Revised: 28 August 2020

Accepted: 2 October 2020

DOI: 10.1002/jca.21849

CASE REPORT

Paradoxical embolic strokes in a liver transplant recipient
with atrial septal defect undergoing therapeutic plasma
exchange
Shannon A. Rodgers1 |

Aarushi Suneja2 |

Marwan S. Abouljoud2 |

Zaher K. Otrock1

Atsushi Yoshida3 |

1

Department of Pathology and Laboratory
Medicine, Henry Ford Health System,
Detroit, Michigan

2

Department of Neurology, Henry Ford
Health System, Detroit, Michigan

3

Transplant and Hepatobiliary Surgery,
Henry Ford Health System, Detroit,
Michigan
Correspondence
Zaher K. Otrock, Transfusion Medicine
Division, Department of Pathology and
Laboratory Medicine, Henry Ford
Hospital, 2799 W Grand Blvd, Detroit, MI
48202, USA.
Email: [email-masked]; zaherotrock@
hotmail.com

Abstract
Therapeutic plasma exchange (TPE) is a technique used to separate blood components into layers based on their density difference, thus removing plasma and
exchanging it with replacement fluids. A variety of adverse reactions has been
described during TPE. Thrombotic events, especially strokes, are extremely rare
complications of TPE. Our patient was a 55-year-old female with history of
decompensated nonalcoholic steatohepatitis (NASH) liver cirrhosis. She underwent an orthotopic liver transplant (OLT) that was complicated with asystole
during reperfusion. Cardiac workup revealed a new atrial septal defect (ASD)
with left to right flow. Within the first 5 days after surgery, she developed refractory and persistent hyperbilirubinemia, with total bilirubin levels as high as
42 mg/dL. Our plasmapheresis service was consulted to initiate TPE. Towards
the end of the first and only session of TPE, the patient developed hypoxia and
left-sided hemiplegia. Stroke response was initiated, and the patient was
intubated. MRI done 24 hours after the incident showed multiple acute small
embolic infarcts scattered within the bilateral cerebral and cerebellar hemispheres. Bilateral lower and upper extremities venous duplex studies were positive for acute left internal jugular (IJ) vein thrombosis. Patient was treated with
anticoagulation and the IJ catheter was removed. Patient also had closure of her
ASD. On last follow up, she was doing well with complete reversal of neurologic
deficits and stable liver function. Our patient had an uncommon complication of
TPE. Her thrombosis manifested with multiple embolic strokes that would not
have happened without an ASD with left to right flow.
KEYWORDS
atrial septal defect, embolic strokes, liver transplantation, paradoxical, plasma exchange

1 | INTRODUCTION
Therapeutic plasma exchange (TPE) is a technique
performed with centrifugation- or filtration-based
devices. TPE using centrifugation separates blood
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© 2020 Wiley Periodicals LLC

components into layers based on their density difference, thus removing plasma with the protein bound
substances from the blood. The plasma is usually
exchanged with replacement fluids such as albumin or
thawed plasma.1

wileyonlinelibrary.com/journal/jca

J Clin Apher. 2021;36:206–210.

RODGERS ET AL.

Although TPE is a relatively safe and well-tolerated
procedure, different kinds of associated adverse reactions
have been described. These adverse events have been
attributed to the procedure itself, replacement fluid, anticoagulation used, or intravenous catheter access. The frequency of complications ranges from 4 to 30%.2-5
Frequently, the reported complications are mild and can
be quickly managed. Rarely, severe events occur, mainly
related to vasovagal reactions or severe citrate toxicity;
these have been mostly reported in thrombotic thrombocytopenic purpura, leukostasis syndrome, and septic
shock.2 TPE can affect patients' hemostasis due to the
reduction of coagulation factors, which is further compounded in patients with an underlying risk for bleeding
or thrombosis.
Thrombotic events, especially strokes, are extremely
rare complications of TPE.6-8 We hereby report our experience with a case of paradoxical embolism resulting in
stroke during TPE, which was complicated by the presence of an atrial septal defect (ASD).

2 | C AS E HI S T O R Y
Our patient was a 55-year-old Caucasian woman with a
history of hypertension, hypothyroidism, end stage liver
disease and cirrhosis secondary to non-alcoholic
steatohepatitis (NASH) who underwent orthotopic liver
transplantation (OLT). Cardiac echocardiogram and catheterization before transplant were negative. Her laboratory parameters showed a Model for End-Stage Liver
Disease (MELD) score of 35 at transplant. During transplant, patient became coagulopathic with an estimated
blood loss of 14 L and required transfusion with multiple
blood components. She went into asystole during reperfusion and was revived with chest compressions and sent to
the surgical intensive care unit. Cardiac workup revealed
a new ASD with left to right flow and without evidence
of pulmonary hypertension. Within her first postoperative week, she developed refractory persistent hyperbilirubinemia, with total bilirubin levels as high as
42 mg/dL. Patient's workup was negative for antibodyrelated graft dysfunction or mechanical cholestasis. Her
postoperative course was further complicated by ascites,
peritonitis (treated with antibiotics), and abdominal wall
mesh closure. Patient eventually recovered and was
doing well.
Transfusion Medicine service was consulted to initiate TPE for her refractory hyperbilirubinemia. Although
there are no ASFA (American Society for Apheresis)9
guidelines for the use of TPE for liver graft dysfunction in
the setting hyperbilirubinemia, the decision to proceed
with TPE was based on our institution's experience with

207

managing similar situations and published literature
demonstrating the utility of early TPE in liver graft dysfunction by removing excess bilirubin.10
After obtaining informed consent, TPE was performed
using the COBE Spectra apheresis system processing one
blood volume with thawed plasma replacement
(2600 mL) to reduce the risk of bleeding from worsening
thrombocytopenia and coagulopathy. A central venous
catheter was placed in the left internal jugular (IJ) vein
for vascular access. Anticoagulant citrate dextrose solution, solution A (ACD-A) was used with a whole blood to
anticoagulant ratio of 15 to 1. A total of 5 g of IV Calcium
gluconate was infused throughout TPE to treat ACD-Ainduced hypocalcemia, and 25 mg IV Benadryl was given
before TPE to treat allergic reactions to plasma. The
patient did well during the first session of TPE; however,
at the end the procedure, she became unresponsive,
tachypneic, hypoxic and left-hemiplegic. The extracorporeal volume was not rinsed with saline, thus aborting the
return of contents to the patient. Oxygen saturation failed
to improve with nasal cannula or bag mask ventilation;
thus, the patient was intubated, and a stroke response
was initiated. After stroke code activation, patient developed left upper extremity and left lower extremity hemiplegia with right-gaze deviation. Immediate CT head
without contrast and CT angiography of head/neck with
contrast were obtained (part of the acute stroke protocol)
and were negative for acute findings. The patient's neurological symptoms resolved within 30 minutes, leaving
only mild residual deficits. Complete blood counts and
basic electrolytes drawn within 10 minutes of the acute
event showed persistent thrombocytopenia (Table 1).
Therefore, due to her severe thrombocytopenia and
resolving symptoms, she was not a candidate for any
interventions including IV tissue plasminogen activator
(tPA) or mechanical thrombectomy.
MRI of the brain without contrast 24 hours after initial symptom onset and resolution revealed multiple
acute infarcts bilaterally in the cerebral and cerebellar
hemispheres thought to be presumably embolic in nature
(Figure 1). Subsequent transthoracic echocardiogram and
transesophageal echocardiogram revealed preserved ejection fraction, a moderate size patent foramen ovale with
bowing of the atrial septum to the right, and left to right
shunting with no left atrial appendage thrombus. Telemetry monitoring did not show any atrial fibrillation. Bilateral upper and lower venous duplex studies were positive
for an acute left internal jugular vein thrombosis;
although it was unclear whether this was a consequence
of the plasmapheresis or a culprit of thrombosis. The presumed etiology of the patient's acute embolic infarcts
was paradoxical emboli related to ASD. In the setting
of acute ischemic infarcts, the patient was placed on

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RODGERS ET AL.

Blood test

Prior to TPE

Post TPE

Normal reference range

Hgb

13.4

13.7

12-15 g/dL

Platelet count

40 000

48 000

150-450 K/μL

PT

19

17

12.1-14.5 seconds

PTT

30

29

22-36 seconds

Fibrinogen

177

Not done

200-450 mg/dL

Bilirubin, total

36.5

20.2

<1.2 mg/dL

T A B L E 1 Summary of laboratory
parameters before and 10 minutes after
therapeutic plasma exchange

F I G U R E 1 A, Diffusion weighted imaging (DWI) and B, FLAIR magnetic resonance imaging (MRI) revealing areas of acute ischemic
infarcts in bilateral cerebral and cerebellar hemispheres

anticoagulation, so the closure of her ASD was delayed
5 days after stroke. It is worth noting that the transplant
team was concerned about the ASD before starting plasmapheresis given the patient's intraoperative course;
however, the cardiology team did not anticipate an
increased risk with plasmapheresis and recommended
closing the ASD after the patient has been stabilized.
Our patient had no personal or family history of
thrombosis. Thrombophilia workup was not pursued for
two reasons. First, her management will not change
based on the thrombophilia results. Second, there was
concern that the results of the workup, especially for natural anticoagulants activities, would reflect the patient's
donor liver, instead of her pretransplant dysfunctional
liver, and her initial recovery from a challenging surgery.
The patient had a prolonged and complicated course
following her stroke. She had infectious complications,
renal impairment, and she required intubation more than
once. She also underwent ERCP with sludge removal and
biliary sphincterotomy. Her liver function tests improved
gradually. On last follow up after 24 months from the
incident, the patient was doing well with stable liver function and without neurologic deficits from the strokes.

3 | DISCUSSION
Despite significant advances in orthotopic liver transplantation (OLT), graft dysfunction continues to be a serious
complication that is associated with high morbidity and
mortality.11,12 Biliary complications are the most common adverse events after OLT and can be seen in 10% to
25% of cases.12 Hyperbilirubinemia is a serious, significant determinant of early graft dysfunction following
OLT. Without recovery of the liver graft, the mortality
from early graft dysfunction is high. Retransplantation is
considered a treatment for severe graft dysfunction; however, only a small number of patients would be rescued
due to shortage of organ donors and possibly the unfavorable retransplantation outcomes among the severely ill.11
Thus, other methods of graft rescue and support are
needed.
TPE is an extracorporeal blood purification procedure
designed for the removal of pathogenic antibodies and
proteins, immune complexes, cryoglobulins, endotoxins,
and other high-molecular weight substances. The basis of
TPE is that the removal of these substances will help
reverse the pathologic processes caused by these

RODGERS ET AL.

“substances.”13 TPE can remove toxic substances including plasma bilirubin. Most of the coagulation factors are
synthesized in the liver; thus, by replacing with fresh frozen plasma (FFP) TPE can also replace coagulation factors which are required in patients with liver failure and
coagulopathy. A few reports have suggested the efficacy
of TPE in liver support.10,14-17 In this regard, TPE can be
used as a temporary support in liver failure until graft
recovery or retransplantation.
According to a report from Johns Hopkins Hospital,
TPE provided an effective treatment option for dysfunctional liver allograft in four of five patients, and all four
patients had functioning grafts 1 year after liver transplantation.14 Akdogan and colleagues assessed the efficacy of TPE in 39 patients with fulminant hepatic
failure.15 TPE was performed daily until adequate clinical
response was obtained, the patient passed away, or transplantation
occurred.
Their
findings
suggested
coagulopathy and hyperbilirubinemia were significantly
improved through daily TPE. Twenty-one patients survived (54%), 12 required liver transplantation, and
18 patients expired. TPE was realized to be very effective
in correcting coagulopathy and improvement of liver
function. In another study from Japan, 11 patients with
progressive liver failure after liver transplantation
showed improved liver function after TPE, particularly in
those with total bilirubin levels of 13 to 24 mg/dL.17
More recently and of more relevance to our case
study, Choe et al10 published their experience evaluating
the effects of TPE in early liver graft dysfunction. They
defined early liver graft dysfunction as a sustained hyperbilirubinemia (≥10 mg/dL) within 30 days of liver transplantation without concurrent biliary complications. In a
13-year period, 107 early liver graft dysfunction patients
underwent TPE while 36 patients did not. Patients managed with TPE had 82.2% and 53.8% survival rates at
1 month and 1 year respectively, whereas the non-TPE
managed patients showed significantly lower survival
rates of 58.3% and 22.2%, respectively (P < .001). In the
TPE group, total bilirubin and INR statistically significant
decreased after the final TPE session. TPE improved
patients' survival and decreased the hazard risk of death.
Adverse events were documented in 44/1132 (4%) TPE
sessions. Hypotension was the most common type of
adverse events. Other minor adverse events comprised
chills, abdominal pain, itching, and tingling. Alveolar
hemorrhage was documented once. None of the patients
had any thrombotic events or strokes from TPE.10
Although there are no ASFA (American Society for
Apheresis) guidelines for the use of TPE for liver graft
dysfunction in the setting hyperbilirubinemia, the decision to proceed with TPE for managing our case was
made based on our institution experience with managing

209

similar cases. This decision was further supported by
published evidence in the medical literature on the utility
of TPE to remove excess bilirubin from plasma to help
reduce any damage caused on the liver graft.10,14,15,17
Bilirubin is associated with toxicity and its removal by
TPE may help decrease its adverse effects.14,16,18 High
levels of bilirubin can interfere with regeneration of the
biliary duct cells. Therefore, hyperbilirubinemia has been
considered a significant determinant of early graft loss in
liver transplant patients.10,19 Thus, it seems reasonable to
remove the excess bilirubin that cannot be processed by
the transplanted liver especially during the early stage
after transplantation.
Two distinct mechanisms have illustrated how ASD
can cause cerebral embolic events: paradoxical embolism
or atrial fibrillation. Our patient underwent extensive cardiac monitoring and imaging, revealing no evidence of
atrial fibrillation or left associated atrial appendage
thrombus; thus, the etiology of the patient's acute ischemic strokes was hypothesized to be due to a paradoxical
embolism, in which her known left to right shunt was
temporarily reversed to a right to left shunt, allowing for
the formed embolisms to travel from her venous system
to her brain. Perhaps this change in shunting was due to
the flow of the plasmapheresis procedure, or a transient
increase in abdominal pressure due to coughing or
Valsalva maneuver that was enough for the right sided
heart pressure to overcome the pressure within the left
heart. Our patient had an uncommon complication of
TPE, most likely fragmented thrombi from the
thrombosed IJ vein although we cannot rule out thrombosis triggered by the patient's coagulopathy. Thrombosis
manifested with multiple embolic strokes that would not
have happened without an ASD.
Patients with liver disease including liver transplant
patients are usually considered at risk for bleeding complications as reflected in their prolonged PT/aPTT. However, recent evidence suggests that the balance between
prohemostatic and antihemostatic factors can be
disrupted with a compensation for deficient liver-derived
procoagulants resulting in a relative hypercoagulable
state which may cause thrombotic complications. This is
why coagulopathy in liver transplant patients is often
coupled to thrombosis and it can extend for months following transplantation.20,21
In our patient, thrombosis manifested with multiple
embolic strokes that would not have happened without
an ASD. Our review of the literature yielded a single case
report of a 68-year-old woman who developed a paradoxical embolism during discontinuous-flow plasmapheresis
through a right jugular venous access.6 Her workup revealed a patent foramen ovale (PFO) with interatrial
shunt. The authors hypothesized that the presence of the

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RODGERS ET AL.

venous catheter could have triggered an increase in the
right atrium blood pressure, thus driving a paradoxical
embolic stroke through the PFO.6 Our patient might have
had the same mechanism of increased atrium blood pressure leading to a paradoxical embolism through the ASD.
Our case report is intended to caution physicians
about thrombosis as a rare complication of TPE. The
question remains whether ASDs should be corrected
before TPE in the setting of increased risk of
coagulopathy as in liver transplant patients. In our case,
we decided to proceed with plasmapheresis as the priority was to treat the patient's liver graft dysfunction and
manage coagulopathy. We believe ASD correction before
plasmapheresis would have been a risky procedure. We
do not think ASD should be corrected before plasmapheresis especially in the setting of clinically unstable
patients with coagulopathy.
CONFLICT OF INTEREST
The authors declare that they have no conflicts of
interest.
ORCID
Zaher K. Otrock

https://orcid.org/0000-0002-5823-2694

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How to cite this article: Rodgers SA, Suneja A,
Yoshida A, Abouljoud MS, Otrock ZK. Paradoxical
embolic strokes in a liver transplant recipient with
atrial septal defect undergoing therapeutic plasma
exchange. J Clin Apher. 2021;36:206–210. https://
doi.org/10.1002/jca.21849