CASE REPORT

Effect of Plasmapheresis on the Anti–Factor Xa Activity of

Enoxaparin in an Obese Adolescent Patient
Kassim W. Rahawi,1 Kristi L. Higgins,1 Cady Noda,1,2 and Jeremy S. Stultz,3,4,*
1
Virginia Commonwealth University School of Pharmacy, Richmond, Virginia; 2Department of Pharmacy
Services, Virginia Commonwealth University Health, Richmond, Virginia; 3Virginia Commonwealth University
Health, Richmond, Virginia; 4Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth
University School of Pharmacy, Richmond, Virginia

To our knowledge, the effect of plasmapheresis on the anti–factor Xa activity of enoxaparin has never
been reported. We describe a 13-year-old, obese (92-kg) girl who was treated with enoxaparin for a
pulmonary embolism while receiving plasmapheresis for suspected autoimmune encephalitis and who
experienced clinically significant reductions in anti–factor Xa activity after plasmapheresis. She
received five courses of plasmapheresis, with the final two administered during treatment with enoxa-
parin. Her anti–factor Xa concentrations were highly variable, and we hypothesized that plasmaphere-
sis was affecting these levels. To test this hypothesis, anti–factor Xa concentrations were measured
before and immediately after the patient’s last plasmapheresis treatment, and then again 2 days after
plasmapheresis. The rate of anti–factor Xa activity decline was 0.28 IU/mL/hour with plasmapheresis
and only 0.088 IU/mL/hour on the day without plasmapheresis, representing a greater than 3-fold
difference. The changes in anti–factor Xa activity due to plasmapheresis altered the final enoxaparin
dosage required to remain in the therapeutic range of 0.5–1 IU/mL (0.98 mg/kg/dose while receiving
plasmapheresis vs 0.69 mg/kg/dose without plasmapheresis). Our patient’s data suggest that plasma-
pheresis can significantly alter enoxaparin’s anticoagulant effect as measured by anti–factor Xa concen-
trations, which could cause a decreased anticoagulant effect during plasmapheresis and an increased
risk of bleeding on plasmapheresis discontinuation. If concurrent enoxaparin-based anticoagulation
and plasmapheresis are necessary, close monitoring of anti–factor Xa levels is advisable. Dose escala-
tions and reductions of enoxaparin may be necessary when initiating and discontinuing plasmaphere-
sis, respectively.
KEY WORDS plasmapheresis, low-molecular-weight heparin, enoxaparin, blood coagulation factors,
factor Xa, pulmonary embolism, anti-N-methyl-D-aspartate receptor encephalitis.
(Pharmacotherapy 2017;37(4):e16–e20) doi: 10.1002/phar.1907

Low-molecular-weight heparins (LMWHs), adult patients, LMWHs have been shown to be

such as enoxaparin, potentiate antithrombin III
and indirectly inactivate several clotting factors,
with the greatest inhibition of factor Xa.1 In
*Address for correspondence: Jeremy S. Stultz, Assis-
tant Professor, Department of Pharmacotherapy and
Outcomes Science, Virginia Commonwealth University
School of Pharmacy, Smith Building, Room 435, 410 N
12th Street, P.O. Box 980533, Richmond, VA, 23298;
e-mail:jstultz12@gmail.com.
Ó 2017 Pharmacotherapy Publications, Inc.
more efficacious than unfractionated heparin in
the treatment of acute venous thromboembolism
(VTE).2 In adolescent patients, LMWHs are
often the anticoagulant of choice because of
their lower risk of heparin-induced thrombocy-
topenia, lack of drug or diet interactions, and
extensive clinical experience.3, 4 In instances
where monitoring is recommended due to vari-
able pharmacokinetics and pharmacodynamics
(e.g., obese patients, pediatric and adolescent
patients), an anti–factor Xa assay can determine
 EFFECT OF PLASMAPHERESIS ON ENOXAPARIN Rahawi et al
the level of anticoagulation of a particular
LMWH.
Plasmapheresis is a procedure for removing
blood components, including plasma, antibodies,
or cells, and is an immunotherapy used for the
management of autoimmune-mediated encephalo-
pathy in children.5 Separation of blood compo-
nents is accomplished through the use of
semipermeable membranes or centrifugation.
Plasmapharesis has been reported to remove drugs
such as dalteparin, verapamil, gentamicin, and
basiliximab.6 In addition, daily plasmapheresis has
been shown to reduce levels of clotting factors
including factors I, II, V, VII, VIII, IX, and X,7 and
it has even been used therapeutically as a method
of removing fibrinogen in a patient experiencing
repeated clotting during renal replacement ther-
apy.8 Alternatively, the removal of the anticoagu-
lant antithrombin III may be greater than the
removal of clotting factors and could produce a
procoagulant state in some patients, with levels
believed to return to baseline 1–2 days after a
plasmapheresis procedure.7, 9
A previous case report described decreased
dalteparin activity in a patient being treated
with plasmapheresis.10 To our knowledge, this
effect of plasmapheresis has never been
reported in a patient receiving enoxaparin. In
this case report, we describe an obese adoles-
cent patient who was treated with enoxaparin
for a pulmonary embolism (PE) while receiv-
ing plasmapheresis for suspected autoimmune
encephalitis and who experienced clinically sig-
nificant reductions in anti–factor Xa activity
after plasmapheresis.
Case Report
A 13-year-old, obese (92 kg, height 158 cm [5
feet 2 inches], body mass index 37 kg/m2
[> 99th percentile for age]) girl with a history of
asthma and a concussion presented to an outside
hospital with myalgias, difficulty ambulating,
and temperatures reaching 102.9°F. Her chief
complaints were diffuse abdominal pain, head-
ache, neck pain, and generalized malaise. Her
home medications consisted of topiramate and
an unknown antibiotic. The patient’s basic meta-
bolic panel revealed an acute kidney injury with
a serum creatinine concentration (SCr) of
2.02 mg/dL (normal range 0.50–1.00 mg/dL),
Bedside Schwartz estimated glomerular filtration
rate (eGFR) of 32 mL/min/1.73 m2, 11 and blood
urea nitrogen (BUN) level of 29 mg/dL (normal
range 8–23 mg/dL), and she was transferred to
e17
the Children’s Hospital of Richmond at Virginia
Commonwealth University.
Due to suspected obstructive uropathy, she
required frequent Foley catheterization to
remove urine and decompress the bladder, and
her acute kidney injury eventually resolved.
However, less than 24 hours after admission,
her mental status became altered, including
auditory and visual hallucinations. She had
disconjugate eye movement in all directions and
upper extremity dysmetria. Empiric acyclovir,
ceftriaxone, and vancomycin were initiated for
concerns of meningoencephalitis, but the infec-
tious workup was ultimately negative. She was
transferred to the pediatric intensive care unit
due to her altered mental status, worsening
weakness, and hypopnea leading to desaturation.
Magnetic resonance imaging revealed lep-
tomeningeal enhancement as well as an abnor-
mality in the corpus callosum. Due to the
concern for autoimmune anti–N-methyl-D-aspar-
tate receptor encephalitis or acute disseminated
encephalomyelitis, the patient received intra-
venous immune globulin (IVIG) 1 g/kg. Because
her symptoms continued, she was also scheduled
to receive five courses of plasmapheresis, with
IVIG 0.5 g/kg administered after each course.
Her plasmapheresis procedures used albumin 5%
as replacement fluid with approximately 3 L of
exchanged volume for each procedure, and she
did not receive fresh frozen plasma or cryopre-
cipitate. Before the initiation of plasmapheresis,
her SCr was 0.37 mg/dL (eGFR of 176 mL/min/
1.73 m2), and BUN level was 11 mg/dL. Unfrac-
tionated heparin 5000 units (54 units/kg) subcu-
taneously every 8 hours was also started for
thromboprophylaxis.
After receiving two sessions of plasmaphere-
sis, the patient was noted to be more tachy-
cardic and complained of chest pain. A
computed tomography scan of her chest
revealed bilateral, moderate to large pul-
monary emboli. An echocardiogram did not
show signs of right ventricular strain and
therefore no further invasive interventions
were performed. She was transitioned to hep-
arin, with a loading dose of 5250 units
(57 mg/kg) intravenously over 10 minutes and
then continuous infusion of 1400 units/hour
(15 units/kg/h), adjusted to achieve an acti-
vated partial thromboplastin time equivalent to
an anti–factor Xa concentration of 0.3–0.7 IU/
mL based on our institutional assay. As well,
IVIG was discontinued for the remaining three
plasmapheresis sessions.
e18 PHARMACOTHERAPY Volume 37, Number 4, 2017

One day after her third plasmapheresis ses-

sion, the patient was transitioned to enoxaparin
100 mg (1.1 mg/kg/dose) subcutaneously every
12 hours. Before initiation of enoxaparin, her
SCr was 0.77 mg/dL (eGFR of 84 mL/min/
1.73 m2), BUN level was 15 mg/dL, and urine
output was 2250 mL/day. Given the patient’s
age, history of acute kidney injury, and obesity,
anti–factor Xa monitoring was warranted to help
ensure the safety and efficacy of enoxaparin
therapy. The anti–factor Xa concentration,
obtained approximately 4 hours after the second
Figure 1. Anti–factor Xa (anti-Xa) concentrations after
dose, was 1.06 IU/mL. This was slightly above enoxaparin administration on the plasmapheresis day
the goal range of 0.5–1 IU/mL,4 and the enoxa- and plasmapheresis-absent day. aEnoxaparin dose was
parin dose was decreased to 90 mg (0.98 mg/kg/ 90 mg; benoxaparin dose was 70 mg; ↓time of plasma-
dose) subcutaneously every 12 hours. The pheresis on plasmapheresis day.
patient received her fourth plasmapheresis
session just prior to her first 90-mg dose. An
(Figure 1). Assessment of the anti–factor Xa
anti–factor Xa concentration was obtained
concentrations with and without plasmapheresis
approximately 5 hours after the second 90-mg
found an anti–factor Xa decay rate over a 4-
dose and was 0.90 IU/mL, and no dosage adjust-
hour period was 0.28 IU/mL/hour with plasma-
ments were made. Her SCr was 0.38 mg/dL
pheresis but only 0.088 IU/mL/hour without
(eGFR of 170 mL/min/1.73 m2), BUN was
plasmapheresis. This effect constitutes a greater
13 mg/dL, urine output was 2300 mL/day, and
than 3-fold difference. Assuming a one-compart-
weight was 87.4 kg.
ment anti–factor Xa elimination model, the anti–
Two days later, a repeat anti–factor Xa con-
factor Xa half-life was 1.61 and 7 hours with
centration obtained approximately 4 hours after
and without plasmapheresis, respectively. Of
the sixth enoxaparin 90-mg dose (with no
note, the patient’s daily urine output, weight,
plasmapheresis sessions in the last 48 h) was
and clinical status were similar on both assess-
1.34 IU/mL. The team noted bleeding at her
ment days, and SCr was 0.48 mg/dL (eGFR of
central line insertion site and hematuria poten-
135 mL/min/1.73 m2) on the second assessment
tially related to higher anti–factor Xa concentra-
day. Hematuria and bleeding at the central line
tions. Her enoxaparin dose was decreased to
site resolved after dosage reductions.
70 mg (0.80 mg/kg/dose, weight 87.4 kg) subcu-
Finally, to reflect the anti–factor Xa concen-
taneously every 12 hours based on the anti–fac-
tration of 1.07 IU/mL 4 hours after the fourth
tor Xa concentration of 1.34 IU/mL; however,
70-mg dose, the enoxaparin dose was decreased
she was scheduled to receive her last plasma-
to 60 mg (0.69 mg/kg/dose, weight 86.9 kg)
pheresis therapy that afternoon. It was suspected
subcutaneously every 12 hours. The 4-hour
that the increased anti–factor Xa concentration
anti–factor Xa concentration was 0.85 IU/mL
(despite consistent renal function and no
after 4 doses of 60 mg subcutaneously every
changes in dosage) was due to the absence of
12 hours. This dose was continued for the
plasmapheresis in the past 48 hours.
remainder of her admission, and she was eventu-
To assess the impact of plasmapheresis on the
ally discharged on this regimen. One month
anti–factor Xa activity, a second anti–factor Xa
after discharge, her weight and 4-hour anti–factor
assay was obtained following her final plasma-
Xa concentration were 92 kg and 0.63 IU/mL,
pheresis session, approximately 4 hours after the
respectively.
previous anti–factor Xa concentration of
1.34 IU/mL (Figure 1). To compare anti–factor
Xa activity with and without plasmapheresis, a
Discussion
second set of anti–factor Xa concentrations were
obtained without plasmapheresis. These concen- In this patient’s case, plasmapheresis increased
trations were obtained 48 hours following the the rate of decline in anti–factor Xa concentra-
completion of the patient’s final plasmapheresis tions after enoxaparin dosing, suggesting that
procedure and after receiving 4 doses of enoxa- plasmapheresis may remove enoxaparin,
parin 70 mg subcutaneously every 12 hours antithrombin III, and/or factor Xa. To our
 EFFECT OF PLASMAPHERESIS ON ENOXAPARIN Rahawi et al
knowledge, this is the second case report illus-
trating the effect of plasmapheresis on anti–fac-
tor Xa activity in a patient treated with LMWH,
with the first reported in a patient receiving dal-
teparin.10 However, we believe that we are the
first to describe this phenomenon in an adoles-
cent patient treated with enoxaparin.
The serial anti–factor Xa levels revealed an
increase in decay of >300%. The patient’s clini-
cal status, urine output, and weight were similar
over the 3 days during which anti–factor Xa
concentrations were measured; therefore, it is
unlikely that a change in enoxaparin renal clear-
ance was responsible for this difference in decay
rate. To calculate the drug half-lives, we used
one-compartment model kinetics. Although it is
reported that enoxaparin may follow a two-com-
partment pharmacokinetic model,12 previous
reports have described anti–factor Xa elimina-
tion rates using a more practical one-compart-
ment model.13 It has been previously reported
that decay rates, when plasmapheresis followed
dalteparin dosing, increased from 0.06 IU/mL/
hour to 0.35 IU/mL/hour (a > 480% increase).10
The slower decay rate observed in our patient’s
case could be due to multiple factors. The previ-
ous case was using dalteparin and measured
anti–factor Xa concentrations during plasma-
pheresis,10 whereas the current case was using
enoxaparin and measured anti–factor Xa concen-
trations several hours prior to and just after
plasmapheresis. In addition, antithrombin III
removal by plasmapheresis has varied between
patients and could affect the anti–factor Xa
decay rate.9 Plasmapheresis procedures could
also have been different, although our patient
did receive 5% albumin as replacement fluid,
which is similar to previous reports of plasma-
pheresis practices.6, 10 Fresh frozen plasma
has also been used as part of the replacement
during plasmapheresis procedures,6 but it is not
a standard of practice, nor commonly used at
our institution, and its impact on antithrombin
III and/or factor Xa concentrations has not been
evaluated.
The literature suggests that obese adolescents
require lower than recommended enoxaparin
doses to achieve therapeutic anti–factor Xa con-
centrations when enoxaparin is dosed on total
body weight,14 with reported mean therapeutic
dosages of 0.81 mg/kg/dose subcutaneously every
12 hours,15 compared with 1 mg/kg/dose subcu-
taneously every 12 hours for nonobese adoles-
cents.4 Our patient required higher dosing based
on her weight (0.98 mg/kg/dose subcutaneously
e19
every 12 h) during plasmapheresis even with a
higher SCr, but her final dose without plasma-
pheresis (0.69 mg/kg/dose subcutaneously every
12 h) was even lower than the dosages reported
in the literature for obese patients.15
Three hypotheses are proposed that may
explain the observed reduction in anti–factor Xa
activity due to plasmapheresis: (i) enoxaparin
itself is removed by plasmapheresis; (ii) factor
Xa and/or antithrombin III is removed via
plasmapheresis; and (iii) the enoxaparin–an-
tithrombin complex and/or enoxaparin–an-
tithrombin–factor Xa complex is removed via
plasmapheresis. The first hypothesis can be sup-
ported by reports that plasmapheresis removes
drugs.6 This has also been reported in extracor-
poreal membrane oxygenation, where unfrac-
tionated heparin is removed.16 The second
hypothesis is supported by studies illustrating
the removal of clotting factors and antithrombin
III by plasmapheresis, with antithrombin III
removed to a greater degree (50–100% removed
after plasma exchange).7, 9 To our knowledge, no
studies investigating removal of enoxaparin–
antithrombin or enoxaparin–antithrombin–factor
Xa complexes via plasmapheresis have been
reported. The alterations in enoxaparin activity
when a patient receives plasmapheresis may be a
combination of all three mechanisms.
We did not measure antithrombin III or
enoxaparin serum concentrations, which could
have provided insights into the proposed mecha-
nisms by which plasmapheresis reduced anti–
factor Xa activity. However, it is not standard of
care at our institution to measure antithrombin
III and enoxaparin concentrations in patients
receiving enoxaparin treatment. This was also a
single case, and generalizability is limited by
complicating factors such as the acute kidney
injury, suspected autoimmune encephalitis, and
presence of obesity in an adolescent patient.
Further study is warranted to confirm the effect
of plasmapheresis on enoxaparin activity.
Conclusion
In this case report, an obese adolescent receiv-
ing enoxaparin experienced clinically significant
reductions in anti–factor Xa activity after plasma-
pheresis, which could cause a decreased anticoag-
ulant effect while receiving plasmapheresis, with
an increased risk of bleeding on plasmapheresis
discontinuation. If concurrent LMWH-based anti-
coagulation and plasmapheresis are necessary,
close monitoring of anti–factor Xa levels is
e20 PHARMACOTHERAPY Volume 37, Number 4, 2017
advisable. Dose escalations and reductions of
LMWHs may be necessary when initiating and
discontinuing plasmapheresis, respectively.
References
1. Bergqvist D. Low molecular weight heparins. J Intern Med
1996;240:63–72.
2. Wells PS, Forgie MA, Rodger MA. Treatment of venous
thromboembolism. JAMA 2014;311:717–28.
3. Dabbous MK, Sakr FR, Malaeb DN. Anticoagulant therapy in
pediatrics. J Basic Clin Pharm 2014;5:27–33.
4. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic
Therapy in Neonates and Children: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of
Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest 2012;141:e737S–801S.
5. Khair AM. Utility of plasmapheresis in autoimmune-mediated
encephalopathy in children: potentials and challenges. Neurol
Res Int 2016;2016:7685807.
6. Ibrahim RB, Liu C, Cronin SM, et al. Drug removal by
plasmapheresis: an evidence-based review. Pharmacotherapy
2007;27:1529–49.
7. Chirnside A, Urbaniak SJ, Prowse CV, Keller AJ. Coagulation
abnormalities following intensive plasma exchange on the cell
separator. II. Effects on factors I, II, V, VII, VIII, IX, X and
antithrombin III. Br J Haematol 1981;48:627–34.
8. Fulop T, Cosmin A, Juncos LA. Recurring extracorporeal cir-
cuit clotting during continuous renal replacement therapy
resolved after single-session therapeutic plasma exchange. J
Clin Apher 2011;26:214–5.
9. Sultan Y, Bussel A, Maisonneuve P, Poupeney M, Sitty X,
Gajdos P. Potential danger of thrombosis after plasma
exchange in the treatment of patients with immune disease.
Transfusion 1979;19(5):588–93.
10. Sabloff M, Wells PS. The effect of plasmapheresis on the
serum activity level of dalteparin: a case report. Blood Coagul
Fibrinolysis 2000;11:395–400.
11. Schwartz GJ, Work DF. Measurement and estimation of GFR
in children and adolescents. J Am Soc Nephrol 2009;4
(11):1832–43.
12. Trame MN, Mitchell L, Krumpel A, Male C, Hempel G,
Nowak-Gottl U. Population pharmacokinetics of enoxaparin in
infants, children and adolescents during secondary throm-
boembolic prophylaxis: a cohort study. J Thromb Haemost
2010;8:1950–8.
13. Dunaway KK, Gal P, Ransom JL. Use of enoxaparin in a pre-
term infant. Ann Pharmacother 2000;34(12):1410–3.
14. Kendrick JG, Carr RR, Ensom MH. Pediatric obesity: pharma-
cokinetics and implications for drug dosing. Clin Ther
2015;37:1897–923.
15. Richard AA, Kim S, Moffett BS, Bomgaars L, Mahoney D Jr,
Yee DL. Comparison of anti-Xa levels in obese and non-obese
pediatric patients receiving treatment doses of enoxaparin. J
Pediatr 2013;162:293–6.
16. Green TP, Isham-Schopf B, Irmiter RJ, Smith C, Uden
DL, Steinhorn RH. Inactivation of heparin during extracor-
poreal circulation in infants. Clin Pharmacol Ther
1990;48:148–54.