Curr Emerg Hosp Med Rep (2013) 1:8397

DOI 10.1007/s40138-013-0014-6

THROMBOSIS (D SLATTERY, SECTION EDITOR)

Anticoagulants: A Review of the Pharmacology, Dosing,

and Complications
Mohammed Alquwaizani Leo Buckley
Christopher Adams John Fanikos

Published online: 21 April 2013

 The Author(s) 2013. This article is published with open access at Springerlink.com

Abstract Anticoagulants remain the primary strategy for

the prevention and treatment of thrombosis. Unfractionated
heparin, low molecular weight heparin, fondaparinux, and
warfarin have been studied and employed extensively with
direct thrombin inhibitors typically reserved for patients
with complications or those requiring intervention. Novel
oral anticoagulants have emerged from clinical development and are expected to replace older agents with their
ease of use and more favorable pharmacodynamic profiles.
Hemorrhage is the main concerning adverse event with all
anticoagulants. With their ubiquitous use, it becomes
important for clinicians to have a sound understanding of
anticoagulant pharmacology, dosing, and toxicity.
Keywords Thrombosis
Coagulation
Anticoagulants

Unfractionated heparin
Low molecular weight heparins

Direct thrombin inhibitors
Warfarin
Dabigatran

Rivaroxaban
Apixaban

Introduction
Anticoagulants are the cornerstone therapy for thrombosis
prevention and treatment. While anticoagulants are commonly employed, their use is often associated with adverse
drug events and increased readmission rates. In older patients
presenting to an Emergency Department with a warfarin
adverse drug event, about half required hospitalization [1].
Despite novel anticoagulants being touted as replacements
for warfarin and heparin products, rivaroxaban has been

associated with serious thrombotic events while dabigatran

has been associated with serious bleeding [2, 3]. Since
anticoagulant use enhances the risk for Emergency Department visits by as much as 35-fold [4], clinicians must be
familiar with anticoagulants, their pharmacological properties, pharmacodynamics, dosing, monitoring, and toxicity.

Pathophysiology
The coagulation cascade is triggered by tissue factor release
from tissue trauma or vascular injury (Fig. 1) [5]. Tissue
factor forms a complex with factor VIIa in the presence of
calcium and cleaves clotting factors X and IX to their activated forms (factors Xa and IXa). The prothrombinase
complex is then assembled on a phospholipid membrane and
cleaves prothrombin (factor II) to factor IIa (thrombin).
Thrombin is one of the most potent activators of primary
(platelet-mediated) and secondary (clotting factor-mediated) hemostasis. Thrombin may also potentiate clot formation by fibrin polymerization, platelet receptor activation,
endothelium activation, and activation of factors V, VIII, XI,
and XIII. Anticoagulant agents can inhibit thrombogenesis
by altering various pathways within the clotting cascade or
by targeting thrombin directly, attenuating thrombin generation. Indirect inhibitors, however, target and bind to naturally occurring plasma cofactors, such as antithrombin (AT),
catalyzing their interaction with clotting enzymes [5].

Pharmacology of Heparins and Fondaparinux

M. Alquwaizani
L. Buckley
C. Adams
J. Fanikos (&)
Pharmacy Department, Brigham and Womens Hospital,
75 Francis Street, Boston, MA 02115, USA
e-mail: [email protected]

Unfractionated heparin (UFH) and low molecular weight

heparin (LMWH) are the anticoagulants of choice in
acute thrombosis due to their rapid onset of

123

84

Curr Emerg Hosp Med Rep (2013) 1:8397

EXTRINSIC PATHWAY
(physiologic activation)
INTRINSIC PATHWAY
(contact activation)
Factor XII

Tissue trauma,
Vascular injury
Tissue Factor

Factor XIIa
Factor XI

UFH + antithrombin
LMWH + antithrombin

Factor XIa
Factor IX

UFH + antithrombin
LMWH + antithrombin

Factor VIIa, Ca++

and Tissue Factor

Factor IXa

Factor X

Factor X
Factor Xa

Indirect Factor Xa inhibitors;

fondaparinux + antithrombin
Vitamin K antagonists (warfarin):
Inhibit vitamin K-dependent
carboxylation of factors II,VII,IX, X
Factor II (Prothrombin)

UFH + antithrombin
LMWH + antithrombin

Prothrombinase complex:
Factor Xa-Factor Va-Ca++
(phospholipid surface)
Factor IIa (Thrombin)

Direct Factor Xa inhibitors:

rivaroxaban, apixaban
Direct thrombin inhibitors:
Argatroban
Bivalirudin
Dabigatran

Fibrinogen
Fibrin monomer
Factor XIIIa

Fibrin polymers

Fig. 1 The coagulation cascade is comprised of the intrinsic (contact

activation) pathway and the extrinsic (tissue factor) pathway. Each
pathway generates a series of reactions in which inactive circulating
enzymes and their co-factors are activated. These activated factors
then catalyze the next reactions in the cascade. Thrombin plays a
pivotal role by triggering the conversion of soluble fibrinogen to

insoluble fibrin monomers, which serve as the foundation for

thrombus formation. Thrombin also activates factors VIII, V, and
XIII. Factor XIII generates the covalent bonds that link fibrin strands
ensuring structural integrity. Anticoagulants, either through their
interaction with Antithrombin (AT) or through a direct inhibition of
thrombin, interrupt these enzymatic reactions

antithrombotic activity. Since heparins are dependent on

the presence of AT for clotting factor inhibition, they are
considered indirect anticoagulants (Table 1) [6, 7, 8].
Heparins have no fibrinolytic activity and will not lyse
existing thrombi. Heparins contain an active pentasaccharide sequence that binds to AT. Once heparin binds
and activates AT, it can readily dissociate and bind to
additional AT, providing a continuous anticoagulant
effect. This binding produces a conformational change,
accelerating AT binding and inactivation of coagulation
factors XIIa, IXa, XIa, Xa and thrombin. The active
pentasaccharide sequence responsible for catalyzing AT is
found on one-third and one-fifth of the chains of UFH and
LMWH, respectively. Fondaparinux is a synthetic analog
of the naturally occurring pentasaccharide found in heparins [6, 7, 8]. Fondaparinux selectively and irreversibly
binds to AT. This results in neutralization of factor Xa,
which ultimately inhibits thrombin formation and thrombus development.

Unfractionated Heparin

123

Pharmacodynamics and Monitoring

Intravenous (IV) infusion or subcutaneous injections are
the available routes for UFH administration and IV is
preferred [6, 79]. When given via subcutaneous injection for therapeutic anticoagulation, doses need to be large
enough ([30,000 U/day) to overcome UFHs low bioavailability. UFH readily binds to plasma proteins, which
contributes to its variable anticoagulant response after
parenteral administration. Despite these limitations IV
administration rapidly achieves therapeutic plasma concentrations that can be effectively monitored and adjusted
based on infusion rates [7].
UFH clearance from the systemic circulation is doserelated and occurs through two independent mechanisms
[6, 8]. The initial phase is the rapid and saturable binding
to endothelial cells, macrophages, and local proteins where

Curr Emerg Hosp Med Rep (2013) 1:8397

85

Table 1 Comparison of the pharmacologic features of heparin and its

derivatives
Features

Heparin

LMWH

Fondaparinux

Source

Biological

Biological

Synthetic

Molecular weight (Da)

15,000

5,000

1,500

Target

Xa:IIa

Xa [ IIa

Xa

Bioavailability (%)

30

90

100

Half-life (h)

17

Renal excretion

No

Yes

Yes

Protamine reversal
Incidence of HIT (%)

Complete
\5.0

Partial
\1.0

None
Case reports

Da Dalton, h hours, HIT heparin-induced thrombocytopenia

UFH is depolymerized. The second phase is a slower, nonsaturable, renal-mediated clearance. At therapeutic doses,
UFH is cleared primarily via depolymerization, with the
higher molecular weight chains being cleared more rapidly
than lower weight counterparts. As clearance becomes
dependant on the kidney, increased or prolonged UFH
dosing provides a disproportionate increase in both the
intensity and the duration of the anticoagulant effect.
The anticoagulant response to UFH administration is
monitored using the activated partial thromboplastin time
(aPTT). The aPTT should be measured every 6 h with IV
administration, and doses adjusted accordingly, until the
patient has sustainable therapeutic levels. Once steady state is
reached the frequency of monitoring can be extended [8, 10].
To overcome variables delivering UFH, weight-based
dosing nomograms are recommended for treatment of
thromboembolic disease. Dosing nomograms have been
associated with significantly higher initial UFH doses,
shorter time to therapeutic activated aPTT, and no increase
in bleeding events. UFH dosing nomograms will differ
from hospital to hospital due to differences in thromboplastin agents and inter-laboratory standardizations in
aPTT measurements [10].
Clinical Indications
Clinical indications for UFH include treatment of acute
coronary syndromes (ACS), treatment or prevention of
venous thromboembolism (VTE), bridge therapy for atrial
fibrillation (AF), and cardioversion (Table 2) [6, 1113].
UFH utilization has diminished with LMWH and fondaparinux availability and their superior pharmacokinetic
profiles [6, 7]. UFH, with a short half-life and reversal
capability, remains the best option in patients requiring
higher UFH doses, in patients with underlying bleeding
risk, or in those critically ill with organ dysfunction.
Patients with fluctuating renal function or with a creatinine
clearance less than 30 mL/min are not candidates for
LMWH or fondaparinux due to the risk of accumulation

and increased bleeding risk [14]. When used for thromboprophylaxis in medical patients, three times daily UFH
dosing provides better efficacy in preventing VTE events
compared to twice daily dosing but generates more major
bleeding episodes [15].
Complications and Reversal of Effect
The major complications of UFH therapy include bleeding
(major bleeding, 07 %; fatal bleeding, 03 %) and heparin-induced thrombocytopenia (HIT, 15 %). Patients
receiving UFH for periods of more than 1 month are also at
an increased risk for osteoporosis and development of
vertebral fractures (approximately 2 % incidence) [16].
Hemorrhagic episodes are associated with the intensity of
anticoagulation, route of administration (continuous infusions are associated with lower rates), and concomitant use
of glycoprotein (gp) IIB/IIIA inhibitors, aspirin or fibrinolytic therapy [1618]. The relationship between supratherapeutic levels of UFH (elevated aPTT, heparin levels or
anti-Xa levels) and major bleeding is not well established
and has not been prospectively compared in clinical trials.
Major bleeding can occur within therapeutic levels of
anticoagulation. Patient-specific risk factors are the most
important consideration when determining the bleeding
risk, including: age, gender, renal failure, low body weight,
and excessive alcohol consumption [1618].
Anticoagulation management before and after surgery is
a patient specific, risk versus benefit decision. It is based on
the procedure and patients risk factors for bleeding and
thrombosis. For patients requiring peri-operative anticoagulation in elective procedures or surgery, discontinuing
therapeutic IV UFH doses 4 h prior to the procedure and
measuring an aPTT is usually sufficient, as normal
hemostasis is restored in this time frame in most cases. If
the aPTT remains elevated, then hourly measurements are
advised until the aPTT returns to baseline [1921]. Therapeutic UFH therapy can be restarted 12 h after major
surgery, but should be delayed longer for evidence of
continued bleeding. In patients receiving low-dose UFH
subcutaneously, there is no contraindication to neuraxial
techniques, as the risk for developing spinal hematoma
appears to be minimal. In patients who are to receive
intraoperative anticoagulation with UFH, the UFH infusion
should be started at least 1 h after needle placement.
Indwelling catheters should be removed 24 h after discontinuation of the UFH infusion and only after the
patients coagulation status has been assessed [22].
Since UFH has a short half-life, reversal is not required in
most bleed episodes. The treatment of clinically severe UFHrelated bleeding includes anti-heparin therapy (protamine
sulfate), transfusion therapy, and supportive care. Protamine
dosing is dependent on timing of the last UFH dose. For

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7,50015,000 U SC every 12 h
Prophylaxis of VTE in
pregnancy (with prior VTE)

Target aPTT, 60 s, range 5070 s

5,000 U SC every 812 h
Prophylaxis of VTE in the
medically ill or surgical
population

VTE venous thromboembolism, aPTT activated partial thromboplastin time, CBC complete blood count, HIT heparin-induced thrombocytopenia, HITT heparin-induced thrombocytopenia and
thrombosis, ACS acute coronary syndrome, IV intravenous, SC subcutaneous

Risk of delayed onset of HIT and HITT

Neonates and infants weighing \10 kg

Premature infants weighing less than 1 kg

Menstruation

Hereditary AT III deficiency and

concurrent use of AT
IV infusion: 6080 U/kg bolus

Bridge therapy for AF,

cardioversion

HIT antibody testing (not warranted in

the absence of thrombocytopenia,
thrombosis, heparin-induced skin
lesions, or other signs pointing to a
potential diagnosis of HIT
Signs and symptoms of bleeding

CBC

Anti-Xa Levels (alternative if

available, consider if patients with
heparin resistance)

Gastrointestinal ulceration and ongoing

tube drainage of the small intestine or
stomach

IV bolus: 60 U/kg (max 4,000 U) 12

U/kg/h (max 1,000
U) fibrinolysis, adjusted to
maintain aPTT 1.52 times control
or per local heparin nomogram
Treatment of ACS

123

Congenital or acquired bleeding disorders

Indwelling epidural catheter

Allergic or hypersensitivity-type reactions

aPTT: at least 6 h after initiation, then

at least once daily

80 U/kg bolus then 18 U/kg/h infusion

adjusted to maintain aPTT 22.5
times control or per local heparin
nomogram
Treatment of VTE
Unfractionated heparin

Precautions
Monitoring
Dosing, timing, duration
Indications

Hepatic disease with impaired hemostasis

Curr Emerg Hosp Med Rep (2013) 1:8397

Drugs

Table 2 Clinical uses of UFH

86

immediate reversal (\30 min since the last UFH dose), 1 mg

of protamine is administered for every 100 U of UFH and a
follow up aPTT can evaluate the reversal response. When
UFH is given as a continuous IV infusion, only UFH delivered during the preceding 22.5 h should be included in the
calculation to determine the protamine dose. If the UFH dose
is unknown, protamine 50 mg can be administered slowly
over 10 min followed by serial measurements of aPTT.
Severe adverse reactions to protamine, such as hypotension
and bradycardia, are common. Reaction severity may be
reduced by slowing the administration over 13 min (maximum administration rate is 5 mg/min). Allergic responses
to protamine are more common in patients who have been
previously exposed to the drug for UFH neutralization, or
treated with protamine-containing insulin (neutral protamine
Hagedorn insulin), have undergone vasectomy, or have
hypersensitivity to fish. Patients at risk of developing antiprotamine antibodies can be pretreated with corticosteroid
and anti-histamine medications [2324].

Low Molecular Weight Heparins

Pharmacodynamics and Monitoring
LMWHs have increased bioavailability after subcutaneous
injection, renal clearance that is dose-independent, and a
longer half-life (1721 h) when compared to UFH.
LMWHs are administered in fixed doses for thromboprophylaxis, or in total body weight adjusted doses for therapeutic anticoagulation (Table 3) [5, 25].
With their predictable dose response (peak anti-Xa
activity occurring 35 h after injection) laboratory monitoring is usually not necessary. Anti-Xa monitoring is an
option in high-risk patient populations (renal insufficiency,
obesity, pregnancy, non-compliance) where dosing
adjustments may be required to tailor therapy. In these
cases anti-Xa plasma levels are drawn 4 h after administration, and subsequent dosing adjusted to peak target
levels of 0.51.1 IU/mL [26, 27]. Anti-Xa tests should be
monitored and interpreted per the manufacturer of the
specific LMWH being used.
Clinical Indications
For medically ill and post-operative patients requiring
parenteral VTE prophylaxis, LMWHs have become a
suitable replacement for UFH [28, 29]. LMWHs require
fewer injections and produce fewer adverse events. In
hospitalized medical patients receiving thromboprophylaxis, LMWH was associated with a lower risk of deep vein
thrombosis (DVT), fewer injection site hematomas, and no
differences in bleeding when compared with UFH [30].

40 mg SC every 24 h

Treatment of DVT

Prophylaxis of VTE in the

medically ill or surgical
population

Initial dose: 2,500 IU SC once

Prophylaxis of VTE after hip

or other major surgery (first
month) [8]

175 international units anti-Xa/kg SC

daily

5,000 IU SC every 24 h

Maintenance: 2,5005,000 IU SC every

24 h [8]

120 IU/kg SC every 12 h (MAX

10,000 IU/dose)

[99 kg: 18,000 IU SC daily

8398 kg: 18,000 IU SC daily

5768 kg: 12,500 IU SC daily

\56 kg: 10,000 IU SC daily

Treatment of ACS

Treatment of VTE

OR

30 mg SC every 12 h

CrCl \30 mL/min: 1 mg/kg SC daily

40 mg SC every 24 h

CrCl \30 mL/min: 1 mg/kg SC every

24 h

1.5 mg/kg SC every 24 h

OR

CrCl \30 mL/min: not recommended

1 mg/kg SC every 12 h

Unstable angina/non-Q wave MI: 1 mg/

kg SC every 12 h

ST-segment elevation MI: 30 mg bolus

IV plus 1 mg/kg with tenecteplase
followed by 1 mg/kg SC every 12 h

CrCl \30 mL/min: 1 mg/kg SC every

24 h

1.5 mg/kg SC every 24 h

Signs and symptoms of bleeding

HIT antibody testing (not warranted in the

absence of thrombocytopenia,
thrombosis, heparin-induced skin
lesions, or other signs pointing to a
potential diagnosis of HIT

Serum creatinine

CBC

Indwelling epidural catheter

Anti-Xa level in with significant renal

impairment, those experiencing
bleeding or abnormal coagulation
parameters, pregnant patients, obese or
low-weight patients, and children

Uncontrolled hypertension

Diabetic retinopathy

Concomitant use of antithrombotic drugs

Renal impairment (CrCl \30 mL/min),

consider UFH

Liver disease

Bacterial endocarditis
History of heparin-induced
thrombocytopenia

Congenital or acquired bleeding disorders

History of recent major bleed

(gastrointestinal, intracranial, etc.)

Recent spinal or ophthalmologic surgery

Precautions

Monitoring

VTE venous thromboembolism, SC subcutaneous, h hours, CrCl creatinine clearance using the CockroftGault Equation, CBC complete blood count, HIT heparin-induced thrombocytopenia,
ACS acute coronary syndrome, IV intravenous, IU international units

Tinzaparin (InnohepTM)

Dalteparin (FragminTM)

Prophylaxis of VTE in the

trauma patients

Prophylaxis of VTE in the

medically ill or surgical
population

Prophylaxis/bridge therapy
for AF/cardioversion [3]

Treatment of ACS [7]

1 mg/kg SC every 12 h

Treatment of VTE [2]

Enoxaparin
(LovenoxTM)
OR

Dosing, timing, duration

Indications

Drugs

Table 3 Clinical uses of LMWHs

Curr Emerg Hosp Med Rep (2013) 1:8397

87

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88

LMWHs have largely replaced IV UFH in patients with

acute VTE who are able to continue therapy, unmonitored
in the ambulatory setting [31]. In ACS, patients with STsegment elevation myocardial infarction treated with
fibrinolysis and LMWH had a lower incidence of death or
non-fatal recurrent myocardial infarction but a higher rate
of major bleeding than those treated with fibrinolysis and
UFH [32]. Similarly, in unstable angina/non-ST-segment
elevation myocardial infarction, LMWH therapy reduced
the incidence of death, myocardial infarction, or urgent
revascularization when compared to UFH [33].

Curr Emerg Hosp Med Rep (2013) 1:8397

monitored every other day for the first 410 days of therapy. The incidence of HIT is approximately one-tenth
lower with LMWH than with UFH [37]. In the setting of a
HIT allergy or if positive HIT antibodies have been
detected, LMWH cannot be used due to cross reactivity
between glycosaminoglycans. Direct thrombin inhibitors
(DTIs) are the treatment of choice for patients with HIT or
HITT [38, 39].
Osteoporosis reportedly occurs less frequently in
patients treated with LMWH as compared to UFH, and it
typically is associated with long-term therapy [6].

Complications and Reversal of Effect

Fondaparinux
Hemorrhage is the major complication of LMWH, with
some data supporting decreased rates of bleeding compared
to UFH. Rates of fatal bleeding are reported in 00.8 %
and major bleeding in 03 % of patients [16]. In the surgical setting, peri-procedural thromboembolic risk assessment, bleeding risk assessment, and physician preference
will play a role in determining whether LMWH prophylactic dosing is continued or withheld. For patients
receiving therapeutic LMWH dosing, discontinuation
should be considered 1224 h prior to procedure, or longer
in patients with renal dysfunction. Therapeutic doses of
LMWH should not be restarted for 24 h after a major
procedure or after neuraxial anesthesia [19, 32].
In the setting of overdose or life-threatening hemorrhage,
protamine is administered IV. Protamine does not fully
reverse LMWH but can neutralize the AT effect. Because
longer heparin chains bind to protamine, protamine completely reverses the anti-factor IIa activity of LMWH but
only reverses 60 % of the anti-factor Xa activity. If
immediate reversal is warranted within 8 h of LMWH
administration, a protamine dose of 1 mg neutralizes 100 U
anti-Xa or 1 mg of LMWH. If bleeding continues, a second
dose of 0.5 mg of protamine per 100 U anti-Xa may be
administered. Smaller protamine doses are required if the
LMWH administration interval is beyond 8 h [34, 35].
HIT and HIT with thrombosis (HITT) are immunemediated disorders that result from antibodies being
formed against the heparinplatelet factor IV complex. The
incidence of HITT in critically ill patients ranges from 1 to
5 % and is associated with the development of thrombocytopenia and life-threatening thrombosis in approximately
3050 % of HIT positive patients [36]. This immunemediated response typically occurs in patients exposed to
UFH or LMWH for 57 days, or sooner if the patient was
previously exposed. A 50 % decrease in platelet count
occurring 410 days after the initiation of UFH or LMWH
therapy or formation of a new thrombus while anticoagulated may be indicative of HIT. Platelet counts should be
measured prior to the initiation of UFH or LMWH and

123

Pharmacodynamics and Monitoring

After subcutaneous administration, fondaparinux is rapidly
and completely absorbed, exhibiting a half-life of 1721 h
in patients with normal renal function [6]. Fondaparinux
is excreted primarily unchanged in the urine with clearance
reduced in patients with renal impairment. Similar to
LMWH, with predictable pharmacokinetics, monitoring
anti-Xa levels is not recommended during fondaparinux
administration.
Clinical Indication
Fondaparinux has been proven to be at least as safe and
effective as treatment of DVT and pulmonary embolism
(PE) as LMWH and UFH, respectively [40, 41] (Table 4).
Fondaparinux has been studied extensively for thromboprophylaxis in medically ill and surgical patients [42, 43].
In three trials fondaparinux showed superior efficacy in
reducing VTE in patients undergoing knee arthroplasty, hip
arthroplasty, and hip fracture surgery [4446]. In a combined analysis, the overall incidence of major bleeding was
statistically higher with fondaparinux (2.7 %) compared
with LMWH (1.7 %) [47]. However, the incidence of
clinically relevant bleeding, as defined as bleeding leading
to death, reoperation, or occurring in a critical organ, did
not differ between the agents. The differences in efficacy
and safety outcomes could be related to dosing as well as
the timing of peri-operative drug administration. The
administration of fondaparinux given less than 6 h after
surgery has been associated with an increased frequency of
major bleeding [48]. Holding therapy for at least 6 h postprocedure may be recommended in patients at risk of
bleeding. Fondaparinux may be a potential option for
thromboprophylaxis in the setting of an HIT allergy but no
conclusive data is available [49]. While fondaparinux has
been studied in ACS, it has not received Food and Drug
Administration (FDA) approval.

Complications and Reversal of Effect

Fondaparinux is contraindicated in patients with severe renal
impairment (calculated creatinine clearance less than 30 mL/
min). Fondaparinux should not be used for VTE prophylaxis in
patients weighing less than 50 kg. Fondaparinux reversal is
further complicated by its prolonged half-life [50]. While no
specific antidote exists for the fondaparinux-related hemorrhage, recombinant activated factor VII (rFVIIa) administration
can normalize coagulation times and thrombin generation [51].
Direct Thrombin Inhibitors (DTIs)
DTIs exert their antithrombotic effect through direct,
selective, and reversible binding to the active site of
thrombin. This leads to inhibition of thrombin-catalyzed or
-induced reactions, including fibrin formation, activation of
coagulant factors V, VIII, XIII, protein C, and platelet
aggregation. The hirudin analogs, desirudin and bivalirudin, and argatroban are three currently approved DTIs [52].

Indicates off label use of medication

Pharmacology, Pharmacodynamics, and Monitoring

VTE venous thromboembolism, SC subcutaneous, CrCl creatinine clearance using the CockroftGault Equation, CBC complete blood count, STEMI ST-elevation myocardial infarction,
NSTEMI non-ST-elevation myocardial infarction

2.5 mg SC daily
Prophylaxis of VTE in major surgery and
acute medically illa

Hepatic function
2.5 mg SC daily

CrCl less than 30 mL/mincontraindicated

Treatment of STEMI and NSTEMIa

CrCl 3050 mL/min40 % reduction in total

clearance; consider empiric dosage reduction

CrCl 5080 mL/min25 % reduction in total

clearance; consider empiric dosage reduction

Renal impairment

89

Congenital or acquired bleeding

disorders

History of recent major bleed

(gastrointestinal, intracranial,
etc.)

Anti-Xa level in patients with

significant renal impairment, those
experiencing bleeding or abnormal
coagulation parameters, pregnant
patients, obese or low-weight
patients, and children

Recent spinal or ophthalmologic

surgery

Indwelling epidural catheter

50100 kg: 7.5 mg SC daily

[100 mg kg: 10 mg SC daily [2, 10]

Serum creatinine
Signs and symptoms of bleeding

\50 kg: 5 mg SC daily

Treatment of VTE [2, 10]

Treatment is for 59 days; continue

treatment until a therapeutic oral
anticoagulant effect is established

Fondaparinux
(ArixtraTM)

CBC

Dosing, timing, duration

Indications
Drug

Table 4 Clinical uses of fondaparinux

Monitoring

Precautions

Curr Emerg Hosp Med Rep (2013) 1:8397

Bivalirudin and desirudin are synthetic analogs of r-hirudin

that exert anticoagulant activity by reversible binding at the
enzymatic catalytic site and the anion binding site of
thrombin. Argatroban, derived from the amino acid arginine, is a small synthetic thrombin inhibitor that reversibly
binds non-covalently to thrombin active site [52].
The DTIs differ in their pharmacokinetic parameters
(Table 5) [52]. Bivalirudin has the shortest half-life, making
it a particularly useful agent in the procedural or peri-procedural period. DTI selection often depends on patientspecific characteristics such as age, compromised cardiac
function, hemodynamic instability, and hepatic or renal
dysfunction [52, 53]. Critically ill patients typically require
lower infusion rates than recommended by the manufacturer
due to the presence of comorbidities and organ dysfunction.
DTIs are monitored using aPTT, with a goal of 1.53 times
control or baseline (argatroban), 1.52.5 times control
(bivalirudin) (Table 6). Desirudin does not need routine
coagulation monitoring. The aPTT level should be measured
every 6 h until the patient has sustainable therapeutic levels,
then the frequency of monitoring can be extended. Because
of inconsistencies in aPTT measurements, the plasma diluted thrombin time has shown to be an alternative to for
monitoring DTI levels, especially in patients with lupus
inhibitors or low levels of vitamin K-dependent factors [54].
Clinical Indications
DTIs can be used as an alternative anticoagulant to UFH
for the treatment of HIT or HIT-T [55]. Argatroban

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90

Curr Emerg Hosp Med Rep (2013) 1:8397

Table 5 Pharmacokinetic and pharmacodynamic properties of DTIs

Feature

Desirudin

Argatroban

Bivalirudin

Molecular weight (Da)

6963

526

2180

FDA-approved
indication

Prophylaxis of DVT in patients

undergoing elective hip replacement
surgery

Management of HIT, or use in

patients with HIT who are
undergoing PCI

Use in patients with or at risk for HIT

or HITTS who are undergoing PCI

Primary elimination
route

Renal

Hepatic

Enzymatic

SC = 120 min

3951 min

1024 min

4050

16

20

Not required

aPTT, ECT

aPTT, ACT, ECT

Elimination half-life

IV = 60 min
Fraction eliminated
unchanged by kidney
(%)
Laboratory test to
monitor
Target range

n/a

aPTT: 1.539 control

aPTT: 1.52.59 control

Effects on INR

Minimal

Moderate to clinically significant

Minimal to moderate

Da Dalton, FDA Food and Drug Administration, HIT heparin-induced thrombocytopenia, HITTS HIT with thrombosis syndrome, PCI percutaneous coronary intervention, SC subcutaneous, IV intravenous, aPTT activated partial thromboplastin time, ECT ecarin clotting time, ACT
activated clotting time, INR international normalized ratio
Table 6 Clinical uses of DTIs
Drugs

Indications

Dosing, timing, duration

Monitoring

Precautions

Bivalirudin
(AngiomaxTM)

PCI (with or without

glycoprotein IIB/IIIA
inhibitor)

0.75 mg/kg IV bolus dose, followed by an infusion

of 1.75 mg/kg/h for the duration of the procedure

CBC

Indwelling epidural
catheter

CrCl less than 30 mL/min, a reduction of initial

infusion rate to 1 mg/kg/h should be considered;
no bolus dose reduction is necessary

ACT

Argatroban

PT/INR (false
elevation
while on
infusion)

Recent major, spinal or

ophthalmologic
surgery

Treatment of ACS

Initial IV bolus dose of 0.1 mg/kg, followed by

0.25 mg/kg/h.

Treatment and prophylaxis

of HITTa

0.150.2 mg/kg/h, titration to aPTT 1.52.5 times

control

Blood pressure

Treatment and prophylaxis

of HITT

0.51.2 lg/kg/min continuous IV infusion to start

titration to goal aPTT of 1.53 times baseline

ECG

Congenital or acquired
bleeding disorders

Renal function
(bivalirudin)

Recent cerebrovascular
accident

Hepatic
function
(argatroban)

Hepatic impairment
(argatroban)

Begin VKA therapy, measure INR daily. Stop

argatroban when INR [4. Repeat INR in 46 h,
if INR is below desired range then resume
argatroban infusion
PCI

Bolus: 350 lg/kg

Initial infusion: 25 lg/kg/min maintain ACT
greater than 300 seconds

Desirudin

aPTT

Prophylaxis of DVT in
patients undergoing
elective hip replacement
surgery

Heart rate

History of recent major

bleed
(gastrointestinal,
intracranial, etc.)

Renal dysfunction
(bivalirudin)

15 mg SC every 12 h given 515 min prior to

surgery but before induction of regional block
anesthesia (if used)

PCI percutaneous coronary intervention, IV intravenous, CrCl creatinine clearance using the CockroftGault Equation, CBC complete blood
count, aPTT activated partial thromboplastin time, ACT activated clotting time, PT prothrombin time, INR international normalized ratio, ECG
echocardiogram, HITT heparin-induced thrombocytopenia and thrombosis, VKA vitamin K antagonist, ACS acute coronary syndrome
a

Indicates off label use of medication

administration significantly reduced the rates of thromboembolic complications in patients with HIT [56]. Bivalirudin has been safely used in critically ill and HIT
patients [57]. Argatroban and bivalirudin are indicated as

123

an anticoagulant for thrombosis prevention in patients

undergoing percutaneous coronary intervention (PCI).
Bivalirudin is indicated for use as an anticoagulant in the
treatment of patients with moderate to high-risk ACS,

Curr Emerg Hosp Med Rep (2013) 1:8397

91

unstable angina/non-ST-segment elevation myocardial

infarction who are undergoing early invasive management,
and in patients undergoing PCI (Table 6) [5].

men, and for the prevention of stroke, recurrent infarction,

or death in patients with acute myocardial infarction
(Table 7) [59, 6568].

Complications and Reversal of Effect

Complications and Reversal of Effect

Hemorrhage is the most common complication with DTIs

and no specific reversal agent is available. Anecdotally,
rFVIIa has been reported to be useful and could be considered for immediate treatment of life-threatening hemorrhage [58]. DTIs can produce a misleading elevation in
the international normalized ratio (INR), complicating the
transition to warfarin in HIT. A clinical strategy to bridge
safely and effectively should be undertaken in order to
avoid thrombosis or bleeding. Steps in a bridging strategy
include determining a baseline INR while on the DTI,
identifying a target INR level (desired 1.52-point
increase) while considering the INR elevation induced by
the DTI, once INR goal is reached withhold the DTI for
48 h, and recheck the INR and aPTT. If the INR is 23
with an aPTT close to baseline after the clinician accounts
for the independent warfarin-related elevation in the aPTT,
the DTI can be discontinued [49].

Bleeding is a major concern with warfarin therapy due to

the influence of environmental factors and drug interactions
in the setting of a narrow therapeutic index. Treatment with
VKA increases the risk of major bleeding by 0.30.5 % per
year and the risk of intracranial hemorrhage by approximately 0.2 % per year compared to controls. The most
important risk factors for hemorrhage in VKA therapy
include: intensity of anticoagulant effect, time within therapeutic range, and patient characteristics. Higher goal INRs
(INR [3) have been directly associated with increased rates
of hemorrhage, and patients at high risk of bleeds may
benefit from lower target goals [59, 60].
Reversal of warfarins anticoagulant effect requires withholding therapy. The duration of effect can last up to several
days in the absence of reversal agent administration. In
patients with clinically significant bleeding, the administration of vitamin K is crucial to reversing the anticoagulant
effects of VKAs. In the setting of an INR between 4.5 and 10
and no significant bleeding, the next doses of warfarin should
be held and the INR evaluated [60]. When the INR is [10 and
the patient has no significant signs of bleeding, the guidelines
recommend holding warfarin and giving oral vitamin K. In the
setting of serious/life-threatening bleeding at any INR, warfarin should be held and vitamin K 10 mg by slow IV infusion
is recommended. Higher doses of vitamin K are effective but
may lead to VKA resistance for more than a week. Vitamin K
may be given orally or parenterally, with the IV route providing a more rapid response. The intramuscular or subcutaneous routes are not recommended in the critically ill due to
unpredictable absorption. In cases where immediate reversal
of the INR is necessary the supplementation of clotting factors
with fresh frozen plasma (FFP), or prothrombin complex
concentrate (PCC) are more effective. PCCs contain more
clotting factors in a smaller volume and have been shown to be
more effective in the reversal of warfarin therapy. Recombinant factor VIIa may be of benefit in patients with refractory
bleeding in the setting of elevated INRs [60, 6169].
Non-hemorrhagic adverse events of warfarin include
acute skin necrosis and limb gangrene; these uncommon
complications are observed on the third to eighth day of
therapy. Skin necrosis is caused by extensive thrombosis of
the venules and capillaries within the subcutaneous fat,
typically associated with protein C deficiencies. Limb
gangrene, however, is due to massive outflow obstruction
of the venous circulation of the limb, and can be seen in
HIT patients treated with warfarin without adequate initial
bridging with a DTI [59].

Oral AnticoagulantsVitamin K Antagonists

Vitamin K antagonists (VKAs) produce their anticoagulant
effect by inhibiting vitamin K epoxy reductase, which is
required for the conversion of vitamin K to its active form
vitamin KH2. Vitamin K dependant proteins such as clotting factors II, VII, IX, and X require c-carboxylation by
vitamin KH2 for biological activity [59].
The relationship between the dose of warfarin and the
response varies between patients and is modified by genetic
and environmental factors (dietary intake, drug interactions, critical illness, etc.) that can influence the absorption
of warfarin, its pharmacokinetics, and its pharmacodynamics [59, 60, 6163].
A wide dosing range is required to maintain a therapeutic INR with relatively low doses often required for the
elderly and patients with underlying comorbidities.
Nomogram based dosing is considered safer and more
effective at reaching targeting INR goals [64]. Larger initial doses suppress proteins C and S, producing a hypercoagulable response and are associated with overanticoagulation and higher rates of bleeding.
Clinical Indications
Warfarin is effective for the primary and secondary prevention of VTE, for the prevention of systemic embolism
in patients with prosthetic heart valves or AF, for the primary prevention of acute myocardial infarction in high-risk

123

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Curr Emerg Hosp Med Rep (2013) 1:8397

Table 7 Clinical uses of warfarin

Drug

Indications

Dosing, timing, duration

Monitoring

Precautions

Warfarin
(CoumadinTM,
JantovenTM)

Treatment of VTE

Initial dosing: 2.510 mg every 24 h

(see precautions) titrated to range
INR: 2.03.0; target of 2.5

Atrial fibrillation

Initial dosing: 2.510 mg every 24 h

(see precautions) titrated to range
INR: 2.03.0; target of 2.5

Signs and
symptoms
of
bleeding

Lower initial dosing (less than 5 mg may be

warranted in patients who are debilitated, are
malnourished, have congestive heart failure,
have liver disease, have had recent major
surgery, or are taking medications known to
increase sensitivity to warfarin)

CBC
PT/INR

Initial dosing: 2.510 mg every 24 h

(see precautions) titrated to range
INR: 2.03.0; target of 2.5

Cerebrovascular disease

Mechanical valve
in the atrial
position

Initial dosing: 2.55 mg every 24 h

(see precautions) titrated to range
INR: 2.03.0; target of 2.5

Moderate to severe hypertension

Mechanical valve
in the mitral
position

Initial dosing: 2.55 mg every 24 h

(see precautions) titrated to range
INR: 2.53.5; target of 3.0

Mechanical valve
in both the atrial
and mitral
position

Initial dosing: 2.55 mg every 24 h

(see precautions) titrated to target
INR: 2.53.5; target of 3.0

Bioprosthetic
valve in the
mitral position

Initial dosing: 2.55 mg every 24 h

(see precautions) titrated to target
INR: 2.03.0; target of 2.5 for
3 months

Post-MI

Coronary disease
CYP2C9 and VKORC1 genetic variation
Malignancy
Renal impairment
Recent trauma
Malignancy
Collagen vascular disease
Conditions that increase risk of hemorrhage,
necrosis, and/or gangrene, pre-existing
Congestive heart failure
Sever diabetes
Excessive dietary vitamin K
Elderly or debilitated patients (lower dosing
may be required)
Hepatic impairment
Hyperthyroidism/hypothyroidism
Epidural catheters
Infectious diseases or disturbances of intestinal
flora, such as sprue or antibiotic therapy
Poor nutritional state
Protein C deficiency
Heparin-induced thrombocytopenia
Vitamin K deficiency

VTE venous thromboembolism, h hours, INR international normalized ratio, CBC complete blood count, PT prothrombin time, MI myocardial
infarction

Patients on VKAs requiring surgery should hold therapy

approximately 5 days prior to the intervention. Depending
upon the patients history and risk of VTE or arterial
thromboembolism, bridging with LMWH or UFH may be
warranted. VKA may be resumed 1224 h post-surgery,
depending on bleeding risk and hemostasis. Assessment of
the INR should be undertaken before neuraxial anesthesia is
performed. For patients with an indwelling catheter who are
receiving warfarin, the catheter should be removed when
the INR is less than 1.5. Patients with a low risk of bleeding
may undergo surgery with an INR of 1.31.5 [1921, 70].
Target-Specific Oral Anticoagulants
Dabigatran, rivaroxaban, and apixaban are novel oral
anticoagulants that offer major advantages over current

123

agents. They have rapid onset and more predictable anticoagulants response that eliminates the need for monitoring. Clinical trials have been completed with all three
agents in the prevention and treatment of the three leading
causes of cardiovascular death: myocardial infarction,
stroke, and VTE. Novel agents have shown reduced or
similar rates of thrombosis, major bleeding, and adverse
events when weighed against either LMWH or warfarin.
Pharmacology, Pharmacodynamics, and Monitoring
Dabigatran etexilate mesylate is a prodrug. After oral
administration, non-specific plasma and hepatic esterases
hydrolyze the compound into the active anticoagulant,
dabigatran [71]. Dabigatran is DTI that exerts its action
through reversible, competitive binding to the active site on

Curr Emerg Hosp Med Rep (2013) 1:8397

Table 8 Pharmacokinetic and
pharmacodynamic properties of
target-specific oral
anticoagulants

P-glycoprotein (P-gp)
inhibitors include verapamil,
clarithromycin, and quinidine

Cytochrome (CYP) P450 3A4

inhibitors include but are not
limited to: ketoconazole,
macrolide antibiotics, and
protease inhibitors

93

Features

Dabigatran etexilate

Rivaroxaban

Apixaban

Target

Thrombin

Factor Xa

Factor Xa

Prodrug

Yes

No

No

Dosing

Fixed

Fixed

Fixed

Bioavailability (%)

80

90

Food effects

Delay Tmax 24 h

Delays Tmax

Not reported

Half-life (h)

1217

59

12

Renal excretion (%)

80

65

25

Coagulation monitoring

No

No

No

Antidote

None

None

None

Interactions

P-gp inhibitorsa

Combined P-gp and

CYP3A4 inhibitorsb

Potent 3CYP3A4 inhibitorsb

thrombin. Furthermore, dabigatran indirectly exerts an

anti-platelet effect by reducing thrombins impact on promoting platelet activation and aggregation [72].
Dabigatran is eliminated through renal filtration with up
to 80 % of the dose excreted unchanged in urine (Table 8).
Dabigatrans mean terminal elimination half-life is prolonged in patients with severe renal dysfunction. There is
no antidote available to reverse or attenuate dabigatrans
anticoagulant effect [72].
Rivaroxaban is an oral, highly selective, direct, competitive inhibitor of factor Xa [73]. Inhibition of factor Xa
leads to interruption of the both intrinsic and extrinsic
coagulation pathways, thus preventing thrombin generation
and subsequent thrombus formation. Rivaroxabans inhibition of both free and fibrin-bound factor Xa differentiates
its action from LMWH or fondaparinux. Rivaroxaban
exerts minimal effect on platelet function.
In patients with CrCl 1530 mL/min, the dabigatran
dose should be reduced to 75 mg twice daily [71]. The
manufacturer does not recommend the use of rivaroxaban
in patients with an estimated creatinine clearance less than
15 mL/min [74].

Clinical Indications
While dabigatran has been compared with enoxaparin for
VTE prophylaxis, and with warfarin in acute VTE treatment and secondary prevention, it only has FDA approval
for stroke prevention in AF (Table 9).
RE-LY was a non-inferiority trial designed to determine the long-term safety and efficacy of dabigatran
administered twice daily as compared to warfarin (INR
goal 2.03.0) in patients with non-valvular AF [75].
Patients were required to have at least one addition
thromboembolism risk factor. The primary efficacy outcome was defined as the occurrence of stroke or systemic

embolism. The dabigatran 150 mg twice daily regimen

was statistically superior to warfarin in reducing the rate
of stroke and systemic embolism, 1.11 % per year versus
1.69 % per year, respectively (p \ 0.001). As any other
anticoagulant, bleeding is the major adverse event. In ReLY trial, the primary safety outcome was major bleeding.
There was no difference in the rate of major bleeding in
the dabigatran 150 mg group compared with the warfarin
group.
Rivaroxaban has been studied in a large clinical trial
program and has FDA approval for a variety of indications.
The orthopedic surgery program compared rivaroxaban to
enoxaparin for VTE prevention in patients undergoing total
hip and total knee arthroplasty [7679]. The primary efficacy endpoint was total VTE, the composite of any DVT,
non-fatal PE, and all-cause mortality. In the RECORD1, -2,
-3 and -4 studies rivaroxaban 10 mg daily was superior to
enoxaparin and associated with a similar safety profile.
Rivaroxaban has been evaluated for stroke prevention in
patients with non-valvular AF [80]. In the ROCKET-AF
trial rivaroxaban 20 mg once daily was non-inferior to
warfarin in reducing all-cause stroke and non-central nervous system embolism in with a similar rate of major
bleeding. Rivaroxaban has been studied for the acute DVT
and PE treatment and for the long-term secondary prevention of recurrent VTE [81, 82]. The EINSTEIN-DVT
study found rivaroxaban 15 mg twice daily for 3 weeks
followed by 20 mg daily was non-inferior to enoxaparin
followed by a VKA in the prevention or recurrent VTE
[81]. In the EINSTEIN-Extension trial, rivaroxaban 20 mg
daily extended for an additional 612 months significantly
reduced recurrent VTE without an increase in major or
clinically relevant non-major bleeding when compared
with placebo. In EINSTEIN-PE rivaroxaban was found to
be non-inferior to enoxaparin combined with a VKA in the
prevention of recurrent VTE while providing a significant
reduction in major bleeding [82].

123

94

Curr Emerg Hosp Med Rep (2013) 1:8397

Table 9 Clinical uses of target-specific oral anticoagulants

Drugs

Indications

Dosing, timing, duration

Monitoring

Precautions

Dabigatran etexilate
(Pradaxa)

Stroke and systemic

embolism
prophylaxis in
non-valvular AF

CrCl [30 mL/min: 150 mg twice

daily

No specific assay
available

Bioprosthetic heart valves

CrCl 1530 mL/min: 75 mg twice

daily

Stroke prophylaxis
in non-valvular AF

CrCl [50 mL/min: 20 mg once

daily with the evening meal

No specific assay
available

Spinal/epidural anesthesia or
puncture

Rivaroxaban (Xarelto)

Apixaban (Eliqiuis)

P-gp inducers and inhibitors

CrCl 1550 mL/min: 15 mg once

daily with the evening meal

CrCl \15 mL/min in nonvalvular AF

Treatment of DVT
or PE

15 mg twice daily with food for

21 days then 20 mg daily with
food for remaining treatment

CrCl \30 mL/min in treatment

or prevention of DVT, PE

DVT or PE
secondary
prophylaxis

20 mg once daily with food

DVT prophylaxis
following hip or
knee replacement
surgery

10 mg once daily for 35 days (hip

replacement) or 12 days (knee
replacement)

Stroke and systemic

embolism
prophylaxis in
non-valvular AF

5 mg twice daily or 2.5 mg twice

daily in patients with at least
two of: age [80 years, body
weight \60 kg, serum
creatinine \1.5 mg/dL

P-gp inducers or inhibitors

CYP3A4 inducers or inhibitors
Pregnancy

No specific assay
available

CrCl creatinine clearance, DVT deep vein thrombosis, PE pulmonary embolism

While apixaban has been evaluated in thromboprophylaxis following orthopedic surgery, secondary prevention
of VTE, and ACSs, its sole FDA approval is in stroke
prevention in AF [83].
In the ARISTOTLE trial, investigators compared apixaban 5 mg twice daily with warfarin titrated to a goal INR
of 23 [84]. The primary outcome, a composite of stroke
and systemic embolism, occurred significantly less frequently in the apixaban patients compared to the warfarin
patients. Bleeding was significantly less frequent in the
apixaban patients compared to the warfarin patients across
several bleeding definitions tested.

Complications and Reversal of Effect

The most common adverse events reported with dabigatran
include dyspepsia, dizziness, headache, dyspnea, and
shortness of breath. Abdominal pain and gastritis-like
symptoms may be related to the capsule formulation which
can be combated by taking the medication with food [83].
There are no specific coagulation assays for laboratory
monitoring of novel oral anticoagulants. Thrombin time
and aPTT can be used to detect the presence of dabigatran
in the plasma [85]. Similarly, rivaroxaban and apixaban
prolong prothrombin time and aPTT. The role of other

123

newer assays (Heptest, prothrombinase-induced clotting

time, Anti-FXa chromogenic assays) have yet to be
established.
Currently, there is no antidote available to reverse dabigatran, rivaroxaban, or apixaban. In the event of overdose, the early use of activated charcoal is recommended
[83]. Cessation of dabigatran, rivaroxaban, or apixaban
therapy may be sufficient to reverse any excessive anticoagulant effect due to their short half-lives. While dialysis,
for 23 h removes up 60 % of dabigatran, it has no impact
on rivaroxaban or apixaban [85].
Limited data exists for treatment of life-threatening
bleeding produced by novel anticoagulants. Recent trials
have suggested PCCs or rFVIIa may offer benefit by normalizing coagulation parameters [74, 86, 87]. Their
evaluation, use, and role in the clinical setting are still
required. In the event of bleeding symptomatic treatment of
the hemorrhage should be initiated [83].
For the novel agents, confusion and debate may ensue if
prescribed in patient populations, such as those with
pregnancy, mechanical heart valves, and thrombophilias,
where little study data and clinical experience exists.
Similarly, surgical and invasive procedures add additional
levels of complexity where therapy may be continued,
interrupted, or replaced with short-term parenteral or
bridge therapy.

Curr Emerg Hosp Med Rep (2013) 1:8397

Conclusions
UFH, LMWHs, fondaparinux, DTIs, and warfarin have been
studied and employed extensively for prevention and treatment of thrombosis. Novel oral anticoagulants have
emerged from clinical development and are expected to
replace older agents with their ease of use and more favorable pharmacodynamic profiles. Hemorrhage is the main
concerning adverse event with all anticoagulants. With their
ubiquitous use, it becomes important for clinicians to have a
sound understanding of anticoagulant pharmacology, dosing, monitoring, and toxicity. Working knowledge becomes
crucial for intercepting and averting problems.
Disclosure No potential conflicts of interest relevant to this article
were reported.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original
author(s) and the source are credited.

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