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Journal of Pediatric and Neonatal Individualized Medicine 2022;11(2):e110231
doi: 10.7363/110231
Received: 2021 Jan 27; revised: 2021 Apr 11; accepted: 2021 Apr 13; published online: 2022 Jul 14

Review

Neonatal bleeding disorders.

A practical diagnostic approach
Georgios N. Katsaras, Dimitra Gialamprinou, Euthimia Papacharalampous,
Ilias Chatziioannidis, Georgios Mitsiakos

2nd Department of Neonatology and Neonatal Intensive Care Unit, Faculty of Medicine, Aristotle
University School of Health Sciences, Papageorgiou Hospital, Thessaloniki, Greece

Abstract

Since developmental hemostasis was introduced by Andrew et al. in

the early 90s, age-related variations in coagulation components have been
a well-established knowledge. In parallel with age-dependent hemostatic
status maturation, coagulation disorders assessment stands as an important
prerequisite for bleeding management. However, discrepancies observed
between neonatal coagulation reference ranges and standard coagulation
assays extrapolated from adults make neonatal disease evaluation and
therapeutic management challenging. This study aims to provide a
diagnostic approach to neonatal bleeding based on a current literature
search on bleeding disorders in the neonatal period.

Keywords

Developmental hemostasis, bleeding disorders, neonates, practical diagnostic

approach, reference ranges, diagnostic algorithm.

Corresponding author

Georgios Mitsiakos, 2nd Department of Neonatology and Neonatal Intensive Care Unit, Faculty of
Medicine, Aristotle University School of Health Sciences, Papageorgiou Hospital, Thessaloniki, Greece;
tel.:+30-697-472-9879; e-mail: mitsiakos@auth.gr.

How to cite

Katsaras GN, Gialamprinou D, Papacharalampous E, Chatziioannidis I, Mitsiakos G. Neonatal bleeding

disorders. A practical diagnostic approach. J Pediatr Neonat Individual Med. 2022;11(2):e110231. doi:
10.7363/110231.

Introduction

The hemostatic system is a complex protective pathway against bleeding that

begins as soon as an endothelial injury occurs and tissue factor (TF) is released.

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The formation of a strong clot induced by activated clinical signs and proper laboratory tests evaluation.
platelets and fibrinogen aims to stop bleeding. Bleeding in a healthy newborn is suggestive of an
Furthermore, the hemostatic system is protective underlying congenital coagulation dysfunction
against excessive fibrin formation and deposition, or a quantitative coagulation defect, whereas a
mainly by the inhibitory function of antithrombin sick premature neonate is more likely to suffer
and protein C. Fibrinolysis is an additional protective from an acquired coagulation disorder, presented
mechanism regarding the appropriate dissolution of the detrimental as DIC. A positive family history
clot. Otherwise, the hemostatic system prevents both could be indicative of congenital coagulation factor
bleeding and thromboembolic events in a complex but deficiency, while obstetric complications and events
well-balanced way, which is extended equally from during labor may also affect the fetal hemostatic
the early neonatal period to later childhood and adult system, resulting in coagulation activation and DIC.
life [1]. Finally, medication ad­ministered to the mother by
Bleeding disorders are scarcely reported in the interfering with vitamin K metabolism is strongly
overall neonatal population, but, as commonly associated with bleeding events in the neonatal
observed among hospitalized neonates, they pose a period (Tab. 1) [9, 10].
great challenge to the treating physician. Published Regarding the laboratory tests, activated partial
studies have shown an incidence of 0.3% for thromboplastin time (aPTT), prothrombin time
bleeding disturbances in neonatal life [2]. Even (PT) or international normalized ratio (INR),
though thrombocytopenia is the most common complete blood count (CBC) along with PLT,
cause of disorders pertained to primary hemostasis, fibrinogen and D-dimers should be included
bleeding intension is equally observed at hemostasis [11]. Reference ranges instead of normal values
dysregulation other than low platelet count (PLT). concerning coagulation components in full-term
Major or minor bleeding occurs in hospitalized and preterm neonates have been published by
neonates, mostly secondary due to acquired rather few investigators according to gestational age.
than congenital disorders in hemostasis [3]. Since However, institutional reference ranges have
congenital coagulation factor deficiency is rarely been established based on particular reagent and
recorded, causative agents of acquired coagulation analyzer settings which may widely vary among
deficiency, such as liver failure or disseminated research centers. The latter make reference values
intravascular coagulation (DIC) due to sepsis or not easily manageable for other institutes (Tab. 2)
asphyxia, have become prominent in Neonatal
Intensive Care Units (NICUs). Consequently, a proper
Table 1. Possible causes of bleeding according to family,
diagnosis of the underlying cause is challenging obstetric, perinatal and postnatal history.
as misdiagnosis can lead to inadequate treatment
Family history Family bleeding disorder
with severe clinical implications [4]. The fact that
Chorioamnionitis
hemostasis in newborns is still immature and differs Maternal illness
HELLP syndrome
significantly from that of older children and adults Acetylsalicylic acid
complicates the differential diagnosis. Particularly, Maternal medication
Warfarin
the levels of plasma pro-coagulant proteins are Placenta previa
low in neonates, except for those of factors V, Abruption
VIII, XIII (FV, FVIII, FXIII) and von Willebrand Obstetric/perinatal Vasa previa
factor (vWF), which almost reach adult values [5- events Cord accident
7]. Natural anticoagulants are reduced except for Fetal-to-maternal transfusion
α-macroglobulin, which is markedly increased. TTTS
The activity of the plasmin/plasminogen system, Congenital infections
additionally to the fibrinolysis capacity, decreases, Intracranial hemorrhage
although vitamin K-dependent coagulation pro­teins Cephalhematoma

and thrombin generation capacity ensure the neonatal Subgaleal hemorrhage

Newborn
Hemolytic disease of the newborn
hemostasis balance [3, 8].
Heparin-induced thrombocytopenia
Polycythemia/hyperviscosity
Diagnostic approach to the bleeding neonate
IUGR
HELLP: hypertension, elevated liver enzymes, low platelets;
Optimal diagnosis and management of co­ IUGR: intrauterine growth restriction; TTTS: twin-to-twin
agulation disorders depend on early assessment of transfusion syndrome.

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Table 2. Reference ranges of parameters of coagulation, inhibitors and fibrinolysis in healthy full-term, preterm, small for
gestational age (SGA) and appropriate for gestational age (AGA) newborns.
SGA full-term AGA full-term SGA preterm AGA preterm Laboratory
newborns newborns newborns newborns reference range
(n = 90), (n = 98), (n = 68), (n = 71), for healthy full-
mean ± SD a mean ± SD a mean ± SD b mean ± SD b term newborns
INR 1.30 ± 0.21 1.23 ± 0.15 1.35 ± 0.22 1.32 ± 0.20 1.26 (1.15-1.35) c
PT (sec) 16.20 ± 2.40 15.50 ± 1.40 16.60 ± 2.10 16.40 ± 1.98 15.6 (14.4-16.4) c
aPTT (sec) 44.0 ± 8.0 42.0 ± 6.6 51.0 ± 11.0 51.0 ± 12.0 38.7 (34.3-44.8) c
Fibrinogen (mg/dL) 184 ± 55 185 ± 86 158 ± 46 183 ± 80 2.80 (1.92-3.74) (g/L) c
FII c (%) 42.0 ± 8.0 43.0 ± 7.0 37.6 ± 6.5 37.2 ± 9.0 54 (41-69) c
FV c (%) 67.0 ± 25.0 73.0 ± 24.0 61.0 ± 22.0 62.0 ± 20.4 81 (64-103) c
FVII c (%) 64.0 ± 19.0 67.0 ± 18.0 61.2 ± 20.5 68.8 ± 23.7 70 (52-88) c
FVIII c (%) 238 ± 167 212 ± 158 142 ± 80 116 ± 57 182 (105-329) c
FIX c (%) 37.0 ± 15.0 39.0 ± 13.6 32.0 ± 22.0 28.0 ± 11.0 48 (35-56) c
FX c (%) 42.0 ± 10.0 43.8 ± 10.0 41.2 ± 9.7 41.5 ± 10.0 55 (46-67) c
FXI c (%) 45.2 ± 17.0 45.0 ± 17.0 33.5 ± 14.2 30.5 ± 11.0 30 (7-41) c
FXII c (%) 55 ± 24 65 ± 30 50 ± 22 47 ± 24 58 (43-80) c
AT Act (%) 53.0 ± 17.0 51.0 ± 12.0 37.2 ± 11.0 39.0 ± 13.7 76 (58-90) c
Protein C Act (%) 31 ± 9 31 ± 8 24 ± 8 24 ± 9 28.2 (14-42) d
Free protein S Act (%) 34.7 ± 8.0 37.8 ± 6.8 31.5 ± 9.0 31.1 ± 5.9 36 (28-47) c
APCr 2.24 ± 0.47 2.21 ± 0.27 2.30 ± 0.30 2.20 ± 0.34 1.13 ± 0.22 e
tPA (ng/mL) 12.2 ± 7.7 8.5 ± 3.9 13.8 ± 8.2 11.4 ± 7.0 9.6 (5-18.9) f
PAI-1 (ng/mL) 63.0 ± 35.0 67.0 ± 33.0 55.3 ± 24.4 46.0 ± 24.0 6.4 (2-15.1) (U/mL) f
vWF Ag (%) 210 ± 85 219 ± 71 202 ± 64 193 ± 59 153 ± 67 (U/mL) g
Act: activity; Ag: antigenic value; AGA: appropriate for gestational age; APCr: activated protein C resistance; aPTT: activated partial thromboplastin
time; AT: antithrombin; c: coagulant activity; CBC: complete blood count; DIC: disseminated intravascular coagulation; FII: factor II; FV: factor V;
FVII: factor VII; FVIII: factor VIII; FIX: factor IX; FX: factor X; FXI: factor XI; FXII: factor XII; INR: international normalized ratio; PAI-1: plasminogen
activator inhibitor-1: PT: prothrombin time; SGA: small for gestational age; tPA: tissue plasminogen activator; vWF: von Willebrand factor.
a
Mitsiakos et al., 2009 [16]; b Mitsiakos et al., 2010 [17]; c Monagle et al., 2006 [12], values: median (IQR); d Reverdiau-Moalic et al., 1996
[14], values: median (IQR); e Sifontes et al., 1997 [13], values: mean ± SD; f Andrew et al., 1987 [15], values: mean (IQR); g Andrew et al.,
1987 [15], values: mean ± SD.

[12-17]. When interpreting abnormal coagulation (Fig. 1). Health status terminology is critical
test results, further evaluation is required to for the clinical assessment of sick neonates.
distinguish between factor deficiencies and factor As coagulation disorders may appear with no
inhibitors. The mixing test with normal plasma specific clinical signs, sharing clinical traits of
is a method that aids the clinician in resolving various neonatal morbidities and awareness of
such discrepancies. If a mixing test corrects PT critical illness are essential. Heart rate alterations
or aPTT, then a factor deficiency is present, but defined as tachycardia (> 180 beats/min) or
if there is no correction, a factor inhibitor is the bradycardia (< 90 beats/min) may early indicate
cause of the bleeding [18]. In terms of platelet neonatal disease. Abnormal respiratory rate and
contribution to clot strength, little is known about pattern may be slow (< 40 breaths/min) or rapid
platelet functionality which is better demonstrated (> 60 breaths/min) and shallow, while the neonate
by platelet activation than PLT itself. Platelet may present with grunting, recession, gasping or
function in accordance with developmental apnoea. Furthermore, a sick neonate may be pale
hemostasis could provide valid information for or severely jaundiced, hypothermic or pyrexial,
bleeding etiology and treatment management. lethargic or poorly feeding [19]. Consequently,
Given the aforementioned concerns, a diagnostic abnormal traits may be indicative of an entire
algorithm was conducted for optimal management pathology. Particularly in sick neonates, acquired
prevailing over misleading interpretations. At the bleeding disorders lie on the underlying pathology.
end of this study, the neonate’s clinical status On the contrary, healthy neonates should be
(sick or healthy), along with the alterations of evaluated mainly in terms of inherited bleeding
the coagulation system parameters, is included disturbances diagnosis.

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b c

e
e
e

d d d d

Figure 1. Algorithm for the diagnostic approach of the bleeding neonate (vitamin K given).
aPTT: activated partial thromboplastin time; CBC: complete blood count; DIC: disseminated intravascular coagulation; DOACs: direct oral
anticoagulants; FII: factor II; FV: factor V; FVII: factor VII; FVIII: factor VIII; FIX: factor IX; FX: factor X; FXI: factor XI; FXII: factor XII; FXIII:
factor XIII; LA: lupus anticoagulant; PLT: platelet count; PT: prothrombin time; RDS: respiratory distress syndrome; TORCH: Toxoplasma,
Other, Rubella, Cytomegalovirus, Herpes, Hepatitis; vWD: von Willebrand disease.
a
Normal PLT; b plus, laboratory test for DIC diagnosis (see Tab. 3), Go et al., 2020 [25]; c Henter et al., 2007 [30]; d Palla et al., 2015 [53];
e
Favaloro, 2020 [18].

Bleeding disorders of the sick neonate hypoxic-ischemic encephalopathy are dominant risk
factors for DIC in the neonatal population, others
Disseminated intravascular coagulation being shock, acidosis, hypothermia and scarcely
met causes including vascular malformations
DIC is globally defined as a disorder pertaining and metabolic diseases. Prompt DIC diagnosis is
to thrombotic and hemorrhagic irregularity, challenging. Clinical presentation and laboratory
which affects the coagulation system’s integrity. findings are constantly changing according to the
Regarding the microvasculopathy/microangiopathy severity of the underlying disease, liver function,
damage, DIC is an over-activation condition of bone marrow status and the function of the
pro-coagulant proteins and fibrinolysis while being reticuloendothelial system [21, 22]. As a result, the
consumptive for coagulopathy inhibitors presenting laboratory findings of DIC are widely variable and
clinical and biochemical evidence of end-organ time-dependent. Furthermore, the interpretation of
failure [20]. Although data clearly reporting DIC neonatal coagulation assays needs the age-related
incidence among term and preterm infants are reference ranges established for each laboratory
lacking, its prevalence is worrisome among NICU institution. In addition, there is no reliable normal
hospitalized patients. Despite developmental range for D-dimers, and the limited data from
hemostatic system evolution in newborns, the existing studies suggest that their concentration
majority of authors refer that “healthy” neonates and reference values may be higher during the
demonstrate a balanced hemostatic system, neonatal period [4, 23, 24]. Nevertheless, the
delimited, neither providing thrombosis nor DIC diagnostic criteria of the Japanese Society of
hemorrhage. Therefore, DIC manifests itself as a Obstetrical, Gynecological & Neonatal Hematology
secondary event associated with many perinatal (JSOGNH) (Tab. 3) can aid the Neonatologists
and neonatal complications. Sepsis or infection and significantly [25].

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Table 3. Disseminated intravascular coagulation (DIC) and PLT [4]. Liver disease cannot easily be
diagnostic criteria of the Japan Society of Obstetrical, distinguished from DIC, as overlapping conditions
Gynecological & Neonatal Hematology (JSOGNH)
(modified from: Go et al., 2020 [25]).
may occur. Liver failure counter to DIC presents
itself with PLT that is usually stable in low
BW BW
≥ 1,500 g < 1,500 g levels, D-dimers that are mildly increased and
≥ 70 × 103/μL and
stable FXIII levels. Particularly, the alpha subunit
50% reduction within 1 point 1 point of FXIII is produced in megakaryocytes and
24 hours white blood cells, but not in the liver, where the
PLT
≥ 50 × 103/μL and production of the beta subunit of FXIII occurs
1 point 1 point
< 70 × 103/μL
[28]. Another severe disorder that can lead to liver
< 50 × 103/μL 2 points 2 points
failure is hemophagocytic lymphohistiocytosis. It
≥ 50 mg/dL and
< 100 mg/dL
1 point - is a condition characterized by an overabundance
Fibrinogen
of tissue macrophages or histiocytes and is
< 50 mg/dL 2 points 1 point
provoked by excessive immune system activation
≥ 1.6 and < 1.8 1 point -
PT and INR [29]. It is believed to be triggered by infections or
≥ 1.8 2 points 1 point
other immune activators and may be congenital or
< 2.5-fold upper limit
of normal range
-1 point -1 point idiopathic. It manifests clinically with fever and
≥ 2.5-fold upper limit
hepatosplenomegaly, while laboratory findings are
FDP or of normal range and increased serum ferritin, abnormal liver function
1 point 1 point
D-dimer < 10-fold upper limit of tests, increased triglyceride levels, decreased
normal range
fibrinogen and cytopenia [30].
≥ 10-fold upper limit of
2 points 2 points
normal range
Bleeding disorders of the healthy neonate
BW: birth weight; FDP: fibrin degradation products; PLT: platelet
count; PT: prothrombin time; INR: international normalized ratio.
Notes: Vitamin K deficiency bleeding
• For a PLT of ≥ 70 × 103/μL, a point is added if the PLT is reduced
by 50% within 24 hours. A point is not added if the patient had
thrombocytopenia due to myelosuppression disease. Vitamin K deficiency bleeding (VKDB) appears
• For fibrinogen, a point is added if the underlying disease of the as a consequence of inadequate levels of vitamin K
patient was an infection. during the first 6 months of life [31]. Concentrations
• Since the upper limit of D-dimer is different among D-dimer kits,
a point is added if FDP and D-dimer increased by 2.5- or 10- of vitamin K-dependent FII, FVII, FIX and FX are
fold of the upper limit of normal. reduced in the neonatal period due to vitamin K
Interpretation: absence. VKDB has traditionally been classified in
• ≥ 4 points:
• symptoms: overt DIC, its early, classic, and late forms depending on the
• no symptoms: non-overt DIC; time of manifestation. The early form of VKDB
• 3 points: suspected DIC; is typically associated with maternal medication
• ≤ 2 points: low possibility for DIC.
that blocks vitamin K metabolism, while the
classic and late forms are related to breastfeeding
Liver failure and vitamin K malabsorption. Particularly,
in the VKDB late form, there is a relatively
Pro- and anticoagulant proteins, as well as high incidence of intraventricular hemorrhage
thrombopoietin, are synthesized in the liver, (IVH), which is associated with morbidity and
with the exception of FVIII and vWF. Disruption mortality. VKDB should be suspected when the
of liver function results in dysregulation of results of conventional coagulation tests show
the coagulation system, which in turn leads to prolongation of PT, followed by a prolongation
bleeding or thrombotic diathesis [3, 4]. Probable of aPTT in combination with normal fibrinogen
causes of liver failure are primary liver disease, concentration and normal PLT. Proteins induced
inborn errors of metabolism, bacterial or viral by vitamin K absence II (PIVKA-II), which are the
sepsis, hematologic disorders, hypoxic-ischemic inactive under-γ-carboxylated forms of vitamin
injury (e.g., due to perinatal asphyxia) and fetal- K-dependent clotting factors, are greater diagnostic
maternal hemorrhage that can lead to intrauterine markers for VKDB. Confirmation of the diagnosis
insult and multiorgan failure [26, 27]. Laboratory requires measurement of vitamin K-dependent
findings in liver failure are increased PT, aPTT factors [32, 33]. Regarding prophylaxis against
and D-dimers and decreased fibrinogen activity VKDB, oral or intramuscular administration of

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vitamin K prevents the classic form but not from the observed in neonates with severe or even mild forms
late one. This is why prolonged oral administration, of the disease, especially in cases of dystocia [10].
especially in breastfed infants, is recommended In both HA and HB, conventional hemostasis tests
[34]. In the last years, parents have started to refuse usually reveal only prolonged aPTT. The diagnosis
the administration of intramuscular vitamin K. is confirmed by estimating FVIII and FIX levels.
The relief of harm from the injection, a desire to FVIII concentrations are within the normal range of
be natural, and the reliance on alternative methods adult values or slightly increased at birth. On the
of prophylaxis are the reported reasons for the other hand, FIX concentrations are reduced at birth,
observed refusal. The possible neurologic sequelae which precludes the diagnosis of mild forms of HB
of VKDB, along with the observed aforementioned by the age of 3-6 months due to overlap with the
refusal, render it necessary for a renewed focus on normal range of values at this age [38, 39].
the education of the parents [35].
von Willebrand disease
Hemophilia
von Willebrand disease (vWD) is a relatively
Hemophilia A and B (HA and HB) are the most common inherited bleeding disorder, with 1.3%
common congenital bleeding disorders that occur frequency in mixed population, due to quantitative
in the neonatal period. These disorders are due to or qualitative abnormalities of the vWF [40]. The
FVIII and FIX deficiencies, respectively, and of disease can be subdivided into three types (Tab.
varying severity. Both show an X-linked recessive 4); type I vWD is the most frequent and usually
inheritance pattern, and clinical manifestations leads to a mild clinical phenotype [41, 42]. Due to
in early life are limited to males. A great number the increased concentrations of vWF at birth, type
of hemophilia cases (1/3) occur in the absence of I vWD usually does not manifest in the neonatal
positive family history, and therefore, in these period, so that, even when there is a positive family
cases, there is no clinical suspicion at birth, while history, a definite diagnosis during the neonatal
15-33% of these cases may present with bleeding period is quite difficult. Some subtypes of type
during the first month of life [10, 36]. While in II vWD are associated with thrombocytopenia,
older children with HA mucocutaneous and joint which may be evident during the neonatal period
bleeding, and in those with HB muscle bleeding and can result in bleeding. Type III vWD is a rare
and deep tissue hematoma, as well as bleeding autosomal recessive condition that is commonly
within the internal organs, are observed, in the found in populations where interracial marriages
neonatal population the sites of bleeding differ [37]. take place. Usually, both parents are asymptomatic
Prolonged bleeding or hematoma formation after and, because vWF concentrations are almost non-
a venous puncture or intramuscular administration existent, the result is serious bleeding diathesis
of vitamin K are relatively common events in the that occurs during the neonatal period. Clinical
affected newborn. Both large IVH and extracranial manifestations are variable, and mucosal bleeding
hemorrhage such as cephalhematoma are also is more frequently seen in type III vWD compared

Table 4. Classification of von Willebrand disease (vWD) and laboratory findings (from: Sadler et. al., 2006 [42], and Yawn
et. al., 2009 [44]).
vWF RCo vWF Ag
Classification Pathophysiology FVIII
(IU/dL) (IU/dL)
Type I Partial quantitative deficiency of vWF < 30 < 30 ↓ or normal
Type II Qualitative vWF defects - - -
Decreased vWF-dependent platelet adhesion and a selective
Type II A < 30 < 30 to 200 ↓ or normal
deficiency of high-molecular-weight vWF multimers
Type II B Increased affinity for platelet glycoprotein Ib < 30 < 30 to 200 ↓ or normal
Decreased vWF-dependent platelet adhesion without a selective
Type II M < 30 < 30 to 200 ↓ or normal
deficiency of high-molecular-weight vWF multimers
Type II N Markedly decreased binding affinity for FVIII 30 to 200 30 to 200 ↓↓
Type III Virtually complete deficiency of vWF <3 <3 ↓ ↓ ↓ (< 10 IU/dL)
Normal - 50 to 200 50 to 200 Normal
Ag: antigen; FVIII: factor VIII; RCo: ristocetin cofactor activity; vWF: von Willebrand factor.

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to hemophilia. Coagulation testing usually reveals Viscoelastic tests

prolongation of aPTT only, as in hemophilia, and
the diagnosis is confirmed by measuring antigen Despite conventional coagulation tests’ omni­
levels and the activity of FVIII and vWF (Tab. presence, aPTT, PT, fibrinogen levels and PLT
4) [43, 44]. The vWF activity (ristocetin cofactor fail to qualitatively illustrate intrinsic and extrinsic
activity) has been shown to be more sensitive (71- coagulation pathways, respectively [56]. As these
80%) than antigen levels of FVIII or vWF for the tests are performed in plasma, in the absence of red
diagnosis of vWD [45-47]. It should be noted that blood cells and platelets, they are lacking in precision
retesting is needed for the diagnosis, because only for depicting cellular and enzymatic coagulation
42% of the carriers of vWD may have abnormal components’ mutual reliance [57]. Hence, there is
vWF activity on their initial testing [48, 49]. This can neither an accurate interpretation of the hemostatic
be explained by the fact that in some cases of type I mechanisms in vivo nor clinical accuracy in
vWD there is a gene defect concerning the release of providing hemostatic profile and patient’s bleeding
vWF from the endothelium and not a gene defect in diathesis [58]. Although aPTT, PT and PLT do not
the vWF gene [50]. completely represent the pathophysiology of the clot
formation in vivo, they are of paramount importance
Rare bleeding disorders in the laboratory workup of blood coagulation.
The cell-based model, which is based on the
Rare coagulation disorders are defined as idea that hemostasis involves both cellular com­
a group of autosomal recessive deficits of FII, ponents and coagulation proteins, mirrors more
FV, FVII, FX, FXI, FXII and FXIII, which in qualitative hemostasis in vivo [56]. The visco­
either homozygous or combined heterozygous elastic teststhromboelastography/rotation-thrombo­
heredity, may predispose to bleeding. These rare elastometry (TEG/ROTEM®), by measuring multiple
bleeding disorders represent 3-5% of all congenital parameters of clot formation and dissolution,
coagulation factor deficiencies [51]. better reflects the blood cells and coagulation
Due to the inheritance pattern, these abnormalities proteins interdependence and thus more effectively
are usually found in populations or countries where interprets the hemostasis in vivo [58]. The
marriage between relatives is common [32, 52]. Severe obtained measurements lie on the dynamics of clot
fibrinogen, FVII, FX and FXIII deficiencies are the development, stabilization, and dissolution, and the
most probable coagulation disorders that can occur gained information concerns coagulation elements’
during the neonatal period. Bleeding in the soft tissues functionality [59].
and mucosal membranes, as well as the umbilical Although the viscoelastic tests have not been
cord, is frequent. Umbilical cord bleeding after stump used in the diagnosis and management of bleeding
falling is noted in 80% of the cases with severe FXIII disorders in the neonatal population, they seem to be
deficiency. It is also clear that IVH is a main feature promising. The published thresholds of ROTEM®
of these disorders. FVII deficiency is expressed in parameters for the diagnosis of coagulopathy are
some people with mild hemorrhagic diathesis, while mainly derived from adult studies. Even more,
in others with severe type, it can present from the there is no strong evidence in the current literature
first days of life. The severe form manifests with supporting diagnostic reference values [60].
IVH. FXI and FXII deficiencies are mainly detected Regarding neonates, available data are limited
accidentally, as a result of routine preoperative testing. and are mainly extrapolated from even more
Neonates with severe FXI deficiency have excess restricted studies, including neonates undergoing
hemorrhage only after injury or surgery. In contrast, cardiac surgery or suffering from neonatal
FXII deficiency does not involve substantial bleeding, complications such as sepsis, IVH, and hypoxic-
even after surgery. It is necessary to determine the ischemic encephalopathy undergoing therapeutic
specific factor deficiency so as to confirm the diagnosis hypothermia [58, 61].
[52, 53].
Finally, we must not neglect a possible Fletcher Conclusions
factor (prekallicrein) or Fitzgerald factor (high
molecular weight kininogen – HMWK) deficiency Even though the hemorrhagic events are
when dealing with prolongation of aPTT, despite relatively rare in the neonatal period, accurate and
the fact that these deficits do not cause clinical prompt diagnosis is crucial. Guided, individualized
bleeding [54, 55]. management results in unnecessary blood products

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reduction, whose adverse effects are considerable. So 13. Sifontes MT, Nuss R, Hunger SP, Jacobson LJ, Waters J, Manco-
far, dealing with a bleeding disorder, neonatologists Johnson MJ. Correlation between the Functional Assay for Activated
should first distinguish whether the neonate is sick or Protein C Resistance and Factor V Leiden in the Neonate. Pediatr
not. Ruling out DIC or thrombocytopenia should be Res. 1997;42(6):776-8.
the next step. Treating physicians should be aware 14. Reverdiau-Moalic P, Delahousse B, Body G, Bardos P, Leroy J,
of the existence and prevalence of rare bleeding Gruel Y. Evolution of blood coagulation activators and inhibitors in
disorders. The laboratory values interpretation the healthy human fetus. Blood. 1996;88(3):900-6.
should be placed in parallel with the age-related 15. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen
reference ranges evaluation for neonates. Optimal DM, Powers P. Development of the human coagulation system in the
management/treatment requires multidisciplinary full-term infant. Blood. 1987;70(1):165-72.
approach from Obstetricians/Gynecologists, Pedia­ 16. Mitsiakos G, Papaioannou G, Papadakis E, Chatziioannidis E,
tricians/Neonatologists and Hematologists. Giougi E, Karagianni P, Evdoridou J, Malindretos P, Athanasiou
M, Athanassiadou F, Nikolaidis N. Haemostatic profile of full-
Declaration of interest term, healthy, small for gestational age neonates. Thromb Res.
2009;124(3):288-91.
The Authors declare that no conflict of interest exists. Funding: there 17. Mitsiakos G, Giougi E, Chatziioannidis I, Karagianni P, Papadakis
was no funding. E, Tsakalidis C, Papaioannou G, Malindretos P, Nikolaidis N.
Haemostatic profile of healthy premature small for gestational age
References neonates. Thromb Res. 2010;126(2):103-6.
18. Favaloro EJ. Coagulation mixing studies: Utility, algorithmic
1. Barcellona D, Marongiu F. The hemostatic system. 1st Part. J Pediatr strategies and limitations for lupus anticoagulant testing or follow up
Neonatal Individ Med. 2020;9(1):e090106. of abnormal coagulation tests. Am J Hematol. 2020;95(1):117-28.
2. Udoma E, Udo J, Etuk S, Duke E. Morbidity and Mortality among 19. Lowe MC, Woolridge DP. The Normal Newborn Exam, or Is It?
Infants with Normal Birth Weight in a New Born Baby Unit. Niger J Emerg Med Clin North Am. 2007;25(4):921-46.
Paediatr. 2001;28(1):13-7. 20. Levi M, Sivapalaratnam S. Disseminated intravascular coagulation:
3. Hanmod SS, Jesudas R, Kulkarni R, Chitlur M. Neonatal Hemostatic an update on pathogenesis and diagnosis. Expert Rev Hematol.
Disorders: Issues and Challenges. Semin Thromb Hemost. 2018;11(8):663-72.
2016;42(7):741-51. 21. Trotter L. Disseminated intravascular coagulation in the neonatal
4. Jaffray J, Young G, Ko RH. The bleeding newborn: A review of period. Newborn Infant Nurs Rev. 2004;4(4):176-80.
presentation, diagnosis, and management. Semin Fetal Neonatal 22. Bick RL. Disseminated intravascular coagulation. Hematol Oncol
Med. 2016;21(1):44-9. Clin North Am. 2003;17(1):149-76.
5. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen 23. Shirahata A, Shirakawa Y, Murakami C. Diagnosis of DIC in Very
DM, Castle V, Powers P. Development of the human coagulation Low Birth Weight Infants. Semin Thromb Hemost. 1998;24(05):
system in the healthy premature infant. Blood. 1988;72(5):1651-7. 467-71.
6. Will A. Neonatal haemostasis and the management of neonatal 24. VanVooren DM, Bradshaw WT, Blake SM. Disseminated
thrombosis. Br J Haematol. 2015;169(3):324-32. Intravascular Coagulation in the Neonate. Neonatal Netw.
7. Monagle P, Massicotte P. Developmental haemostasis: Secondary 2018;37(4):205-11.
haemostasis. Semin Fetal Neonatal Med. 2011;16(6):294-300. 25. Go H, Ohto H, Nollet KE, Kashiwabara N, Ogasawara K, Chishiki
8. Diaz-Miron J, Miller J, Vogel AM. Neonatal hematology. Semin M, Hiruta S, Sakuma I, Kawasaki Y, Hosoya M. Risk factors and
Pediatr Surg. 2013;22(4):199-204. treatments for disseminated intravascular coagulation in neonates.
9. Kamphuis MM, Paridaans NP, Porcelijn L, Lopriore E, Oepkes Ital J Pediatr. 2020;46(1):54.
D. Incidence and Consequences of Neonatal Alloimmune 26. Campbell SE, Bolton-Maggs PHB. Congenital and acquired bleeding
Thrombocytopenia: A Systematic Review. Pediatrics. 2014;133(4): disorders in infancy. Early Hum Dev. 2015;91(11):637-42.
715-21. 27. Roumiantsev S, Shah U, Westra SJ, Misdraji J. Case 20-2015 – A
10. Kulkarni R. Bleeding in the Newborn. Pediatr Ann. 2001;30(9): Newborn Girl with Hypotension, Coagulopathy, Anemia, and
548-56. Hyperbilirubinemia. N Engl J Med. 2015;372(26):2542-53.
11. McMillan D, Wu J. Approach to the bleeding newborn. Paediatr 28. Levi M. Pathogenesis and diagnosis of disseminated intravascular
Child Health. 1998;3(6):399-401. coagulation. Int J Lab Hematol. 2018;40(Suppl 1):15-20.
12. Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan 29. McLean J, Katebian R, Suh E, Mirza K, Amin S. Neonatal
A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock Hemophagocytic Lymphohistiocytosis. Neoreviews. 2019;20(6):
C, Roy N, Rowlands S. Developmental haemostasis. Impact for e316-25.
clinical haemostasis laboratories. Thromb Haemost. 2006;95(2): 30. Henter J-I, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku
362-72. S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-

8/9 Katsaras • Gialamprinou • Papacharalampous • Chatziioannidis • Mitsiakos

Journal of Pediatric and Neonatal Individualized Medicine • vol. 11 • n. 2 • 2022 www.jpnim.com Open Access

2004: Diagnostic and therapeutic guidelines for hemophagocytic 46. Rodeghiero F, Castaman G, Tosetto A. von Willebrand factor
lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. antigen is less sensitive than ristocetin cofactor for the diagnosis of
31. Williams MD, Chalmers EA, Gibson BE; Haemostasis and type I von Willebrand disease – results based on an epidemiological
Thrombosis Task Force, British Committee for Standards in investigation. Thromb Haemost. 1990;64(3):349-52.
Haematology. The investigation and management of neonatal 47. Miller CH, Graham JB, Goldin LR, Elston RC. Genetics of classic
haemostasis and thrombosis. Br J Haematol. 2002;119(2):295-309. von Willebrand’s disease. I. Phenotypic variation within families.
32. Sutor AH, von Kries R, Cornelissen EA, McNinch AW, Andrew M. Blood. 1979;54(1):117-36.
Vitamin K deficiency bleeding (VKDB) in infancy. ISTH Pediatric/ 48. Miller CH, Graham JB, Goldin LR, Elston RC. Genetics of
Perinatal Subcommittee. International Society on Thrombosis and classic von Willebrand’s disease. II. Optimal assignment of the
Haemostasis. Thromb Haemost. 1999;81(3):456-61. heterozygous genotype (diagnosis) by discriminant analysis. Blood.
33. Dituri F, Buonocore G, Pietravalle A, Naddeo F, Cortesi M, 1979;54(1):137-45.
Pasqualetti P, Tataranno ML, Agostino R. PIVKA-II plasma levels as 49. Abildgaard CF, Suzuki Z, Harrison J, Jefcoat K, Zimmerman
markers of subclinical vitamin K deficiency in term infants. J Matern TS. Serial studies in von Willebrand’s disease: variability versus
Fetal Neonatal Med. 2012;25(9):1660-3. “variants”. Blood. 1980;56(4):712-6.
34. Lembo C, Buonocore G, Perrone S. The challenge to define the 50. Nichols WC, Cooney KA, Mohlke KL, Ballew JD, Yang A, Bruck
optimal prophylactic regimen for vitamin K deficiency bleeding in ME, Reddington M, Novak EK, Swank RT, Ginsburg D. von
infants. Acta Paediatr. 2021;110(4):1113-8. Willebrand disease in the RIIIS/J mouse is caused by a defect outside
35. Loyal J, Shapiro ED. Refusal of Intramuscular Vitamin K by Parents of the von Willebrand factor gene. Blood. 1995;86(6):2461.
of Newborns: A Review. Hosp Pediatr. 2020;10(3):286-94. 51. Peyvandi F, James P, Salomon O, Mikovic D. Rare bleeding disorders
36. Chambost H, Gaboulaud V, Coatmélec B, Rafowicz A, Schneider P, – bleeding assessment tools, laboratory aspects and phenotype and
Calvez T. What factors influence the age at diagnosis of hemophilia? therapy of FXI deficiency. Haemophilia. 2014;20:71-5.
Results of the French hemophilia cohort. J Pediatr. 2002;141(4): 52. Chalmers EA. Neonatal coagulation problems. Arch Dis Child Fetal
548-52. Neonatal Ed. 2004;89(6):F475-8.
37. Amin C, Sharathkumar A, Griest A. Bleeding diathesis and 53. Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis
hemophilias. Handb Clin Neurol. 2014;120:1045-59. and treatment. Blood. 2015;125(13):2052-61.
38. Myles LM, Massicotte P, Drake J. Intracranial Hemorrhage in 54. Rasmussen KL, Philips M, Tripodi A, Goetze JP. Unexpected,
Neonates with Unrecognized Hemophilia A: A Persisting Problem. isolated activated partial thromboplastin time prolongation: A
Pediatr Neurosurg. 2001;34(2):94-7. practical mini-review. Eur J Haematol. 2020;104(6):519-25.
39. United Kingdom Haemophelia Centre Doctors’ Organisation. 55. Pramanik AK. Bleeding Disorders in Neonates. Pediatr Rev.
Guidelines on the selection and use of therapeutic products to treat 1992;13(5):163-73.
haemophilia and other hereditary bleeding disorders. Haemophilia. 56. Hoffman M, Monroe D. A Cell-based Model of Hemostasis. Thromb
2003;9(1):1-23. Haemost. 2001;85(06):958-65.
40. Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire 57. Haas T, Fries D, Tanaka KA, Asmis L, Curry NS, Schöchl H.
TC. Prevalence of von Willebrand disease in children: A multiethnic Usefulness of standard plasma coagulation tests in the management
study. J Pediatr. 1993;123(6):893-8. of perioperative coagulopathic bleeding: is there any evidence? Br J
41. Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Anaesth. 2015;114(2):217-24.
Haemost. 1999;82(4):1207-14. 58. Konstantinidi A, Sokou R, Parastatidou S, Lampropoulou K,
42. Sadler JE, Budde U, Eikenboom JCJ, Favaloro EJ, Hill FGH, Katsaras G, Boutsikou T, Gounaris AK, Tsantes AE, Iacovidou N.
Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Clinical Application of Thromboelastography/Thromboelastometry
Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero (TEG/TEM) in the Neonatal Population: A Narrative Review. Semin
F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery Thromb Hemost. 2019;45(05):449-57.
RR, Federici AB; Working Party on von Willebrand Disease 59. Schmidt AE, Israel AK, Refaai MA. The Utility of
Classification. Update on the pathophysiology and classification Thromboelastography to Guide Blood Product Transfusion. Am J
of von Willebrand disease: a report of the Subcommittee on von Clin Pathol. 2019;152(4):407-22.
Willebrand Factor. J Thromb Haemost. 2006;4(10):2103-14. 60. Veigas PV, Callum J, Rizoli S, Nascimento B, da Luz LT. A
43. Sadler JE. A Revised Classification of von Willebrand Disease. systematic review on the rotational thrombelastometry (ROTEM®)
Thromb Haemost. 1994;71(04):520-5. values for the diagnosis of coagulopathy, prediction and guidance
44. Yawn B, Nichols WL, Rick ME. Diagnosis and management of von of blood transfusion and prediction of mortality in trauma patients.
Willebrand disease: guidelines for primary care. Am Fam Physician. Scand J Trauma Resusc Emerg Med. 2016;24(1):114.
2009;80(11):1261-8. 61. Oswald E, Stalzer B, Heitz E, Weiss M, Schmugge M, Strasak
45. Werner EJ, Abshire TC, Giroux DS, Tucker EL, Broxson EH. A, Innerhofer P, Haas T. Thromboelastometry (ROTEM®) in
Relative value of diagnostic studies for von Willebrand disease. J children: age-related reference ranges and correlations with standard
Pediatr. 1992;121(1):34-8. coagulation tests. Br J Anaesth. 2010;105(6):827-35.

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