Blood Reviews xxx (xxxx) xxx

Contents lists available at ScienceDirect

Blood Reviews
journal homepage: www.elsevier.com/locate/issn/0268960X

Review

Contemporary tools for evaluation of hemostasis in neonates. Where are we

and where are we headed?
Rozeta Sokou a, *, Stavroula Parastatidou b, Aikaterini Konstantinidi a, Andreas G. Tsantes c,
Nicoletta Iacovidou d, Daniele Piovani e, f, Stefanos Bonovas e, f, Argirios E. Tsantes c
a
Neonatal Intensive Care Unit, "Agios Panteleimon" General Hospital of Nikea, Piraeus, Greece
b
Neonatal Intensive Care Unit, “Elena Venizelou” Maternity Hospital, Athens, Greece
c
Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Greece.
d
Neonatal Department, National and Kapodistrian University of Athens, Aretaieio Hospital, Athens, Greece
e
Department of Biomedical Sciences, Humanitas University, Milan, Italy
f
IRCCS Humanitas Research Hospital, Milan, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: The assessment of hemostatic disorders in neonates is crucial, but remains challenging for clinicians. Although

t.me/neonatology
Hemostatic disorders the concept of developmental hemostasis is widely accepted among hemostasis specialists globally, it is probably
Neonatal hemostasis under-recognized by clinicians and laboratory practitioners. In parallel with age-dependent hemostatic status
Coagulation tests
maturation, comprehension of the differences between normal values is crucial for the accurate diagnosis of
Viscoelastic coagulation tests
potential hemorrhagic and thrombotic disorders of the vulnerable neonatal population. This review outlines the
Thromboelastography/rotational
thromboelastometry basics of developmental hemostasis and the features of the available coagulation testing methods, with a focus on
Calibrated automated thrombogram novel tools for evaluating the neonatal hemostatic profile. Common errors, issues, and pitfalls during the
assessment of neonatal hemostasis are discussed, along with their impact on patient management. Current
knowledge gaps and research areas are addressed. Further studying to improve our understanding of develop­
mental hemostasis and its reflection on everyday clinical practice is warranted.

1. Introduction secondary hemostasis and clot lysis and contributes to restoration of

Hemostasis is a complex, dynamic, homeostatic mechanism that
balances procoagulant and anticoagulant forces aiming to prevent blood
loss from hemorrhage while ensuring vascular patency [1–6]. Some­
times, instead of “hemostasis”, the term “coagulation” is used, but this
depicts only one part of hemostasis. The three stages of hemostasis
include primary hemostasis, secondary hemostasis and fibrinolysis
[6,7].
Primary hemostasis refers to the interaction between platelets, von
Willebrand factor (vWF), plasma agglutinins, and endothelial cells of the
affected vessel, resulting in the formation of platelet clot. Secondary
hemostasis mainly refers to the sequential activation of procoagulant
proteins (“coagulation cascade”) that leads to the conversion of fibrin­
ogen to fibrin through formation of thrombin. The purpose of the anti­
coagulant system, the anticoagulant cascade, is to regulate secondary
hemostasis by controlling the hemostatic enzymes in order to limit and
dissolve the clot. Fibrinolysis further controls the balance between
vascular patency and circulation. When the interactions between these
mechanisms proceed smoothly, optimal hemostasis is achieved [1].
However, when the hemostatic equilibrium is disturbed, either hemor­
rhage or thrombosis occurs [7].
The hemostatic elements are not independent, but rather inter­
connected. For example, vWF facilitates adhesion and aggregation of
platelets by binding to collagen and glycoprotein (GP) Iba in primary
hemostasis. In the context of secondary hemostasis, vWF prevents factor
VIII from proteolysis and delays its plasma clearance. As a result, pa­
tients with von Willebrand disease present hemorrhage due to
derangement of both primary and secondary hemostasis [8]. Similarly,
fibrinogen is mainly involved in secondary hemostasis, as it is converted
to fibrin. Nevertheless, fibrinogen also serves as the most important
adhering factor for activated platelets, contributing to primary hemo­
stasis [7,9].
According to the cellular model, hemostasis takes place in specific
cellular surfaces that affect the process depending on the type of their

* Corresponding author at: Neonatal Intensive Care Unit, “Agios Panteleimon” General Hospital of Nikea, 3 D.Mantouvalou Str.,18454, Nikea, Piraeus, Greece.
E-mail address: sokourozeta@yahoo.gr (R. Sokou).

https://doi.org/10.1016/j.blre.2023.101157

Available online 25 November 2023

0268-960X/© 2023 Elsevier Ltd. All rights reserved. T.ME/NEONATOLOGY

Please cite this article as: Rozeta Sokou et al., Blood Reviews, https://doi.org/10.1016/j.blre.2023.101157

t.me/neonatology
R. Sokou et al.
surface receptors [3,10]. The three overlapping phases (initiation,
amplification, and propagation) occur in different cellular surfaces. In
particular, coagulation is initiated in cells expressing tissue factor (TF),
amplified in activating platelets and propagated in the phospholipid
surface of the fully activated platelets.
Hemostasis comprises complex biochemical mechanisms and in­
teractions between vascular endothelium, coagulation factors, and
cellular (mostly platelets') blood components.
The assessment of hemostatic disorders is challenging for clinicians
especially neonatologist who are faced with these entities in every day's
clinical practice. This review outlines the basics of developmental he­
mostasis and the features of the available coagulation testing methods,
with a focus on the novel tools for evaluation of the neonatal hemostatic
profile. The common errors, issues, and pitfalls during the assessment of
neonatal hemostatic status are discussed, along with their impact on
patient management.
2. Developmental hemostasis
The concept of developmental hemostasis may be widely accepted
among hemostasis specialists globally, but it is probably under-
recognized by clinicians and laboratory practitioners.
The term “developmental hemostasis” was first introduced by
Andrew M. during 1980s, to describe the age-dependent changes in
procoagulant and anticoagulant coagulation factors involved in sec­
ondary hemostasis and fibrinolysis. Hemostasis is evolving dynamically
from fetal until adult life [11–14]. These findings were later confirmed
by Monagle, Ignjatovic, et al. [13,14]. Neonates are born with qualita­
tive and quantitative differences in their hemostatic system compared to
adults' that depend on gestational age, birth weight, vitamin K levels and
liver maturity (outlined in Fig. 1) [11,12,15–40]. Reduced levels of
coagulation factors in neonates are attributed to decreased production
and/or increased clearance, and may be due to functions other than
hemostasis, like involvement in angiogenesis and inflammation. Despite
these quantitative and qualitative differences in multiple hemostatic
factors between neonates and adults, the hemostatic system is consid­
ered adequate and functionally counterbalanced in healthy, full-term
and preterm neonates. However, in conditions like sepsis, asphyxia,
and injury, hemostatic reserves are challenged and neonates tend to
present hemorrhagic or thrombotic events, which further aggravate
their clinical status.
Reduced platelet aggregation and adhesion and platelet hypo-
Fig. 1. Differences between neonatal and adult hemostatic system.
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reactivity have been reported in preterm neonates. However, studies
investigating primary hemostasis using the platelet function analyzer
100 (PFA-100) have exhibited decreased closure time in full-term neo­
nates compared to adults, indicating a paradoxically enhanced neonatal
platelet activity in neonates. This finding could be attributed to the
higher vWF concentrations, the prevalence of polymers with higher
adhesion capability, and the higher neonatal levels of hematocrit and
mean corpuscular volume (MVC), resulting in a well-functioning system
of primary hemostasis [41].
Comprehension of the differences between normal values is crucial
for the accurate diagnosis of potential hemorrhagic and thrombotic
disorders. The discrepancies between blood samples from the umbilical
cord and the neonate, the effect of analysis systems and reagents on the
results, and the rapid physiological changes in the first days of life
should be taken into consideration.
Furthermore, developmental hemostasis has an impact on thera­
peutic interventions for hemostatic disorders, which is still unclear and
under investigation. The role of coagulation proteins in other systems is
yet to be elucidated. Understanding all the complex interactions will
allow optimal hemostatic management of neonatal patients.
3. Conventional coagulation testing
Universally, the first step in investigating hemostatic disorders usu­
ally includes the following tests:
1. platelet count.
2. prothrombin time (PT), expressed by international normalization
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ratio (INR).
3. activated partial thromboplastin time (aPTT).
4. fibrinogen levels.
Assessment of the hemostatic state of patients routinely begins with
traditional coagulation tests, like PT and aPTT. These are in vitro plasma
tests that solely assess involvement of procoagulant factors, without
estimating the role of anticoagulant factors and cellular components in
hemostasis. Conventional tests assess only partially the hemostatic sys­
tem, hence failing to provide information regarding platelet function
and fibrinolysis [42,43]. Prolonged times have been recorded in
screening PT and aPTT tests in neonates compared to values of children
and adults. This may be due to the decreased plasma levels of K-
dependent factors VII, X, V, II, and fibrinogen, along with the reduced
R. Sokou et al.
contact system factors XII, XI, VIII, and IX; a reflection of developmental
hemostasis [11,44].
Routine use of these tests is frequently questioned in neonates, as the
reagents are not standardized for this age group and because of practical
issues with blood drawing, including the significant blood volume
required for a comprehensive test. Additionally, clot formation during
PT and aPTT measurements differs depending on the reagents and the
methodology used.
Both age and analyzer should be considered and age-specific refer­
ence reagents should be used to prevent overdiagnosis or misdiagnosis
and wrong or potentially harmful treatment. International Society of
Thrombosis and Hemostasis (ISTH) recommends that every laboratory
uses an appropriate analyzer and reagents to establish age-specific
reference values- range for coagulation tests [14]. Conventional coag­
ulation tests are insightful regarding the activation of coagulation, but
their diagnostic efficacy is dubitable [45], while presenting limitations
in predicting hemorrhage and guiding transfusion therapy in critically ill
patients, specifically neonates [46–50]. Conducting conventional coag­
ulation tests as a routine in NICU is not recommended [42].
Another disadvantage of these tests is the relatively significant blood
volume required (0.8–2 mL), which becomes an issue, particularly in
very low birth weight (VLBW) neonates at risk of iatrogenic anemia
[51]. Moreover, practical problems with blood drawing and testing
procedure may result in inaccurate findings and laboratory errors
[52,53]. In neonatology, emergent incidents often arise, and the repe­
tition of conventional tests in case of inconclusive results, becomes
dysfunctional, undesirable, and time-consuming.
4. Viscoelastic coagulation tests
Monitoring of hemostasis and fibrinolysis with a portable, point-of-
care device that requires a small blood sample and rapidly provides
accurate results to contribute in prompt patient management is
appealing for neonatologists [54]. Viscoelastic coagulation tests (VCT),
like thromboelastography (TЕG) / rotational thromboelastometry
(ROTEM), and viscoelastic coagulation monitoring (VCMTM) represent
diagnostic methods with the potential to overcome some of the limita­
tions of the conventional coagulation tests. They provide information
regarding the clot formation and lysis, allowing for monitoring of the
entire hemostatic procedure [55,56]. Low volume of whole blood is
necessary, while the results outline a comprehensive assessment of
coagulation and fibrinolysis mechanisms. The complex process of he­
mostasis with the interactions between procoagulant factors, fibrinolytic
proteins, cellular components, and platelets is depicted, according to the
cellular coagulation model.
The most significant advantage of VCTs is their ability to assess the
hemostatic state of the patient, numerically and graphically, in real
time, compared to conventional tests. VCTs provide insight on important
parameters including:
1. Clot formation.
2. Clot kinetics.
3. Clot stability and elasticity.
4. Clot lysis.
5. Representation of viscoelastic changes taking place during fibrin
dissolution.
6. Differential diagnosis of congenital and acquired primary coagula­
tion disorders from hemorrhage of surgical/ traumatic cause [56].
VCTs can be used at the patient's bedside by clinicians, in the context
of perioperative care or emergency medicine, allowing for targeted,
individualized therapeutic interventions when needed [53]. VCTs can
detect the anticoagulant effect of acidosis and hypothermia, and reveal
subsequent coagulation disorders, including thrombocytopenia, de­
ficiencies of coagulation factors, the heparin effect, hypofi­
brinogenemia, and hyperfibrinolysis, contributing to appropriate
3
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patient management [46,57].
ROTEM is a practical method and its results are readily available,
accurate and repeatable, with lower variability between sequential tests
and different operators, in a standardized point-of-care test [58]. VCTs
have demonstrated reliability in prediction of hemorrhage and are
useful in monitoring and treating critically ill patients [46,59].
Although no elaborate laboratory training is necessary for the
operator, still VCTs, like most laboratory tests, are dependent on the
operator and there is always the risk of preanalytical errors related to
handling and processing of samples. However, repeatability rates of
TEG/ ROTEM in VLBW or critically ill neonates (coefficient of variation
<10%) is reassuring regarding use of these methods in NICUs
[46,60,61]. Furthermore, introducing automated analyzer systems
seems to further reduce preanalytical variability. ClotPro analyzer is a
novel, new generation thromboelastometry analyzer that avoids
handling of reagents using automated pipettes and incorporated dried
reagents [62].
Classic TEG/ ROTEM analyzers have limitations in detecting hemo­
static disorders related to platelet adhesion and vWF functionality,
therefore, modified TEG for platelet mapping (TEG-PM) and ROTEM
with an impedance aggregometry analyzer have been introduced for
studying platelets [63].
Recently, a portable VCM device has been developed, with numerous
advantages, that conducts an automated analysis in approximately an
hour requiring only 300 μL of blood without the addition of anticoag­
ulant [64]. VCM analysis can be conducted in neonatal capillary blood
[65]. VCM is easy to use, a promising tool for hemostatic evaluation in
NICU [62].
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The contemporary VCTs have similarities and differences in their
technique, tests, and measurement parameters (Table 1).
According to the developmental hemostasis model the establishment
of reference values based on gestational and postnatal age is necessary
for each method in case to avoid postanalytical errors [42,66].
4.1. Viscoelastic coagulation tests in healthy neonates
The evidence regarding the role of TEG / ROTEM in the early diag­
nosis of hemostatic disorders in neonates is scarce [61,67–69]. The use
of VCTs in this population is limited due to the lack of reference values
for neonates [70,71].
Both TEG and ROTEM have been studied in cord blood samples of
healthy neonates [72–76]. Cord blood samples have traditionally been
easily collected and used to assess neonatal hemostasis [49,77]. How­
ever, cord blood samples are probably not representative of the neonatal
hemostatic state, not even in the first hours of life. Recently, Raffaeli
et al. [78], suggested that cord blood samples should not be used for
TEG/ ROTEM parameters as they do not reflect the hemostatic profile of
neonates. Therefore, VCTs were conducted in whole blood of healthy
neonates and reference values have been reported for both preterm and
full-term neonates [70,71,79–82]. Oswald et al. have presented age-
specific reference values for ROTEM parameters, while conventional
coagulation tests have the same reference values for all age groups [83].
Evidence from ROTEM results shows that initiation of coagulation and
clot formation directly depend on age, while clot firmness and fibrino­
lysis are similar across age groups. Although infants 0–3 months exhibit
prolonged clotting times in the conventional coagulation tests, ROTEM
parameters revealed an accelerated induction of coagulation, with clot
firmness within normal adult limits. Sokou et al. [70], established
reference ranges for ROTEM parameters (EXTEM) in 84 healthy preterm
and 198 full-term neonates. There were no significant differences in
ROTEM values between preterm and full-term neonates, with the
exception of LI60, which could be attributed to lower levels of fibrino­
lysis inhibitors in preterm neonates. Theodoraki et al. [71], defined
reference ranges for ROTEM parameters (EXTEM, INTEM, FIBTEM) in
215 healthy full-term neonates. No impact of gender, mode of delivery,
and history of maternal gestational diabetes on ROTEM parameters was
R. Sokou et al. Blood Reviews xxx (xxxx) xxx

Table 1
The main viscoelastic coagulation testing measurement parameters.
TEG ROTEM Clot Pro VCM Definition Explanation Hemostatic process

K CT CT CT Coagulation Time (sec): time from test start until the Speed of thrombin 1. Enzymatic activity of coagulation
formation of a 2 mm amplitude clot. generation factors
2. Concentration of anticoagulants and
fibrin degradation products
3. Expression of tissue factor in circulating
cells
R CFT CFT CFT Clot Formation Time (sec): Clot formation 1. Thrombin generation
Time from the formation of a 2 mm clot until the kinetics 2. Platelet count and function
formation of a 20 mm clot 3. Fibrinogen concentration and fibrin
polymerization
α α α А A angle (◦ ): Clot formation
the angle between the baseline and a tangent to the kinetics
clotting curve through the 2 mm point
MA MCF MCF MCF Maximum Clot Firmness (mm): Mechanical firmness 1. Fibrin polymerization
Maximum clot amplitude of the clot 2. Platelet count and functionality
3. Factor ХІІІ activity
LY30; LI30- LY30; LY30; Lysis Index at 30 or 60 min (%): Clot firmness and 1. Activity of fibrinolytic enzymes
LY60 LI60 LY60 LY60 Residual clot firmness at 30 or 60 min after CT or R, fibrinolysis 2. Fibrinolytic enzymes
described in % of MCF 3. Factor XIII
ML ML Maximum Lysis (%): Fibrinolysis grade/ 1. Activity of fibrinolytic enzymes
Maximum lysis detected during run time displayed as rate 2. Fibrinolytic enzymes
% of MCF 3. Factor XIII

noted. An interesting finding of this study was the hypocoagulable
profile observed in neonates with higher hematocrit (Ht), expressed
with prolonged CT, and CFT, and reduced clot amplitude (A5, А10,
MCF) and speed of clot formation, which is in accordance with previous
reports [84]. This finding has been correlated with the mean concen­
undergoing cardiothoracic operations and ExtraCorporeal Membrane
Oxygenation (ECMO), as hemostatic disorders are main contributors of
mortality and morbidity [93]. Exposing blood to the non-endothelial
circuit surface ultimately leads to a prothrombotic state [94], while a
constant platelet activation results in prolonged and intense release of

tration of hemoglobin (MCH) of red blood cells and respective fibrin­
ogen dilution in whole blood [85]. The clot's structure and mechanical
functionality is influenced in proportion to the concentration of red
blood cells [86]. Neonates of mothers who smoked during pregnancy
exhibited a hypercoagulable hemostatic profile, demonstrated by pro­
longed ROTEM CT. This may not be clinically evident in healthy neo­
nates, but could have an impact when comorbidity is present [87].
ROTEM results were similar in appropriate for gestational age (AGA, n
= 48) and small for gestational age (SGA, n = 45) preterm and full-term
neonates, unlike the conventional coagulation tests [68].
4.2. Viscoelastic coagulation tests in ill neonates
Preterm and ill neonates are at risk of multifactorial hemostatic
derangement. Critically ill neonates, preterm ones in particular, are at
high risk of hemorrhage, one of the most common issues in NICU. Of all
the neonates admitted in 8 different NICUs, 25% presented with epi­
sodes of hemorrhage during their hospitalization; with 11% categorized
as major/ severe, 1% as moderate and 13% as mild bleedings, using a
standardized, validated tool for assessment of neonatal hemorrhage
(NeoBAT) [88].
In critically ill neonates, systematic inflammation is followed by
activation of the coagulation cascade, and on the other hand, coagula­
tion factors impact the inflammatory response [89]. This interaction
between inflammation and coagulation is complex. The release of
proinflammatory cytokines induces the generation of coagulation fac­
tors, that act as mediators of inflammation through binding to endo­
thelial and immunologic cells [90]. The systemic immunologic response
to infection results in activation of the coagulation cascade, consump­
tion of anticoagulant factors, and inhibition of fibrinolysis [91].
Inflammation and coagulation pathways interact with each other in a
way that augments systemic inflammatory response, leading to
enhanced activation of coagulation, endothelial changes, microvascular
thrombi with subsequent ischemic dysfunction of multiple organs, and
multisystemic failure induced by severe inflammation [92]. Assessment
of the hemostatic status of these patients is challenging.
The risk of hemostatic disorders is further increased in neonates
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granules [95]. Platelets become hyporeactive and dysfunctional and the
risk for hemorrhage increases [94,96].
Studies of TEG and ROTEM in neonates undergoing cardiopulmo­
nary bypass (CPB) showed that VCTs reflect the functional integrity of
fibrinogen better than its levels and can detect thrombocytopenia and
hypofibrinogenemia, allowing for optimization of hemostasis and
minimization of complications associated with transfusions [97,98].
Additionally, they provide useful real-time information to drive heparin
infusion [94,99–102].
Perinatal hypoxia is associated with increased risk of hemostatic
disorders. Konstantinidi et al. [126] assessed the hemostatic profile of
neonates with perinatal hypoxia/ asphyxia comparing it with that of
healthy neonates using ROTEM. Neonates with perinatal asphyxia and
mild hypoxia or fetal distress presented a hypocoagulable profile in
comparison to healthy neonates. Neonates with perinatal asphyxia had a
more pronounced hypocoagulable profile than neonates with fetal
distress. Therapeutic hypothermia, the most effective, first-line treat­
ment for neonates with hypoxic- ischemic encephalopathy (HIE) affects
hemostatic state [103] accelerating thrombi formation in the capillary
[104], decelerating the activity of coagulation enzymes [105], and
negatively affecting the functionality of platelets as expressed by pro­
longation of clotting time and coagulation time in PFA100 [106]. For­
man et al. [107], investigated effects of therapeutic hypothermia on
hemostasis conducting TEG in neonates with HIE. There were differ­
ences in TEG parameters based on temperature; coagulation was
impaired in hypothermic conditions. Moreover, it was concluded that
TEG is predictive of clinical hemorrhage in neonates undergoing ther­
apeutic hypothermia and can be considered as the optimal method for
monitoring coagulation in this subgroup. Changes in ROTEM parame­
ters were observed in neonates with respiratory distress syndrome, with
a hypocoagulable profile and hyper-fibrinolytic capacity in comparison
to healthy neonates [108].
TEG has also been investigated in neonates with sepsis. TEG pa­
rameters exhibited better diagnostic sensitivity for sepsis compared to
leukocyte and platelet counts [109]. Neonates with confirmed sepsis
presented a hypocoagulable profile in ROTEM, while the degree of he­
mostatic derangement correlated with bleeding severity. Contrarily,

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R. Sokou et al.
neonates with suspected sepsis presented hypercoagulability, attributed
to the dynamic and changing hemostatic profile during inflammation
[69]. Thus, detection of hypocoagulability could help in the early
diagnosis and prompt management of sepsis. Lampridou et al. [67],
evaluated the diagnostic value of ROTEM in early detection of fibrino­
lysis disorders in septic neonates. There was no evidence of hyper­
fibrinolysis, but rather fibrinolysis shutdown in this population.
However, the clinical utility of LI60 and ML in discriminating between
neonates with confirmed and suspected sepsis and healthy neonates and
in predicting the outcome was limited. Fibrinolysis shutdown has also
been detected by ROTEM LI parameters in adult patients as part of the
host response to severe infection [110,111]. Neonatal sepsis is one of the
predominant causes of morbidity and mortality in NICUs. It may present
with mild or non-specific symptoms often attributed to non-infective
conditions. Prognosis and outcome of septic neonates are aggravated
with the establishment of DIC or multisystemic failure. Identification of
diagnostic criteria allowing for early diagnosis of neonatal sepsis is of
the utmost importance. In this context, the same research team created
and validated a diagnostic model applied to neonates with suspected
sepsis [112]. The strongest predictors that were included in the NeoSeD
(Neonatal Sepsis Diagnostic) model were gestational age, CRP, skin
discoloration, liver enlargement, neutrophil left shift, and ROTEM
ЕХΤЕМ А10. NeoSeD showed excellent discriminating capacity in
identifying sepsis and septic shock, which was significantly higher than
Töllner and nSOFA scores. Decision curve analysis demonstrated the
superiority of NeoSeD among all the strategies that were evaluated.
Although external validation is required before clinical application,
NeoSeD seems as a practical, feasible tool for accurate and timely
diagnosis of sepsis in neonates with clinical suspicion [112].
A large, longitudinal study assessed the hemostatic state of 423 ill
neonates in NICU with ROTEM [113]. A hypocoagulable profile in
EXTEM at disease onset emerged as an independent risk factor for in-
hospital mortality, possibly due to overconsumption of coagulation
factors and platelets.
Furthermore, incorporating ROTEM variables (ЕХΤЕМ А10) in
already established disease severity scores for ill neonates (SNAP II,
SNAPPE II) that do not include coagulation parameters enhance their
prognostic value for in-hospital neonatal mortality [114]. ROTEM pa­
rameters detected differences in hemostatic status between survived and
deceased septic neonates, and they had also a good predictive ability for
in-hospital mortality in this delicate population [115]. In neonates,
expression of hemostatic disorders may range from mild to severe and
life-threatening. Therapeutic management of hemostatic disorders in
neonates lacks robust evidence and guidelines. The primary target
should be to prevent major hemorrhagic events, and especially, intra­
ventricular hemorrhage (IVH) in preterm neonates. Since platelets play
a significant role in primary hemostasis, thrombocytopenia is a main risk
factor for hemorrhage [116]. The prevalence of thrombocytopenia is
estimated between 1% and 5% in general neonatal population, rises to
22–35% of neonates in NICUs, and reaches 70% in neonates with birth
weight < 1000 g [117]. Therefore, platelets are the second most often
transfused blood analogue in neonates, following red blood cells (RBC).
Thrombocytopenia may be a risk factor for hemorrhage, however, a
correlation between severity of thrombocytopenia and clinical presen­
tation of hemorrhage has not been confirmed. Additional risk factors,
including prematurity (gestational age lower than 28 weeks), postnatal
age (lower than 10 days), and comorbidity (necrotizing enterocolitis and
sepsis) are stronger prognostic factors of hemorrhage compared to
platelet count [116,117]. VCTs, like TEG/ ROTEM, reflecting the func­
tional dynamic of platelets more accurately than their count, compre­
hensively assess the hemostatic profile of patients (both adults and
children) and may enhance prediction of hemorrhagic risk [118]. The
role of ROTEM, and specifically its parameters expressing clot elasticity
(MCE) and platelet component (PLTEM MCЕ and PLTEM MCF), for
prediction of hemorrhagic events in thrombocytopenic neonates has not
been extensively studied. In a recent study, EXTEM A5 and EXTEM A10
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emerged as strong prognostic factors of hemorrhage in thrombocyto­
penic, critically ill neonates [119]. This can be attributed to the fact that
these parameters incorporate the contribution of platelet count and
functionality, fibrinogen concentration, fibrin polymerization, and fac­
tor XIII participation in the clot stability [120,121].
ROTEM NATEM is considered very sensitive to endogenous coagu­
lation activators, like tissue factor and circulating monocytes in patients
with sepsis, liver cirrhosis, or trauma. It can also detect coagulation
disorders not diagnosed by EXTEM/ INTEM [122]. The discriminating
capacity of NATEM compared to EXTEM in predicting the risk of hem­
orrhage was evaluated in ill neonates. Both ROTEM EXTEM and NATEM
parameters demonstrated a hypocoagulable profile in neonates with
clinical bleeding. NATEM test seems to be a sensitive prognostic tool of
hemorrhage in ill neonates, even superior to EXTEM test in certain pa­
rameters [123,124]. The establishment of an index for prediction of
hemorrhage that could simultaneously assess the severity of hemor­
rhagic events in ill neonates may help in timely diagnosis of hemostatic
disorders, in prompt decision making, and in targeted therapeutic
intervention. Several models have been developed for prediction of
hemorrhage risk in neonates, with most of them being based mainly on
clinical variables without taking into account the progress and hemo­
static profile of neonates [125–129]. Recently, EXTEM A10 and LI60,
platelet count, and serum creatinine levels were identified as the
strongest predictors of hemorrhage and were included in the NeoBRis
(Neonatal Bleeding Risk) prediction model. The model performance was
excellent [130,131]. NeoBRis seems promising and after its external
validation it could enable the quantification of the immediate risk of
hemorrhage in neonates and the development of individualized thera­
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peutic strategies [130,131]. In a recent study, Raffaeli et al. [132]
showed that a Quality Improvement project based on TEG, staff training,
and transfusion algorithm led to the improvement of the hemostatic
management of surgical neonates by reducing intraoperative FFP
transfusion. Relevant information regarding the studies on VCTs use in
critical ill neonates is summarized in Table 2.
There is evidence that VCTs have advantages versus conventional
coagulation tests and can contribute to the reduction of transfusion re­
quirements in adults or children with bleeding [133,134]. ROTEM may
become a valuable tool and a first-line method for evaluation of neonatal
hemostasis.
5. The calibrated automated thrombogram (CAT)
This is a method for global assessment of hemostasis, which evalu­
ates the endogenous thrombin potential (ETP). A specific activator
(usually tissue factor and Ca++) is added to patient plasma and the
generated thrombin is measured through enzymic modification of a
substrate by produced thrombin [135]. CAT is conducted in platelet-
poor plasma (PPP) or platelet-rich plasma (PRP). In PRP, CAT can
evaluate the contribution of platelet count and functionality in thrombin
generation [136].
The method is conducted in calibrated automated analyzers
(thrombograms) and records 4 parameters:
1) the Lag Time, time from the test initiation until the generated
thrombin reaches 10 nM
2) the Peak Thrombin, the maximum amount of generated thrombin
3) the Time To the Peak (ttpeak) of generated thrombin
4) the ETP, the AUC, representing the total amount of thrombin
generated during the coagulation process. ETP is the best index for
prediction of hemorrhage or thrombosis [137].
5.1. Hemostatic assessment in healthy neonates with the use of CAT
Six studies have used PPP CAT to evaluate thrombin generation in
full-term neonates and compare it with adults [138–143]. The findings
R. Sokou et al. Blood Reviews xxx (xxxx) xxx
T.ME/NEONATOLOGY
Table 2
Studies investigated the use of viscoelastic methods in critical ill neonates.
Author (Year) Country Study design Study aim Study population Method Coagulation Conclusions
variables evaluated

Neonates undergoing cardiothoracic operations and ECMO

To evaluate if the
incorporation of a
comprehensive ECMO
Northrop anticoagulation laboratory
Prospective
et al., 2015 USA protocol following anti Xa
cohort
[102] levels, antithrombin levels,
and thromboelastography
would lead to fewer
hemostatic complications.
To investigate if conventional
coagulation tests and ROTEM
Kim et al., Retrospective variables could predict
Korea
2016 [98] observational perioperative excessive blood
loss after congenital cardiac
surgery.
To assess whether ROTEM
guided transfusion algorithms
Scott et al., Prospective
USA could be effective in the
2018 [97] cohort
reduction of neonatal peri-
CPB bleeding.
To investigate the correlation
between TEG and
conventional coagulation
tests, and to determine
Henderson Retrospective, optimum cut-off values for
The incorporation of
ACT, platelet count, antithrombin levels and
366 children prothrombin time, thromboelastography were
TEG
undergoing ECMO INR, aPTT, TEG found to be promising for the
variables. management of patients on
ECMO.
Prothrombin
119 infants and time, INR aPTT, Post-CPB FIBTEM-A10 and
children younger than platelet EXTEM-A10 variables were
10 years old count, fibrinogen found promising tools for
ROTEM
undergoing CHD concentration, A10, guiding intraoperative
surgical intervention A20, MCF and ML transfusion in congenital
with CPB. variables of EXTEM cardiac surgery.
and FIBTEM assays.
ROTEM parameters during
EXTEM A10 and neonatal cardiac surgery were
44 neonates MCF, FIBTEM A10 found sensitive and specific
ROTEM
undergoing CPB and MCF, PltemA10 for the identification of
and PltemMCF thrombocytopenia and
hypofibrinogenemia.
Anti-Xa activity of 0.25 units
238 pediatric and ACT, aPTT, and a TEG RCK of >17 min

t.me/neonatology
et al., 2018 USA single-center TEG RCK time and anti-Xa neonatal patients who TEG fibrinogen, anti-Xa, minimize the risk of
[101] coohort activity in an effort to received ECMO and TEG RCK. thrombosis in pediatric and
minimize bleeding and neonatal ECMO patients.
thrombotic complications in
pediatric and neonatal
patients requiring ECMO.
Neonates with perinatal hypoxia
TEG is predictive of clinical
hemorrhage in neonates
To investigate the effects of undergoing therapeutic
Forman 24 hypoxic neonates
Prospective therapeutic hypothermia on R, K, LY30, MA, α hypothermia and can be
et al.,2014 USA undergoing therapeutic TEG
cohort the hemostatic status of angle and CI considered as the optimal
[107] hypothermia
neonates with HIE using TEG. method for monitoring
coagulation in this
population.
Neonates with perinatal
asphyxia and mild hypoxia or
To assess the hemostatic EXTEM variables fetal distress presented a
Konstantinidi profile of neonates with 164 neonates with (CT, CFT, A10, A20, hypocoagulable profile,
et al., 2020 Greece Case-control perinatal hypoxia/ asphyxia perinatal asphyxia and ROTEM A30, α angle MCF, demonstrated by prolonged
[61] comparing with healthy 273 healthy neonates LI60) and platelet CT and CFT and reduced A10,
neonates using ROTEM count A20, A30, α angle and MCF, in
comparison to healthy
neonates.
Neonates with respiratory distress syndrome
EXTEM, INTEM, and
Neonates with RDS presented
FIBTEM variables
To evaluate the hemostatic 48 neonates with RDS a hypocoagulable profile and
Katsaras et al., Prospective (CT, CFT, A10, A20,
Greece status of neonates with RDS and 282 healthy ROTEM hyper-fibrinolytic capacity in
2021 [108] observational A30, α angle MCF,
using ROTEM neonates comparison to healthy
LI60) and platelet
neonates.
count
Neonates with sepsis
43 sick neonates (16
To assess sepsis associated non septic, 12 with TEG parameters exhibited
R, K, and MA
Grant et al., South changes in TEG and evaluate confirmed sepsis, and better diagnostic sensitivity
Case-control TEG variable of TEG and
1997 [109] Africa if TEG variables could be used 15 with suspected for sepsis compared to
platelet counts.
as biomarker for early sepsis. sepsis) and 60 healthy leukocyte and platelet counts.
neonates
EXTEM variables A hypocoagulable profile, was
91 neonates (confirmed
To evaluate the hemostatic (CT, CFT, A10, A20, found among septic neonates
Sokou et al., sepsis: 35, suspected
Greece Case-control profile of neonates with ROTEM A30, α angle MCF, while hypercoagulability was
2017 [69] sepsis: 56) and 274
confirmed or suspected sepsis. LI45, LI60) and noted in neonates with
healthy neonates
platelet count. suspected sepsis.
(continued on next page)

T.ME/NEONATOLOGY
6

t.me/neonatology
R. Sokou et al.
Table 2 (continued )
Author (Year) Country Study design Study aim
Lampridou Greece Case-control To evaluate the diagnostic
et al., 2020 value of ROTEM in early
[67] detection of fibrinolysis
disorders in septic neonates.
Sokou et al., Greece Retrospective To develop and validate a
2022 [112] cohort diagnostic model applied to
neonates with suspected
sepsis, by incorporating
ROTEM parameters,
maternal/neonatal risk
factors, clinical signs/
symptoms and laboratory
variables
Viscoelastic test in predicting morbidity and mortality in critical ill neonates
To assess the hemostatic state
in neonatal critical illness
Sokou et al., using ROTEM, and to
Greece Cross-sectional
2021 [113] investigate the prognostic role
of ROTEM parameters in this
clinical setting.
To assess whether the
addition of ROTEM
parameters to already
Sokou et al., Retropective established neonatal disease
Greece
2022 [114] cohort scoring systems could further
improve their prognostic
accuracy for in-hospital
neonatal mortality.
To evaluate the role of
ROTEM assays in the
Sokou et al., Retrospective
Greece prediction of in-hospital
2023 [115] cohort
mortality of neonates with
sepsis.
Viscoelastic test in predicting bleeding risk in critical ill neonates
To investigate the role of
ROTEM, and specifically its
parameters expressing clot
Parastatidou
Prospective elasticity (MCE) and platelet
et al., 2021 Greece
cohort component (Pltem MCЕ and
[119]
Pltem MCF), for prediction of
hemorrhagic events in
thrombocytopenic neonates
Sokou et al., Prospective To develop and internally
Greece
2021 [130] cohort validate a prediction model
t.me/neonatology
Blood Reviews xxx (xxxx) xxx
Study population Method Coagulation Conclusions
variables evaluated
66 neonates (44 with ROTEM EXTEM and APTEM There was no evidence of
confirmed sepsis, 22 variables (CT, CFT, hyperfibrinolysis, but rather
with suspected sepsis) A10, A20, and A30, fibrinolysis shutdown in
and 110 healthy α angle, MCF, LI 60, septic neonates. The clinical
neonates ML) and platelet utility of LI60 and ML in
count discriminating between
neonates with confirmed and
suspected sepsis and healthy
neonates and in predicting the
outcome was limited.
291 neonates with ROTEM EXTEM variables NeoSeD showed excellent
presumed sepsis (CT, CFT, A10, A20, discriminating capacity in
A30, α angle MCF, identifying sepsis and septic
LI45, LI60) and shock, with AUC of 0,918
platelet count (95% CI, 0,884–0,952) and
0,974 (95% CI, 0,958–0,989),
respectively, which was
significantly higher than
Töllner and nSOFA scores.
Decision curve analysis
demonstrated the superiority
of NeoSeD among all the
strategies that were
evaluated.
A hypocoagulable profile in
EXTEM assay at disease onset
emerged as an independent
risk factor for in-hospital
EXTEM variables mortality. Among ROTEM
t.me/neonatology
(CT, CFT, A10, A20, parameters, CT and A10
423 critically ill
ROTEM A30, α angle MCF, exhibited the best prognostic
neonates
LI60) and platelet value for survival (AUC =
count 0.781; 95%CI:0.697–0.862,
and AUC = 0.761; 95%
CI:0.667–0.856, respectively),
with optimal cut-off values
CT ≤ 62 s and A10 ≥ 38 mm.
Incorporating ROTEM
variables (ЕХΤЕМ А10) in
EXTEM variables already established disease
(CT, CFT, A10, A20, severity scores for ill neonates
473 critically ill
A30, α angle MCF, (SNAP II, SNAPPE II) that do
neonates
LI60) and platelet not include coagulation
count parameters enhance their
prognostic value for in-
hospital neonatal mortality
Among all ROTEM
parameters, INTEM MCF
demonstrated the best
prognostic performance for
NICU mortality in septic
neonates (AUC = 0.731; 95%
EXTEM and INTEM CI: 0.593–0.869), with an
variables (CT, CFT, optimal cut-off value for MCF
129 neonates with
ROTEM A10, A20, A30, α < 40 mm for the prediction of
confirmed sepsis
angle MCF, LI60) mortality. The mortality risk
and platelet count for septic neonates was 8.5%
(95% CI: 4.7–15.4) per 10
days after sepsis onset for
INTEM MCF value<40 mm,
and 1.4% (95% CI: 0.7–2.8)
for INTEM MCF value≥40
mm.
Among ROTEM variables
EXTEM and FIBTEM
quantifying clot elasticity and
parameters: CT,
platelet component, EXTEM
CFT, A10, A20, A30,
110 thrombocytopenic A5 and EXTEM A10 emerged
ROTEM α angle MCF, LI60,
critically ill neonates as strong prognostic factors of
ML; Pltem MCF and
hemorrhage in
Pltem MCE) and
thrombocytopenic critically
platelet count
ill neonates.
332 critically ill ROTEM EXTEM, EXTEM A10 and LI60, platelet
ROTEM
neonates. INTEM, and FIBTEM count, and serum creatinine
(continued on next page)
R. Sokou et al. Blood Reviews xxx (xxxx) xxx

Table 2 (continued )
Author (Year) Country Study design Study aim Study population Method Coagulation Conclusions
variables evaluated

for hemorrhagic risk in parameters: (CT, levels were identified as the

critically ill neonates by CFT, A10, A20, A30, strongest predictors of
combining ROTEM α angle MCF, LI60, hemorrhage and were
parameters and clinical ML) and platelet included in the NeoBRis
variables. count prediction model. The model
performance was excellent,
with AUC 0.908 (95%
CI:0.870–0.946).
Sokou et al., Greece Prospective To perform a prospective 137 critically ill ROTEM ROTEM EXTEM, The temporal validation has
2021 [135] cohort temporal validation of neonates. INTEM, and FIBTEM confirmed excellent
NeoBRis index. parameters: (CT, performance of NeoBRis with
CFT, A10, A20, A30, AUC 0.938 (95% CI:
α angle MCF, LI60, 0.874–0.999).
ML) and platelet
count
Sokou et al. Greece Prospective To investigate the 158 ill neonates ROTEM EXTEM and NATEM Using optimal cut-off values
2023 [123] cohort discriminative power of variables: (CT, CFT, for prediction of hemorrhage,
NATEM parameters in A10 α angle MCF, NАΤЕМ CFT and A10
predicting the risk of bleeding LI60, ML) and demonstrated the highest
in critically ill neonates platelet count prognostic value among all
ROTEM parameters. NATEM
CFT ≥ 147 s had a 95.2%
sensitivity and a 65.6%
specificity in detecting
neonates with clinical
bleeding, while NATEM A10
≤ 42 mm had an 80.8%
sensitivity and 76.0%
specificity
Raffaeli et al., Italy Retrospective To assess the effect of a TEG- 139 neonates TEG Prothrombin time, The Quality Improvement

2022 [132] pre-post based Quality Improvement
implementation Project (here called
intervention) on FFP
transfusion of neonates
undergoing surgery.
undergoing major non-
cardiac surgery
t.me/neonatology
fibrinogen, aPTT, project based on TEG, staff
platelet count, R and training, and transfusion
MA algorithm led to the
improvement of the
hemostatic management of
surgical neonates by reducing
intraoperative FFP
transfusion.

Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; CDH; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane
oxygenation; HIE, hypoxic- ischemic encephalopathy; NeoBris, Neonatal Bleeding Risk; NeoSeD, Neonatal Sepsis Diagnostic score; nSOFA, Neonatal Sequential Organ
Failure Assessment; RDS, respiratory distress syndrome; SNAP, score for neonatal acute physiology; SNAPPE, score for neonatal acute physiology with perinatal
extension; TEG (thromoelastography): R, reaction time; K, kinetics; α, slope between R and K; MA, maximum amplitude; CL, clot lysis; CI, coagulation index, LY, lysis
index; TEG RCK, citrated kaolin TEG R time; ROTEM (rotational thromboelastometry):APTEM, extrinsically activated assays with addition of aprotinin; EXTEM,
extrinsically activated ROTEM assay; INTEM, intrinsically activated; FIBTEM, fibrin-based extrinsically activated; NATEM, non-activated rotational ROTEM assay; CT,
clotting time; CFT, clot formation time; α, slope of tangent at 2 mm amplitude; MCF, maximal clot firmness; LI, lysis index; ML, maximum lysis; MCE, clot elasticity;
Pltem, platelet-specific ROTEM variables calculated by subtracting the FIBTEM from the EXTEM clotting variables.

indicated accelerated lag time and ttpeak in neonates. On the other
hand, neonates demonstrated significantly reduced ETP and peak
thrombin compared to adults in all but 1 study [141]. Similar results
were reported in studies with PRP CAT [144].
Shorter lag time and ttpeak in neonates exhibit a state of hyperco­
agulability that could be attributed to lower levels of TFPI. Contrarily,
lower ETP and peak thrombin values, due to reduced levels of procoa­
gulant factors (in particular, factor II- prothrombin) indicate a hypo­
coagulable state which could be further counterbalanced by the low
concentrations of anticoagulants (like antithrombin) in neonates
[21,142]. Evidence suggests that despite the low concentration of pro­
coagulant proteins, physiological low levels of antithrombin allow
adequate formation of thrombin in cord blood plasma following acti­
vation with lipidated tissue factor [21]. Therefore, and although pro­
thrombin and thrombin levels are lower, full-term and preterm neonates
have a functionally adequate hemostatic system.
Three studies compared CAT parameters in PPP of preterm and full-
term neonates. Newborns >30 weeks had ETP values higher than full-
term neonates [145]. More recently, Tripodi et al. [146], evaluated
thrombin formation in peripheral blood of VLBW <1500 g. VLBW ne­
onates had higher ETP than full-term neonates. However, neonates <30
weeks had significantly lower ETP than preterm neonates >30 weeks; no
comparison between this group and full-term neonates was provided.
Thrombin generation was higher in preterm compared to full-term ne­
onates at birth, and remained high throughout the first month of life.
Moreover, there was no difference in ETP values between SGA and AGA
neonates. This corroborates the findings by Sokou et al. on ROTEM [68].
Furthermore, using thrombomodulin, the main cofactor for protein C
pathway, the authors concluded that ETP following thrombomodulin
addition was higher in preterm neonates, indicating resistance to protein
C and a procoagulant proclivity [146]. This procoagulant imbalance in
plasma of preterm neonates could predispose to IVH, through increased
risk of venous infract and hemorrhage [147]. Interestingly, there are
data describing high risk of IVH in case of hereditary thrombophilia
[148]. The effect of neonatal and adult platelets on thrombin generation
have also been studied using CAT. Bernhard et al. compared CAT pa­
rameters in PPP of 12 adult- neonate pairs after the addition of neonatal
platelets and after the addition of adult platelets [149]. Their findings
show a similar impact on thrombin generation for both adult and
neonatal platelets. Schlagenhauf et al. demonstrated that following
stimulation, neonatal platelets release less inorganic polyphosphates, a
procoagulant factor deriving from activated platelets [141]. CAT in
neonatal PPP showed decreased impact of exogenous polyphosphates on
thrombin generation parameters, but their effect was greater on lower

T.ME/NEONATOLOGY
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R. Sokou et al.
concentrations compared to adults. Lower TFPI levels rendered neonates
more sensitive to the effect of polyphosphates, limiting their potential
consequences.
5.2. Hemostatic assessment in different clinical settings with the use of
CAT
Numerous studies have assessed the role of CAT parameters as
prognostic factors for hemorrhage in adults [150,151]; however, rele­
vant data in neonates are scarce. Peterson et al., reported that CAT failed
to predict postsurgical hemorrhage following CPB [152]. Tripodi et al.
found no difference in ETP measurements at birth between VLBW who
did and those who did not develop IVH [146]. Similarly, Neary et al. did
not observe differences in thrombin generation parameters in neonates
with severe (or any grade) IVH and neonates without IVH [153]. At
present, the clinical application of CAT in neonates is limited by the lack
of evidence on the role of CAT on hemorrhage prediction.
Two studies assessed thrombin generation in neonates before and
after CPB [138,154]. Their findings demonstrated prolongation of lag
time and increase of peak thrombin after CPB. Peterson et al. [152],
evaluated CAT parameters in PRP in comparison with other coagulation
tests in neonates undergoing CPB. CAT results were compared with
thrombin-initiated fibrin clot kinetics (TFCK). Thrombin peak was
inversely associated with high TFCK values (blood samples with higher
heparin activity).
Preterm neonates are in risk of cholestasis due to prolonged paren­
teral nutrition. Cholestasis reduces the absorption of vitamin K, and
subsequently, K-dependent coagulation factors. It was hypothesized that
neonates with intestinal failure- associated liver disease may have
impaired thrombin generation [155]. CAT was conducted in PPP at
birth, and on day 30, in the presence of thrombomodulin. Although
conventional coagulation tests were prolonged in neonates with liver
disease, no difference was observed in ETP between the 2 groups in any
time period.
5.3. CAT as a preclinical method for the evaluation of hemostatic effect of
medication in neonates
CAT is a useful tool for the detailed assessment of neonatal hemo­
static process and the detection of respective differences with adults.
CAT can diagnose both hypo- and hyper- coagulability reliably and
repeatedly [136]. CAT has been used as a preclinical method for the
evaluation of potential hemostatic effect of medicines in neonates.
The impact of ex vivo addition of Novo- Seven® (recombinant factor
VIIa) or prothrombin-3 factors complex concentrate (3f-PCC, including
FII, FIX, FX, and a small amount of FVII) in PPP of full-term neonates
following CPB has been evaluated [154]. NovoSeven® reduced lag time,
whereas 3f-PCC significantly increased the peak thrombin and velocity
index above the levels prior to CPB.
Franklin et al. [138], studied the effect of 2 different prothrombin
complex concentrates (4f-PCCs), one with factor VII and the other with
factor VIIa, in PPP of neonates who had undergone CPB [19]. While both
concentrates increased the peak thrombin and velocity index, only the
concentrate with factor VIIa decreased the lag time in the prior CPB
levels. Lower doses of both drugs that were tested were adequate for
enhancing thrombin generation in neonates. Due to a high frequency of
reported thrombotic adverse events after the administration of NovoS­
even® in the neonatal population, its effect on PRP cord and adult blood
samples was investigated [144,156]. NovoSeven® altered clot dy­
namics. It did not change ETP in any group, however, it reduced the lag
time and ttpeak in both groups, while peak thrombin was decreased only
in the neonatal group. Lower neonatal TFPI and prothrombin levels
possibly result in higher prothrombin rate converted from recombinant
factor VIIa to thrombin. Thus, less prothrombin is left for maximum
thrombin generation through factor VIII/ factor IX. The in vitro effect of
recombinant factor VIIa in vitro did not seem to depend on platelets.
t.me/neonatology
Blood Reviews xxx (xxxx) xxx
Additionally, the dose response to recombinant factor VIIa was com­
parable between neonatal and adult PRP.
Although CAT results cannot replace RCTs findings in evaluating
clinical effects of hemostatic medications, it provides useful information
on the impact of these treatments on neonatal coagulation.
CAT may be a valuable method for the assessment of the function­
ality of specific coagulation plasma proteins, however it has several
pitfalls. It requires manual preparation of plasma and addition of re­
agents. The reagents can be prepared before analysis or be purchased,
which is more costly. Moreover, CAT needs software and equipment that
are usually not available in clinical laboratories. There are challenges
with the interchangeability- variability of results between different
laboratories, especially with preanalytical steps and standardization of
reagents. However, studies have shown acceptable interchangeability
when standardized protocols are followed [157,158]. CAT does not
assess primary hemostasis, or the effect of red or white blood cells, of
vascular endothelium, or of blood flow on secondary hemostasis.
Presently, neonatal reference ranges or algorithms guiding trans­
fusion therapy based on evidence from CAT do not exist. This method is
only used as a research tool and not in clinical practice, and relevant
studies are still lacking.
6. Discussion
Results of laboratory tests are crucial for clinical decisions, accurate
diagnosis, and the choice of the most appropriate treatment option for
patients with hemostatic disorders. The overall quality of laboratory
testing encompasses patient identification, proper test orderings and
t.me/neonatology
extends to prompt and effective communication of the results to clini­
cians, the “brain-to-brain loop” phenomenon, introduced by Lundberg
in 1980 [159].
Long-standing experience supports the idea that most diagnostic
errors occur before the analysis (preanalytical phase) or after it (post­
analytical phase), namely during reporting and interpretation of test
results [160].
The accuracy in analysis of blood samples is important for diagnosis
and therapeutic management of neonatal hemostasis. In this age group,
particular caution should be exerted to preanalytical factors [17,161],
which entail procedural aspects of blood collection, including the size
and type of needle used. The external coagulation pathway can be
activated by a difficult venipuncture, and prolonged tourniquet pressure
may also initiate hemostasis.
The accuracy of laboratory testing relies on the quality of the blood
sample and the tubes. A blood to anticoagulant ratio of 9:1 should be
achieved. Insufficient blood sample provides unreliable results, with
prolongation of PT and aPTT. In case of polycythemia, plasma is rela­
tively decreased and the anticoagulant is relatively increased compared
to plasma proteins in the tube, leading to prolonged PT and aPTT [162].
Hemolyzed, jaundiced or lipemic blood samples are also unsuitable.
Handling the blood sample appropriately is necessary for accurate
results. The samples should be slightly inverted, while exposure to
extremely low temperatures must be avoided. Measurements should be
conducted shortly after blood collection, otherwise the samples need to
be appropriately handled and stored [163]. Factor VII may be activated
after the sample has remained at low temperature, causing shortened PT
[164].
The practical challenges of blood drawing in neonates have been
thoroughly investigated.
The erroneous choice of laboratory testing for each patient is one of
the most frequent clinical mistakes and may result in suboptimal treat­
ment interventions. For example, conducting conventional coagulation
testing routinely upon NICU admission seems to lead to increased
administration of FFP without proven benefit [42].
Laboratory aspects of the analysis, including the choice of analyzer,
are equally important. Laboratories of NICUs may need to have access to
specialized systems and equipment for the analysis of neonatal blood
R. Sokou et al. Blood Reviews xxx (xxxx) xxx

samples [13,165]. Laboratory diagnosis of hemostatic disorders can be
demanding, as the tests need to be adapted to small blood samples [17].
Retaining the integrity of the blood sample is another issue in neonatal
coagulation studies and the repeatability of measurements is crucial for
prevention of erroneous results [165,166].
Overdiagnosis and misdiagnosis are common when age-specific
reference analyzer and reagents are not used. The maturation of the
hemostatic system in children is complex, with qualitative and quanti­
tative differences dependent on age. Our knowledge on neonatal he­
mostasis has advanced significantly over the last years. However, there
are still unaddressed concerns; like the role of vascular endothelium,
which is usually ignored, despite evidence of its contribution in regu­
lating several hemostatic procedures.
Frequently, the “prolongation” of PT and aPTT in neonates compared
to adult values has been interpreted as a hemostatic deficit, which has
resulted in FFP transfusions to preterm neonates with “abnormal” values
in an effort to prevent bleeding, particularly IVH [167]. “Prolonged” PT
and aPTT in neonates when compared to adults should not be regarded
as a developmental defect or a hemorrhagic inclination, but rather a
reflection of age-dependent hemostatic adaptation [42,168]. Data
derived from VCTs and corroborated by CAT indicate a faster coagula­
tion initiation and propagation. These results confirm the develop­
mental, stage-specific nature of hemostasis. Differences in conventional
coagulation tests, VCTs, and CAT parameters between preterm and full-
term neonates and adults are outlined in Table 3.
Studies concerning conventional coagulation tests reported that
although these tests provide important information regarding the acti­
vation of blood coagulation and consumption of coagulation factors,
management of hemostatic disorders in neonates.
To overcome these limitations, the development of techniques that
eliminate handling and processing of the sample and the introduction of
automized analyzer systems that contribute to the reduction of pre­
analytical variability should be encouraged.
Furthermore, differential diagnosis of hemostatic disorders in neo­
nates is extensive. Therefore, a comprehensive understanding of their
development, risk factors, and underlying pathophysiology is essential
for the optimal therapeutic approach. More sensitive coagulation tests
and novel diagnostic and monitoring methods for transfusion therapy in
neonatal population are required.
Developmental hemostasis which significantly implicates in the
diagnosis of neonatal hemostatic derangement, along with other
comorbidities as well as the clinical status of neonates further compli­
cate the assessment of hemostatic profile in this delicate population.
It is obvious that no coagulation variable by itself is so robust to
diagnose or predict nor the risk of hemorrhagic/thrombotic events no
the outcome of critically ill neonates.
Finally, the establishment of a prognostic index for hemorrhage or
thrombosis in neonates based on clinical variables and taking into ac­
count the disease progress and the hemostatic profile of neonates should
be considered as a prerequisite for the timely diagnosis of hemostatic
disorders, prompt decision making, and targeted therapeutic
intervention.
Practice points
• Assessment of the hemostatic profile of neonates routinely begins

their diagnostic value is ambiguous, and also present limitations in their
capacity to predict bleeding risk and guide transfusion therapy in neo­
nates [42,46–50]. Despite these limitations, the conventional coagula­
tion tests are widely used in NICUs to evaluate neonatal hemostatic
status and guide transfusion practices. According to the currently
available data, VCTs comprehensively reflect hemostatic disorders in
various neonatal clinical settings and seems to predict risk of hemor­
rhage in ill neonates [112,113,115,119,123,130,169]. Transfusion al­
gorithms based on VCTs are applied in adult and pediatric patients,
demonstrating improved bleeding management and use of blood prod­
ucts [133,134,170]. Relevant data and experience in neonates is scarce.
CAT, although promising, is still experimental and studies on its use in
NICUs clinical practice are lacking. The quest for the optimal tool for
assessment of the neonatal hemostatic system is still inconclusive.
Available testing methods differ in advantages and limitations, which
are summarized in Table 4. No head-to-head comparison of the clinical
value of the different tests has been conducted in neonates to date.
7. Future considerations
The interpretation of coagulation tests in neonates remains a chal­
lenge. Practical difficulties of blood collection, preanalytical and post­
analytical errors, and the need to establish age-specific reference ranges
for coagulation tests by each laboratory, complicate the diagnosis and
t.me/neonatology
with traditional coagulation tests, which are in vitro plasma tests that
solely assess involvement of procoagulant factors, without esti­
mating the role of anticoagulant factors and cellular components in
hemostasis. Partially assessing the hemostatic system, conventional
tests fail to provide information regarding platelet function and
fibrinolysis.
• VCT tests represent diagnostic methods with the potential to over­
come some of the limitations of conventional coagulation tests. Low
volume of whole blood is required, while the results outline a
comprehensive assessment of coagulation and fibrinolysis
mechanisms.
• There is evidence that ROTEM as a VCT test has advantages versus
conventional coagulation tests in adult and pediatric patients.
Whether VCTs could become first-line tools for evaluation of
neonatal hemostasis contributing to the reduction of transfusion re­
quirements remains at question.
• CAT may be a valuable method for assessing the functionality of
specific coagulation plasma proteins, however it does not assess
primary hemostasis, or the effect of red or white blood cells, of
vascular endothelium, or of blood flow on secondary hemostasis. In
neonates CAT is only used as a research tool and not in clinical
practice.

Table 3
Differences in conventional tests, viscoelastic tests, and calibrated automated thrombogram between preterm neonates, full-term neonates, and adults.
Conventional tests Viscoelastic tests Calibrated automated thrombogram

Parameters Preterm vs Neonates vs older Parameters Preterm vs Neonates vs older Parameters Preterm vs Neonates vs older
term neonates children/adults term neonates children/adults term neonates children/adults

aPTT Longer Longer Clotting time Same Shorter Lag Time Shorter Shorter
Prothrombin Clot formation Peak Higher or
Longer Same or longer Same Shorter Reduced
time time Thrombin similar
Similar or Time To the
INR Higher Same or higher Clot amplitude Stronger Shorter Shorter
lower Peak
Lysis index Thrombin Higher or
Thrombin time Longer Same or longer Lower Lower Reduced
(LY30, 60) potential similar

Abbreviations: Activated Partial Thromboplastin Clotting Time, aPTT; International Normalised Ratio, INR.

10

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R. Sokou et al. Blood Reviews xxx (xxxx) xxx

Table 4 • The erroneous choice of laboratory testing for each patient is one of
Differences between mostly used hemostatic testing methods. the most frequent clinical errors and may result in suboptimal
Conventional Thrombin Viscoelastic assays treatment interventions.
coagulation tests generation assays (VCTs)
(CCTs) (CAT) Research agenda
Provide
In vitro plasma
tests that solely
information • Further studying to improve our understanding of developmental
regarding the clot hemostasis and its reflection on everyday clinical practice is
assess involvement
formation and
of procoagulant A method for
lysis, allowing for
warranted.
coagulation global assessment • There is a need for more sensitive laboratory tests and novel tools for
monitoring of the
factors, without of hemostasis,
entire hemostatic the evaluation of the hemostatic status of neonates.
estimating the role which evaluates
of anticoagulant the endogenous
procedure. The • The development and validation of diagnostic and prognostic models
complex process of
factors and cellular thrombin for the assessment of the risk of hemostatic derangements in neo­
hemostasis with
Essence of components in potential. CAT
the interactions nates are required.
assay hemostasis. may be a valuable
between
Partially assessing method for the
the hemostatic assessment of the
procoagulant Declaration of Competing Interest
factors, fibrinolytic
system, functionality of
proteins, cellular
conventional tests specific
components, and
The authors declare that they have no conflict of interest.
fail to provide coagulation
platelets is
information plasma proteins.
depicted, Acknowledgment
regarding platelet
according to the
function and
cellular
fibrinolysis. The authors did not receive, for this research, any specific grant from
coagulation model.
Volume dependent funding agencies in the public, commercial, or not-for-profit sectors.
Volume dependent
on clinical case,
on the analyzer, but
Necessary
larger whole blood
but larger whole Whole blood References
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