Pediatric Cardiac Intensive Care Society 2014 Consensus Statement: Pharmacotherapies in Cardiac Critical Care Anticoagulation and Thrombolysis
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Pediatric Cardiac Intensive Care Society 2014
Consensus Statement: Pharmacotherapies in Cardiac
Critical Care Anticoagulation and Thrombolysis
Therese M. Giglia, MD, FACC, FAAP, SCCM1; Char Witmer, MD2;
David E. Procaccini, PharmD, BCPS3; Jonathan W. Byrnes, MD4
Objective: Thrombotic complications are increasingly being rec- have been approved for a limited number of indications in adults,
ognized as a significant cause of morbidity and mortality in pedi- studies on the safety and efficacy of these agents in children are
atric and congenital heart disease. The objective of this article is pending. (Pediatr Crit Care Med 2016; 17:S77–S88)
to review the medications currently available to prevent and treat Key Words: anticoagulation; congenital heart disease; Coumadin;
such complications. heparin; pharmacokinetics; thrombolysis
Data Sources: Online searches were conducted using PubMed.
Study Selection: Studies were selected for inclusion based on their
scientific merit and applicability to the pediatric cardiac population.
T
Data Extraction: Pertinent information from each selected study or hrombotic complications are increasingly being recog-
scientific review was extracted for inclusion. nized as a significant cause of morbidity and mortal-
Data Synthesis: Four classes of medications were identified ity in pediatric and congenital heart disease (1–3). The
as potentially beneficial in this patient group: anticoagulants, purpose of this article is to review the medications available to
antiplatelet agents, thrombolytic agents, and novel oral antico- prevent and treat such complications. Four classes of drugs are
agulants. Data on each class of medication were synthesized potentially efficacious; three classes are currently approved for
into the follow sections: mechanism of action, pharmacokinet- the use in children: 1) anticoagulants, 2) antiplatelet agents,
ics, dosing, monitoring, reversal, considerations for use, and and 3) thrombolytic agents. Although the fourth class, novel
evidence to support. anticoagulants, has been approved for the use in adults with
Conclusions: Anticoagulants, antiplatelet agents, and thrombolytic selected conditions, none of the drugs in this class have yet been
agents are routinely used successfully in the pediatric patient with approved in children because the pharmacokinetics, safety, and
heart disease for the prevention and treatment of a wide range of efficacy have not yet been established in this population.
thrombotic complications. Although the novel oral anticoagulants For each drug in this section, the mechanism of action
(MOA), pharmacokinetics, dosing, therapeutic goal, monitoring,
1
Division of Cardiology, Department of Pediatrics, Children’s Hospital of reversal, considerations for use, and evidence to support use will
Philadelphia, Perelman School of Medicine at the University of Pennsyl- be reviewed. This article should be used in conjunction with the
vania, Philadelphia, Pennsylvania. recently published guidelines for anticoagulation and treatment
2
Division of Hematology, Department of Pediatrics, Children’s Hospital of of thrombosis in children with pediatric and congenital heart
Philadelphia, Perelman School of Medicine at the University of Pennsyl-
vania, Philadelphia, Pennsylvania. disease (1, 4) where specific clinical indications are elaborated.
3
Department of Pediatrics, Pediatric Pharmacy, Johns Hopkins Medical
Center, Baltimore, MD.
4
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center,
ANTICOAGULANTS
University of Cincinnati College of Medicine, Cincinnati, OH.
Unfractionated Heparin
Dr. Witmer disclosed off-label product use: All anticoagulants but one
are off label. Dr. Byrnes’ institution received support from Daiichi-Sanyo
MOA. Unfractionated heparin (UFH) is composed of a het-
(Edoxaban) (no direct financial support, but site PI for a phase I study. erogeneous mixture of highly sulfated glycosaminoglycans (5).
Dr. Byrnes’ portion of the article had no mention of this or related prod- UFH acts as an anticoagulant protein by binding antithrombin
ucts). The remaining authors have disclosed that they do not have any
potential conflicts of interest. and potentiating its anticoagulant activity over 1,000-fold inacti-
For information regarding this article, E-mail: gigliat@email.chop.edu vating coagulant factors IIa (thrombin), Xa, XIa, and XIIa (6–9).
Copyright © 2016 by the Society of Critical Care Medicine and the World Pharmacokinetics. UFH is available as a continuous IV
Federation of Pediatric Intensive and Critical Care Societies infusion or a subcutaneous injection. The half-life is short at
DOI: 10.1097/PCC.0000000000000623 1.5 ± 0.5 hours (10). Unfortunately, UFH can interact with
Pediatric Critical Care Medicine www.pccmjournal.org S77
Unauthorized reproduction of this article is prohibitedGiglia et al
other plasma proteins, endothelial cells, and macrophages, UFH. There can also be poor correlation between the aPTT
which alter the pharmacokinetics and anticoagulant effect and the UFH anti-Xa level.
resulting in a high inter- and intrapatient dose-response. Heparin resistance has been reported in up to 22% of adult
Elimination is thought to be via binding to endothelial cell patients undergoing surgery with cardiopulmonary bypass
receptors and macrophages (11). Pediatric patients represent (14) and may be the result of low antithrombin levels. Heparin
a challenge for heparin therapy secondary to developmental resistance should be suspected when increased dosing does not
hemostasis with age-dependent changes in the target proteins result in therapeutic aPTT or UFH anti-Xa levels and is treated
for UFH (12). Specifically, neonates have low antithrombin with infusion of antithrombin or fresh frozen plasma.
levels. In addition, the clearance of UFH in infants is faster sec- Reversal. Full reversal of heparin can be obtained with the
ondary to a larger plasma volume of distribution (13). use of protamine sulfate (9). Approximately 1 mg of protamine
Dosing. To achieve steady state more quickly, IV UFH is will neutralize 100 U of UFH. Calculations should be made
usually started as a bolus followed by a continuous infusion based on the total amount of heparin received in the prior
(4). The bolus should be deferred if there is a concern for sig- 2–2.5 hours (9).
nificant bleeding. Consideration for Use. UFH therapy can be a challenge in
Initial loading bolus (if indicated): 75 U/kg over 10 minutes pediatric patients secondary to the need for frequent monitor-
followed by age younger than 1 year old: continuous rate 28 U/ ing, high inter- and intrapatient dosing variability, and the need
kg/hr and age more than 1 year old: continuous rate 20 U/kg/hr. for a dedicated line for the continuous infusion. The benefits
Further adjustments to the continuous infusion are based on of UFH include the short half-life and the ability to completely
monitoring (see below). reverse the anticoagulation effect. In addition, UFH can be used
Monitoring. No clinical trials have determined the thera- in the setting of renal failure, whereas low molecular weight
peutic range for UFH in pediatric patients, thus it is extrapo- heparins (LMWH) cannot. In clinically unstable patients at risk
lated from the adult literature. The two most common assays for hemorrhage who require anticoagulation, UFH should be
used to monitor UFH include the activated partial thrombo- strongly considered. Transition to an alternative anticoagulant
plastin time (aPTT) and the UFH anti-Xa level. should occur once the patient is clinically stable.
Therapeutic Goal. aPTT: 1.5–2.5 times control (60–85 s) or The predominant risk associated with UFH therapy is hem-
UFH anti-Xa level: 0.3–0.7 U/mL (Table 1). orrhage. To minimize this bleeding risk, concurrent antiplatelet
At this time, it is unclear as to the best method for monitor- therapy should be avoided if possible. It is important to treat con-
ing UFH therapy in pediatric patients (4). The aPTT is not a comitant severe thrombocytopenia and coagulopathy as well.
direct measure of the UFH effect and can be affected by many Nonhemorrhagic complications associated with UFH include
other parameters. An elevated factor VIII or fibrinogen (acute heparin-induced thrombocytopenia (HIT) and osteopenia.
phase reactants) will shorten the aPTT making it appear that Prolonged use of UFH is associated with osteoporosis in adults,
the patient is heparin resistant (aPTT not prolonging despite and there are case reports in children (15, 16). UFH-associated
receiving UFH). Alternatively, a deficiency in a coagulation fac- HIT is characterized by thrombocytopenia and resultant arterial
tor (i.e., from liver failure or consumption) or the presence of or venous thrombosis that can be catastrophic. The prevalence
an antiphospholipid antibody will prolong the aPTT making it of HIT in the pediatric population appears to be less than adults
appear that the patient is therapeutic. Although the UFH anti- with a reported range of 0–2.3% (17–20). Higher risk pediat-
Xa level is a direct measure of the heparin effect on coagulation ric groups include those patients undergoing cardiopulmonary
factor X, it does not reflect additional anticoagulant targets of bypass (21). The treatment of HIT includes the removal of all
Table 1. Unfractionated Heparin Continuous Infusion Dose Titration
Activated Partial
Thromboplastin Unfractionated Heparin
Time (s) Anti-Xa (U/mL) Dose Adjustment Laboratory Monitoring
< 50 < 0.1 Bolus: 50 IU/kg 4-hr postrate change
Increase infusion rate by 10%
50–59 0.1–0.29 Increase infusion rate by 10% 4-hr postrate change
60–85 0.3–0.7 No change 4-hr then q24 hr
86–95 0.71–0.9 Decrease infusion rate by 10% 4-hr postrate change
96–120 0.91–1 Hold infusion for 30 min 4-hr postrate change
Decrease infusion rate by 10%
> 120 >1 Hold infusion for 60 min 4-hr postrate change
Decrease infusion rate by 15%Supplement
heparin from the patient including avoidance of LMWH (i.e., Monitoring. Routine monitoring is currently recommended
Enoxaparin). Anticoagulation should be initiated with a non- for pediatric patients receiving LMWH therapy (4). The target
heparin anticoagulant, such as a direct thrombin inhibitor (DTI) therapeutic range is extrapolated from adult studies.
(i.e., argatroban or bivalirudin). In this setting, warfarin should LMWH Anti-Xa (Peak Level). A dose level of 0.5–1 U/mL
never be initiated by itself due to an increased risk of skin (drawn 4–6 hr post administration), see Monagle et al (4) for
necrosis and further thrombotic events. Warfarin can be ini- adjustment recommendations based on peak anti-Xa level.
tiated once the platelet count has normalized and should be Reversal. LMWH can be partially reversed (≈70%) with
overlapped with the nonheparin anticoagulant until the inter- protamine.
nationalized ratio (INR) is therapeutic. Consideration for Use. In general, LMWH is easier to use in
pediatric patients because it does not require a dedicated line,
Evidence to Support and frequent monitoring is not needed. Unfortunately, a sub-
Indications for the use of UFH include the treatment of venous, cutaneous injection, bid, is not insignificant for many pediatric
arterial, or intracardiac thrombi or to prevent thrombosis. patients. It should not be used in the setting of renal failure.
Extensive reviews have been completed regarding the effective- The predominant risk associated with LMWH therapy is
ness of UFH, and a complete discussion is beyond the scope hemorrhage. To minimize this bleeding risk, concurrent anti-
of this article, but the authors refer readers to review the 2012 platelet therapy should be avoided if possible and treating severe
Chest guidelines on Antithrombotic Therapy in Neonates (4) thrombocytopenia and coagulopathy. HIT has been reported
and Children as well as the 2013 American Heart Association with the use of LMWH in pediatric patients (27, 28). Overall,
guidelines for the Prevention and Treatment of Thrombosis in LMWH-induced HIT is thought to be less frequent when com-
Pediatric Congenital Heart Disease (1). pared with UFH (29). The frequency of osteoporosis from
LMWH in pediatrics has not been studied, but in adults, LMWH
LMWH is associated with less bone loss when compared with UFH (9).
MOA. LMWH are derived from UFH by chemical or enzy- Evidence to Support. Indications for LMWH therapy are
matic depolymerization and contain shorter length polysac- the same as UFH and include the treatment of venous or arte-
charide chains. Similar to UFH, LMWH exert an anticoagulant rial thrombi or prevention of thrombosis. Readers are referred
effect through binding antithrombin and potentiating the to recent reviews that have been completed regarding the effec-
antithrombin anticoagulant activity, but when compared with tiveness of LMWH (1, 4) .
UFH, there is a reduced inhibitory activity against factor IIa Enoxaparin has been demonstrated to be effective in the
(thrombin) relative to factor Xa. treatment of catheter-associated arterial thrombosis in pediat-
Pharmacokinetics. LMWH are administered as a subcu- ric patients with congenital heart disease (30, 31). In addition,
taneous injection. The pharmacokinetics properties are more Enoxaparin has been associated with a reduction in the risk
stable than UFH. The half-life is 3–6 hours. Unlike UFH, of thrombotic complications when compared with no therapy
LMWH is predominantly cleared by the kidneys. These favor- in one study of pediatric patients with single ventricle cardiac
able pharmacokinetic features, when compared with UFH, lesions after initial palliation (stage I) and after superior cavo-
have resulted in an increasing use of LMWH in children, and pulmonary connection (stage II) (32).
Enoxaparin is currently the most common anticoagulant used
and studied in pediatric patients (22, 23). Fondaparinux
Dosing. Pediatric patients exhibit a significant variation in MOA. Fondaparinux is a synthetic analog of the antithrom-
LMWH dosing based on age and weight. Younger children and bin-binding pentasaccharide found in heparin and LMWH.
neonates require higher doses of LMWH secondary to increased The structure was modified to enhance its affinity for anti-
volume of distribution, increased clearance, and developmental thrombin increasing the specific activity and half-life. Unlike
hemostasis (4, 24–26). Baseline laboratories should be obtained UFH or LMWH, fondaparinux has no inhibitory activity
to ensure whether patient has a normal baseline coagulation against factor IIa (thrombin) and only inactivates factor Xa.
state: complete blood count (CBC) (Thrombocytopenia is a Pharmacokinetics. Fondaparinux is administered via a
relative contraindication to anticoagulant therapy and should subcutaneous injection. The half-life is longer than LMWH at
be corrected to ≥ 75,000 per mL before use), prothrombin time 17 hours. The clearance is exclusively renal.
(PT), aPTT, and serum creatinine (Enoxaparin is not recom- Dosing. Pediatric: 0.1 mg/kg subcutaneous daily (33).
mended in the presence of renal failure). Monitoring. Routine coagulation monitoring is recom-
Initial Enoxaparin Dose. Less than 3 months old: 1.7 mg/kg mended for children. Specific assays calibrated for fondaparinux
subcutaneously every 12 hours. should be used (34). Therapeutic goal is a fondaparinux anti-
Three months–2 years old: 1.2 mg/kg subcutaneously every Xa (peak): 0.5–1 mg/L (drawn 4 hr post administration).
12 hours. Reversal. There are no reversal agents available for
More than 2 years old: 1 mg/kg subcutaneously every fondaparinux. Unlike other forms of heparin, protamine does
12 hours. not bind fondaparinux. There are reports of using various
Obese patients approximately 0.8 mg/kg subcutaneously hemostatic therapies (prothrombin complex concentrates,
every 12 hours to maximum dose of 170 mg. activated prothrombin complex concentrates, or recombinantGiglia et al
factor VIIa) to treat life-threatening bleeding secondary to complex subunit 1 loci to create a nomogram for Coumadin
fondaparinux (35). dosing showed promise in reducing time to a therapeutic level,
Consideration for Use. Similar to other anticoagulants, the but further research is needed (42).
highest risk associated with fondaparinux therapy is hemor- Monitoring. Coumadin monitoring relies on the INR; ther-
rhage. Due to the long half-life and lack of a reversal agent, apeutic ranges vary with the indication. Limited studies exam-
this medication should only be used in patients who are clini- ining patient self-testing have improved quality of life and time
cally stable with a low risk of hemorrhage. It should not be in the therapeutic range (43, 44).
used in patients with renal insufficiency. Off-label use has been Reversal. Reversal of Coumadin and related compounds is
reported in both adults and pediatric patients in the treatment related to the urgency in which reversal is desired, the throm-
of HIT although further studies are warranted (36, 37). botic risk associated with treatment and the severity of bleed-
Evidence to Support. There is limited evidence in pediatrics ing (45–47). Choices for reversal include vitamin K, fresh
regarding the use of fondaparinux. The strongest data include one frozen plasma, and discontinuing Coumadin. In general, vita-
prospective dose-finding, single arm, pharmacokinetics study in min K is avoided when the risk of thromboembolism is high,
24 pediatric patients and a long-term follow-up study of 34 pedi- such as left ventricular assist devices (VADs) and mechanical
atric patients who received fondaparinux (33, 36). These limited prosthetic heart valves; however, recently, a population of adult
data suggest that fondaparinux may be safe and efficacious. left VAD patients overall tolerated reversal well (48).
Consideration for Use. Coumadin has traditionally been
Warfarin avoided in pregnancy because of risk of fetal loss and birth
MOA. Coagulation factors II, V, VII, X, and proteins C, S, and Z defects although by targeting a lower therapeutic range, these
undergo the vitamin K–dependent process of γ-carboxylation. risks may be mitigated (49). After the Fontan procedure, the
The group of 4-hydroxycoumarin–related molecules, where use of aspirin versus warfarin for thromboembolic prophylaxis
Coumadin is included, exerts their action by inhibiting vita- remains controversial. Indications and INR ranges for warfa-
min K epoxide reductase preventing vitamin K1 regeneration rin that are encountered in the cardiac ICU are discussed in
after γ-carboxylation. more detail in the recommendations of the American College
Pharmacokinetics. Coumadin is a racemic mixture of the of Chest Physicians (4, 50) as well as in the 2013 American
R- and S-enantiomers. The S-enantiomer is more potent, but Heart Association guidelines for the Prevention and Treat-
is more rapidly cleared. The half-life of racemic warfarin is ment of Thrombosis in Pediatric Congenital Heart Disease (1).
36–42 hours. Significant variability in dose-response is related Recommendations for the prophylaxis of mechanical valves
to genetic variation in vitamin K epoxide reductase com- (51), arrhythmias (1), and cardiac systolic dysfunction (1) are
plex subunit 1, which is responsible for reducing vitamin K extrapolated from the adult literature. Recommendations for
2,3-epoxide to active vitamin K1 (38–40). prophylaxis of VADs are specific to each particular device and
Dosing. The interaction of age, varying targeted ranges, are provided by the manufacturers.
genetic polymorphism of enzymatic breakdown, and active
site of vitamin K epoxide reductase makes pediatric Coumadin Parental DTIs
dosing difficult. Initial bolus dosing of 0.2 mg/kg (maximum MOA. DTI are direct, specific, and reversible inhibitors of
initial dose 10 mg) with adjustments on subsequent days based thrombin. The three commercially available DTIs are bivali-
on daily INR values has been applied in two trials where all sub- rudin, argatroban, and lepirudin. Argatroban is a univalent
jects attained an INR greater than 2 and most reached a target DTI, which reversibly inhibits thrombin’s catalytic site. Bivali-
INR in less than 7 days (4, 41). See the 2012 Chest guidelines for rudin and lepirudin are known as bivalent DTIs, which bind
suggested subsequent day dosing based on daily INR (4). the active catalytic site of thrombin, as well as the thrombin-
Patients who have had a Fontan procedure or have liver fibrinogen binding site.
disease are generally more sensitive to warfarin, and so a con- Pharmacokinetics. Steady state levels of argatroban are
servative loading dose of 0.1 mg/kg is recommended. Patients attained after 1–3 hours. The elimination half-life is 39–51
under the age of 1 year often require much higher doses of minutes and is principally excreted by the biliary route
warfarin. Guidance of a hematologist may be helpful. (52, 53). After discontinuation of the drug, aPTT normalized
Initiation of warfarin without a bolus dose: an alternative in less than 4 hours, but may take up to 20 hours in the context
regime approximates the dose of warfarin based on age and of severe liver dysfunction. Bivalirudin is an engineered syn-
weight without the use of a bolus: age 2–12 years old: 0.09 mg/kg thetic hirudin with a half-life is 25 minutes (54). It is cleaved
day, age more than 12 years old: 0.08 mg/kg day. by thrombin and subsequently excreted by the liver with
Continue heparin and warfarin for 5 days. Check INR on 20% excreted by the kidney (55). Lepirudin is a recombinant
day 5. If the INR is therapeutic, stop the heparin (UFH or hirudin with a half-life of 60 minutes, which is cleared by the
LMWH) and check INR in 3–5 days. If day 5 INR is subthera- kidneys. Steady state levels are attained after 1–3 hours. Anti-
peutic, increase warfarin based on the table above and con- bodies to the drug can form in as many as 40% of patients (56)
tinue heparin (UFH or LMWH) until INR is therapeutic. although anaphylaxis is rare (57).
Recently, a pilot study using the genotype of the cytochrome Dosing. The recommendations of DTI dosing are extrapo-
p450 enzyme (CYP2C9) and vitamin K epoxide reductase lated from adult experience/protocols. Recent survey results
S80 www.pccmjournal.org March 2016 • Volume 17 • Number 3 (Suppl.)Supplement
provide insight to commonly used pediatric dosing. Argatro- (76). The disadvantage is that methods to monitor these medi-
ban is not commonly bolused and the initial infusion rate is cations are not readily available (76). It is unclear at this time
typically 0.25–1 μg/kg/min. In advanced liver disease, arg- whether monitoring will be required for pediatric patients.
atroban dosing must be reduced (58). Bivalirudin is bolused Reversal. There are no reversal agents for NOACs (77).
at 0.125 mg/kg IV and then an infusion of 0.125 mg/kg/hr is Dabigitran can be partially removed with hemodialysis (78).
initiated. According to national pediatric surveys and reviews There are reports of using various hemostatic therapies (pro-
of administrative databases, lepirudin has not been reported thrombin complex concentrates, activated prothrombin
or used frequently enough to have guidelines that are different complex concentrates, or recombinant factor VIIa) to treat
from adult guidelines (59, 60). life-threatening bleeding secondary to NOACs (77, 79). Spe-
Monitoring. Most institutions report titrating the DTIs cific antidotes are currently being developed (79).
based on aPTTs every 2–4 hours to aim for an aPTT 1.5–2.5× Consideration for Use. At this time, NOACs should only be
normal (60). Issues with aPTT in monitoring DTIs are as fol- used in pediatric patients in the setting of a clinical trial.
lows: aPTT does not reliably detect supratherapeutic DTI lev- Evidence to Support. In adult studies, NOACs have been
els as the dose response curves are not linear at higher ranges; demonstrated to be efficacious and in the United States are
there can be variation among aPTT reagents; and there can approved for the use in stroke prevention from atrial fibrilla-
be unreliability in the context of antiphospholipid antibodies tion, the treatment of acute deep vein thrombosis (DVT), sec-
(61–63). The diluted thrombin time assays and ecarin clotting ondary prevention of DVT, DVT prevention post elective knee
assays are the most accurate and reproducible tests for moni- and hip surgery (80), and in the treatment of acute pulmonary
toring DTIs (62, 64–66). embolus (81, 82).
Reversal. Limited DTI clinical application has led to lim- At this time, NOACs should not be used in the setting of
ited knowledge of optimal means of reversal. Isolated products mechanical heart valves. A clinical trial comparing dabigi-
(fresh frozen plasma and cryoprecipitate) or factors (activated tran with warfarin in patients with either an aortic or mitral
factor VII) have been shown to be of inconsistent benefit in mechanical heart valve was halted early secondary to increased
DTI-associated bleeding (66–69). The definitive reversal ther- thrombotic and bleeding events in those patients receiving
apy is renal replacement therapy (70–72). Adult protocols for dabigitran when compared with warfarin (83). A phase 2 clini-
reversal and management of DTI-associated hemorrhage are cal trial is currently underway using rivaroxaban in the set-
reported elsewhere (73). ting of mechanical aortic valve replacement (ClincalTrials.gov
Consideration for Use. The only labeled indication for DTIs Identifier: NCT02128841).
is for HIT and for coronary intervention in adults. DTIs are
increasingly used for HIT, and trials are underway examining
Antiplatelet Agents
their role in ischemic stroke and renal replacement therapy
(74, 75). Aspirin Acetylsalicylic Acid
Evidence to Support. At present, there are no large trials of MOA. It irreversibly inhibits cyclooxygenase (COX-1 and
use of DTIs in pediatrics and no Food and Drug Administra- COX-2) activity in the arachidonic acid pathway, inhibiting the
tion–approved uses; however, the use in HIT is accepted, and formation of thromboxane (TXA2), inhibiting platelet activa-
the pediatric experience of its use continues to grow. tion and aggregation (84).
Pharmacokinetics. Upon oral administration, aspirin ace-
Novel Oral Anticoagulants tylsalicylic acid (ASA) is rapidly absorbed after administration.
Since 2010, novel oral anticoagulants (NOACs) received Food It is hydrolyzed to salicylate (active) by esterases in the fastrin-
and Drug Administration approval for use in adult patients. testinal mucosa, RBC, synovial fluid, and readily distributes
Pediatric trials are currently ongoing, and we await these into most body fluids and tissues. ASA is hepatically metabo-
results to direct the use of these medications in children. lized and renally excreted. Although dose dependent, the half-
MOA. All of the NOACs bind directly to a key coagulant life (t½) is 15–20 minutes (84).
protein to inhibit fibrin formation. There are two broad cat- Dosing for Antiplatelet Effect. Antiplatelet: 1–5 mg/kg/d
egories for MOA including direct anti-Xa inhibitors (rivar- (maximum: 91 mg) (4, 85).
oxaban, apixaban, and edoxaban) and direct thrombin (IIa) Monitoring. There are no studies that link outcome to
inhibitors (dabigitran). measuring aspirin effect; however, platelet aggregation assays
Pharmacokinetics. The advantage to all of the NOACs is (i.e., light transmission aggregometry) may be used to inter-
more predictable pharmacokinetics with a wide therapeutic pret arachidonic acid (goal < 40% of normal activity for aspi-
window and limited drug-drug interactions when compared rin) and adenosine diphosphate (ADP) activity to monitor
with warfarin. They also have a relative rapid onset of action theoretical response. The thromboelastogram with platelet
and shorter half-lives than warfarin. mapping assay is a modification of the standard thromboelas-
Dosing. Pediatric dosing is not available at this time. togram and is used to assess the effectiveness of antiplatelet
Monitoring. The key advantage to predictable pharmacoki- medications. This assay uses whole blood that is heparinized to
netics and a wide therapeutic window for NOACs is that rou- suppress thrombin generation, and then known platelet ago-
tine therapeutic monitoring is not necessary in adult patients nists are added to the sample to assess platelet activation. The
Pediatric Critical Care Medicine www.pccmjournal.org S81Giglia et al
thromboelastogram with platelet mapping is commonly used Reversal.
in pediatric patients with a left VAD to monitor antiplatelet ●● No reversal agents available.
therapy (86). ●● Platelet aggregation has been shown to fully recover 4 days
Reversal. after discontinuation of clopidogrel; however, it is com-
●● No reversal agents available. mon to discontinue therapy 5–7 days prior to surgery.
●● Platelet aggregation may recover within 4 days after dis- ●● Type and cross pheresis.
continuation of aspirin, 11 however due to the irreversible ●● Platelets 4–20 U/kg.
platelet inhibition it is commonly recommended to dis-
Evidence to Support. Clopidogrel is used instead of ASA in
continue ASA 7 days before the surgery to allow full plate-
the presence of ASA allergy or intolerance. It has also been used
let regeneration.
in combination with ASA in selected patients when additional
●● Type and cross pheresis.
antiplatelet effect is desired, for example, children with Kawasaki
●● Platelets (4–20 U/kg) may be given to counteract the plate-
disease and moderate sized aneurysms (1, 4, 89). Adding clopi-
let aggregation inhibition from ASA.
dogrel to chronic low-dose, ASA did not reduce overall mortality
Evidence to Support. Low-dose aspirin has become the main- or shunt-related morbidity in the Clopridigrel to Lower Arterial
stay of thromboprophylaxis for Blalock-Taussig shunts (1, 4, 87, Thrombotic Risk in Neonates and Infants Trial (101)
88) and in the long-term management of coronary aneurysms in
Kawasaki Disease (1, 4, 89). Aspirin may be recommended after Dipyridamole
stroke in children with heart disease depending on the age of the MOA. It inhibits the activity of adenosine deaminase and
child, the etiology of the stroke (ischemic vs embolic), and the phosphodiesterase, which causes an accumulation of adenos-
time after the stroke and the risk of recurrence (1, 4, 90). Aspirin ine, adenine nucleotides, and cyclic AMP which inhibit platelet
is often used as a part of the thromboprophylaxis regime with aggregation. Vasodilation, including coronary artery vasodila-
VADs although specifics vary with device. Controversy exists in tion, has been reported (1, 102–104).
the use of aspirin in single hypoplastic left heart disease palliated Pharmacokinetics. Although dipyridamole is available in IV
with a stage I with Sano modification (1, 4, 91), single ventricle form, the oral formulation is what is primarily used in clinical
physiology beyond stage I (1, 4, 32, 92–94), and with intravas- practice. Oral dipyridamole is absorbed slowly and with much
cular stents (1, 4). Aspirin has been recommended as an adjunct variability (26–66%) (96, 105). Peak serum concentrations are
to warfarin in the thromboprophylaxis of mechanical valves in reached around 75 minutes, and the t½ is 10–12 hours on aver-
the mitral and aortic positions although the practice in children age (106, 107). Dipyridamole is hepatically metabolized and
varies (51, 95). excreted in bile as glucuronide conjugates and unchanged drug
and eliminated in feces (103, 106, 107).
Clopidogrel Dosing. 1–5 mg/kg/d (1, 4).
MOA. It undergoes in vivo biotransformation to an active thiol Monitoring. Although there are no studies that link out-
metabolite, which irreversibly blocks the P2Y12 component of come to measuring dipyridamole effect, platelet aggregation
ADP receptors on the platelet surface, which prevents platelet panels that assess arachidonic acid and ADP activity (goal
activation and therefore aggregation (96). 20–40% of normal activity), as well as platelet mapping tech-
Pharmacokinetics. Clopidogrel is only available in oral niques, such as thromboelastogram monitoring (MA, α), are
formulations and is rapidly absorbed after administration. It often used (86).
undergoes extensive hepatic metabolism via esterase-hydro- Reversal.
lysis to an inactive carboxylic acid derivative and CYP2C19- ●● No reversal agents available.
mediated oxidation to an active thiol metabolite. The t½ of the ●● Type and cross pheresis.
parent drug is around 6 hours, however, that of the active thiol ●● Platelets 10–20 U/kg.
metabolite is approximately 30 minutes (96).
Evidence to Support. Currently, the main use of dipyri-
Dosing. Infants and children less than or equal to 24 months:
damole is as adjunct therapy to other anticoagulant/antiplate-
initial dose of 0.2 mg/kg/dose once daily (97–99)
let medications in the maintenance of mechanical circulatory
Children 2 years old or older: initial dose of 1 mg/kg once
support (108–112). Dipyridamole, in a dose-related fashion
daily; titrate to response (97–99)
when combined with aspirin, has been shown to decrease both
Monitoring. Although there are no studies in pediatric
platelet aggregation and platelet adhesiveness more than aspirin
patients that link outcome to measuring clopidogrel effect, the
alone (113).
VerifyNow platelet aggregation assay that measures percentage
of P2Y12 receptor inhibition is often used in clinical practice
(100); a level of less than 236 platelet activity units is generally THROMBOLYTIC THERAPY
accepted as a therapeutic response based on positive outcomes Unlike the anticoagulants and antiplatelet agents that prevent
in adults patients undergoing elective coronary stent implan- thrombus formation and/or thrombus extension, the throm-
tation (100). thromboelastogram monitoring (MA, α) is also bolytic agents augment the body’s natural systems of dissolv-
commonly used to monitor response to the drug (86). ing blood clots. The only available thrombolytic agents in the
S82 www.pccmjournal.org March 2016 • Volume 17 • Number 3 (Suppl.)Supplement
United States currently are the biosynthetic (recombinant DNA The decreased level of plasminogen in neonates (≈50% of
origin) forms of the enzyme human tissue-type plasminogen that in adults) slows the generation of plasmin and reduces
activator (tPA): alteplase (TPA), recteplase, and tenecteplase. the effect of thrombolytics in an in vitro system (120).
Urokinase, obtained from human neonatal kidney cells grown Supplementation with plasminogen increases the thrombo-
in tissue culture and streptokinase, obtained from bacterial lytic effect and may be helpful (4).
cultures, are no longer available in the United States. Whenever
possible, a hematology consultation is recommended to assist Dosing
in evaluation of eligibility, administration, and monitoring. Numerous dosing strategies for alteplase (tPA) have been used
in pediatrics, and there is currently no consensus as to which
Safety and Efficacy approach is optimal. Higher doses may restore flow more rap-
Before initiation of thrombolytic therapy, hematologic idly, but appear to have a higher risk of bleeding. A 2009 survey
derangements, such as thrombocytopenia or vitamin K defi- of hematology-oncology specialists showed no consensus in
ciency, should be corrected. The risk of bleeding with throm- indications for thrombolysis, dose, mode of delivery, or length
bolytic therapy in children is significant mandating serious of therapy (121).
consideration of the risk and benefits in each situation prior Alteplase may be delivered systemically or locally by cath-
to initiation of therapy and consultation with a bleeding and eter-directed therapy with the following dosing regimens (1):
clotting expert whenever possible. Older studies reported a 40–
●● Systemic thrombolysis:
60% prevalence of bleeding complications when higher doses
of alteplase were used (> 0.5 mg/kg/hr). A report of alteplase ○○ Low-dose alteplase (tPA) regimen: this regimen was
for femoral artery thrombosis in children documented a 1.5% initially recommended for patients with non–life-
prevalence of intracranial hemorrhage with the highest preva- threatening venous thrombotic events although it has
lence in preterm infants when compared with older children been successfully used in patient with prosthetic valve
(114). A more recent review reported major and minor bleed- thrombosis and more critical arterial thrombi.
ing complications with TPA as 17% and 26%, respectively ◾◾ Initial dose: 0.03–0.06 mg/kg/hr. Maximum dose for
(115). In the event of minor bleeding, local pressure and sup- low-dose alteplase (tPA) 2 mg/hr.
portive care are usually sufficient. Major bleeding is treated by ◾◾ Duration: this dose may be continued for a relatively
stopping the thrombolytic and administering cryoprecipitate prolonged duration (24–86 hr) and may be increased
(usual dose of 1 U/5 kg or 5–10 mL/kg), an antifibrinolytic, or within the 0.03–0.06 range providing that hema-
both along with other blood products as needed (4). tologic parameters are appropriate and there is no
Complete resolution of thrombosis with TPA has been hemodynamically significant bleeding.
reported to range from 39% to 87% with no response to ther- ◾◾ Ongoing monitoring of hematologic parameters (see
apy in about 20% (4) and resolution in arterial thrombi supe- monitoring below) and thrombus assessment are
rior to venous (116). essential.
MOA. It initiates local fibrinolysis by binding to fibrin in a ○○ High-dose alteplase (tPA) regimen: This regimen may
thrombus and converting entrapped plasminogen to plasmin be considered for patients with arterial or more critical
that in turn degrades fibrinogen (Lexicomp Online, Pediatric & thrombotic events.
Neonatal Lexi-Drugs, Lexicomp, Hudson, OH; April 7, 2015). ◾◾ Initial dose: 0.1–0.6 mg/kg/hr.
There is an evidence that the tPAs, especially alteplase, have ◾◾ Duration: the duration will depend upon the chosen
antiplatelet properties as well by inhibiting platelet aggregation. dose. For patients receiving doses of 0.5–0.6 mg/kg/hr,
Alteplase-related inhibition of platelet aggregation appears to be hematologic parameters and thrombus assessment
independent of plasmin generation, fibrinogen degradation and should be performed (see monitoring below) at 6 hours.
glycoprotein IIb/IIIa receptor, and P-selectin expression (117). If the progress is not adequate, hematologic parameters
Pharmacokinetics. Pharmacokinetics have not been estab- are within acceptable range (see contraindications for
lished in infants and children. Pharmacokinetics in adults has thrombolysis) and the patient is stable, a second 6-hour
been described as followed: infusion can be administered. Patients at the lower end
●● Duration: more than 50% present in plasma cleared approx- of this dose range may tolerate longer infusions.
imately 5 minutes after infusion terminated, approximately ○○ Pulmonary embolism protocol: thrombolysis may
80% cleared within 10 minutes; fibrinolytic activity per- be considered for patients with massive pulmonary
sists for up to 1 hour after infusion terminated (Lexicomp embolus (PE) who are hemodynamically unstable.
Online, Pediatric & Neonatal Lexi-Drugs) (118). Patients who are hemodynamically stable with PE are
●● Excretion: rapidly cleared from circulating plasma treated with anticoagulation. The following protocol
(572 ± 132 mL/min) (119), primarily hepatic; more than 50% has been used in adults and would need to be individu-
present in plasma is cleared within 5 minutes after the infusion alized for younger patients.
is terminated, approximately 80% cleared within 10 minutes ◾◾ Adult dose/duration: 10-mg alteplase over 10 minutes,
(Lexicomp Online, Pediatric & Neonatal Lexi-Drugs) (118). followed by 90 mg over 2 hours.
www.pccmjournal.org S83
Pediatric Critical Care MedicineGiglia et al
○○ Stroke protocol: thrombolysis for stroke has not been mL before initiation of therapy. Patients are often admitted to
studied in pediatric patients and should be performed an ICU for close monitoring during tPA therapy and must be
under the guidance of a Stroke Team whenever pos- on strict bed rest. A blood drawing IV or arterial line is rec-
sible. Thrombolysis is considered when treatment can ommended for frequent laboratory draws prior to initiation
be initiated less than 4.5 hours after onset of symptoms of therapy. Heparin flushes and heparin-containing solution
and where imaging demonstrates thrombotic occlusion. should not be used for this line.
Onset of symptoms is defined as the time the patient
●● Check PT, PTT, CBC, fibrinogen, D-dimer prior to start-
was last seen well, or at usual clinical baseline.
ing, and then every 4–6 hours while the patient is receiving
◾◾ Dose/duration: 0.9 mg/kg alteplase (maximum of the thrombolytic. An elevated D-dimer and drop in the
90 mg) infused over 60 minutes with 10% of the total fibrinogen is indicative of a lytic state.
dose administered as an initial IV bolus over ●● Monitor neurologic status q1 hour for possible ICH. In
1 minute. infants or critically ill patients, whose neurologic status is
●● Catheter-directed thrombolysis: usually administered via a difficult to assess, consider a daily head ultrasound or CT
pulse-spray catheter located in the thrombus during therapy.
●● Dose adjustment: if the fibrinogen drops to less than
○○ Dose/duration: 0.5–2 mg/hr. The duration will vary
125 mg/dL, decrease the dose of thrombolytic by 50%.
depending on the dose and indication, but long infu-
If the fibrinogen drops greater than 100 mg/dL, consider
sions (96 hr) have been well tolerated. Ongoing moni-
holding thrombolytic or give cryoprecipitate.
toring of hematologic parameters (see monitoring
●● Avoid invasive procedures (blood draws, placement of
below) and thrombus assessment are essential.
arterial or venous catheters, intramuscular injections,
●● Pharmacomechanical thrombolysis: it refers to the use of nasogastric tubes, rectal temperature probes, and place-
alteplase in conjunction with one of several devices for ment of urinary catheters) during therapy and for at least
mechanical disruption of clot. Specific devices include: 24 hours after high-dose tPA therapy.
○○ Angiojet: saline is injected under high pressure into ●● Avoid drugs that affect platelet function (e.g., aspirin,
the thrombus, which helps to break up the thrombus. nonsteroidal anti-inflammatory, dipyridamole) as they
Simultaneously, the saline and thrombus are suctioned may potentiate the risk of hemorrhage.
back into the catheter. In patients without contraindi- ●● If a patient has significant bleeding, stop the thrombolytic
cations to thrombolysis, alteplase may be added to the agent and heparin, administer cryoprecipitate, and con-
saline infusion. For an adolescent patient (> 50 kg),\mg sider reversing heparin with protamine in life-threatening
of alteplase is a typical dose. Although some of the situations. Antifibrinolytics (aminocaproic acid) can also
alteplase will be suctioned back, much will be systemic. be considered.
○○ Trellis device: this device is placed into the thrombus Reversal. Alteplase (tPA) cannot be reversed, but has a rel-
and balloons inflated above and below. Alteplase is atively short half-life. Holding alteplase (tPA) and heparin a
instilled between the balloons, while a small wire rotates minimum of 6 hours prior to surgical procedure or lumbar
to disrupt the clot. The standard dose is 10 mg of tPA puncture is recommended.
for patients more than 50 kg, administered at a rate of Consideration for Use. Thrombolytics have a low margin
1 mg/min. After 10 minutes, the liquefied thrombus and of safely and variable efficacy in children and therefore should
remaining alteplase are aspirated back through the cath-
be used with caution. Although anticoagulation alone is often
eter so that the alteplase is not systemic.
effective at managing thromboembolism, there are times when
Use of Concomitant Anticoagulation. The use of UFH dur- more rapid clot resolution is necessary or desirable. Indications
ing systemic and catheter-directed thrombolytic therapy may for thrombolysis in the treatment of pediatric thromboembo-
be helpful in preventing ongoing thrombus formation but will lism are not well established, primarily due to the paucity of
increase the risk of bleeding. This decision should be made on an well-designed clinical studies. The benefit of rapid clot resolu-
individual basis. Usually low-dose heparin is used at 10 U/kg/hr. tion must be weighed against the risk of major bleeding, which is
In cases where alteplase is used to treat acute ischemic stroke, greater than with anticoagulation alone. Thrombolytic therapy
other antithrombotic treatments, such as heparin, warfarin, in children should be restricted to situations in which the benefit
aspirin, are held for at least 24 hours. of rapid thrombus resolution is thought to outweigh the risk of
Monitoring. Because of the risk of bleeding with tPA the major hemorrhage and is usually reserved for thrombosis which
following laboratories are recommended prior to initiation of is hemodynamically significant and/or limb threatening.
therapy: CBC, PT, PTT, fibrinogen, D-dimer, and to exclude Evidence to Support. Thrombolytic therapy has been used
intracranial hemorrhage, a head ultrasound in neonates and in infants and children since this early 1980s; initially uroki-
infants younger than 1 month old and head CT in older chil- nase and streptokinase (122–125) and then subsequently tPA
dren whose neurologic status is difficult to assess. Thrombocy- were used (126–129). Although there have been no random-
topenia is a relative contraindication to thrombolytic therapy ized trials, a substantial recent experience has been reported in
and should be corrected to greater than or equal to 75,000 per children with heart disease in the following areas:
S84 www.pccmjournal.org March 2016 • Volume 17 • Number 3 (Suppl.)Supplement
●● General (1, 4, 130). 20. Spadone D, Clark F, James E, et al: Heparin-induced thrombocytope-
nia in the newborn. J Vasc Surg 1992; 15:306–311
●● Postcatheterization (1, 4, 130).
21. Risch L, Huber AR, Schmugge M: Diagnosis and treatment of hepa-
●● DVT (1, 4). rin-induced thrombocytopenia in neonates and children. Thromb Res
●● Mechanical prosthetic valves (95, 131–133). 2006; 118:123–135
●● Intracardiac (130, 134–138). 22. Raffini L, Huang YS, Witmer C, et al: Dramatic increase in venous
●● In combination with AngioJet/angioplasty (139). thromboembolism in children’s hospitals in the United States from
2001 to 2007. Pediatrics 2009; 124:1001–1008
●● Occluded Blalock-Taussig Shunt (95) in combination with 23. Dix D, Andrew M, Marzinotto V, et al: The use of low molecular weight
balloon angioplasty/stent (140). heparin in pediatric patients: A prospective cohort study. J Pediatr
●● Stroke (90, 141, 142). 2000; 136:439–445
24. Michaels LA, Gurian M, Hegyi T, et al: Low molecular weight heparin
in the treatment of venous and arterial thromboses in the premature
infant. Pediatrics 2004; 114:703–707
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