Gerhard Cvirn

Right ventricular function in infants, children and adolescents: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 640 healthy patients and calculation of z score values.

BACKGROUND Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measurement to assess right ventricular systolic function in adults. The aim of this study was to determine growth-related changes in TAPSE to establish references values. METHODS A prospective study was conducted in a group of 640 healthy pediatric patients (age range, 1 day to 18 years; body surface area range, 0.12-2.25 m(2)). The effects of age and body surface area on TAPSE were determined. RESULTS TAPSE ranged from a mean of 0.91 cm (z score +/- 3, 0.56-1.26 cm) in neonates to 2.47 cm (z score +/- 3, 1.84-3.10 cm) in 18-year-olds. TAPSE values showed positive correlations with age and body surface area. There was no significant difference in TAPSE values between female or male children. CONCLUSION In this study, z scores of TAPSE values were calculated and percentile charts were established to serve as reference data for ready application in patients with congenital heart disease in the future.

Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates

Summary.  Neonates have an excellent hemostasis despite, in comparison to adults, markedly decreased and delayed ability to generate thrombin. Only 30–50% of peak adult thrombin activity can be produced in neonatal plasma by means of conventional in vitro assays. We show that in contrast to conventional activation, activation with small amounts of lipidated tissue factor (<10 pmol L−1) results in shorter clotting times and faster activated factor X‐ and thrombin generation in neonates compared with adults due to the concomitant action of low tissue factor pathway inhibitor and antithrombin. The concentrations of both inhibitors in cord plasma are approximately 50% of the respective adult values. After addition of 2.5 pmol L−1 lipidated tissue factor, cord plasma clotted ∼90 s earlier than adult plasma and the amount of free thrombin generated was ∼90% of adult value (291 ± 14 vs. 329 ± 16 nmol L−1 min−1, P < 0.01). Our results might help to explain the clinically observed excellent hemostasis of neonates despite low levels of procoagulant factors.

Systolic Right Ventricular Function in Preterm and Term Neonates: Reference Values of the Tricuspid Annular Plane Systolic Excursion (TAPSE) in 258 Patients and Calculation of Z-Score Values

Background: The tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measurement to assess right ventricular systolic function in adults and children. Objective: We determined growth- and birth weight-related changes of TAPSE to establish reference values in preterm and term neonates. Methods: A prospective study was conducted in a group of 258 preterm and term neonates (age: 25+0 to 40+6 weeks of gestation, birth weight: 530–4,200 g). Results: The TAPSE ranged from a mean of 0.44 cm (Z-score ±2: 0.30–0.59 cm) in preterm neonates in the 26th week of gestation to 1.03 cm (Z-score ±2: 0.85–1.21 cm) in term neonates in the 41st week of gestation. The TAPSE values increased in a linear way from the 26th to 41st week of gestation. TAPSE, week of gestation and weight are strongly correlated: Pearson’s correlation coefficient was 0.93 for week of gestation – TAPSE (p < 0.001), 0.93 for week of gestation – birth weight (p < 0.001), and 0.89 for birth weight – TAPSE (p < 0.001). There was no statistically significant difference of normal TAPSE values between female and male patients (p = 0.987). Conclusion: Z-scores of TAPSE values were calculated and percentile charts were established to serve as reference data for ready application in preterm and term neonates with structurally normal hearts and with congenital heart disease in the future.

Reference values of tricuspid annular peak systolic velocity in healthy pediatric patients, calculation of z score, and comparison to tricuspid annular plane systolic excursion.

The tricuspid annular peak systolic velocity (TAPSV) is an echocardiographic measurement assessing right ventricular systolic function in children and adults. We determined the growth-related changes of the TAPSV to establish the references values for the entire pediatric age group. A prospective study was conducted of a group of 860 healthy pediatric patients (age 1 day to 18 years; body surface area [BSA] 0.14 to 2.30 m(2)). We determined the effects of age, gender, and BSA on the TAPSV values. Stepwise linear multiple regression analysis was used to estimate the TAPSV from the age, BSA, and gender. A correlation of normal TAPSV with normal tricuspid annular plane systolic excursion values was performed. The TAPSV ranged from a mean of 7.2 cm/s (z score ± 2: 4.8 to 9.5 cm/s) in the newborn to 14.3 cm/s (z score ± 2: 10.6 to 18.6 cm/s) in the 18-year-old adolescent. The TAPSV values showed a positive correlation with age and BSA, with a nonlinear course. No significant difference was found in the TAPSV values according to gender. A significant correlation was found between the TAPSV and tricuspid annular plane systolic excursion values in our pediatric population. In conclusion, the z scores of the TAPSV values were calculated, and percentile charts were established to serve as reference data for patients with congenital heart disease.

Systolic Right Ventricular Function in Children and Young Adults with Pulmonary Artery Hypertension Secondary to Congenital Heart Disease and Tetralogy of Fallot: Tricuspid Annular Plane Systolic Excursion (TAPSE) and Magnetic Resonance Imaging Data

OBJECTIVE   The tricuspid annular plane systolic excursion (TAPSE), as echocardiographic index to assess right ventricular (RV) systolic function, has not been investigated thoroughly in children and young adults with tetralogy of Fallot (TOF) and pulmonary artery hypertension secondary to congenital heart disease (PAH-CHD). PATIENTS   TAPSE values of 49 patients with PAH-CHD and 156 patients with TOF were compared with age-matched normal subjects. TAPSE values were also compared with RV ejection fraction (RVEF) and RV indexed end-diastolic volume (RVEDVi) determined by magnetic resonance imaging in PAH-CHD and TOF patients. RESULTS   Patients with a PAH-CHD showed a positive correlation between TAPSE with RVEF (r= 0.81; P < 0.001) and a negative correlation between TAPSE with RVEDVi (r=-0.67; P < 0.001). Similarly, in our TOF patients, a positive correlation between TAPSE with RVEF (r= 0.65; P < 0.001) and a negative correlation between TAPSE with RVEDVi (r=-0.42; P < 0.001) was seen. CONCLUSIONS   Significant pressure overload in PAH-CHD patients and volume overload in TOF patients lead to a decreased systolic RV function, determined by TAPSE and magnetic resonance imaging and to increased RVEDVi values, determined by MRI, with time.

Effects of antithrombin and protein C on thrombin generation in newborn and adult plasma.

It has been suggested that antithrombin (AT) and protein C (PC) might be less important in newborn plasma than in adult plasma for the inhibition of clotting activation. To assess the importance of AT and PC for the regulation of thrombin generation in newborn as compared with adult plasma, thrombin generation was determined in the presence of different concentrations of AT and PC. In both, newborn and adult plasmas, reduction of AT and PC resulted in an increase of thrombin generation after intrinsic activation. On the other hand, supplementation of AT and PC decreased thrombin generation in a dose-dependent manner. Clotting times were influenced by different PC concentrations, whereas clotting times were almost not affected by different amounts of AT. Our study suggests that the significance of AT and PC in the regulation of thrombin generation is the same in newborn and adult plasma. Our experimental results also support the notion that administration of AT or protein C concentrates may be beneficial in some clinical situations leading to an increased clotting activation in newborns.

Systolic right ventricular function in pediatric and adolescent patients with tetralogy of Fallot: echocardiography versus magnetic resonance imaging.

OBJECTIVE The tricuspid annular plane systolic excursion (TAPSE) as an echocardiographic index to assess right ventricular (RV) systolic function has not been investigated thoroughly in pediatric patients and adolescents with tetralogy of Fallot (TOF) after surgical repair. METHODS TAPSE was determined in 131 patients with TOF and 252 age-matched normal subjects. TAPSE values were compared with RV ejection fraction (EF) and indexed RV end-diastolic volume (EDVi) determined by magnetic resonance imaging in a cross-sectional study design. TAPSE values were also correlated to QRS duration (QRSd) determined by electrocardiogram. RESULTS The TAPSE values showed a positive correlation with age in normal subjects. The TAPSE was not decreased in infants and young children with TOF compared with normal subjects. A significant reduction of TAPSE values with increasing time after surgical repair was observed. After a mean of 7 years after surgical repair, the TAPSE values become significantly reduced compared with age-matched controls, being below the lower bound of -2 standard deviations. A positive correlation between TAPSE with RVEF and a negative correlation between TAPSE with RVEDVi were observed. A significant positive correlation was found between QRSd and RVEDVi, and a significant negative correlation was found between QRSd and RVEF. CONCLUSION Although TAPSE was initially preserved, impaired TAPSE was observed with increasing time after surgical repair in pediatric patients with TOF.

Alpha 2-macroglobulin enhances prothrombin activation and thrombin potential by inhibiting the anticoagulant protein C/protein S system in cord and adult plasma.

Protein S (PS) is a vitamin K-dependent plasma protein and serves as a cofactor for the anticoagulant activities of activated protein C (APC). We investigated the effects of different PS concentrations on prothrombin activation and thrombin generation in cord and adult plasma containing APC and different amounts of alpha 2-macroglobulin (a2-M). Prothrombin activation was assessed by monitoring the time-course of prothrombin fragment 1+2 (F1+2) generation. Thrombin generation curves were determined by means of a subsampling technique using the chromogenic substrate S-2238. We demonstrate a dose-dependent inhibition of the anticoagulant action of PS by a2-M: suppression of F1+2 and thrombin generation due to addition of PS was stronger in plasma containing low amounts of a2-M than in plasma with elevated a2-M levels. Since no complex formation between a2-M and PS was observed by means of SDS-PAGE, we attribute decreased anticoagulant action of PS at high a2-M levels to enhanced complex formation between APC and a2-M. Thereby, APC is subtracted from its cofactor PS, resulting in suppressed formation of the anticoagulant APC/PS complex. Thus, our data suggest that a2-M, besides its well-known anticoagulant effects, also acts as a procoagulant by suppressing the formation of the anticoagulant APC/PS complex. Our findings have implications particularly on thrombin generation and inhibition in cord plasma, since a2-M levels in newborns are elevated over adult values and the antithrombotic APC/PS pathway is up-regulated at birth. Therefore, elevated levels of a2-M might restrict the up-regulation of the APC/PS pathway.

Elevated thrombin-forming capacity of tissue factor-activated cord compared with adult plasma.

Summary.  Clinically observed excellent hemostasis in neonates despite low levels of clotting factors is not completely understood so far. Therefore, we investigated whether physiological low levels of the inhibitor protein C (PC) facilitate thrombin formation in tissue factor (TF)‐activated plasma samples. PC was activated by endogenously generated thrombin after addition of soluble thrombomodulin (TM). The capability of activated PC (APC) to suppress thrombin formation was significantly more pronounced in adult than in cord plasma. Addition of 4 nm of TM decreased the thrombin potential (TP) in cord plasma by 10%, and in adult plasma by 52% in the presence of 5 pm TF. We demonstrate that this low anticoagulant action of PC is attributable to the low levels of tissue factor pathway inhibitor (TFPI) and antithrombin (AT) physiologically present in cord plasma. Addition of 4 nm TM decreased the TP by 58% in cord plasma adjusted to contain TFPI and AT at adult levels in the presence of 5 pm TF. Thus, the combined low anticoagulant action of the three inhibitors APC, TFPI, and AT in cord plasma allows enhanced thrombin formation associated with shorter clotting times compared with adult plasma when low amounts of TF are applied to initiate clot formation. Although our laboratory experiments do not allow definite conclusions for various clinical situations, our data might contribute to explain excellent hemostasis in neonates despite low levels of procoagulants.

Thrombin generation in factor VIII‐depleted neonatal plasma: nearly normal because of physiologically low antithrombin and tissue factor pathway inhibitor

Summary.  Background: Bleeding in hemophilic neonates has a low incidence. A possible explanation for this could be the peculiarities of the neonatal hemostatic system, especially low levels of the inhibitors tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Objective: We investigated the influence of an elevation of these inhibitors to adult levels on the thrombin generation (TG) in normal neonatal plasma and factor (F) VIII‐depleted neonatal plasma by means of incubation with anti‐FVIII‐antibodies. Patients/methods: TG was measured after activation with low amounts of tissue factor (TF) by using Calibrated Automated Thrombography. Results: TG in FVIII‐depleted neonatal plasma was nearly as high as in normal neonatal plasma. TG decreased after elevation of AT in both neonatal plasmas. After elevation of TFPI TG decreased much more in FVIII‐depleted neonatal plasma than in normal neonatal plasma. After elevation of both inhibitors their synergistic effect led to a stronger decrease of TG in FVIII‐depleted neonatal plasma. TG measured in plasma of one hemophilic newborn showed the same pattern as in FVIII‐depleted neonatal plasma. Conclusion: Our observation provides a biochemical basis for the rare bleeding in hemophilic neonates and shows the important role of the natural inhibitors in the hemostatic system of hemophilic patients.