Clin Pharmacokinet
DOI 10.1007/s40262-013-0094-1
REVIEW ARTICLE
Pharmacokinetics and Pharmacodynamics of Anticoagulants
in Paediatric Patients
Donald L. Yee • Sarah H. O’Brien •
Guy Young
Ó Springer International Publishing Switzerland 2013
Abstract Given the rising incidence of thrombotic com-
plications in paediatric patients, understanding of the
pharmacologic behaviour of anticoagulant drugs in chil-
dren has gained importance. Significant developmental
differences between children and adults in the haemostatic
system and pharmacologic parameters for individual drugs
highlight potentially unique aspects of anticoagulant
pharmacology in this special and vulnerable population.
This review focuses on pharmacologic information rele-
vant to the dosing of unfractionated heparin, low molecular
weight heparin, warfarin, bivalirudin, argatroban and
fondaparinux in paediatric patients. The bulk of clinical
experience with paediatric anticoagulation rests with the
first three of these agents, each of which requires higher
bodyweight-based dosing for the youngest patients, com-
pared with adults, in order to achieve comparable phar-
macodynamic effects, likely related to an inverse
correlation between age and bodyweight-normalized
clearance of these drugs. Whether extrapolation of thera-
peutic ranges targeted for adult patients prescribed these
agents is valid for children, however, is unknown and a
high priority for future research. Novel oral anticoagulants,
D. L. Yee (&)
Texas Children’s Hospital, Baylor College of Medicine,
6701 Fannin Street, Suite 1580, Houston, TX 77030, USA
e-mail: dlyee@txch.org
S. H. O’Brien
Center for Innovation in Pediatric Practice,
The Research Institute at Nationwide Children’s Hospital,
Columbus, OH, USA
G. Young
Children’s Hospital Los Angeles, University of Southern
California Keck School of Medicine, Los Angeles, CA, USA
such as dabigatran, rivaroxaban and apixaban, hold prom-
ise for future use in paediatrics but require further phar-
macologic study in infants, children and adolescents.
1 Introduction
Thrombosis was once considered a rare disorder in children,
but multiple reports in recent years have confirmed its rising
incidence [1–3]. Although venous thromboembolism (VTE)
is the most commonly recognized manifestation of throm-
botic disease in paediatrics, pathologic thrombi can develop
in the arteries as well, generally classified as either arterial
thrombosis or arterial ischemic stroke, depending on the site
of involvement. Each of these forms of thrombosis can
require treatment via anticoagulation given for several
weeks or months, according to current practice guidelines
[4]. The major risk associated with anticoagulation is
bleeding, which can have catastrophic consequences,
including long-term neurologic sequelae and death. On the
other hand, the primary risk associated with inadequate
anticoagulation of an existing thrombus is its growth,
recurrence or embolization, which can have similarly lasting
deleterious effects. Because optimal anticoagulant therapy
must occur within this narrow therapeutic window, the
pharmacologic behaviour of agents used in this setting
requires precise understanding. Furthermore, the complex
array of haemostatic proteins regulating thrombus formation
and breakdown is highly age dependent, with plasma con-
centrations often varying significantly between pre-mature
infants, neonates, older infants, children, adolescents and
adults [5, 6] (see the next section). Finally, age-dependent
pharmacokinetic parameters such as the volume of distri-
bution, drug elimination and drug-protein binding add a
final layer of complexity to proper dosing and monitoring.
 D. L. Yee et al.

Given these considerations, it is expected that in paedi- 2 Developmental Haemostasis

atric patients, anticoagulant pharmacokinetics and phar-
macodynamics would demonstrate unique, age-dependent
characteristics compared with those in adults. Such differ-
ences clearly hold clinical relevance for proper anticoagu-
lant management in children. Whereas other published
reviews have provided a more general, clinical perspective,
including information on risk factors and epidemiology
pertinent to thrombosis in children [7–9], this critical
review focuses specifically on published pharmacokinetic
and pharmacodynamic data on commercially available
anticoagulants in paediatric patients. In compiling this
review, a systematic review of the literature was performed
using PubMed to analyze pharmacokinetic and pharmaco-
dynamic studies of anticoagulant medications in paediatric
subjects. Each drug name with the ‘pharmacokinetic’ sub-
heading attached was ‘or’ed with the drug name combined
with the term ‘pharmacodynamics’. The retrieval was then
limited to ‘human’ and the ‘0–18 year old’ age group, and
to the time period of 1988–2013. Reference lists of retrieved
articles were searched for additional articles that were
included in this review. The background on each agent
(Table 1) is briefly reviewed, followed by a summary and
critical analysis of relevant studies.
The well-established paradigm of ‘developmental haemo-
stasis’ holds significant implications for anticoagulant use
in paediatrics, given the dependence of anticoagulation on
critical interactions between these drugs and age-dependent
plasma proteins, such as antithrombin, prothrombin and
factor Xa [5, 6]. With respect to thrombosis, antithrombin
holds a central role as a natural anticoagulant, down-reg-
ulating multiple procoagulant proteins but especially factor
IIa (the activated form of prothrombin) and factor Xa. In
the presence of heparin, binding of antithrombin to factors
IIa and Xa increases several hundred- to thousand-fold,
leading to accelerated deactivation of these procoagulant
molecules; antithrombin is thus also critical to the antico-
agulant effect of pharmacologically administered heparin
[5]. Full-term neonates have plasma concentrations of
antithrombin that are only 50–75 % of adult levels, while
pre-term infants may have levels that are significantly
lower. Adult levels are typically not attained until
6–12 months of age [6], necessitating exogenous admin-
istration of antithrombin concentrate in some young infants
and in other children with serious medical conditions
receiving heparin anticoagulation [10].

Table 1 Basic properties of anticoagulants used in children

Anticoagulant Route of Dosing interval Half-life Antithrombin Antidote Comments
administration dependence

Heparin Intravenous Bolus followed 30 min–2 h Yes Protamine Higher bodyweight-based dosing is required
by continuous in neonates to achieve comparable anti-Xa
infusion levels; the optimal pharmacodynamic assay
for monitoring the drug effect in paediatrics
has not been determined
Enoxaparin Subcutaneous Every 12 h 6h Yes Protamine Higher bodyweight-based dosing is required
(partial) in neonates to achieve comparable anti-Xa
levels; graduated syringes are available for
only certain vial sizes, necessitating
judicious prescribing for paediatric
patients; a multiple-dose vial is available
Warfarin Oral Once daily 40 h No Vitamin K, Higher bodyweight-based dosing is required
factor in infants and young children to achieve a
repletion comparable INR; no liquid formulation is
available
Bivalirudin Intravenous Bolus followed 25 min No None The mean half-life is 15–18 min in infants
by continuous and children; bodyweight-based clearance
infusion decreases with age
Lepirudin Intravenous Continuous 70 min No None No prospective studies have been published
infusion
Argatroban Intravenous Continuous 40 min No None This is the only anticoagulant with specific
infusion paediatric dosing information on the drug
label
Fondaparinux Subcutaneous Once daily 17 h Yes None The limited available information in children
suggests a similar pharmacologic profile to
that of adults
INR international normalized ratio
Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients
3 Unfractionated Heparin
Unfractionated heparin (UFH) comprises a heterogeneous
mixture of glycosaminoglycans derived from porcine intes-
tine or bovine lung, and functions as an anticoagulant by
potentiating the inhibitory effects of antithrombin on
thrombin (factor IIa) and factor Xa, as well as tissue factor
pathway inhibitor [11]. Its major advantages include its long
history of clinical use and its short half-life and easy
reversibility—the latter two are advantageous in critical care
and perioperative settings. Its significant limitations include
UFH’s high inter- and even intra-patient variability in the
dose response, leading to poor achievement and mainte-
nance of the therapeutic effect, and potentially an increased
risk of bleeding or worsening thrombosis. This variability
necessitates frequent monitoring and exists in addition to the
inherent technical limitations of the assays [the activated
partial thromboplastin time (aPTT) and anti-factor Xa assay]
most commonly used to measure anticoagulant or anti-
thrombotic effects [12–14], as discussed further below.
3.1 Pharmacokinetics
Clinical pharmacokinetic data on UFH use in adults has
been summarized, including that UFH has a half-life of
30 min to 2 h, which varies directly with the dose admin-
istered, has a usual volume of distribution approximating the
plasma volume, and does not largely depend on renal
elimination mechanisms [15]. In comparison, a recent pae-
diatric study characterized UFH’s pharmacokinetic behav-
iour using a one-compartment model, describing its mean
clearance, volume of distribution and half-life (0.6 mL/kg/min,
37.3 mL/kg and 45.6 min, respectively) in a group of 64
children who received a single bolus dose prior to cardiac
angiography [16]. In distinction, a similar analysis in 25
preterm newborns revealed increased clearance, an
increased volume of distribution and a shorter half-life in
this even younger population (1.37–1.49 mL/kg/min,
58–81 mL/kg and 36–42 min, respectively) [17]. Further
paediatric pharmacokinetic data are limited, but these results
in aggregate suggest significant age-dependent pharmaco-
kinetic differences between neonates, infants, children,
adolescents and adults—differences that may in part account
for the age-related pharmacodynamic differences described
below. Indeed, the UFH concentration itself showed sig-
nificant age dependence in another paediatric study,
increasing by 0.6 U/mL for every year of patient age in
samples collected soon after bolus injection of UFH [18].
3.2 Pharmacodynamics
From the standpoint of pharmacodynamics, evidence has
accumulated that supports age dependence of the mechanism
of action and the ultimate physiologic and clinical effect of
UFH in paediatric patients. These lines of evidence have
included an increase in the antithrombotic effect, as measured
by anti-Xa [19] and anti-IIa activity [18], and a decrease in the
anti-Xa/anti-IIa ratio with increasing age [18, 20] for a given
UFH dose. The physiology underlying this age dependence is
not fully understood but may be related to age-related differ-
ences in the protein structure and/or binding between UFH and
the many other moieties with which it interacts [21]. More-
over, the clinical laboratory assays used to monitor UFH’s
pharmacodynamic effects appear to perform differently in
children compared with adults. For example, although treat-
ment guidelines for thrombotic disease in adults imply that the
UFH concentration as measured by protamine titration
between 0.2 and 0.4 U/mL should correspond to anti-Xa
activity of 0.35–0.7 U/mL and aPTT values that are elevated
but usually measurable [22], recent studies have demonstrated
that these target ranges do not in fact correspond with each
other in children [14]. Furthermore, aPTT values corre-
sponding to these target ranges are often elevated signifi-
cantly, even to the point of being unmeasurable [14, 23].
In a recent study of 100 young infants requiring UFH via
continuous infusion, only 15 % of patients achieved anti-
Xa activity in the target range within 24 h of therapy ini-
tiation, compared with 81 % who achieved a target aPTT
within the same timeframe [24], a percentage comparable
with those observed in other cohorts for which the aPTT
was utilized [25]. Perhaps not surprisingly, correlation of
these two commonly used pharmacodynamic measures
with each other [24, 26, 27], as well as with the pharma-
cokinetic measure of heparin concentration determined by
protamine titration (not routinely used in clinical practice
due to the lack of an automated method) [14], are poor,
raising additional questions about the optimal assay
method for monitoring antithrombotic therapy with UFH in
children [28]. The specific assay reagents used in a given
laboratory also appear to be extremely important [13].
Despite these issues, current guidelines for antithrom-
botic therapy in children [4] continue to utilize a body-
weight-based dosing nomogram that accounts for patient
age dichotomously between infants (\1 year old) and all
other children, and extrapolate pharmacodynamic moni-
toring parameters directly from evidence obtained from
adult patients [22]. Although dose adjustments beyond
what is outlined in the current dosing nomogram [4] are not
typically suggested for specific patient populations, a
recent retrospective study has suggested that obese patients
may require a lower bodyweight-based dose in order to
achieve and maintain comparable anticoagulation; the
study further confirmed discrepancies between the aPTT
and anti-Xa monitoring assays [29].
Recent modifications to the United States Pharmacopeia
monograph for UFH may have resulted in a change in the

potency and hence the pharmacodynamic effect of UFH
produced and marketed in the US, at least as measured by
the activated clotting time (ACT), the method most com-
monly used to monitor UFH in the setting of cardiovascular
surgery [30], although it is known that the ACT correlates
poorly with the heparin concentration [31]. At this time,
however, no additional paediatric studies have corrobo-
rated this finding using alternative pharmacodynamic
measures such as the aPTT or anti-Xa activity.
As with other anticoagulants discussed below, appro-
priate therapy targets for UFH use in children may differ
from those for adults due to underlying age-related dif-
ferences attributable to developmental haemostasis, such as
in thrombin formation and regulation [32]. In accordance
with a recent International Society on Thrombosis and
Haemostasis position paper [28], future research must first
identify the optimal pharmacodynamic assay method and
then incorporate paediatric-specific clinical outcome data
in formulating the most appropriate target therapeutic
range for optimal use and monitoring of UFH in children.
4 Low Molecular Weight Heparins
Low molecular weight heparins (LMWHs) are derived from
UFH but are enriched for shorter-length polysaccharide
chains. This feature changes several of the LMWHs’ proper-
ties [33]. First, LMWHs have a more profound inhibitory
effect on factor Xa than on thrombin, with resulting ratios of
the anti-Xa to anti-IIa effect of 1.5 to[10, which may confer a
lower bleeding risk [34, 35]. In addition, LMWHs have stable
pharmacokinetics and thus a more predictable clinical
response than UFH, resulting in a less frequent need for
monitoring. LMWHs are also administered rather conve-
niently via the subcutaneous route and possess longer half-
lives, making them particularly useful in the outpatient setting.
As a result, LMWH use in children has increased substantially
over the past decade, replacing UFH as the agent of choice in
the initial treatment of thrombosis and joining warfarin as a
viable option for longer-term management [1]. Although
LMWHs appear to be the most commonly used anticoagulants
in children, pharmacokinetic–pharmacodynamic studies have
been sparse. Most were performed based on measurements of
anti-Xa activity and so are technically pharmacodynamic in
nature. A review published in 2008 identified five paediatric
LMWH pharmacologic studies [34].
4.1 Pharmacology
The initial paediatric dose-finding study of an LMWH was
published in 1996 [36]. In this prospective study of 20
patients receiving enoxaparin, anti-Xa levels peaked 4 h
after a subcutaneous injection of enoxaparin. Ten children
D. L. Yee et al.
reproducibly achieved an anti-Xa level of 0.5–1.0 IU/mL
with a dose of 1 mg/kg. Infants \2 months of age (n = 6)
required higher doses (average dose 1.64 mg/kg twice
daily). All subjects had measurable levels of anti-Xa at
hour 12, demonstrating that twice-daily dosing was feasible
in paediatric patients.
In 2000, Punzalan et al. [37] performed a study in six
patients receiving twice-daily enoxaparin (1 mg/kg per
dose). Enoxaparin pharmacodynamics were found to
approximate the profile in adults. In 2005, Kuhle et al. [38]
performed a single-centre, open-label, phase II study of
tinzaparin, administered once daily (175 IU/kg; 250 IU/kg
in infants \3 months) in 35 children with VTE. Population
pharmacokinetic analysis using nonlinear mixed-effect
modelling techniques was performed. Samples were
obtained after patients had achieved target anti-Xa levels.
Pharmacokinetic data for anti-Xa activity were reported by
age group and included maximum observed anti-Xa
activity ranging from 0.63 to 0.78 IU/mL, a time of max-
imum activity (Tmax) ranging from 2.2 to 4.3 h, a half-life
ranging from 3.45 to 8.83 h, and extravascular plasma
clearance ranging from 0.023 to 0.048 L/h/kg. Younger
children had higher dose requirements, more rapid clear-
ance, a shorter time to peak anti-Xa levels, and an
increased volume of distribution, and were more likely to
be below the target anti-Xa range than older children, with
the majority of patients \1 year of age being subthera-
peutic. Based on their findings, the authors recommended
that anti-Xa levels be drawn 2–3 h post-injection in patients
\5 years of age, and that anti-Xa levels be monitored at
least twice monthly in infants due to their rapid growth.
While enoxaparin is typically administered twice daily,
it has also been used successfully as a once-daily medi-
cation in the treatment of adult VTE. In 2007, O’Brien
et al. [39] published a dose-finding study of once-daily
enoxaparin in 14 paediatric patients (aged 3 months–
16 years). Target anti-Xa activity at hours 4–6 (1–2 IU/mL
in adults) was achieved in only one patient using the adult
recommended dose of 1.5 mg/kg. Eight children required a
final dose of [2 mg/kg to achieve target activity. Eight
patients completed 24-h pharmacodynamics monitoring.
The shape of the pharmacodynamics curve in this cohort
approximated the profile in healthy adults after adminis-
tration of 1.5 mg/kg [40]. However, total drug exposure
differed, with a mean area under the plasma concentration–
time curve (AUC) of 10.1 IU
h/mL in children, compared
with 16.4 IU
h/mL in adults (P \ 0.001). Children also
demonstrated faster clearance; seven of eight participants
demonstrated sub-therapeutic anti-Xa activity (\0.5 IU/mL)
by hour 12 post-dose, and four of the eight had undetectable
levels by hour 18 post-dose.
These findings of sub-optimal pharmacodynamics from
once-daily dosing of enoxaparin contrast with those of a
Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients

Fig. 1 Two-compartment
population pharmacokinetics
model describing enoxaparin
kinetics for a twice-daily
enoxaparin dosing; and b once-
daily enoxaparin dosing in 126
paediatric patients. The dashed
lines indicate the 90 %
confidence interval, the solid
line indicates the model-
predicted median and dots
indicate the observed anti-factor
Xa (anti-FXa) activity levels.
The starting dose was 1 mg/kg
(1.5 mg/kg for patients
\12 months of age), adjusted to
achieve a peak anti-FXa level of
0.5–0.8 IU/mL. Reproduced
with permission from Trame
et al. [41]. Copyright 2010, John
Wiley & Sons, Inc.

more recent and larger study performed by Trame et al.
[41], in which a population pharmacokinetic model was
developed using anti-Xa activity data from 126 children
receiving enoxaparin. Patients received enoxaparin
1 mg/kg twice daily during the acute treatment period
(7–14 days) and transitioned to either once-daily dosing
(starting dose 1.5 mg/kg/day) or twice-daily dosing
(starting dose 1 mg/kg/day) to complete their course of
anticoagulation [42]. In both treatment arms, the prede-
fined target anti-Xa activity was 0.5–0.8 IU/mL at hour 4
and [0.1 IU/mL at hour 24 [41]. A two-compartment
model was found to be adequate for describing enoxap-
arin kinetics. Bodyweight (as opposed to age and body
surface area) proved to be the most predictive covariate
for clearance and the central volume of distribution.
Parameter estimates were as follows: clearance 15 mL/kg/h,
central volume of distribution 169 mL/kg, intercompart-
mental clearance 58 mL/h, peripheral volume of distri-
bution 10 L and absorption rate 0.414/h. Inter-individual
variability was found to be 54 % for clearance and 42 %
for the volume of distribution, underscoring the need for
close monitoring of anti-Xa activity and dose individu-
alization in paediatric patients. The median 24 h trough
level was above 0.1 IU/mL in only 53.2 % of study
samples. However, a substantial proportion of children on
once-daily dosing had peak anti-Xa levels below the
target range (Fig. 1). Increasing the enoxaparin dose
based on these peak levels may have led to a higher
proportion of children with measureable levels at
hour 24.
Two studies have investigated the pharmacodynamics of
prophylactic (low-dose) LMWH in paediatric patients at
risk of VTE. In a study of 154 children undergoing open
heart surgery (with a peak anti-Xa target of 0.2–0.4
IU/mL), it was demonstrated that age and bodyweight
influenced the pharmacokinetic parameters of nadroparin
calcium, with bodyweight being the covariate that pro-
duced the largest improvement in the model fit [43]. Age
was redundant when bodyweight was included in the
model. Large inter-patient variability was also described
and was only partially explained by bodyweight. Massi-
cotte et al. [44] performed a pharmacologic study of pro-
phylactic doses of reviparin in 19 children with central
venous lines. Eighty percent of anti-Xa levels were within
the target range, with infants aged \3 months (starting
dose 50 IU/kg twice daily) and older children (starting
dose 30 IU/kg twice daily) having similar average peak
levels (0.26 IU/mL) and trough levels (0.13 IU/mL). Intra-
individual variability in pharmacologic profiles was higher
in patients \3 months of age.
Several other relevant prospective [45–49] and retro-
spective studies [50–56] on the use of LMWH for treat-
ment of paediatric VTE have been published. These studies
highlighted the need for higher doses of enoxaparin in
infants \2 months of age to achieve target anti-Xa levels,
especially for neonatal dosing higher than the currently

recommended 1.5 mg/kg every 12 h [57]. Possible mech-
anisms that may account for the altered pharmacodynamics
of enoxaparin in neonates include decreased thrombin
generation, decreased vitamin K-dependent coagulation
factors, and decreased natural anticoagulants such as anti-
thrombin and protein C [57]. Another large retrospective
study demonstrated two- to threefold variation in individ-
ual dose requirements for LMWH and a need for higher
enoxaparin dosing in children up to 5 years of age [53].
The increased dosing needs of younger children appear to
be due not only to differences in absorption and drug
clearance but also to differences in competitive binding to
the endothelium, as studies of plasma samples from healthy
infants, children, and adults have demonstrated that the
in vitro response to enoxaparin, as measured by the anti-Xa
assay, is actually not age dependent [58]. In a retrospective
review of two cohorts, Bauman et al. [50] showed that
using a higher starting dose in neonates (1.7 mg/kg dose)
and older children (1.2 mg/kg dose) results in faster
attainment of therapeutic anti-Xa levels and significantly
fewer venipunctures as compared with standard dosing (1.5
and 1.0 mg/kg). Fluctuations in anti-Xa levels during
maintenance enoxaparin therapy also appear to be a con-
cern, particularly in neonates [46, 51, 52, 54]. However, in
these retrospective studies, no correlation was found
between the quality of LMWH therapy (time in the target
range) and treatment outcomes or adverse events [51, 52].
While it is known that children with renal disease
require lower doses of LMWH due to the renal clearance of
these medications, studies have also shown that children
with congenital heart disease appear to be at risk of supra-
therapeutic anti-Xa levels [49, 52]. Very few studies have
investigated the effects of obesity, an increasing epidemic
in paediatrics, on the pharmacokinetics and dosing of
LMWH in children. A recent retrospective study has sug-
gested that dosing adjustments to the usual bodyweight-
based enoxaparin initiation regimen may not be required,
but also that more frequent therapeutic drug monitoring
may be advisable in obese patients [59]. Additionally,
many children receive LMWH injections via a subcutane-
ous catheter in order to reduce the number of needle
insertions, but it is not known how LMWH absorption may
differ with use of such catheters.
In summary, published studies of LMWH pharmacol-
ogy in paediatrics have clearly established the age-
dependent dosing required to achieve the anti-Xa target
(0.5–1.0 IU/mL) recommended for adults. It is also clear
that bodyweight is the strongest predictor covariate of
LMWH pharmacodynamics. Neonates and younger
children require higher doses of LMWH due to faster
clearance, an increased volume of distribution and
developmental changes in haemostasis. Children with
D. L. Yee et al.
underlying disorders such as renal insufficiency or con-
genital heart disease may require lower doses and closer
monitoring. What remains unclear is whether the anti-Xa
targets (0.5–1.0 IU/mL) utilized in the management of
adult thrombosis are appropriate for younger patients. To
date, no clinical studies have assessed the safety and
efficacy of this target range in children. Additional pae-
diatric pharmacologic studies in LMWH are needed to
(i) compare once- versus twice-daily dosing of enoxapa-
rin; (ii) determine the timing of peak target anti-Xa levels
in various age groups; and (iii) most importantly, deter-
mine the relationship between anti-Xa levels and efficacy
and safety for paediatric patients.
5 Vitamin K Antagonists
Orally administered vitamin K antagonists (VKAs) are
currently the most commonly used anticoagulants in adults
and are also frequently used in children to prevent and treat
thrombotic events. Most of the published data in children
pertain to warfarin [60, 61], which is the focus of this
section, but limited information exists for acenocoumarol
[62–64], phenprocoumon [65–67] and fluindione [64, 68].
The major advantage of warfarin is the oral route of
administration and long half-life, allowing for once-daily
dosing. However, warfarin’s significant disadvantages
include its narrow therapeutic index, its numerous drug
interactions, its dependence on an individual’s vitamin K
status and the lack of an adequate liquid formulation for
facile dosing in younger patients. Finally, the required
frequent monitoring of the drug’s pharmacodynamic effect
is inconvenient and can be difficult, especially in infants
and small children.
Warfarin is a racemic mixture of R and S enantiomers,
the latter possessing about three to five times the antico-
agulant potency of the former [69]. The drug is rapidly and
nearly completely absorbed, achieving the peak plasma
concentration (Cmax) between 2 and 6 h after dosing [70].
It binds extensively to plasma proteins such as albumin and
is metabolized by the hepatic cytochrome P450 (CYP)
system for elimination; only trace amounts of warfarin
appear in the urine. The elimination half-life of S-warfarin
is between 35 and 40 h [70]. R-warfarin has an even longer
half-life, due to its reduced clearance, but is not discussed
further in this review, given the anticoagulant dominance
of the S-congener. Warfarin exerts its anticoagulant effect
through competitive inhibition of vitamin K epoxide
reductase (VKOR), which regenerates vitamin K in its
reduced form. This reduced form of vitamin K is required
as a cofactor for gamma carboxylation of vitamin
K-dependent clotting factors and intrinsic anticoagulants.
Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients
5.1 Pharmacokinetics
Specific pharmacokinetic data on warfarin in paediatric
patients are limited, but a cross-sectional study from Japan
of 38 prepubertal patients (1–11 years), 15 pubertal
patients (12–18 years) and 81 adult patients on long-term
warfarin therapy is instructive [71]. In this study, mean
plasma concentrations of S-warfarin did not differ by age.
However, bodyweight-normalized clearance of the drug
was greater among prepubertal patients compared with
adults and showed a negative correlation with age [71].
Interestingly, drug clearance normalized for liver weight
was similar between the prepubertal and adult groups,
suggesting that liver size may be of primary importance in
determining dosing requirements, potentially accounting
more completely for warfarin dosing needs than such
currently ascribed parameters as bodyweight, age and
height (see the next subsection). Pharmacokinetic param-
eters for pubertal patients did not differ significantly from
those for adults (Table 2) [71].
5.2 Pharmacodynamics and Clinical Experience
in Paediatrics
Warfarin’s pharmacodynamic effect is most commonly
assessed in the clinical arena via the international nor-
malized ratio (INR). A target INR range of 2.0–3.0 is most
commonly applied, although other target ranges exist,
depending on the specific clinical setting (e.g., 2.5–3.5 or
1.5–1.9) [4]. Wide variation in warfarin dosing require-
ments between individuals (especially in infants and chil-
dren) to achieve a target INR has long been recognized in
clinical practice. Historically, a large proportion of such
variability seemed attributable to other unknown variables
(see the next subsection on pharmacogenetics), even with
adoption of a uniform bodyweight-based dosing regimen
Table 2 Pharmacokinetic parameters for S-warfarin with normalization to various physiological parameters in prepubertal, pubertal and adult
patients (adapted with permission from Takahashi et al. [71])
Parameter
Plasma unbound fraction (%)
Plasma unbound concentration (ng/mL)
Unbound oral clearance (mL/min)
Unbound oral clearance normalized to bodyweight (mL/min/kg)
Unbound oral clearance normalized to body surface area (mL/min/m2)
Unbound oral clearance normalized to liver weight (mL/min/kg liver weight)
Statistical comparisons were made among the groups for the respective parameters. The values are expressed as means ± standard deviations
* P \ 0.01 for the comparison between the prepubertal and adult groups
** P \ 0.05 for the comparison between the prepubertal and adult groups
P \ 0.05 for the comparison between the prepubertal and pubertal groups
[72]. It has also been recognized that other aspects of
developmental haemostasis, such as increased levels of
haemostatic regulatory plasma proteins like alpha-2 mac-
roglobulin, could influence the response to warfarin in
paediatric patients [73].
Such challenges of warfarin management in paediatrics,
especially in younger patients, were well documented in
the largest prospective study to date, which included 319
consecutive patients seen over a 5-year period at a single
centre, treated with warfarin under a uniform dosing and
monitoring regimen [61]. Compared with older paediatric
patients, patients under 1 year of age required increased
bodyweight-based dosing, longer periods of time to
achieve the targeted INR range and more frequent INR
monitoring and dose adjustments; they also had fewer INR
values within the target range. Children between 1 and
6 years of age also demonstrated similar findings when
compared with patients between 7 and 18 years of age.
Clinical factors such as a history of a Fontan procedure; use
of corticosteroids, phenobarbital or carbamazepine; and
enteral nutrition were all found to influence the required
warfarin dose and/or INR measurements [61]. In this
clinical setting, 79 % of patients achieved an INR within
the target range in less than 7 days, but maintaining an INR
within the target range proved difficult, as only 49–61 % of
measurements from this cohort during the 5-year study
period were within the target range [61], consistent with
findings from other studies of patients receiving warfarin.
A highly clinically relevant finding from the study by
Streif et al. [61] was the clear and distinctive inverse rela-
tionship between age and the maintenance dose requirement
per kilogram, with mean doses of 0.33, 0.15, 0.13 and
0.09 mg/kg/day for the age groups B1 year, [1 and \6
years, C6 and \13 years and 13–18 years, respectively.
Others have confirmed these findings in children; Nowak-
Gottl et al. [66] reported that of several clinical parameters
Prepubertal patients Pubertal patients Adult patients
(n = 38) (n = 15) (n = 81)
0.83 ± 0.28 0.82 ± 0.26 0.88 ± 0.17
1.80 ± 1.01 1.95 ± 1.02 1.93 ± 0.80
346 ± 217* 533 ± 285 637 ± 298
18.1 ± 9.2* 12.6 ± 8.1 11.6 ± 5.4
575 ± 282** 387 ± 270 438 ± 200
481 ± 244 419 ± 231 458 ± 209

that were analyzed, age was the single most important
variable affecting the VKA dose requirement, accounting
for 28 % of dose variation. Subsequent studies extended
these results by identifying patient height as an even better
variable to explain warfarin dose requirements, accounting
for 30–48 % of dose variability [68, 74]. Physiologically,
these somewhat disparate findings can perhaps be best
explained by the positive correlation between liver size,
patient age and height; the fact that clearance of warfarin
normalized for liver weight does not appear to be dependent
on age (Table 2) [71, 75]; the apparent direct relationship
between liver size and warfarin clearance [76]; and the
liver’s disproportionately large size compared with overall
patient size during early life [77]. Such notions may also
explain similar age-dependent variability in bodyweight-
based dosing requirements for other VKAs such as aceno-
coumarol [62]. Additional patient-related factors such as
dietary vitamin K status and concurrent illnesses, which
impact vitamin K absorption, may contribute significantly
to the variable pharmacodynamic response to warfarin
within and between individuals, especially for children,
whose dietary intake may be variable and in whom acute
gastrointestinal illness is not uncommon [78]. However,
recommended dosing strategies for warfarin in children
remain entirely bodyweight-based for the time being [4], as
they have over the last 20 years [60, 61].
5.3 Impact of Pharmacogenetics: Towards a More
Rational Dosing Strategy
In recent years, two genes—CYP2C9 and VKORC1, which
affect warfarin pharmacokinetics and pharmacodynamics,
respectively—have been found to account for an important
portion of the sources of interindividual variability in dos-
ing requirements. A third gene, CYP4F2, affects vitamin K
status and has been shown to have a minor effect on war-
farin dosing in adults [79] but was not found to be a sig-
nificant independent contributor to dosing requirements in
the two largest studies of children to date [68, 74]. CYP2C9
is a cytochrome P450 microsomal hepatic enzyme that
oxidizes warfarin to inactive metabolites (primarily 7-hy-
droxywarfarin); single nucleotide polymorphisms at resi-
dues 144 and 359 (CYP2C9*2 and CYP2C9*3,
respectively) can result in enzyme variants with reduced
metabolic activity, leading to relatively elevated plasma
warfarin concentrations in affected individuals compared
with individuals with the wild-type gene. VKORC1 is
the enzyme inhibited by warfarin; a polymorphism
(-1639G[A) in the promoter region of VKORC1 leads to
decreased enzyme transcription and hence a lower warfarin
dose requirement in affected individuals. Further details
regarding these genes and their associated enzymes have
been well described in recent reviews [77, 80].
D. L. Yee et al.
Over the last decade, pharmacogenetic knowledge rel-
evant to these polymorphisms and their impact on warfarin
dosing has expanded significantly, leading to widely
available dosing algorithms that incorporate an individual’s
genotypic profile along with other clinical variables, such
as age, gender, anthropomorphic measurements and con-
comitant medications. Utilizing these measures, recent
comprehensive models have accounted for approximately
50–60 % of warfarin dose variability in adults and have
proven to accurately predict individual warfarin dose
requirements [80]. However, such models and the under-
lying studies investigating the impact of the relevant gene
polymorphisms on warfarin dosing have generally not
included paediatric patients until very recently [66, 68, 74,
81–85]—these paediatric studies are summarized in
Table 3.
Biss et al. [74] examined the applicability of one of
these widely utilized and validated adult-based dosing
algorithms [86] to a well-characterized cohort of children
receiving a stable dose of warfarin. They found that
although the adult-derived algorithm predicted mainte-
nance doses for the children that were highly correlated
with the actual doses (r = 0.76, P \ 0.001), it also con-
sistently overestimated warfarin doses by, on average,
1.5 ± 1.4 mg/day [74], highlighting the need for dosing
strategies derived from paediatric cohorts. In fact, Biss
et al. [81] utilized the regression equation derived from this
study to perform an independent validation study involving
a separate cohort of 49 children on warfarin. This equation
incorporates patient height along with the warfarin indi-
cation and genotype information on CYP2C9 and VKORC1
status, since these four variables were found to account for
72.4 % of interindividual dose variability [74]. Impor-
tantly, the paediatric-derived equation showed better
agreement (r = 0.833, P \ 0.001), without systematic bias
[81]. Current US Food and Drug Administration (FDA)-
approved labelling for warfarin highlights the availability
of pharmacogenetic testing and its utility in individualizing
the required dosing for patients, but it does not include
specific paediatric recommendations or guidance.
Findings from the single paediatric pharmacokinetic
study of warfarin [71] must be viewed cautiously in light of
its ethnically limited study population. Moreover, such
pharmacokinetic information may hold limited value for an
individual patient, potentially being overridden by phar-
macogenetic and other individualized specific influences.
Instead, individualized dosing algorithms that take into
account clinical and pharmacogenetic information appear
well suited to refine warfarin dosing in children and adults,
although clinical outcome and cost-effectiveness benefits
remain to be clearly demonstrated and nearly a third of
interindividual dose variability remains unaccounted for
[87]. Future pharmacogenetic research should also include
Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients
Table 3 Published reports on
Reference
the impact of pharmacogenetics
on warfarin dosing in Kosaki et al. [84]
paediatrics
Ruud et al. [85]
Nowak-Gottl et al. [66]
INR international normalized
ratio
a Kato et al. [83]
The parentheses indicate
patients receiving alternative
vitamin K antagonists such as Biss et al. [74]
phenprocoumon [66] or
fluindione [68]
b
VKORC1 encodes vitamin K Moreau et al. [68]
epoxide reductase, the enzyme
inhibited by warfarin. CYP2C9
encodes the cytochrome P450
Biss et al. [82]
microsomal hepatic enzyme that
oxidizes warfarin to inactive
metabolites
paediatric patients with more diverse ethnic backgrounds to
more robustly validate recent comprehensive dose predic-
tion models, given the predominance of white children in
study groups to date (Table 3). Finally, as for other anti-
coagulants discussed in this review, the relationship
between warfarin pharmacodynamics and clinical efficacy
and toxicity in paediatrics also lacks sufficiently clear
definition.
6 Direct Thrombin Inhibitors (Intravenous)
Three direct thrombin inhibitors (DTIs) have been used in
children: bivalirudin, argatroban and lepirudin. Several case
reports and series have described children treated with these
agents [88–91]. As their name implies, all DTIs directly
inhibit thrombin, in contrast to UFH and LMWH, which
exert their effect indirectly via antithrombin. The advantages
of DTIs are that they do not require antithrombin for their
function, they have more predictable pharmacokinetics and
pharmacodynamics, and they inhibit both circulating and
clot-bound thrombin. The main disadvantage is their intra-
venous administration, mostly by continuous infusion; they
are used only in the inpatient setting. Another significant
disadvantage is the general lack of paediatric experience
with these agents. While small clinical trials have been
completed for argatroban and bivalirudin, no paediatric trials
have been performed for lepirudin.
6.1 Bivalirudin
Bivalirudin, a synthetic, rationally designed analogue of
hirudin, is indicated for the prevention of thrombosis in
Na Age range (y) Key findingsb
31 12–34 VKORC1 variant status conferred increased warfarin
sensitivity
29 1–14 There was faster achievement of the target INR and
more frequent INRs above the target in patients
with CYP2C9 variants
59 (25) 1–19 VKORC1 accounted for 4 %, CYP2C9 accounted for
0.4 % and age accounted for 28 % of warfarin
dose variation
48 0.42–19.25 VKORC1 variant status conferred increased warfarin
sensitivity; age was another major covariate
120 1–18 VKORC1 accounted for 27 %, CYP2C9 accounted
for 13 % and height accounted for 30 % of
warfarin dose variation
118 (35) 0.25–18 VKORC1 accounted for 18 %, CYP2C9 accounted
for 2 % and height accounted for 48 % of warfarin
dose variation
51 1–17 Higher peak INR values and more values above the
target range at warfarin initiation were observed in
patients with VKORC1 and CYP2C9 variants
adults undergoing percutaneous coronary interventions.
The first prospective study of a DTI in children was per-
formed using bivalirudin in 16 infants less than 6 months
of age with VTE in a single-arm, open-label, dose-finding,
safety and efficacy study [92]. This age group was spe-
cifically chosen due to the physiologically low levels of
antithrombin in infants. The study utilized only a phar-
macodynamic parameter (the aPTT) to assess the degree of
anticoagulation in order to titrate dosing. The study defined
the dosing for children of this age, utilizing a bolus fol-
lowed by a continuous infusion. With respect to the bolus,
12 of 13 subjects with evaluable post-bolus testing
achieved the target aPTT range, while 15 of the 16
achieved the target aPTT range at the first measurement
following initiation of the continuous infusion. A second,
similarly designed, prospective study of bivalirudin in
older children (aged 6 months–18 years) with VTE was
recently completed, which enrolled 18 patients and inclu-
ded evaluation of both pharmacokinetics (plasma biva-
lirudin concentrations) and pharmacodynamics (the aPTT)
[93]. Of note, the appropriate bodyweight-based dosing
strategy appeared to be the same for older children in this
study as that used for infants in the earlier study.
Bivalirudin was also studied prospectively in 110 chil-
dren undergoing cardiac catheterization for the prevention
of thrombosis, about a third of whom were infants [94].
This single-arm, safety, efficacy and dose-finding study
used a higher dosing regimen than the VTE studies
described above, and similar to that used for the licensed
adult indication (a bolus of 0.75 mg/kg/h and a continuous
infusion of 1.75 mg/kg/h). The data from this study dem-
onstrated that the pharmacokinetic–pharmacodynamic
response of bivalirudin was similar in children and adults,

although there was a trend towards increased Cmax, mean
AUC and mean average concentration (Cavg) values with
increasing age from neonates to older children [94]. Mean
half-life values ranged from 15 to 18 min across all of the
age groups that were evaluated. Bodyweight-normalized
clearance decreased with increasing age (11.2 versus
5.98 mL/min/kg for neonates versus children aged 6 to
\16 years, respectively). This study utilized a different
pharmacodynamic endpoint (the ACT); a clear correlation
between the pharmacokinetic and pharmacodynamic
parameters in this study was not established, which may
reflect limitations of the ACT assay.
These three clinical trials of bivalirudin have provided
the largest prospectively collected pharmacologic data set
for any single anticoagulant in paediatrics, yet the hetero-
geneity in patient populations and dosing schemes should
be noted. Although the studies of paediatric VTE totalled
only 34 patients, both studies ultimately confirmed the
same dosing regimen for infants and children for this
indication. Despite bivalirudin’s significant pharmacologic
advantages over UFH, lack of general clinical experience
with this agent has prevented its more widespread adoption
as an anticoagulant in children.
6.2 Argatroban
Argatroban is a small molecule analogue of the amino
acid arginine, is approved in adults for the treatment of
heparin-induced thrombocytopenia (HIT) and is the only
anticoagulant with information on paediatric use in the
prescribing information. The prospective study that pro-
vided this dosing information evaluated the safety, efficacy
and dosing of argatroban in 18 children with either docu-
mented or suspected HIT or who required an alternative
anticoagulant for other reasons [95]. A detailed pharma-
cometric analysis was undertaken [96], which supported
the dosing schema now approved by the FDA. In this study,
a two-compartment population pharmacokinetic model was
adopted, which examined argatroban concentrations and
aPTT results from blood samples obtained from the clinical
study. The key results demonstrated that the pharmacoki-
netic–pharmacodynamic relationship for argatroban in
paediatric patients is similar to that in adult patients, with a
linear relationship between argatroban levels and the aPTT
in the region of therapeutic efficacy. From these data, a
prediction model was developed from which the recom-
mended initial infusion dose of 0.75 lg/kg/min was cho-
sen, which now appears in the paediatric section of the
argatroban prescribing information (Fig. 2).
Based on these important findings, including specific
paediatric dosing information derived from the single
prospective study and subsequent pharmacometric analy-
sis, argatroban is the drug of choice in paediatric HIT [95,
D. L. Yee et al.
Fig. 2 This figure, derived from pharmacometric simulations per-
formed on raw data, was used to determine the most appropriate
initial dose of argatroban in children. The dose in lg/kg/min is shown
on the x-axis. The left y-axis depicts the percentage of patients
expected to have an activated partial thromboplastin time (aPTT)
within the target range of 1.5–3 times the baseline value (squares).
The right y-axis depicts the percentage of patients expected to exceed
the target range [[3 times the baseline aPTT value (triangles)]. Since
nearly 60 % of patients are expected to be within the target range
and only 5 % are expected to exceed this range at a dose of 0.75
lg/kg/min, 0.75 lg/kg/min was chosen as the appropriate initial dose.
Adapted with permission from Madabushi et al. [96]. Copyright 2011,
John Wiley & Sons, Inc.
96]. Although lepirudin, bivalirudin and fondaparinux are
all acceptable options, only argatroban has been prospec-
tively evaluated for this purpose. It should be noted that
argatroban is excreted mainly by the liver, and while FDA-
guided dosing recommendations for argatroban are avail-
able for paediatric patients with liver impairment, an
alternative agent with elimination independent of liver
function, such as bivalirudin, may be appropriate.
7 Fondaparinux Sodium
Fondaparinux is a synthetic, antithrombin-dependent inhibi-
tor of factor Xa, approved in adults for the initial manage-
ment of VTE. It is given subcutaneously and has (relative to
LMWH) a long half-life, such that it is dosed once daily.
Other advantages include no risk of HIT or contaminants,
and no adverse effect on bone mineralization (in contrast to
UFH and LMWH). Several case reports and one prospective
study have described its use in children [97–99].
The only prospective clinical trial of fondaparinux in
children was a single-arm, open-label, dose-finding and
safety study of 24 patients between 1 and 18 years of age
[99]. The pharmacologic analysis featured a pharmacody-
namic endpoint (fondaparinux-based anti-factor Xa levels)
and demonstrated that nearly all patients were therapeutic
Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients
Fig. 3 The observed fondaparinux concentration data from the
paediatric study (open circles) were overlaid on a plot of a simulation
of 1,000 adult subjects receiving the recommended dosing regimen
for treatment. The solid line indicates the median and the dashed lines
indicate the 95% prediction interval. The adult doses are the approved
bodyweight-based dosing for venous thromboembolism (5 mg for
\50 kg, 7.5 mg for 50–100 kg and 10 mg for [100 kg). The
paediatric dosing was 0.1 mg/kg up to a maximum of 7.5 mg. It
can be seen that the observed data from the paediatric study fall
within the 95 % prediction interval of the adult data. Thus, the
fondaparinux exposure achieved in this paediatric population was
similar to that observed in adults given treatment doses of fondapar-
inux. Adapted with permission from Young et al. [99]. Copyright
2011, John Wiley & Sons, Inc.
after the first dose and that once-daily dosing led to ther-
apeutic anticoagulation for 24 h in each patient. Further-
more, a population pharmacokinetic model demonstrated
that a dose of 0.1 mg/kg once daily in children recapitu-
lated the pharmacology of fondaparinux in adults. A
two-compartment model with first-order absorption and
elimination adequately fitted the data, and the pharmaco-
kinetic parameters were in good agreement with the adult
data. Simulations were performed to assess the 0.1 mg/kg/day
dose by comparing steady-state peak and trough concentra-
tions achieved in paediatric patients with corresponding levels
in adults. The observed paediatric data fell within the 95 %
confidence intervals of the expected adult levels (Fig. 3). A
follow-up study of this cohort of patients (supplemented by
additional patients not in the original study) was recently
completed, which assessed long-term pharmacodynamic peak
measurements only [100].
In summary, fondaparinux can be considered an alterna-
tive to the anticoagulant most commonly prescribed in
children, LMWH. The mechanism of action and pharmaco-
logic properties are similar to those of LMWH. The main
advantage of fondaparinux is its longer half-life, allowing for
once-daily dosing. As such, the adoption of fondaparinux
into clinical use in paediatrics may increase in the future.
8 Novel Oral Anticoagulants
In recent years, three novel oral anticoagulants (dabigatran,
rivaroxaban and apixaban) have been approved by major
regulatory agencies and are thus widely available for a
variety of adult indications worldwide. Although the
pharmacology of these agents is well characterized for
adults [101], no specific paediatric studies have been
published to date. However, each agent is being studied
systematically in children and adolescents, including spe-
cific pharmacokinetic and pharmacodynamic studies.
These results, as well as subsequent initiation of larger
clinical trials examining the safety and efficacy of these
agents in paediatrics, are expected in the near future. For-
tunately, the need for such underlying rigour has become
widely recognized (and is required by drug regulatory
authorities), leading to well-defined and adequately funded
paediatric drug development programs for these and other
novel anticoagulants in the pipeline [9, 28].
9 Conclusions
Use of anticoagulants in paediatrics has suffered from a
lack of prospectively designed studies. This dearth of
high-quality information has applied as much to pharmaco-
kinetics and pharmacodynamics—the focus of this review—
as to other arenas, such as drug safety and efficacy, leading
to frequent dilemmas for the practising clinician. For each
anticoagulant, the most pressing need is better under-
standing of the relationship between the drug’s pharma-
cokinetics–pharmacodynamics and its efficacy and
toxicity. Only then can the most age- and indication-
appropriate therapeutic window be targeted, as opposed to
current practice, whereby anticoagulant monitoring and
dosing are merely extrapolated from experience in adults.
This approach is likely to be suboptimal, given develop-
mental differences between children and adults in haemo-
stasis and pharmacology. In contrast, the advent of novel
anticoagulants promising increased convenience and safety
holds forth new hope for the treatment of paediatric
thrombosis. Inclusion of rigorous and systematic paediatric
studies in the drug development process lays proper
groundwork for rationally based dosing strategies for
children in the years ahead.
Acknowledgments The authors thank Linda DeMuro, MLS, and
Susi Miller, MLIS, AHIP, from the Grant Morrow III, MD Medical
Library at Nationwide Children’s Hospital (Columbus, OH, USA) for

their assistance in designing the search strategy and performing the
initial literature search. Drs Yee and Young have no financial conflicts
of interest to disclose. Dr O’Brien is a member of a Bristol-Myers
Squibb advisory board for paediatric apixaban studies.
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