Haemostatic profile of full-term, healthy, small for gestational age neonates

Background

Small for Gestational Age (SGA) neonates often appear with haemostatic alterations, principally due to hepatic dysfunction that results from chronic intrauterine hypoxia. Polycythaemia and thrombocytopenia are common findings in this neonatal population.

Study design

We performed a comparison of coagulation, natural inhibitors and fibrinolysis between SGA and Appropriate for Gestational Age (AGA) infants born full term [gestational age (G.A.) > 37 weeks]. Study population consisted of 188 healthy newborns, 90 of whom were SGA (62 females and 28 males), while the rest were the control group (44 females and 54 males). Blood samples were obtained within 30 minutes following birth and before the administration of vitamin K. Investigation included: PT, INR, APTT, fibrinogen, coagulation factors II, V, VII, VIII, IX, X, XI, XII, vWillebrand factor, protein C and free protein S, antithrombin (AT), APCR, tPA and PAI-1. The independent t-test was used to compare the differences between the values of haemostatic parameters.

Results

Statistical analysis revealed a significant prolongation in PT, INR, elevated levels of tPA (p < 0.015, 0.01 and 0.002 respectively) and a decrease in the values of XII and free protein S (p < 0.045 and 0.007 respectively) in SGA full term neonates. The two groups had similar demographic characteristics (except birth weight), without significant differences in the values of other haemostatic parameters.

Conclusions

Despite of statistically significant differences in PT, INR, values of tPA, XII and free protein S, levels of haemostatic factors range within laboratory references for healthy full term newborns. These findings were not accompanied with clinical manifestations of altered haemostasis.     

Effect of brainstem auditory evoked potential stimulus intensity variations in neonates of small for gestational age

The latencies of brainstem auditory evoked potentials were compared first in 25 small for gestational age (SGA) neonates (conceptional age less than 43 weeks) matched with 25 appropriate for gestational age (AGA) neonates, and then in the 8 younger SGA neonates (less than 37 weeks) matched with 8 AGA neonates. In this last subgroup the results showed that the I-V interval is shorter in SGA than in AGA neonates, as previously described. This shortening effect is essentially linked to a lengthening of wave I. So the results are discussed in terms of immaturity of the basal end of the cochlea, rather than of precocious development of the auditory brainstem neural function in SGA infants.     

Associations of gestational age and birth anthropometric indicators with brain white matter maturation in full‐term neonates

Newborn assessments, including gestational age (GA) and anthropometric measurements (birth weight, crown‐heel length, head circumference) are routinely performed in pediatric settings, being used as important indicators in assessing neonatal development. Close associations of these birth indicators with later cognitive abilities were also reported. However, specific associations of these indicators with white matter (WM) development during the neonatal period remain unclear, as well as the extent to which they influence WM maturation. To address this issue, 51 full‐term neonates (GA range, 37–42 weeks) with no abnormalities on MRI were retrospectively recruited. Specific correlations between birth indicators and WM maturation, quantified by diffusion tensor imaging (DTI)‐metrics (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity), were identified by using DTI tract‐based spatial statistics and automated fiber‐tract quantification. Our findings suggest that (a) higher GA, birth weight, and crown‐heel length may indicate greater WM maturation in full‐term neonates, while head circumference presented weak correlation with WM maturation during early newborn period; (b) among the four indicators examined, GA was the one most associated with WM maturation. We believe that this study advances our knowledge of specific correlations between birth indicators and neonatal brain development and provides a valuable reference for future neonatal studies.     

Morphometric assessment of collagen accumulation in germinal matrix vessels of premature human neonates

Germinal matrix haemorrhage in premature neonates is commonly attributed to vascular immaturity, possibly related to an abbreviated process of angiogenesis. Terminal steps in the progression of angiogenesis are the formation of a subendothelial basal lamina containing collagen IV and an extracellular matrix containing collagens I and III. Immature vessels would predictably be deficient in these collagen subtypes. We analysed germinal matrix (GM), cortical, and white matter (WM) vessels with antibodies specific for collagens I, III and IV to test the hypothesis that GM vessels are immature. Brains were collected during post-mortem from prematurely born human neonates ranging in age from 17 weeks to 36 weeks postconception. All GM vessels were immunoreactive for collagen subtypes I, III and IV. Using digital image analysis, collagen IV immunoperoxidase-labelling was measured in vessels in GM, cortex and WM. Intensity values in GM and WM were normalized relative to cortical intensity within the same subject. At week 17 of gestation, GM vessels exhibited a higher concentration of collagen IV than did WM or cortical vessels. Regression analysis demonstrated that collagen intensity in GM was greater than that in cortex and WM at all stages. We conclude that GM vessels in even the youngest, prematurely born, viable neonates do not exhibit evidence of structural immaturity. The high incidence of GM haemorrhage in premature neonates may be related to factors other than a deficiency in accumulated collagen.     

The effect of dihydroergotamine on platelets, coagulation and fibrinolysis, studied in healthy humans and in dogs

The effect of dihydroergotamine (DHE) on platelets, coagulation and fibrinolysis was studied in healthy volunteers ex vivo before and after intravenous administration (0.5 mg). In addition, the effect of DHE in different concentrations on platelet aggregation was evaluated in vitro. Haematocrit was found to increase, as did factor VIII:C and antithrombin III - though the latter increases were not significant when correction was made for the altered haematocrit. Though platelet function ex vivo was unchanged, inhibition of adrenaline induced platelet aggregation was noted in vitro when the plasma concentrations of added DHE were higher than those obtained with clinically relevant doses. No effect on fibrinolysis was noted.     

Effects of subcutaneously administered dermatan sulfate (MF 701) on the coagulation and fibrinolytic parameters of healthy volunteers

Eight healthy volunteers were given single subcutaneous doses of dermatan sulfate (DS, 100, 200 and 400 mg), heparin (5,000 IU) and placebo in random order. Wash-out between treatments was > 10 days. Serial blood samples were taken before and up to 24 hours after treatment to measure coagulation and fibrinolytic parameters. Thrombin generation was significantly inhibited by DS and heparin as compared to placebo. The effect of DS was dose-dependent. Peak inhibition after 200 mg DS was comparable to that of 5,000 IU heparin, but lasted longer. A small, bordeline significant prolongation of APTT was observed after 400 mg DS and heparin. The changes in PAI and fibrinolytic activities were those of the circadian variation. No changes were seen in the other parameters tested. In conclusion, single s.c. doses of DS (200, or 400 mg) inhibit thrombin generation equally or more than 5,000 IU heparin and for a longer time. The effect of both treatments on fibrinolysis is negligible.     

Associations of gestational age with gyrification and neurocognition in healthy adults

Epidemiological studies have shown that gestational age and birth weight are linked to cognitive performance in adults. On a neurobiological level, this effect is hypothesized to be related to cortical gyrification, which is determined primarily during fetal development. The relationships between gestational age, gyrification and specific cognitive abilities in adults are still poorly understood. In 542 healthy participants, gyrification indices were calculated from structural magnetic resonance imaging T1 data at 3 T using CAT12. After applying a battery of neuropsychological tests, neuropsychological factors were extracted with a factor analysis. We conducted regressions to test associations between gyrification and gestational age as well as birth weight. Moderation analyses explored the relationships between gestational age, gyrification and neuropsychological factors. Gestational age is significantly positively associated with cortical folding in the left supramarginal, bilaterally in the superior frontal and the lingual cortex. We extracted two neuropsychological factors that describe language abilities and working memory/attention. The association between gyrification in the left superior frontal gyrus and working memory/attention was moderated by gestational age. Further, the association between gyrification in the left supramarginal cortex and both, working memory/attention as well as language, were moderated by gestational age. Gyrification is associated with gestational age and related to specific neuropsychological outcomes in healthy adulthood. Implications from these findings for the cortical neurodevelopment of cognitive domains and mental health are discussed.

     

Role of coagulopathy in patients with head trauma

Coagulation disorders are a well known complication in patients with head injuries. A prospective study was undertaken to determine the incidence and prognostic value of haemostatic abnormalities in this group of patients. Clotting mechanisms in 105 patients with an isolated head injury were evaluated using platelet count (PC), prothrombin time (PT), activated partial thromboplastin time (APPT), thrombin clotting time (TCT), plasma fibrinogen concentration (Fib), level of fibrin-fibrinogen degradation products (FDP) and increased consumptive coagulopathy grade (ICCG) in the first 24 h after injury. The clinical severity of the head injuries was represented by the post-resuscitation Glasgow coma score (GCS) divided into four coma groups (CG). Test results were compared between two outcome groups of patients: discharged and dead. The incidence of disseminated intravascular coagulation (DIC) by laboratory criteria in the two groups was 12% and 38%, respectively. The differences between mean values of the discharged and dead patients for GCS, APTT, FDP and ICCG were statistically significant (P < 0.001). There was a very strong correlation between the GCS and values of the FDP, APTT, TCT and ICCG (P < 0.01). Stepwise logistic regression analysis demonstrated that GCS, FDP level, and ICCG predicted outcome in 84% of cases. Other tests did not provide additional predictive value. We conclude that evaluation of coagulation and fibrinolysis in patients with head injuries is not only important in identifying the occurrence of coagulopathy, but also useful in predicting head injury outcome.     

Auditory responsivity and intrauterine growth retardation in small for gestational age human newborns

Auditory responsivity in term small for gestational age (SGA) compared to term appropriate for gestational age (AGA) human newborns reflects functional differences which may be attributable to intrauterine growth retardation (IUGR). Between-group comparisons of percent of responses of averaged late component auditory evoked events (AEEs) to pure tone stimuli (500, 1000, 2000, 4000, 6000 and 8000 Hz) at 63 and 80 dB SPL revealed significantly greater AGA responsivity at 80 dB SPL. Conversely, the AEE mean latencies were significantly shorter for SGA infants at both intensity levels. Between-group responsivity differences suggest developmental retardation in term (38-42 weeks) SGA newborns, but the faster SGA latencies may reflect 'induced' acceleration in auditory neurophysiologic function.     

Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants

Mounting epidemiologic evidence and animal models suggest that stressful conditions during the intrauterine period may increase susceptibility to several adult conditions, including metabolic syndrome, cardiovascular disease, and psychiatric disorders. Increased cortisol levels due to alterations in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis are believed to be one mediating mechanism. Infants born after significant exposure to stressful conditions are often small for gestational age (SGA) based on standardized growth norms. Lifelong programming of the HPA axis has been proposed as a mechanism to explain the association between SGA infants and adult disease. However, few studies have measured HPA axis function proximal to birth as done in this study of SGA infants during the first week of life. Participants included 37 infants in two groups based on birth size (gestational age range: 34-41weeks). SGA infants were <10th percentile for age (n=21) and appropriate for gestational age (AGA) infants (n=16) were from 20 to 90th percentile for age. Cortisol response to a heel lance for blood collection was measured for all infants. Hierarchical Linear Modeling was used to test the effect of AGA/SGA group status on cortisol trajectories in response to the stressor. Group was a significant predictor of quadratic slopes (t=2.84, χ(2)=8.19, p=.004) after controlling for the effect of group on intercepts and linear slopes. Predicted growth curves for ln-cortisol were plotted for each group based on regression coefficients. The predicted curves capture the significant group difference in trajectories, as well as the blunted response for the SGA group and the robust peak in cortisol production in response to the stressor for the AGA group. This evidence suggests SGA neonates have blunted HPA axis responses to stressors in comparison to AGA infants. These findings are consistent with animal models showing that adverse intrauterine conditions can result in blunted cortisol responses to acute stressors and may provide a mechanism for adult susceptibility to disease for individuals that are SGA at birth.     

Neonatal pattern of adrenergic metabolites in urine of small for gestational age and preterm infants

Summary Catecholamines (DA, NE, E), methoxyamines (MT, NMN, MN), DOPA and DOPAC were studied in urine of term small for gestational age infants (SGA) and preterm with appropriate birthweights for gestational age (PT) during the first ten days of life. Results were compared to values obtained for full term infants (FT).As a whole no deficit in urine catecholamines was observed in either group of SGA and PT neonates suggesting that capacities to synthesize catecholamines are already developed at birth. Furthermore, in SGA infants, adrenergic function seems to be enhanced during the first four days of life; however, SGA infants with low blood glucose levels excreted amounts of epinephrine similar to those of FT neonates, but much lower than those obtained in normoglycemic SGA neonates. These data suggest that enhanced release of catecholamines is required in SGA infants to maintain the glycemic homeostasis. In premature infants, the adrenergic pattern was highly altered only in younger preterm neonates (31 weeks of gestational age) who excreted more catecholamines than older preterm babies (33 to 36 weeks) or full term neonates; this catecholamine increase in urine of young preterm infants might be related to immaturity of storage vesicles and/or to thermoregulatory or respiratory events.On the other hand, a striking deficit in excretion of DOPAC was observed in small for gestational age infants and in young preterm neonates during the first ten days of life. DOPAC excretion was even lower in SGA than in young preterm neonates. These findings suggest that the maturation of dopaminergic neurons occurs late in gestational age and is greatly dependent on nutritional factors.Abbreviations DOPA 3, 4-dihydroxyphenylalanine, M. W.: 197.2 - DOPAC 3, 4-dihydroxyphenylacetic acid, M. W.: 168.1 - E epinephrine, M. W.: 183.2 - NE norepinephrine, M. W.: 169 - DA dopamine, M. W.: 153 - MN metanephrine, M. W.: 197 - NMN normetanephrine, M. W.: 183 - MT 3-methoxytyramine, M. W.: 167 - MAO monoaminoxidase - COMT catechol-O-methyltransferase - FT full term neonates with appropriate birthweights - PT preterm neonates with appropriate birthweights for gestational age, ranging from 31 to 36 weeks - YPT young preterm neonates of 31 weeks of gestational age - OPT old preterm neonates with gestational age ranging from 33 to 36 weeks - SGA term small for gestational age infants - H-SGA small for gestational age infants with low blood glucose levels - N-SGA small for gestational age neonates with normal blood glucose levels     

Prognostic value of neonatal electroencephalography in premature newborns less than 33 weeks of gestational age

In a prospective study of 417 premature neonates born before 33 weeks' gestational age, neonatal tracings were reviewed to evaluate the use of EEG in prognosis of neurological injuries. The population was divided into two groups: Group 1, infants who died before the age of 1, and Group 2, survivors in which two categories of motor development were considered. Category A, were abnormal, and Category B, were always normal. Positive rolandic sharp waves (PRSW), which reflect white matter injury, occurred equally in both groups, indicating a similar incidence of white matter damage in Groups 1 and 2. In Group 2, there was a significant correlation of PRSW with developmental motor sequelae (Category A). A frequency of PRSW above 2/min (suggesting more severe periventricular white matter injury) and seizures were significantly more prevalent in Group 1 than in Group 2 and in Category A of Group 2 than in Category B. Background abnormalities occurred equally in both subgroups of extremely premature infants (≤28 weeks' gestation) they were significantly more numerous in the subgroup of very premature infants (between 28 and 33 weeks' gestation) who died, than in the subgroup of very premature infants who survived. This study shows the potential utility of using neonatal EEG in association with transfontanellar ultrasonography in anticipating the neurological development of very (>28 weeks' gestation) and extremely (≤28 weeks' gestation) premature newborns.     

Influence of sleep state and age on body motility in normal premature and full-term neonates

To assess the distribution of body motility according to sleep states and age, we performed polygraphic tracings in 39 normal premature and full-term infants during the neonatal period, grouped according to conceptional age in weeks (wCA): 31-34, 35-36, 37-38, and 39-41 wCA. Movements of the upper and lower limbs (UL, LL) were recorded using piezo-electric crystals. Time passed with movements (TWM) was automatically measured at an accuracy of 0.01 seconds. Sleep states were defined according to EEG and REMs criteria. We did not find any significant difference when TWM was compared between age-groups before the 38 wCA, on both UL and LL. TWM decreases significantly after 39 wCA (p less than 0.01). In all infants studied TWM was significantly higher in active sleep (AS) than in quiet sleep (QS). TWM in indeterminate sleep (IS) was usually similar to that in AS. The prevalence of body motility during AS compared to QS further confirms the observation of differences in the control of physiological variables according to sleep states as early as 31 wCA (the lower limit of our study).     

Behavior of full term infants small for gestational age in the first three months of life

The objective was to compare the behavior of full-term infants small-for-gestational age (SGA) with full-term appropriate-for-gestational age (AGA). The sample considered 20 infants in the 1st, 2nd and in the 3rd months of life. The Bayley Scales of Infant Development-II were used, with attention to items related to Behavior Rate Scale (BRS). It was found that SGA infants showed lower average values in the BRS in the 2nd month. The Motor Quality Factor displayed significantly lower average values in SGA group, in the items Gross-motor Movement Required by Tasks, Control of Movements and Hypertonicity. The Attention/Arousal Factor in the items Exploration of Objects/Surroundings and Orientation to Examiner displayed significantly lower average values in the SGA group.     

新生儿脊髓拴系综合征的显微外科治疗(附48例分析)

目的探讨新生儿脊髓拴系综合征(TCS)的临床特征及显微手术操作要点。方法回顾性分析48例新生儿TCS的临床资料,包括症状、体征、辅助检查结果。术中均采用显微镜进行外科手术治疗,并随访其临床症状的改善程度。结果本组病儿随访疗效良好。6例双下肢及双足不对称中病人中,恢复正常4例,改善2例。4例大小便失禁病人中能自主控制大小便2例,症状略改善2例。3例马蹄内翻足由骨科矫形治疗后均痊愈,2例双下肢轻瘫病人肌力略改善。余病儿术后大小便均正常,双下肢活动好。结论新生儿TCS均由先天因素引起,早期手术可避免日后出现神经功能障碍。     

An immunoassay for human D dimer using monoclonal antibodies

Monoclonal antibodies (MAb) were raised against human D dimer. The hybridomas were screened with a solid phase enzyme immunoassay against D dimer and fibrinogen degradation products. Among the panel of MAb identified, two distinct patterns emerged; the majority belonging to a panspecific class reacting against epitopes present on both D dimer and fibrinogen degradation product Dcate and a monospecific class reacting with determinants apparently present only on D dimer. A number of MAb were further characterised for their ability to specifically capture antigen in a solid phase enzyme immunoassay and assays were developed which have a sensitivity of 10 ng/ml for D dimer or crosslinked fibrin derivatives and may be suitable for detection of crosslinked derivatives in serum and plasma samples in a clinical situation.     

The influence of neurohypophysis hormones and their modified forms on haemostasis

Results of our own studies and literature data on the functional activities of neurohypophysis hormones, including arginine-vasopressin (AVP) and oxytocin (OX), as well as their modified forms and fragments, with respect to the parameters of the haemostasis system were analyzed in this review. Modification of the amino acid composition of the natural hormone was found to cause significant changes in its functional activities on the blood coagulation system. The intact molecule of the peptide is necessary for manifestation of the main effects of AVP and OX. The presence of the C-terminal glycylamide in the molecule determines the fibrinolytic effects of vasopressin, which are associated with an increase in the activity of the tissue plasminogen activator (t-PA). Peptides lacking this group have a more pronounced effect on procoagulant blood activity. Original Russian Text ? M.G. Golubeva, M.E. Grigorjeva, 2008, published in Neirokhimiya, 2008, Vol. 25, Nos. 1–2, pp. 17–22.