Dissertation committee:
Τσαντές Αργύριος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ιακωβίδου Νικολέττα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κοκόρη Στυλιανή, Επίκουρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μπούτσικου Θεοδώρα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ηλιοδρομίτη Ζωή, Aναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Βαλσάμη Σερένα, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κριεμπάρδης Αναστάσιος, Καθηγητής, Σχολή Επιστημών Υγείας και Πρόνοιας, Τμήμα Βιοϊατρικών Επιστημών, Πανεπιστήμιο Δυτικής Αττικής
Summary:
Introduction: The hemostatic system encompasses complex interactions between the vasculature, cellular components, and plasma proteins. The coagulation system develops progressively over time from fetal to neonatal, pediatric, and adult hemostasis. A complex hemostatic mechanism is observed in a healthy full-term newborn, which is characterized by insufficiency of coagulation factors, lack of natural inhibitors and impaired fibrinolysis. Under normal conditions, in all stages of development of the fetus-newborn, the mechanism of coagulation-fibrinolysis is in a state of dynamic balance, constantly evolving until adulthood. However, despite the differences of neonatal hemostasis, on a clinical level, a healthy term or premature newborn is not prone to bleeding or thrombotic events, as a delicate balance is maintained between these conditions. This balance is disturbed and diverted towards bleeding, most often, or less commonly thrombosis, especially when there are hereditary or acquired disorders of hemostasis or concomitant pathological factors, such as infections, asphyxia, etc. Disorders of hemostasis are a daily and critical problem for hospitalized newborns in the intensive care unit and early diagnosis and treatment by the neonatologist is necessary. Laboratory tests, such as activated partial thromboplastin time (APTT) and prothrombin time (PT) are often prolonged in neonates compared to adults’ values, indicating a possible predisposition to bleeding.These conventional tests do not provide information on fibrinolysis or platelet functionality and therefore, do not help in the differential diagnosis of a hemostatic disorder in newborns. Consequently, changes in the hemostatic mechanism of newborns and the lack of routine tests for the comprehensive study of hemostasis often lead to over-diagnosis or even misdiagnosis. Additionally, the “prolongation” of the PT and APTT in a newborn could be attributed either to age or disease. Therefore, age-appropriate reference values for laboratory tests are required, for the treatment to be targeted and effective.
Whole blood assays, including thromboelastography, are based on the cellular hemostasis model. Known as viscoelastic tests, they focus on the role of platelets in thrombin production and thrombin quality. Thromboelastography (TEG) and Rotational Thrombelastometry (ROTEM) methods record changes in the viscosity and elasticity of whole blood during clot formation, and subsequently, its dissolution. ROTEM tests allow the dynamic evaluation of the viscoelastic properties of the clot through graphical representation of thrombin formation, fibrin polymerization and clot lysis, considering the complex interactions between different blood cells, and providing real-time access to the patient's hemostatic profile.
Thromboelastometry assays, such as standard extrinsically activated ROTEM assay (EXTEM) and intrinsically activated ROTEM assay (INTEM) are commonly used diagnostically in case of severe bleeding. However, sometimes bleeding occurs in the patient despite the normal values of EXTEM/INTEM parameters. Studies in adults have shown that non-activated rotational ROTEM assay (NATEM) assay, in which coagulation activation relies exclusively on calcium addition, can detect coagulation disorders that are not detected by EXTEM/INTEM tests.
Additionally, NATEM assay has been reported to be very sensitive to endogenous coagulation activators, such as tissue factor and circulating monocytes, in patients with infection, sepsis, liver cirrhosis, or extracorporeal devices. The role of NATEM assay in the detection of hemostasis disorders in critically ill neonates has not been investigated in the literature.
Objective: In the current study, we aimed to primarily explore the potential ability of NATEM assay to evaluate the haemostatic status of critically ill neonates, and also to study the sensitivity and specificity of NATEM parameters in predicting risk of bleeding in these neonates. Moreover, we aimed to compare the discriminative power of NATEM parameters with that of EXTEM parameters in predicting the risk of bleeding in critically ill neonates.
Material and Μethods: Critically ill neonates (term and preterm), hospitalized in the neonatal intensive care unit (NICU) of General Hospital of Nikea, Piraeus, Greece, over a period of 4 years (07/2017 – 07/2021), were included in the study. Neonates with presumed sepsis, neonates with perinatal hypoxia and preterm neonates with respiratory distress syndrome (RDS), were grouped as critically ill neonates. The ROTEM extrinsically activated (EXTEM) and NATEM assays were performed on the first day of disease onset. The neonatal bleeding assessment tool was used to record and assess clinical bleeding events on the day of ROTEM analysis.
Results: Several EXTEM and NATEM ROTEM parameters differed between neonates with and without clinical bleeding events, indicating a hypo-coagulable state in neonates with clinical bleeding. NATEM parameters had comparable predictive performance for clinical bleeding events with EXTEM parameters for CT, CFT, A10, MCF, LI60 and MCE (p>0.05). However, NATEM A20, A30 and alpha angle demonstrated better predictive ability than EXTEM A20, A30 and alpha angle, respectively (p<0.05). A NATEM CFT value ≥ 147 s presented 95.2% sensitivity (95% CI: 76.1%–99.8%) and 65.6% specificity (95% CI: 57.1%–73.5%) to detect neonates with clinical bleeding, while a NATEM A10 value ≤ 42 mm had 80.8% sensitivity (95% CI: 71.8%–85.9%) and 76.0% specificity (95% CI: 52.8%–91.7%) to detect neonates with clinical bleeding events.
Conclusions: The NATEM assay has shown remarkable sensitivity in predicting bleeding in critically ill neonates, exceeding EXTEM performance in some selected parameters. The incorporation of NATEM test parameters in predictive models for neonatal hemorrhage seems promising and could also contribute to a better assessment of hemostasis in newborns. Further studies are necessary to demonstrate the reliability of the NATEM assay not only as a diagnostic tool for hemostasis disorders but also as a therapeutic guide in the neonatal population.
