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1080 S E C T I O N I X   Pediatric Critical Care: Hematology and Oncology

TABLE
90.4 Assays Used in the Monitoring of UFH Therapy

Assay

Common Uses

Advantages

Disadvantages in Children

aPTT
F-Clot

Coagulation screening assay
Therapeutic UFH monitoring

Low cost
Easy to perform
Widely available

Baseline aPTT often prolonged in children
Wide variability in reagent sensitivity to age-related differences
Nonphysiologic measure of UFH effect
No validation of therapeutic ranges in children

TCT
F-Clot

Coagulation screening assay
Therapeutic UFH monitoring
(rarely)

Easy to perform

Patients previously exposed to topical thrombin may have antibodies
causing prolongation of the clotting time
Optimal concentration of thrombin used for the assay is unknown
No validated reference range for UFH in children

ACT
F-Clot

CPB, extracorporeal circuits

Easy bedside whole blood test
Extensive experience in most PICUs

Does not correlate with any specific measures of heparin activity
Analyzer dependent

Anti-Xa
F-Ch

Calibration of aPTT
reference ranges
Therapeutic UFH monitoring

Direct measure of UFH inhibition

of Xa
Easy to perform

Not as widely available as aPTT and costs significantly more
Does not measure other mechanisms of UFH effect (e.g., anti-IIa) and
assumes constant ration of effect, which is not true in children
Some kits have exogenous AT, others have dextran sulphate, both of
which will introduce in vitro error in small children for different
reasons

Protamine
titration Q

Not used clinically
Used by reference
laboratories

Only assay that directly measures
UFH concentration
Low cost

Not widely available
Automated methods have not been validated for management of
therapeutic UFH and manual methods labor intensive

aPTT, Activated partial thromboplastin time; AT, antithrombin; CPB, cardiopulmonary bypass; F-Ch, functional, chromogenic assay; F-Clot, functional, clot-based assay; PICUs, pediatric intensive care
units; Q, quantitative assay; TCT, thrombin clotting time; UFH, unfractionated heparin.

It is not hard to see how such errors occur in busy units that operate 24 hours per day. Units should actively manage the choices of
UFH preparations available to their staff to minimize the risk of

confusion. Staff should be educated in the dangers of UFH and
encouraged to be vigilant at all times when administering a drug
that consistently ranks in hospital lists of the drugs most commonly involved in medication errors.
Another adverse event from UFH only recently reported has
been anaphylaxis, which in 2007 to 2008 accounted for over 80
deaths due to an unintended contaminant introduced in the manufacturing process.118 Again, while there is almost nothing in the
medical literature describing these events, the FDA released a number of warning statements; one impact of this has been changes to
the labeling of UFH. The potential for contamination of drug products made from biological sources will always be real. An important
mechanism to minimize this risk is to ensure that children receive
UFH only when the risks are clearly outweighed by the benefits.
UFH has been described as being ubiquitous in PICUs; thus, clinicians should actively minimize unnecessary exposure to it.
In summary, anticoagulation in children in the PICU is common, and UFH is currently the most common anticoagulant.
While there remain many concerns about the potential adverse
effects of UFH, there are currently no real alternative anticoagulant agents available for intravenous use in sick children. Many
adverse events are related to dosing errors, and it is likely that
PICUs can significantly improve the safety of UFH by developing
systems to prevent medication errors. In addition, there is emerging evidence that our understanding of the pharmacokinetics of
UFH in children and of the assays used to monitor UFH in children is far from ideal. Urgent research is required to improve the
safety and utility of UFH in critically ill children.

Thromboprophylaxis in the Pediatric Intensive
Care Unit
In critically ill adults, pharmacologic thromboprophylaxis is
highly recommended owing to its proven efficacy and safety in
the prevention of DVT. The patient populations that require
pharmacologic prophylaxis in pediatrics are less well defined.119
One of the many issues with studying this area is the difference
in nomenclature regarding “prophylaxis.” VTE prophylaxis
with UFH or LMWH is often confused with “line prophylaxis”
or “line patency prophylaxis” (usually UFH but at very different doses). The increasing incidence of thromboembolism in

the PICU patient has led several institutions to develop risk
stratification protocols to target patients at the highest risk.120,121
The most common risk factors remain the presence of CVAD,
cardiac disease, and infants younger than 1 year.122 There is a
variety of practice depending on the center; currently, between
0% and 50% of children receive thromboprophylaxis.123–127 A
prospective study examining pediatric trauma patients developed a risk stratification protocol and found a decrease by 65%
in VTE with implementation of this protocol. Of note in this
study of 76 patients determined to be high risk for VTE, only
two received pharmacologic thromboprophylaxis as per their
protocol.128
Generalized routine thromboprophylaxis is unlikely to be of
benefit in the PICU. The development of risk assessment tools
and their effectiveness remains an area of ongoing research.
Nonpharmacologic thromboprophylaxis should be encouraged.
Minimization of concurrent risk factors, early mobilization,
and removal of CVADs as soon as feasible seem to be sensible
strategies.


1080.e1

• eFig.

90.3  ​Preparations of unfractionated heparin (UFH) commonly
found on an Australian pediatric ward. Note the minimal differences in
packaging and the significant differences in UFH concentration, such that
there is potential for a 100-fold overdose should a selection error be
made.

CHAPTER 90  Thrombosis in Pediatric Critical Care

Conclusions
Thromboembolic disease is now a major cause of mortality and
morbidity in critically ill children in the context of children having marked differences in the hemostatic system compared with
adults, which appear to be age related. There remains much to be
learned about the etiology and clinical presentations of thrombosis. Diagnostic strategies are mostly extrapolated from adult studies but are likely suboptimal. Similarly, management strategies
and the use of anticoagulants in children for either treatment or
primary prophylaxis are guided by minimal evidence; thus, there
is a desperate need for further research. In the meantime, clinical
decisions must be made. For the time being, these decisions require consideration of the individual risk-benefit ratios for each
patient.

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1081

Higgerson RA, Lawson KA, Christie LM, et al. Incidence and risk factors
associated with venous thrombotic events in pediatric intensive care
unit patients. Pediatr Crit Care Med. 2011;12(6):628-634.
Huang JY, Ignjatovic V, Sheridan BJ, et al. Bleeding and thrombotic
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Huang JY, Monagle P, Massicotte MP, VanderPluym CJ. Antithrombotic
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Jones S, Butt W, Monagle P, Cain T, Newall F. The natural history of
asymptomatic central venous catheter-related thrombosis in critically
ill children. Blood. 2019;133(8):857-866.
Male C, Chait P, Ginsberg JS, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in
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Monagle P, Cuello CA, Augustine C, et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism:
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Raffini L. Anticoagulation with VADs and ECMO: walking the tightrope. Hematology Am Soc Hematol Educ Program. 2017;2017(1):
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Rizzi M, Albisetti M. Treatment of arterial thrombosis in children: methods and mechanisms. Thromb Res. 2018;169:113-119.
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Vidal E, Sharathkumar A, Glover J, Faustino EV. Central venous catheterrelated thrombosis and thromboprophylaxis in children: a systematic
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Wessel DL, Berger F, Li JS, et al. Clopidogrel in infants with systemic-topulmonary-artery shunts. N Engl J Med. 2013;368(25):2377-2384.

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