Analysis of prothrombotic mutations and polymorphisms in children who developed thrombosis in the perioperative period of congenital cardiac surgery

Department of Pediatrics, Başkent University, Faculty of Medicine, Ankara, Turkey.
Cardiology in the Young (Impact Factor: 0.84). 03/2005; 15(1):19-25. DOI: 10.1017/S1047951105000053
Source: PubMed


In this study, we investigated some of the prothrombothic mutations and polymorphisms in 15 children with congenital cardiac malformations who developed severe thrombosis in the perioperative period following surgical repair. The mutations and polymorphisms included in the study were Factor V Leiden, prothrombin G20210A, methylentetrahydrofolate reductase C677T, endothelial nitric oxide synthase intron 4 VNTR, alpha-fibrinogen Thr312Ala, Factor XIII Val34Leu, and insertion or deletion of angiotensin 1 converting enzyme. Compared to the healthy Turkish subjects, our patients had a similar rate of mutation of Factor V Leiden, Factor XIII Val34Leu, and endothelial nitric oxide synthase a/b polymorphisms, but higher frequency of the prothrombotic angiotensin 1 converting enzyme deletion/deletion genotype, and lower frequency of the antithrombotic alpha fibrinogen Thr/Thr genotype. None of the patients exhibited mutations involving prothrombin G20210A or methylentetrahydrofolate reductase C677T. The results of our study suggest that, in addition to prothrombotic mutations such as Factor V Leiden, single-nucleotide polymorphisms should be considered in all children with congenital cardiac malformations who develop thrombosis. Malformations of the heart are the most common of all serious lesions that are present at birth, with an incidence of 4 to 8 cases per 1,000 live births. If needed, corrective surgery is usually the optimal treatment for these anomalies, but perioperative morbidity and mortality still remain high due to several factors. Arterial or venous thrombosis, or both varieties of thrombosis, is among these factors. Prior to surgery, the most frequent time at which these children develop thrombosis is during cardiac catheterization. Postoperative thrombosis in this group of patients is a more complex disorder, which can affect both small and large vessels, and is associated with a high morbidity and mortality. Recent studies indicate that both point mutations and single-nucleotide polymorphisms of genes that encode proteins involved in the coagulative and anticoagulative cascades are important risk factors for development of thrombosis. Patients with these risk factors are most likely to develop thrombosis when triggering elements, such as placement of catheters, prolonged immobilization, or surgery, are also present. In this study, we investigated some of the above-mentioned mutations and polymorphisms in children who developed thrombosis in the perioperative period after correction of congenital cardiac malformations.

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    • "Pediatric patients with CHD have a high risk of developing bleeding and/or thrombotic complications following heart surgery with a broad spectrum within the different heart diseases [13] [14]. Heying et al. demonstrated a marked imbalance between prothrombotic and antithrombotic activity in pediatric heart patients undergoing cardiac surgery [15]. "
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    ABSTRACT: Thrombin generation was studied in pediatric patients with congenital heart disease (CHD) undergoing cardiac surgery using the calibrated automated thrombography (CAT) in terms of the lag time until the onset of thrombin formation, time to thrombin peak maximum (TTP), endogenous thrombin potential (ETP), and thrombin peak height. The possible suitability to determine the coagulation status of these patients was investigated. CAT data of 40 patients with CHD (age range from newborn to 18 years) were compared to data using standard coagulation parameters such as prothrombin (FII), antithrombin (AT), tissue factor pathway inhibitor (TFPI), prothrombin fragment 1.2 (F 1.2), thrombin-antithrombin (TAT), activated partial thromboplastin time (aPTT), and prothrombin time (PT). A significant positive correlation was seen between ETP and FII (p<0.01; r=0.369), as well as between peak height and F II (p<0.01; r=0.483). A significant negative correlation was seen between ETP and TFPI values (p<0.05; r=-0.225) while no significant correlation was seen between peak height and TFPI. A significant negative correlation was seen between F 1.2 generation and ETP (p<0.05; r=-0.254) and between F 1.2 generation and peak height (p<0.05; r=-0.236). No correlation was seen between AT and ETP or peak. Our data indicate that CAT is a good global test reflecting procoagulatory and inhibitory factors of the hemostatic system in pediatric patients with CHD.
    Thrombosis Research 02/2008; 122(1):13-9. DOI:10.1016/j.thromres.2007.08.016 · 2.45 Impact Factor
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    • "Patients with cyanotic congenital heart disease usually undergo a preoperative analysis of the well known genetic aberrations associated with increased thrombotic potential, eg, the Factor V Leiden and the MTHFR mutations. In patients with thrombosis after cardiac surgery, in which the classical screening parameters were normal, Ozbek and colleagues recently described other polymorphisms that included a higher frequency of the prothrombotic angiotensin 1 converting enzyme deletion/deletion genotype, and a lower frequency of the antithrombotic alpha fi brinogen Thr/Thr genotype (Ozbek et al 2005). "
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    ABSTRACT: Among children, newborn infants are most vulnerable to development of thrombosis and serious thromboembolic complications. Amongst newborns, those neonates who are critically ill, both term and preterm, are at greatest risk for developing symptomatic thromboembolic disease. The most important risk factors are inflammation, DIC, impaired liver function, fluctuations in cardiac output, and congenital heart disease, as well as exogenous risk factors such as central venous or arterial catheters. In most clinically symptomatic infants, diagnosis is made by ultrasound, venography, or CT or MRI angiograms. However, clinically asymptomatic vessel thrombosis is sometimes picked up by screening investigations or during routine imaging for other indications. Acute management of thrombosis and thromboembolism comprises a variety of approaches, including simple observation, treatment with unfractionated or low molecular weight heparin, as well as more aggressive interventions such as thrombolytic therapy or catheter-directed revascularization. Long-term follow-up is dependent on the underlying diagnosis. In the majority of infants, stabilization of the patients' general condition and hemodynamics, which allows removal of indwelling catheters, renders long-term anticoagulation superfluous. Nevertheless, in certain types of congenital heart disease or inherited thrombophilia, long-term prophylaxis may be warranted. This review article focuses on pathophysiology, diagnosis, and acute and long-term management of thrombosis in critically ill term and preterm neonates.
    Vascular Health and Risk Management 02/2008; 4(6):1337-48.
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    ABSTRACT: Background: There have been conflicting reports of the association between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene, and the risk of venous thromboembolism (VTE). We sought to investigate the association between ACE I/D polymorphism, and the risk of VTE in a Chinese population living in Taiwan. Methods: 176 patients with VTE and 321 age and sex-matched controls were analyzed for the ACE I/D polymorphism by polymerase chain reaction. Results: The genotype distribution of the ACE I/D polymorphism was not statistically different between the VTE affected subjects and the group of unaffected subjects (p = 0.057). Notably, the frequency of ACE D allele in patients with VTE were significantly lower than that in the control group (28% vs. 35%, p = 0.018). After adjusting for age, gender, smoking, hypertension, diabetes and body mass index (BMI), the ACE D allele carriers remained significantly associated with a decreased risk of VTE. Further meta-analysis by pooling data from 15 studies revealed that neither the DD, nor the II genotype, was found to be associated with VTE (pooled unadjusted odds ratio were 1.167, 95% confidence intervals, 0.927-1.470, p = 0.189 for DD, and 1.085, 95% confidence intervals, 0.875-1.345 p = 0.460 for II). Conclusion: Our results suggest that the presence of the D allele may confer protection against the development of VTE in an ethnically Chinese population in Taiwan. Further meta-analysis did not support a relationship between the ACE I/D polymorphism and the risk of VTE.
    Acta Cardiologica Sinica 12/2011; 27(4). · 0.33 Impact Factor
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