Transfusion and Apheresis Science 48 (2013) 327330

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Transfusion and Apheresis Science

journal homepage: www.elsevier.com/locate/transci

The results of therapeutic plasma exchange in patients with

severe hyperthyroidism: A retrospective multicenter study
Muzaffer Keklik a,, Leylagul Kaynar b, Mehmet Yilmaz b, Serdar Sivgin a, Musa Solmaz a,
Cigdem Pala a, Sulbiye Aribas c, Gulsah Akyol a, Kursat Unluhizarci c, Mustafa Cetin a,
Bulent Eser a, Ali Unal a
a
b
c

Erciyes University, Department of Hematology and Apheresis Unit, 38039 Kayseri, Turkey
Gaziantep University, Department of Hematology, Gaziantep, Turkey
Erciyes University, Department of Endocrinology, Kayseri, Turkey

a r t i c l e

i n f o

Keywords:
Hyperthyroidism
Therapeutic plasma exchange

a b s t r a c t
Hyperthyroidism characterized by elevated serum levels of circulating thyroid hormones.
The aim of hyperthyroidism treatment is to achieve a euthyroid state as soon as possible
and to maintain euthyroid status. However, drug withdrawal and utilization of alternative
therapies are needed in cases in which leucopenia or impairment in liver functions is
observed during medical therapy. In the present study, we aimed to present our cases
which underwent therapeutic plasma exchange (TPE) due to severe hyperthyroidism.
The results of 22 patients who underwent therapeutic plasma exchange due to hyperthyroidism in Apheresis Units of Erciyes University and Gaziantep University, between 2006
and 2012, were retrospectively reviewed. These cases had severe thyrotoxic values despite
anti-thyroid drug use. After TPE, we observed a signicant decrease in free thyroxin (FT4)
(p < 0.001) and free triiodotyhronin (FT3) (p < 0.004) levels. There was statistically signicant increase in the mean values of TSH levels after TPE (p < 0.001).
Clinical improvement was achieved in hyperthyroidism by TPE in 20 cases (91%). Both
FT3 and FT4 levels remained above the normal limits in two of 22 patients. TPE should
be considered as an effective and safe therapeutic option to achieve euthyroid state before
surgery or radioactive iodine treatment. TPE is a useful option in cases with severe hyperthyroidism unresponsive to anti-thyroid agents and in those with clinical manifestations of
cardiac failure and in patients with severe adverse events during anti-thyroid therapy.
2013 Elsevier Ltd. All rights reserved.

1. Introduction
Endocrine and metabolic emergencies are relatively
common conditions in acute care medicine [1]. Severe
hyperthyroidism is a life-threatening condition. Graves
disease, toxic adenoma and multi-nodular goiter are the
most commonly encountered causes of hyperthyroidism.
In most instances, the excessive production of thyroid hormones by the thyroid gland is the major cause of severe
hyperthyroidism. The three most common treatments for
Corresponding author.
E-mail address: muzafferkeklik@yahoo.com (M. Keklik).
1473-0502/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.transci.2013.04.010

hyperthyroidism are antithyroid drugs, radioactive iodine

(RAI), and thyroidectomy [2,3]. The acute phase must be
treated with standart treatments such as thiamazole, prednisolone, and nonselective beta-blockers. In patients with
severe hyperthyroidism, further therapies are needed to
restore euthyroid hormone status. Therapeutic plasma exchange (TPE) is an alternative treatment that has been proposed since the 1970s for hyperthyroidism [47]. TPE
removes protein-bound substances including thyroid hormones. This retrospective study was performed as an analysis of our experience with TPE with regard to treatment
outcomes and complications in adult patients with severe
hyperthyroidism.

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M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327330

2. Patients and methods

We retrospectively reviewed records of patients who
were treated with TPE between 2006 and 2012 for severe
hyperthyroidism at Apheresis Units of Erciyes and Gaziantep University. The list of patients was obtained from the
TPE log-book of the apheresis units in our facility. These
cases had severe thyrotoxic values despite anti-thyroid
drug use. Data on demographics, etiologies of hyperthyroidism, thyroid hormone status (before and after TPE),
TPE sessions were analyzed. Procedural complications
and outcome are recorded.
The reference ranges for the laboratory indices were
8.0020.00 pg/mL for free thyroxin (FT4), 2.204.70 pg/
mL for free triiodothyronin (FT3), and 0.203.20 IU/mL
for thyroid stimulating hormone (TSH).
Fresh frozen plasma (FFP) was used in all cases as
replacement uid. TPE was performed via central venous
access by using Fresenius ASTEC 204 device (Fresenius
Com.Tec, Germany). TPE was carried out at the predicted
plasma volume for 1.3 times every other day. Plasma volumes were calculated for each patient using the patients
body surface area, sex, and hematocrit. Vital signs were
monitored at the beginning and end of each procedure,
and patients were monitored for adverse events during
apheresis procedures. Serum FT3, FT4 and TSH levels were
measured at 6 h after TPE sessions. In order to avoid severe
hypocalcaemia during the TPE, all patients received an
intravenous infusion of 10% calcium gluconate. Written
informed consent was obtained from all patients after
procedural risks were explained in detail before each procedure. Each session lasted for 2 h.
Analysis were performed using SPSS 20.0 (IBM, Chicago)
with considering a p < 0.05 statistically signicant. ShapiroWilks test was used to check the data normality. To
compare the differences of thyroid hormone levels before
and after TPE, Wilcoxon t test was used.

3. Results
Of the 22 patients, 16 (72.8%) were women and 6 (27.2%)
were men. Median age was 47 (range: 2274) years. Of
these cases, there were nine cases with Graves disease
and 13 cases with multi-nodular goiter. All cases had palpitation while there was tachycardia in 14 cases; sweating in
16 cases and tremor in 12 cases. Drugs were withdrawn by

the attending clinicians because of severe hepatotoxicity

related to anti-thyroid drugs in 8 cases and leucopenia in
12 cases. Drugs were withdrawn by patients due to arthralgia in two cases. All patients received b-receptor antagonist
and steroid drugs. Twenty-two patients received a total of
88 procedures. The median number of apheresis sessions
was four (range: 29). The median processed plasma volume was 3000 mL (range: 18004000) for each cycle. Overall response to TPE was seen in 20/22 (91%) patients. No
response to TPE was seen in two patients (9%). Table 1 lists
laboratory data pre and post TPE.
Table 2 lists pre and post procedural levels of thyroid
hormones. The mean thyroid hormone concentrations
(the mean SD) before TPE for FT3, FT4 and TSH were
17.25 15 pg/mL, 34.31 21 pg/mL and 0.03 0.04 IU/mL,
respectively. In neither case the process was terminated
because of adverse events. Complications were mild and
consisted of hypotension and hypocalcemia. Hypotension
episodes occurred in ve patients and hypocalcemia was
observed in four patients. There was no catheter related
complication such as hematoma, infection or thrombosis.
Clinical improvement was achieved in 20 cases (91%);
subsequently, RAI and surgery was performed to achieve
permanent cure in 15 and ve cases, respectively. After
TPE, the mean FT3, FT4 and TSH levels were 5.34 4 pg/
mL, 15.86 14 pg/mL and 1.02 1 IU/mL, respectively.
There was statistically signicant decrease in the mean
values of FT3 (p < 0.001) and FT4 (p < 0.004) levels after
TPE. We observed signicant increase in the mean values
of TSH levels after TPE (p < 0.001). Thyroid hormone levels
remained high in two cases, one of these cases died as result of complicating the tachyarrhythmia following myocardial infarction. Her illness was toxic multi-nodular
goiter and she was 60 years old (patient 5). For the other
case (patient 6), a second TPE was performed, which again
resulted only in minor and temporally improvement. Despite TPE, this patient had symptoms of thyrotoxicosis
such as palpitation, tachycardia, tremor and sweating.
She was diagnosed with Graves disease and antithyroid
medication was withdrawn by the attending clinician because of arthralgia. Following antithyroid and nonsteroidal
anti-inammatory drugs she recovered.
4. Discussion
Thyrotoxicosis is characterized by extremely elevated
serum levels of circulating thyroid hormones leading to

Table 1
Laboratory data for therapeutic plasma exchange.
Variables

Pretreatment, median (range)

Posttreatment, median (range)

p Value

Normal ranges

Hb (g/dl)
WBC (103/lL)
Plt (103/lL)
BUN (mg/dl)
Cre (mg/dl)
AST (u/L)
ALT (u/L)
Ca (mg/dl)
Alb (g/dl)

11.7 (8.215.3)
4.66 (1.3034.12)
185 (64392)
12.5 (748)
0.65 (0.401.44)
31.5 (181813)
39 (142339)
9.5 (810.7)
3.8 (2.84.6)

11.4 (7.913.6)
6.75 (0.628.3)
220 (77412)
15 (939)
0.70 (0.401.09)
34 (1766)
38 (1680)
9.4 (7.910.6)
3.6 (34.1)

0.244
0.085
0.903
0.329
0.886
0.566
0.186
0.216
0.158

1218
4.810.8
130400
7.921
0.841.44
035
045
8.810.6
3.55.2

Abbreviations: Hb hemoglobin, WBC white blood cells, Plt platelet count, BUN blood urea nitrogen, Cre creatinine, AST aspartate transaminase, ALT alanine
transaminase, Ca calcium, Alb albumin.

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M. Keklik et al. / Transfusion and Apheresis Science 48 (2013) 327330

Table 2
Thyroid hormone levels before and after therapeutic plasma exchange.
Patient

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22

Before TPE

After TPE

FT3 (pg/mL)

FT4 (pg/mL)

TSH (IU/mL)

FT3 (pg/mL)

FT4 (pg/mL)

TSH (IU/mL)

6.08
6.73
4.35
28.43
14.51
6.40
3.10
14.68
13.97
14.70
12.61
3.80
69.73
28.68
15.29
16.30
22.90
26.80
14.50
16.73
26.54
12.86

18.22
50.76
25.65
62.47
58.44
37.50
13.41
62.68
33.04
44.10
54.50
3.02
4.83
49.10
3.56
4.37
49.80
52.90
47.45
5.86
38.10
35.12

.16
.10
.01
.05
.01
.04
.04
.01
.06
.01
.02
.01
.01
.01
.01
.01
.01
.04
.01
.01
.01
.02

4.34
2.54
5.59
2.45
14.20
6.10
3.07
3.89
.91
4.20
5.27
9.17
13.45
2.12
12.38
2.41
3.10
4.80
3.30
3.65
8.24
2.47

15.37
11.06
25.90
14.76
47.20
51.20
12.91
15.20
3.68
23.10
38.50
3.78
6.47
9.80
3.14
1.46
13.40
16.70
17.20
2.34
6.45
9.35

.24
2.71
.27
.03
.01
.02
.10
5.72
4.85
.01
.12
.01
.03
.15
.10
.02
.04
.05
4.56
.15
.10
3.35

Abbreviations: TPE: therapeutic plasma exchange, FT4: free thyroxin, FT3: free triiodothyronin, TSH: thyroid stimulating hormone.

multisystem disease. Even with treatment, mortality stays

high at approximately 30% [8]. It is difcult to estimate its
exact incidence because no denitive and universally-accepted criteria exist for establishing the diagnosis, and in
most cases, the results of laboratory tests are indistinguishable from those observed in patients with otherwise
uncomplicated thyrotoxicosis [1]. But it is believed that thyrotoxicosis is less frequent nowadays than in the past, it
may account for <12% of hospital admissions [9]. All patients with severe hyperthyroidism should be treated in
an intensive care unit setting, given the profound disturbances in temperature, cardiovascular function, uid and
electrolyte balance. Therapeutic intervention has a fourfold
aim: to reduce the production and secretion of thyroid hormones from the thyroid gland; to antagonize the peripheral
action of thyroid hormones; to reverse systemic disturbances; and to address the precipitating event [1]. Antithyroid treatment options include medical therapy (propylthiouracil and methimazole), RAI and surgery. Medical
treatments including antithyroid drugs usually achieve
euthyroidism effectively. Thyroidectomy is performed in
special circumstances such as poor response to antithyroid
drugs, suspicious cytology, iodine-induced thyrotoxicosis,
and upon patients request. But in patients who had elevated thyroid hormones should be rendered euthyroid before surgical procedures to prevent the side effects of
hyperthyroidism [10,11]. TPE is an additional tool for
removing circulating thyroxine in patients who do not respond quickly to conventional therapy [12]. TPE has been
shown to have a clear benet in the severe hyperthyroidism
induced by Graves disease and multinodular goiter
[6,13,14]. In our study, there were nine cases with Graves
disease. Except one patient (case 6), all Graves disease patients recovered by TPE. We also treated 13 cases with multi-nodular goiter. Except one patient (case 5), clinical
improvement was achieved in hyperthyroidism by TPE in

12 cases with multinodular goiter. The therapeutic benet

of TPE results from the removal of the pathological substances from the thyroid storm: hormones, cytokines, toxins, and so on. TPE also removes 50 -monodesiodase which
converts T4 to T3 and this decreases T3 production [15].
However, this effect is usually transient and thyroid hormone levels increase within few days after TPE [1618].
So, in our study, ve patients underwent thyroid surgery
and 15 patients received RAI treatment for permanent cure.
Plasma or human albumin solutions provide new binding
sites for circulating free hormones. In our study, fresh frozen plasma was used in all cases as replacement uid. TPE
is a recommendation of grade IIc and a category III in the last
American Society for Apheresis (ASFA) guideline [8]. TPE
should be conducted as early as possible in order to be efcient. TPE is a relatively safe method of treatment, providing
it is performed by experienced staff and used for appropriate indications with all necessary precautions [19]. Side effects include transfusion reaction, citrate-related nausea
and vomiting, vasovagal or hypotensive reactions, hypocalcemia, catheter dysfunction, bleeding, respiratory distress,
and tetany or seizure. Death is rare and usually due to the
underlying disease [20]. Our patient (case 5) died complicating the tachyarrhythmia in the course of myocardial
infarction. Other complications consisted of hypotension
(n: 5) and citrate related hypocalcemia (n: 4). These complications were mild. All of the hypotensive episodes and
hypocalcemia were resolved briey after intravenous infusion of saline or further calcium infusion. TPE for treatment
of severe hyperthyroidism may be complicated by infections [21]. In the present study, there was no catheter
related complication such as infection or bleeding.
In conclusion, TPE is an effective treatment option for
patients with severe hyperthyroidism. However, it has a
transitory effect and thus several sessions should be performed, and it should be combined with other measures.

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