Effect of delivery modalities on the physiologic inhibition system of coagulation of the neonate

Franzoi, Malida; Simioni, Paolo; Luni, Sonia; Zerbinati, P.; Girolami, Antonio; Zanardo, Vincenzo

doi:10.1016/s0049-3848(01)00407-8

Cited by 25 publications

(3 citation statements)

References 19 publications

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“…A corresponding increase was observed in protein C and anti-thrombin levels. Similarly elevated protein C, protein S, AT, fibrinogen and plasminogen activity have been reported in cord blood after vaginal delivery compared to caesarean section (Franzoi et al, 2002). In our cohort I was able to examine both infants in labour and not in labour to examine this effect in preterm neonates.…”

Section: Deliverysupporting

confidence: 52%

“…Fifty one infants (16%) developed severe IVH (Grades 3 & 4). Franzoni et al who also found that fibrinogen was lower in infants undergoing caesarean section versus vaginal delivery but the difference was not statistically significant (Franzoi et al, 2002). Those associations remained significant in the multivariable linear regression model of all perinatal characteristics.…”

Section: Study 3 -Overall Cohortmentioning

confidence: 90%

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To Characterize Standard Laboratory Coagulation Parameters and Plasma Thrombin Generation in Very Preterm Infants and to Investigate Their Relationship to Clinical Outcomes

Neary

McCallion

Kevane

et al. 2014

Blood

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Very premature infants are at risk of bleeding complications and are frequently given plasma because of a perception that coagulation test results are abnormal. However, “abnormal” clotting times may simply be due to physiological immaturity. We hypothesized that prospective characterization of coagulation tests alongside assessment of thrombin generation would provide information on overall haemostatic balance in this vulnerable patient cohort. In a prospective observational study, blood was drawn into citrated tubes from cord blood of neonates <30/40 and subsequently on day 1, 3 and fortnightly until 30/40 corrected gestational age from non-heparinised lines. Exclusion criteria included antenatal intraventricular haemorrhage and lack of informed consent. Platelet poor plasma was obtained by centrifugation of whole blood. Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, procoagulant and anticoagulant factor activity were measured and tissue factor (TF)-stimulated thrombin generation was characterized in a calibrated automated thrombography assay with a 1pM TF stimulus using Thrombinoscope™ software. Control plasma was obtained from cord blood of term neonates. Between April 2013 and June 2014, 92 patients <30/40 were admitted. Six infants were excluded and 86 recruited. Mean gestational age and birth weight were 27 (23.7-29.9) weeks and 1019 (530-1590) g respectively. Median (5th-95thpercentile) Day 1 PT, APTT, and fibrinogen were 17.5 (12.9-26.7) s, 82.9 (53.4-139.8) s and 1.4 (0.7-3.7) g/L respectively which were significantly prolonged compared with published results of term infants; p<0.001. Serial analysis revealed correction of PT, APTT and fibrinogen with increasing postnatal age; p<0.001. Further analysis of procoagulant and anticoagulant mechanisms was performed in a subset of infants (N=16) where sufficient plasma was available from umbilical cord samples. Despite apparent “prolongations” in clotting times, we found that preterm peak thrombin generated was similar to term infants (94.3 (33.4-149.8) nM vs. 93.5 (74.3-133.8) nM; p=0.94). Minor, non-significant differences in the area under the thombin generation curve (endogenous thrombin potential) were observed (88 (37.1-126.3) nm/min vs. 101.3 (76.8-139.7) nm/min; p=0.09). Alpha-2-macroglobulin (α2M)-bound thrombin cleaves the fluorogenic thrombin substrate utilized in this assay and contributes to measured thrombin generation. However, in keeping with published data in a more mature cohort, α2M activity was lower in preterm vs. term infants. Consequently, we speculate that true ETP in preterm infants may be higher, undermining the current perception that these infants are at risk of bleeding due to “abnormal” clotting times. In keeping with published data in a more mature cohort, mean activity of procoagulant factors II, VII, IX and X were reduced in preterm vs. term infants (0.33 (0.18-0.5) IU/ml vs. 0.45 (0.35-0.6) IU/ml, p=0.003; 0.38 (0.14-0.57) IU/ml vs. 0.42 (0.31-0.59) IU/ml, p=0.29; 0.19 (0.09-0.50) IU/ml vs. 0.28 (0.19-0.37) IU/ml, p=0.004 and 0.33 (0.13-0.52) IU/ml vs. 0.43 (0.32-0.58) IU/ml, p=0.02) respectively. Conversely, activity of anticoagulant factors Protein C (0.14U/ml (0.06-0.24) IU/ml vs. 0.27 (0.18-0.39) IU/ml; p=0.002), free protein S (0.39 (0.28-0.55) IU/ml vs. 0.47 (0.36-0.59) IU/ml; p=0.02), antithrombin (0.22 (0.06-0.36) IU/ml vs. 0.52 (0.38-0.69) IU/ml; p=0.0001) and tissue factor pathway inhibitor (7.7 (2.6-16.9) vs. 10 (4.2-15.6) ng/ml; p=0.14) was lower in preterm vs. term infants. No differences in attenuation in thrombin generation in response to the anticoagulant activated protein C were observed in preterm vs. term infants, p=0.92. In conclusion, in the largest prospective study to date of very preterm infants, we describe typical ranges for widely available coagulation tests. We also demonstrate differences in both procoagulant and anticoagulant pathways, to which standard clotting tests may have limited sensitivity. Finally, we show for first time that thrombin generation is similar in very preterm and term infants. These findings call into question the current practice of exposing infants to plasma products based on standard laboratory parameters, a practice which is associated with enormous potential harm and is not evidence based. These findings have the potential to impact on neonatal practice worldwide. Disclosures Ní Áinle: LEO Pharma: Research Funding; Bayer Healthcare Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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Section: Deliverysupporting

confidence: 52%

Section: Study 3 -Overall Cohortmentioning

confidence: 90%

To Characterize Standard Laboratory Coagulation Parameters and Plasma Thrombin Generation in Very Preterm Infants and to Investigate Their Relationship to Clinical Outcomes

Neary

McCallion

Kevane

et al. 2014

Blood

View full text Add to dashboard Cite

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“…Franzoi et al also reported that fibrinogen was more elevated in vaginally delivered neonates in comparison to those delivered by caesarean section but the difference was not statistically significant [19].…”

Section: Discussionmentioning

confidence: 99%

Hemostatic profile of infants with spontaneous prematurity: can we predict intraventricular hemorrhage development?

et al. 2019

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Background Defining hemostatic profile for preterm infants is a challenge when severe bleedings are frequent. Methods The aim was to define the hemostatic profile at birth of infants with spontaneous prematurity and to evaluate whether characteristic profiles can predict the development of intraventricular hemorrhage (IVH) in prematures. Results We included 122 newborns with a median age of 31 5/7 gestational age (GA) [29 2/7 ;34 0/7 ] and median weight of 1145 g [785;1490]. Levels of fibrinogen, factor II (FII) and factor V (FV) rose with GA ( p = 0.017, p = 0.009, p = 0.001). In the group of 23 0/7 – 28 6/7 GA, the 5th percentile was defined as 0.6 g/L for fibrinogen, 15 IU/dL for FII and 16 IU/dL for factor V ( n = 30). In the group of 29 0/7 –32 6/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 41 IU/dL for factor V ( n = 46). In the group of 33 0/7 –36 6/7 GA, the 5th percentile was defined as 1.0 g/L for fibrinogen, 24 IU/dL for FII and 30 IU/dL for factor V ( n = 46). Level of fibrinogen was higher in case of vaginal delivery and lower in case of IUGR. Only lower level of FV at birth was significantly associated with IVH (63.5 [46.0; 76.5] vs 74.0 [58.0; 89.0], p = 0.026) with an unadjusted OR per SD increase in FV of 0.57 (95%CI, 0.34 to 0.96). After adjustment for age, the association between FV level and IVH was slightly attenuated (adjusted OR, 0.70; 95%CI, 0.40 to 1.23) but remained not significant ( p = 0.22).There was no correlation with FII and fibrinogen. Conclusions We can define hemostastic profile of prematures and corroborate references ranges for studied parameters. Further large studies are still called for, to correlate the grade of hemorrhage and the factor V level at birth.

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The Thrombotic Risk of the Newborn

Claudio¹,

Saracco²

2016

Neonatology

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Effect of delivery modalities on the physiologic inhibition system of coagulation of the neonate

Cited by 25 publications

References 19 publications

To Characterize Standard Laboratory Coagulation Parameters and Plasma Thrombin Generation in Very Preterm Infants and to Investigate Their Relationship to Clinical Outcomes

To Characterize Standard Laboratory Coagulation Parameters and Plasma Thrombin Generation in Very Preterm Infants and to Investigate Their Relationship to Clinical Outcomes

Hemostatic profile of infants with spontaneous prematurity: can we predict intraventricular hemorrhage development?

The Thrombotic Risk of the Newborn

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