Dissertation committee:
Παπαευαγγέλου Βασιλική, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Τσαντές Αργύριος, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Ιακωβίδου Νικολέττα, Αναπληρώτρια Καθηγήτρια, Ιατρική, ΕΚΠΑ
Γιαλεράκη Αργυρή, Αναπληρώτρια Καθηγήτρια, Ιατρική, ΕΚΠΑ
Βαλσάμη Σερένα, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Κοκόρη Στυλιανή, Επίκουρη Καθηγήτρια, Ιατρική ΕΚΠΑ
Μητσιάκος Γεώργιος, Επίκουρος Καθηγητής, Ιατρική, ΑΠΘ
Summary:
Introduction-background: Coagulation system gradually matures throughout infancy until adulthood. Healthy neonates are born with an intrinsic hemostatic deficit directly associated with gestational age, birth weight and maturation of hepatic function. All factors of the coagulation-fibrinolysis sys-tem are immature in neonates when compared with infants, children or adults. However, studies have shown that this immaturity is functionally counterbalanced and therefore the risk for hemor-rhage or thrombosis is not increased in healthy full-term or preterm newborns. This delicate hemo-static balance is deranged in sick neonates, predisposing in hemorrhage and/or thrombosis. Dissemi-nated intravascular coagulation (DIC) is the most common and severe disorder of haemostasis in sick neonates, as neonatal period seems to be particularly vulnerable. In neonates DIC is not a primary diagnosis, but instead a secondary coagulation disorder that complicates various primary conditions, such as respiratory distress, severe asphyxia, NEC, liver dysfunction, and especially sepsis.
Sepsis is a common cause of morbidity and mortality in neonates with a prevalence of 1 to 10 per 1000 live births worldwide, while it causes about one fourth of all neonatal deaths. Its clinical signs are nonspecific and resemble those of a non-infectious disorder; thus, early diagnosis is a major chal-lenge in the management of neonatal sepsis, especially at initial stages that may be indistinguishable from those caused by various non-infectious conditions. Course of septic neonates is dramatically aggravated and prognosis is worsened when DIC or MODS (multi-organ dysfunction syndrome) co-exist. Thus, the necessity to define diagnostic criteria that will help us in the early diagnosis of neona-tal septicemia is of great importance, as a delay in treatment of severe bacterial infections could negatively affect the clinical outcome. Understanding of the multifactorial mechanism of coagulation is considered as a prerequisite for diagnosis of haemostatic disorders. Conventional coagulation tests such as prothrombin time and partial activated thromboplastin time, seems to be unable to provide any kind of information-indication for the functional status of platelets or fibrinolysis, and on the other hand present limitations in predicting bleeding and guiding transfusion therapy in critically ill patients. Rotational thromboelastometry (ROTEM) is an attractive method for rapid evaluation of the whole hemostatic status in neonates. Currently, no reference values exist for ROTEM assays in term and preterm neonates.
Objective: We aimed at establishing reference ranges for standard extrinsically activated ROTEM as-say (EXTEM) in arterial blood samples of healthy term and preterm neonates, and to evaluate the potential role of EXTEM assay in the early detection of neonatal sepsis.
Material and methods: The population of this study is consisted of 282 healthy neonates including 198 term (>36+6 weeks' gestation) and 84 preterm neonates (<37 weeks' gestation), and 91 sick neo-nates categorized in two groups: group A included 35 neonates with confirmed sepsis, while group B included 56 neonates with suspected sepsis.
In the present study, EXTEM assay was performed in healthy neonates, on the 2nd - 3rd day of life for term neonates and on 2nd - 7th day of life (after their stabilization) for preterm neonates, using peripheral arterial whole blood samples. In sick neonates whenever sepsis was suspected, EXTEM assay was performed, Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE) and Tοllner score were calculated, and clinical findings and laboratory results were recorded.
Results: Median values and reference ranges (2.5th and 97.5th percentiles) for the following main parameters of EXTEM assay were determined in healthy term neonates: clotting time (seconds), 41 (range, 25.9-78); clot formation time (seconds), 70 (range, 40-165.2); maximum clot firmness (mm), 66 (range, 41-84.1); lysis index at 60 min (LI60, %), 97 (range, 85-100) and in healthy preterm neo-nates: clotting time (seconds), 44 (range, 32-64,9); clot formation time (seconds), 64 (range, 28.4-138.9); maximum clot firmness (mm), 64 (range, 49.1-83.9); lysis index at 60 min (LI60, %), 95 (range, 52.6-100).
The only parameter with a statistically significant difference between term and preterm neonates was LI60 (p=0.006). Furthermore, it was inversely correlated with gestational age (p=0.002) and birth weight (p=0.016) in preterm neonates.
Septic neonates had significantly prolonged clotting time (CT) and clot formation time (CFT), and re-duced maximum clot firmness (MCF), compared to neonates with suspected sepsis (p values 0.001, 0.001, and 0.009, respectively) or healthy neonates (p values 0.001, 0.001, and 0.021, respectively). EXTEM parameters (CT, CFT, MCF) demonstrated a more intense hypocoagulable profile in septic neonates with hemorrhagic diathesis than those without (p values 0.021, 0.007, and 0.033, respec-tively). In septic neonates, CFT was correlated with platelet count, SNAPPE score, Tollner score, and day of full enteral feeding (p values 0.01, 0.02, 0.05, and 0.03, respectively). Regarding neonates with suspected sepsis, it is noteworthy that signs of hypercoagulability were observed, based on A10, a-angle, and CFT measurements, which significantly differed from those in healthy neonates (p values 0.014, < 0.001, 0.003, respectively)
Conclusions: In conclusion, an enhanced fibrinolytic activity in healthy preterm neonates was noted. For most EXTEM assay parameters, reference ranges obtained from arterial newborn blood samples were comparable with the respective values from other studies using arterial blood sample from newborns. Modified reagents, small size samples, timing of sampling, and different kind of samples might account for any discrepancies among similar studies. Reference values hereby provided can be used in future studies.
However, taking into account the clear hypocoagulable profile noted at the early phase of neonatal sepsis, its diagnostic and prognostic value should be further studied. In conclusion, ROTEM may be a useful tool in the detection of coagulation abnormalities in neonatal sepsis and hypocoagulability could have diagnostic and prognostic applications.
Performing bedside global coagulation tests requiring small blood samples, like ROTEM, seems an attractive method for rapid, feasible evaluation of haemostasis in neonates and could possibly lead to significantly decreased transfusion requirements of term and preterm infants
