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Neonatal coagulation problems

E A Chalmers

Arch Dis Child Fetal Neonatal Ed 2004;89:F475F478. doi: 10.1136/adc.2004.050096

Bleeding problems often occur during the neonatal period. Similarly, concentrations of the naturally occur-
ring anticoagulants, antithrombin, protein C,
Although thrombocytopenia is the most common cause, and protein S, are low at birth, and, as a con-
coagulation problems often occur, and the two problems sequence, both thrombin generation and throm-
may co-exist. The causes, diagnosis, and management of bin inhibition are reduced in the newborn
period.2 3 Plasminogen is the major protein
coagulation problems in newborn infants are reviewed. involved in fibrinolysis, and again this is re-
........................................................................... duced during the neonatal period, resulting in a
relatively hypofibrinolytic state.4
Despite this apparent functional immaturity,

leeding problems are often encountered
during the neonatal period particularly in the neonatal haemostatic system seems to result
intensive care. Thrombocytopenia is prob- in relatively few clinical bleeding problems for
ably the most common cause but coagulation the healthy term infant. The haemostatic system
defects are also observed, and the two problems matures during the early weeks and months of
often co-exist. Although most coagulation pro- life, and the concentrations of most haemostatic
blems reflect acquired disorders, a number of proteins, both in term and preterm infants, are
inherited conditions can also present at this time. very close to adult values by 6 months of age.
Appropriate diagnosis and management of these Platelets are also influenced by age, although
conditions is highly dependent on prompt qualitatively rather than quantitatively. Thus the
recognition of clinically abnormal bleeding and platelet count is within the normal adult range in
the initiation of appropriate investigations. both term and preterm infants. Although neo-
Although acquired disorders most often present natal platelet numbers are normal, studies of
in sick term or preterm infants, many inherited platelet function suggest that neonatal platelets
disorders manifest in otherwise healthy infants. are hyporeactive compared with adult platelets.
Recognition of the clinical setting in which Despite this, the bleeding time, which can be
bleeding occurs is therefore an important viewed as an in vivo assessment of the platelet-
clue to the underlying diagnosis. Investigation vessel wall interaction, is shortened in normal
requires careful observation of age dependent healthy neonates.5 This probably reflects multiple
features, which are especially important during factors including increased concentrations of von
the early weeks of life. Willebrand factor (vWF), the presence of large
vWF multimers, and the high neonatal packed
cell volume.6
Normal haemostasis reflects a highly complex
process, which is dependent on a series of INVESTIGATION OF THE NEONATE WITH
interactions occurring between endothelial cells, ABNORMAL BLEEDING
platelets, and haemostatic proteins. Our under- Clinical considerations
standing of this process has improved consider- A number of clinical considerations are impor-
ably in recent years, and it is now accepted that tant in the investigation of a neonate with a
traditional models of haemostasis do not ade- haemorrhagic problem and a possible underlying
quately reflect events in vivo and are an over- coagulopathy. Most important of these is prob-
simplification of the processes involved. It is now ably the clinical setting in which the bleeding
recognised that the traditional extrinsic pathway, occurs. Bleeding in an otherwise well neonate is
involving tissue factor and factor VIIa, is the much more suggestive of an inherited coagula-
major pathway whereby coagulation is initiated, tion or an immune mediated thrombocytopenia,
and that thrombin plays a crucial role in both the whereas a sick preterm neonate is more likely to
activation and inhibition of coagulation and also have a consumptive coagulopathy with dissemi-
in platelet activation.1 nated intravascular coagulation (DIC). The pre-
An understanding of the haemostatic system sence of a family history of a bleeding disorder
....................... and features unique to the early weeks of life is or of a previously affected infant can also be an
important when it comes to the investigation of important diagnostic pointer. Obstetric compli-
Correspondence to: a neonate with a haemorrhagic problem. The cations and problems at delivery can also affect
Dr Chalmers, Royal
haemostatic system is profoundly influenced by the haemostatic system resulting in coagulation
Hospital for Sick Children,
Yorkhill NHS Trust, age, and the concentrations of many haemostatic activation and DIC. Finally both maternal and
Glasgow G3 8SJ, proteins are dependent on both the gestational
Scotland, UK; and postnatal age of the infant. At birth,
Elizabeth.Chalmers@ Abbreviations: APTT, activated partial thromboplastin
concentrations of the vitamin K dependent (FII, time; DIC, disseminated intravascular coagulation; FII,
FVII, FIX, FX) and contact factors (FXI, FXII) are FVII, FIX, FX, FXI, and FXII, factor II, VII, IX, X, XI, and XII;
Accepted 13 March 2004 reduced to about 50% of normal adult values VKDB, vitamin K deficiency bleeding; vWD, von
....................... and are further reduced in preterm infants.2 3 Willebrand disease; vWF, von Willebrand factor
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F476 Chalmers

Table 1 Laboratory investigation of neonatal coagulation disorders

Diagnostic tests/other
Condition PT APTT Fibrinogen Platelets useful tests

Inherited disorders
Haemophilia A N q N N FVIII assay
Haemophilia B N q N N FIX assay
vWD (type III) N q N N/Q FVIII/vWF assays
FVII q N N N FVII assay
FX q q N N FX assay
Fibrinogen N/q N/q Q N Fibrinogen assay
FXIII N N N N FXIII screen/assay
Acquired disorders
DIC q q Q Q D-Dimers
Vitamin K deficiency q N/q N N FII, VII, IX, X
Liver disease q q N/Q N/Q Factor assays

PT, Prothrombin time; APTT, activated partial thromboplastin time; N, normal; DIC, disseminated intravascular
coagulation; FII, FVII, FIX, FX, FXI, and FXII, factor II, VII, IX, X, XI, and XII; vWD, von Willebrand disease; vWF, von
Willebrand factor.

neonatal drugs, particularly with regard to vitamin K intracranial and extracranial, is also recognised, and, in a
metabolism, may be highly relevant at this time. recent literature review, 41% of all reported cases of bleeding
during the first month of life involved cranial bleeding.11 This
Laboratory investigations type of bleeding is often related to trauma at delivery and is
Initial screening investigations usually comprise a full blood associated with a poor outcome.9
count and a baseline coagulation screen. The results of these On baseline coagulation screening, both haemophilia A
initial screening tests can then be used to guide the direction of and B typically result in isolated prolongation of the APTT,
further investigations. Sampling problems are common in the which in an otherwise healthy male infant is highly sug-
newborn period, and it is particularly important that samples gestive of the diagnosis (table 1). Confirmation of the diag-
for coagulation testing avoid contamination or activation nosis requires measurement of FVIII and FIX concentrations.
before analysis. Reduced procoagulant concentrations result As FVIII concentrations are within the normal adult range or
in prolongation of baseline coagulation variables, particularly mildly increased at birth, it is usually possible to confirm a
the activated partial thromboplastin time (APTT), and it is diagnosis of haemophilia A regardless of the severity of the
therefore very important that results are interpreted in con- condition or the gestational age of the infant. The only excep-
junction with age adjusted normal ranges. Ideally, laboratories tion to this is mild haemophilia A, where an initial result at
processing large numbers of neonatal samples should derive the lower end of normal may warrant repeat screening when
their own in-house reference ranges, as these are both mach- the infant is older. FIX concentrations, on the other hand, are
ine and reagent specific, but in practice this is often difficult to significantly reduced at birth, which precludes the diagnosis
do, and the use of published ranges may be required.2 3 As of mildly affected cases until 36 months because of overlap
many of these ranges were derived some time ago and do not with the normal range at this age.
reflect current technology they must be used with care. The It is important that infants presenting with abnormal
high neonatal packed cell volume also results in a minor bleeding are appropriately investigated for haemophilia and
degree of spurious prolongation of coagulation times, and this other inherited bleeding disorders. Unfortunately, the litera-
is particularly relevant in polycythaemic infants. ture suggests that delays in reaching a diagnosis are quite
Where further investigation is required, this may include common in these conditions.12 13 This may reflect failure to
factor assays, which again must be interpreted using app- recognise bleeding as abnormal or problems in initiating or
ropriate age adjusted ranges. In certain circumstances, more interpreting appropriate investigations. In particular, physio-
specialised techniques may be required to investigate for less logical prolongation of the APTT must be interpreted with
common defects including abnormalities of platelet function.7 care, and it should also be noted that a mildly reduced FVIII
concentration is not incompatible with a normal APTT. Factor
INHERITED COAGULATION DISORDERS assays should therefore always be performed if bleeding
Haemophilia appears excessive.
Haemophilia A and B are the most common inherited Once the diagnosis has been reached, management is
bleeding disorders to present in the newborn period. These usually undertaken in consultation with a paediatric haema-
disorders result from deficiencies of FVIII and FIX respec- tologist with experience in managing haemophilia. Mana-
tively and are of variable severity reflecting the hetero- gement of bleeding problems requires appropriate factor
geneous nature of the underlying molecular abnormalities. replacement therapy, and, in the developed world, recom-
Both conditions are inherited as X linked recessive disorders, binant products are now the treatment of choice.14
and clinical manifestations early in life are almost always
confined to boys. von Willebrand disease
At least a third of all haemophilia cases occur in the von Willebrand disease (vWD) is a relatively common
absence of a positive family history and are therefore inherited bleeding disorder which results from either
unsuspected at birth. Recent cohort studies suggest that quantitative or qualitative abnormalities in the vWF protein.
1533% of cases may present with bleeding manifestations The condition can be divided into three broad subtypes, of
during the first month of life.810 The pattern of bleeding which type I disease is the most common and usually results
observed during the neonatal period differs from that seen in a relatively mild clinical phenotype.15 Owing to the physio-
in older children, and a significant proportion of bleeds logical increase in vWF concentrations at birth, type I disease
are iatrogenic in origin. Oozing or haematoma formation does not usually manifest until later in life, and, even where
following venepuncture or vitamin K administration are there is a family history, it is not usually possible to make a
relatively common manifestations. Major bleeding, both diagnosis of this condition during the newborn period. Some
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Neonatal coagulation problems F477

subtypes of type II disease are associated with thrombocyto- Management of bleeding episodes in this group of con-
penia, which may be apparent during the neonatal period ditions should be with a specific factor concentrate where
and may result in bleeding. this is available. Because of the high risk of intracranial
Type III vWD is a rare autosomal recessive condition, haemorrhage, regular prophylaxis should be started as soon
which is more common in populations where consangui- as a diagnosis of FXIII deficiency has been made and should
neous marriages are common. Typically both parents will be also be considered for both severe FVII and FX deficiency.
asymptomatic. In this condition, vWF concentrations are
almost totally absent, and this results in a severe bleeding ACQUIRED COAGULATION DISORDERS
tendency that may present during the neonatal period.
Manifestations are variable, although bleeding from mucous
DIC is a relatively common problem, especially in the unwell
membranes is more common than in haemophilia.
neonate. The neonatal age group appears to be particularly
In type III vWD, as with haemophilia, coagulation screen-
susceptible. DIC always occurs as a secondary event, and a
ing usually results in an isolated prolongation of the APTT,
number of perinatal and neonatal problems are associated
and the diagnosis is confirmed by measuring FVIII and vWF
with this complication: birth asphyxia, acidosis, respiratory
antigen and activity levels (table 1).
distress syndrome, infection, necrotising enterocolitis, meco-
Management of bleeding in type III vWD is usually with nium aspiration, aspiration of amniotic fluid, brain injury,
factor replacement using an intermediate purity FVIII hypothermia, giant haemangioma, homozygous protein C/S
concentrate containing the high molecular weight multimers deficiency, thrombosis, malignancy. As in older children and
of vWF.14 adults, once established, DIC is often associated with increased
mortality. Although DIC is often regarded as a haemostatic
Rare coagulation disorders problem, it is in fact a complex systemic process involving
The so called rare coagulation disorders comprise a group of activation and dysregulation of both coagulation and inflam-
autosomal recessive deficiencies which in either a homo- matory processes. Clinically both bleeding and thrombotic
zygous or compound heterozygous state may give rise to a problems may occur, and microvascular thrombosis in parti-
major clinical bleeding diathesis. Owing to their mode of cular contributes to multiorgan damage. Failure to regulate the
inheritance, these abnormalities occur more often in coun- coagulation process results in massive uncontrolled thrombin
tries or populations where consanguineous marriage is generation, with widespread fibrin deposition and consump-
common (table 2). Published information on clinical man- tion of coagulation proteins and platelets.
ifestations and management is relatively limited, but it is DIC, particularly in the early stages, can be difficult to
clear that a number of these disorders are associated with a diagnose, and the clinical setting can be an important initial
severe bleeding tendency, which may manifest in the first pointer. The condition is much more commonly observed in
few days of life.16 the sick neonate, who may have obvious sepsis or other
Severe deficiencies of fibrinogen, FVII, FX, and FXIII are complications such as necrotising enterocolitis. The laboratory
the most likely conditions to present neonatally. Soft tissue diagnosis of DIC in older children and adults is usually based
bleeding and umbilical stump bleeding are typical manifesta- on a typical pattern of reduced platelets, prolonged coagulation
tions, with umbilical bleeding reported in 80% of cases of variables (prothrombin time, APTT with or without thrombin
severe FXIII deficiency. It is also clear, however, that clotting time), reduced fibrinogen, and increased D-dimers (or
intracranial bleeding is a relatively common feature of these other markers of fibrin or fibrinogen degradation). Although
disorders. This highlights the need to exclude an inherited this pattern is likely to be present in a neonate with ful-
bleeding disorder in any neonate presenting with an minating DIC, findings can vary, and a number of factors
unexplained intracranial bleed. complicate the diagnosis during the neonatal period.
Except for FXIII deficiency, all of these abnormalities are Thrombocytopenia can be an early manifestation of DIC,
likely to result in some perturbation of the baseline but is an extremely common haematological complication
coagulation screen, although, as with haemophilia, problems during the neonatal period, particularly in the neonatal
with the interpretation of abnormal screen results can result intensive care population. Published studies suggest that
in a delayed diagnosis. Table 1 shows typical coagulation thrombocytopenia develops in up to 2235% of neonates
patterns observed in each disorder. Specific factor assays are admitted to the neonatal intensive care unit and is severe
then required to confirm the diagnosis. FXIII deficiency, even in 20%.17 Up until recently, thrombocytopenia was often
in its most severe form, is associated with a normal attributed to the presence of a consumptive process, but it
coagulation screen and has to be assessed specifically using now seems more likely that many of these episodes of
either a screening test or a FXIII assay. The FXIII screening apparently self limiting thrombocytopenia relate to under-
test is only sensitive to the most severe forms of the production of platelets secondary to placental insufficiency.18
deficiency, and there is currently debate about optimal This contrasts with the development of profound, persistent
testing strategies. These tests are not widely available, and thrombocytopenia a few days after delivery which is more
a local reference centre is usually used. likely to represent underlying DIC.
Coagulation variables, at least initially, may be minimally
Table 2 Rare coagulation disorders deranged, and there may be difficulties distinguishing what
represents an abnormal result particularly in preterm infants.
% of UK inherited bleeding Similarly, there are no reliable normal ranges for D-dimers, and
Deficiency disorders there is limited evidence to suggest that baseline concentra-
Fibrinogen 0.2 tions may be higher during the neonatal period.19 In addition,
Prothrombin 0.02 fibrinogen concentrations normally increase slightly during the
Factor V 0.6 first few days of life and may initially be preserved. Early
Factor VII 1.3
Factor V+VIII 0.3
diagnosis of this condition is likely to be increasingly important
Factor X 0.5 in order to target management, and, with this in mind, scoring
Factor XI 3.3 systems have been developed for use in adults, which may help
Factor XIII 0.5 to predict early non-overt DIC.20
As DIC is a secondary process, it follows that an important
aspect of the management of this complication is prompt and
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F478 Chalmers

effective treatment of the underlying cause. Although this is confirmed, many centres have preferred to use an oral dosing
logical, once DIC is well established, it may be difficult to schedule for prophylaxis. The optimal formulation and
switch off the processes involved. Evidence based guidelines dosing regimen for oral vitamin K prophylaxis remains to
for other specific treatment modalities are lacking, which be defined, but it is clear that regimens consisting of multiple
reflects the absence of recent randomised controlled trials in doses are more effective, particularly for breast fed
this age group. There is considerable interest in the use of infants.26 27 Recent data have also shown that oral adminis-
activated protein C, which has been shown to be of benefit in tration of mixed micellar vitamin K is not superior to older
sepsis associated DIC in adults, but there is only limited vitamin K preparations.28
information on the use of this agent in the neonatal period.21 22
Much of the management of DIC thus continues to centre CONCLUSION
around the use of supportive treatment with fresh frozen A number of different coagulation disorders may manifest
plasma, cryoprecipitate, and platelets to try to maintain with bleeding problems during the neonatal period. Early
adequate haemostasis. Although the use of blood products recognition of abnormal bleeding together with careful use of
and the thresholds set for transfusion are largely empirical, it appropriate diagnostic investigations and recognition of those
would appear reasonable to institute replacement therapy, features unique to the neonatal haemostatic system should
particularly where there is an increased risk of bleeding. facilitate prompt diagnosis and appropriate management for
Guidelines for the transfusion of platelets suggest that the these infants.
platelet count should be maintained above 50 6 109/l by the
transfusion of platelet concentrates (1015 ml/kg).23 Fresh
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Neonatal coagulation problems

E A Chalmers

Arch Dis Child Fetal Neonatal Ed 2004 89: F475-F478

doi: 10.1136/adc.2004.050096

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