). Diagnostic cardiac catheterization was performed in patients with the following CHDs: pulmonary atresia (PA); persistent ductus arteriosus (PDA); total anomalous pulmonary venous return (TAPVR); tetralogy of Fallot (TOF); ventricular septal defect (VSD); Single ventricle, including patients who required a Glenn anastomosis or Fontan Procedure. The median duration of cardiac catheterization was 27 min (8–96 min). Collection of blood and preparation of plasma Samples were obtained from the blood that was collected for the routine coagulation screening before cardiac catheterization and at the end of catheterization. Blood (2.7 ml) was collected into premarked, precitrated S-Monovette tubes from Sarstedt (Nu¨mbrecht, Germany), containing 300 ll 0.1 mol/l citrate, centrifuged at room temperature for 10 min at 28009g, and stored at -70°C in propylene tubes until assayed. Standard laboratory tests Testkit F 1?2 micro and TAT were purchased from Behring Diagnostics GmbH (Marburg, Germany). Fibrinogen concentration (fibrinogen), heparin concentration, and concentrations of clotting factors II, V, VII, and X were determined on a BM/Hitachi 917 from Roche (Vienna, Austria). ROTEM analysis
Materials and methods Patients A total of 50 patients with congenital heart disease (CHD) who underwent diagnostic cardiac catheterization were included in the study. The pediatric patients were selected from individuals referred to our cardiology service for evaluation of heart murmurs or follow-up investigations. The young adult patients were selected from individuals referred to the grown ups with congenital heart defects service for follow-up and elective diagnostic cardiac catheterization. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee (Nr. 17-078 ex 05/06). Patient demographics are summarized in Table 1. Patients scheduled for catheterization received
ROTEM measurements were performed on the TEM coagulation analyzer (ROTEMTM 05) from Matel Table 1 Patient demographic data 1–6 years (n = 19)
7–18 years (n = 15)
[18 years (n = 16)
TOF/PA
5
5
8
PDA
3
2
0
TAPVR
3
1
1
VSD
7
5
4
Single ventriclea
1
2
3
PA pulmonary atresia, PDA persistent ductus arteriosus, TAPVR total anomalous pulmonary venous return, TOF tetralogy of Fallot, VSD ventricular septal defect a
Single ventricle group included patients who required a Glenn anastomosis or Fontan procedure
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Medizintechnik (Graz, Austria). For heparinase-modified thrombelastometry (HEPTEM) measurements samples of 300 ll of citrated PPP were incubated with 20 ll of hep-TEM reagent from Pentapharma GmbH (Munich, Germany) containing heparinase I from flavobacteria, and with 20 ll of in-TEM reagent from Pentapharma GmbH (Munich, Germany) containing partial thromboplastin phospholipid. Using the thrombelastograph, we obtained the following two values: CT, the period of time from initiation of the test to the initial fibrin formation, and MCF, expressing the maximum strength in millimeters of the final clot.
Catheter-related coagulation activation in the different age groups
Statistics
Post-catheter levels of fibrinogen and F II were significantly lower in Gr I compared to Grs II and III. The decrease of F VII levels was significantly higher in Gr I than in Gr II. In Gr III no significant reduction of F VII levels was observed. The decrease of F V and F X levels was essentially the same in all age groups. Data are listed in Table 3.
Statistical analyses were performed using the computer program SPSS (SPSS Inc., Chicago, Il, USA). Correlations between variables were analyzed by Spearman’s coefficient of correlation (r). An r-value of 0.7 or more was considered meaningful. The nonparametric Wilcoxon-Test for paired samples [18] was used to test the significance of parameter differences before and after cardiac catheterization. For statistical comparisons between two agegroups the Mann–Whitney U-Test for two independent samples was applied [19]. P values less than 0.05 were considered statistically significant.
Results Heparin levels in the post-catheter plasma samples ranged between 0.1 and 1.12 IU/ml. Thus, the standard coagulation times PT, APTT, and TT were reasonably solely for the pre-catheter plasma samples. To estimate coagulation times in the post-catheter plasma samples, we measured CTs by means of HEPTEM. For plasma samples containing [0.5 IU/ml heparin, CTs were corrected according to our recent study [20]. No correlations were found in the pre-catheter plasma samples between HEPTEM derived CTs and the three standard coagulation times PT, APTT, and TT. Haemostatic variables before and after cardiac catheterization In the total of 50 consecutive patients following significant changes in the haemostatic parameters were observed: (i) levels of TAT and F 1?2 were higher after the catheter; (ii) levels of fibrinogen and the coagulation factors (F) II, V, VII, and X were lower after the catheter; (iii) CTs evaluated by means of HEPTEM were prolonged after the catheter. Data are listed in Table 2.
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Cardiac catheterization caused a significantly stronger activation of the coagulation system in pediatric patients (Grs I and II) than in adult patients (Gr III): Either TAT and F 1?2 levels were significantly higher in Grs I and II compared to Gr III after the catheter. Data are listed in Table 3. Catheter-related consumption of coagulation factors in the different age groups
Thrombelastometry parameters in the different age groups The catheter-related prolongation of CTs was higher in Gr I than in Gr II and III. Data are listed in Table 4. A significant catheter-related decrease of MCF was observed solely in Gr I (13.18 ± 3.23 vs. 11.76 ± 3.11 mm, P \ 0.017). For all patients a significant high correlation was found between MCF values and fibrinogen levels (r = 0.738, P \ 0.001).
Discussion We show herein that the haemostatic systems of both children and adults are markedly affected by cardiac catheterization. Plasma levels of two markers of coagulation activation, TAT and F 1?2, were significantly higher after the procedure. These results are in good agreement with the findings of Andreotti et al., who reported on significantly increased TAT and F 1?2 levels immediately after cardiac catheterization [1] and with the findings of Vielhaber et al. reporting on increased F 1?2 levels after the procedure [21]. Interestingly, plasma levels of various clotting factors were significantly lower after the procedure. This could be attributable, on one hand, to the imprecise measurement of coagulation factor levels in plasma containing heparin. On the other hand, we assume that coagulation activation during the procedure might lead to consumptive coagulopathy resulting in depletion of clotting factors from the plasma. To our knowledge, no data are available to date
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Table 2 Haemostatic parameters prior and after cardiac catheterization (all patients, n = 50) Pre-catheter TAT (lg/l)
Post-catheter
Alteration (%)
Significance
6.49 ± 11.83
16.65 ± 21.46
?156.60
P = 0.001
F 1?2 (pmol/l)
139.09 ± 127.61
358.05 ± 482.21
?157.40
P \ 0.001
Fibrinogen (mg/dl)
285.94 ± 68.59
203.33 ± 66.08
-28.89
P \ 0.001
F II (%)
78.60 ± 17.82
70.23 ± 17.16
-10.64
P \ 0.001
F V (%)
84.92 ± 25.31
54.83 ± 20.73
-35.43
P \ 0.001
F VII (%)
66.96 ± 18.34
60.83 ± 16.79
-9.15
P \ 0.001
F X (%)
68.94 ± 15.76
39.96 ± 16.46
-42.04
P \ 0.001
156.10 ± 24.38
200.88 ± 36.68
?30.70
P \ 0.001
CT (s)
Table 3 Alterations of parameters of coagulation activation and of coagulation factor levels prior versus after cardiac catheterization in each age group Pre-catheter
Post-catheter
Alteration (%)
Significance
Gr I (n = 19) 1–6 years TAT (lg/l)
10.92 ± 18.80
21.48 ± 20.91
?96.66
n.s.
F 1?2 (pmol/l)
176.7 ± 191.2
523.8 ± 676.2
?196.47
P = 0.001
Fibrinogen (mg/dl) F II (%)
282.4 ± 67.27 72.61 ± 17.82
183.6 ± 75.03 60.33 ± 17.16
-34.98 -16.91
P = 0.012 P \ 0.001
F VII (%)
65.89 ± 18.34
58.00 ± 16.79
-11.97
P = 0.001
Gr II (n = 15) 7–18 years TAT (lg/l)
4.76 ± 3.85
24.47 ± 27.55
?413.66
P = 0.004
F 1?2 (pmol/l)
102.2 ± 43.1
328.2 ± 320.3
?221.10
P = 0.006
Fibrinogen (mg/dl)
288.5 ± 47.3
216.6 ± 50.9
-24.94
P = 0.008
F II (%)
82.71 ± 17.35
71.57 ± 15.35
-13.47
P = 0.003
F VII (%)
73.57 ± 21.50
65.86 ± 20.08
-10.48
P = 0.003
Gr III (n = 16) [18 years 3.28 ± 1.79
3.54 ± 1.26
-7.89
n.s.
F 1?2 (pmol/l)
TAT (lg/l)
126.7 ± 58.3
176.0 ± 154.5
?38.87
n.s.
Fibrinogen (mg/dl)
287.8 ± 89.7
207.2 ± 73.5
-28.01
P = 0.005
F II (%) F VII (%)
81.75 ± 20.33 62.38 ± 20.36
80.19 ± 19.82 59.63 ± 18.83
-1.91 -4.41
n.s. n.s.
n.s. not significant
Table 4 CTs prior and after cardiac catheterization Pre-catheter
Post-catheter
Alteration (%)
Significance
Gr I (n = 19)
155.29 ± 19.73
209.76 ± 47.63
?35.08
P = 0.001
Gr II (n = 15)
153.00 ± 20.33
194.33 ± 27.69
?27.01
P = 0.002
Gr III (n = 16)
159.88 ± 32.19
197.56 ± 30.60
?23.57
P = 0.002
The prolongation of CTs was the highest in Gr I, followed by Gr II and Gr III
reporting on the levels of plasma clotting factors after cardiac catheterization. However, there are studies available reporting on clotting factor levels after cardiopulmonary bypass. The respective data are in good agreement
with our findings. For example, Cardigan et al. [22] and Petaja et al. [23] reported on decreased plasma levels of F VII after bypass and Straub et al. [14] reported on decreased levels of fibrinogen after bypass. Moreover,
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Ternstro¨m et al. have shown reduced plasma levels of F I, II, V, X, and XIII after cardiopulmonary bypass [24]. To our knowledge, no data exist to date reporting on cardiac catheter-related haemostatic changes in children in comparison with that in adults. Because of a relative immaturity of the haemostatic system in the young [10], a difference between children and adults in their response to cardiac catheterization might be anticipated. In fact, we found that the haemostatic system of pediatric patients is markedly more affected by the procedure than that of adults. Levels of the coagulation activation markers TAT and F 1?2 in the post-catheter plasma samples were higher in Gr I (children aged between 1 and 6 years) and Gr II (children aged between 7 and 18 years) than in Gr III (adults [19 years). In Grs I and II most of these changes were significant increases, while in Gr III no significance was observed (Table 3). Moreover, levels of fibrinogen, F II and VII after the procedure were lower in Grs I and II than in Gr III. Again, in Grs I and II we observed significant decreases, while the changes in Gr III were not significant for F II and VII. As mentioned above, postcatheter bleeding or thrombotic complications are possible adverse events following cardiac catheterization. It has been suggested that the risk for thrombotic complications might be higher in infants and young children [25]. The rate of venous thrombosis after cardiac catheterization has been estimated to be as high as 4–7% [26, 27]. In agreement, our data suggest that children might be at a high risk for both catheter-related thrombotic complications and bleeding than adults. On one hand, thrombotic complications might be attributable to the catheter-related massive thrombin generation, as reflected by high postcatheter levels of TAT and F 1?2. On the other hand, the catheter-related consumption of clotting factors is more pronounced in pediatric than in adult patients. Thus, particularly pediatric patients might be in a hypocoaguable state after the procedure, predisposing the young for bleeding events. These findings are in good agreement with our previous study. We found a significant cardiac surgeryrelated decrease of the endogenous thrombin potential, also indicating a hypocoaguable state after the catheter [28]. In accordance, it has been shown that patients who developed catheter-related thrombi were younger and smaller than those who did not [29]. HEPTEM measurements also indicate that the hemostatic system of the young is more affected by cardiac catheterization than that of adult patients (Table 4). Catheter-related prolongation of CTs was higher in Gr I than in Grs II and III. Furthermore, cardiac catheterization led to a significant decrease of MCF in Gr I, indicating a significant decrease of fibrinogen [30, 31]. In this study solely plasma samples were in the hands of the investigator. In an
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ongoing prospective clinical trial HEPTEM measurements will additionally be performed in whole blood which includes phospholipid bearing cells and platelets with an important ability to support coagulation. We have to state that the presence of heparin could have affected the determination of the plasma levels of F II and X. Moreover, the effect of heparin might not be the same in the different age groups so that the comparison among age groups could be biased. In conclusion, our results show that cardiac catheterisation perturbs the haemostatic system of adults, and, more pronounced, that of pediatric patients. Thus, our results indicate that pediatric patients might be at a high risk for either thrombotic complications or post-catheter bleeding events than adults. Acknowledgment We thank Kathrin Wodrig, Nikolaus Heinl and Sandra Guetl for technical assistance.
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