Need for consensus in interpreting coagulation profile in preterm neonates

Vasudevan, Chakrapani; Ibhanesebhor, Samuel; Manjunatha, C. M.; Das, Kedarnath; Ardyll, R

doi:10.1136/adc.2009.162156

Cited by 8 publications

(5 citation statements)

References 2 publications

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“…Thus, our impression that cord blood coagulation tests do not identify the neonates who will go on to have bleeding problems is tentative and subject to modification when thousands of preterm neonates have been similarly screened. The problems of small sample size is common to all previous reports of coagulation tests in preterm neonates . To lessen this problem, we attempted (Table ) to estimate the relevant reference intervals using data from the present plus previous studies and to propose tentative recommendations for management of preterm neonates.…”

Section: Discussionmentioning

confidence: 99%

“…The problems of small sample size is common to all previous reports of coagulation tests in preterm neonates . To lessen this problem, we attempted (Table ) to estimate the relevant reference intervals using data from the present plus previous studies and to propose tentative recommendations for management of preterm neonates. In doing this we endeavored to incorporate the published recommendations from the Poralla and Bartmann group from Germany, and the Venkatesh and Stanworth groups from Great Britan .…”

Section: Discussionmentioning

confidence: 99%

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Reference intervals for common coagulation tests of preterm infants (CME)

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Reference intervals for common coagulation tests of preterm infants (CME)

et al. 2013

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“…Coagulation tests are frequently performed following delivery of extremely premature infants [2,3,22]. Interpretation of results is challenging.…”

Section: Discussionmentioning

confidence: 99%

Laboratory Coagulation Parameters in Extremely Premature Infants Born Earlier than 27 Gestational Weeks upon Admission to a Neonatal Intensive Care Unit

Neary¹,

Okafor²,

Al-Awaysheh³

et al. 2013

Neonatology

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Background: Few published data exist to guide interpretation of coagulation times in extremely premature infants. Objective: To determine coagulation reference ranges on day 1 of life in extremely premature infants. Methods: A retrospective review of day 1 coagulation tests was performed in 144 infants <27 weeks' gestation between 2004 and 2010 in a tertiary neonatal unit. Samples were drawn through a non-heparinized umbilical or peripheral venous catheter as part of routine clinical care. Results: Mean (SD) and median (range) prothrombin times (PT) of 21.5 (5.3) and 20.2 (13.3-39) s, respectively, activated partial thromboplastin times (APTT) of 75.2 (27.8) and 67.4 (34.9-191.6) s, respectively, and plasma fibrinogen levels of 1.9 (1.1) and 1.4 (0.5-4.8) g/l, respectively, were reported. Using reference intervals derived from the 2.5th to 97.5th centiles, ranges of 14.4-36.7 s, 40.5-158.5 s and 0.7-4.8 g/l were determined for PT, APTT and plasma fibrinogen levels, respectively. In a subcohort with grade 0-2 intraventricular haemorrhage (n = 92), mean PT and APTT were 20.9 and 71.3 s, respectively, versus mean PT and APTT of 23.1 and 88.4 s (p = 0.06 and p = 0.03), respectively for those with grade 3-4 intraventricular haemorrhage. Mean PT and APTT in a cohort of infants defined to be small for gestational age were 22 and 76.8 s. These results did not differ significantly from non-small for gestational age infants, with a mean PT and APTT of 19.5 and 73.4 s (p = 0.09 and p = 0.7). Conclusions: Reference ranges based on retrospective data were determined for PT, APTT and fibrinogen in a large cohort of extremely preterm infants.

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“…Coagulation tests are frequently performed following delivery of extremely premature infants (Andrew et al, 1988, Vasudevan et al, 2010 . Interpretation of results is challenging.…”

Section: Discussionmentioning

confidence: 99%

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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Need for consensus in interpreting coagulation profile in preterm neonates

Cited by 8 publications

References 2 publications

Reference intervals for common coagulation tests of preterm infants (CME)

Reference intervals for common coagulation tests of preterm infants (CME)

Laboratory Coagulation Parameters in Extremely Premature Infants Born Earlier than 27 Gestational Weeks upon Admission to a Neonatal Intensive Care Unit

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

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