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Intravenous immunoglobulin in the treatment of human immunodeficiency virus-related thrombocytopenia.

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American Journal of Hematology 38:261-266 (1991)
Intravenous Immunoglobulin in the Treatment of Human
Immunodeficiency Virus-Related Thrombocytopenia
Mark U. Rarick, Terri Montgomery, Susan Groshen, Jane Sullivan-Halley, Denise Jamin,
Amitabha Mazumder, Parkash S. Gill, Carmen Loureiro, and Alexandra M. Levine
Departmentsof Internal Medicine (M.U.R., T.M., A.M., P.S.G., C.L., A.M.L.), Section of Hematology, Preventive Medicine (S.G., J.S.-H.),
and Pharmacology (D.J.), University of Southern California School of Medicine, Los Angeles, California
Fourteen patients with sexually transmitted human immunodeficiency virus (HIV)-related
immune thrombocytopenia were treated with intravenous gammaglobulin (IVIG). The
patients were treated with a uniform program consisting of 1g/kg of IVlG on day 1and day
2, followed by 1 g/kg on day 15. Most patients had pretreatment bleeding symptoms,
which included petechiae, spontaneous and traumatic ecchymoses, gum bleeding, and
epistaxis. Median baseline platelet count was 17,000/mm3(range 3-61 ,000/mm3). After the
infusion of the IGIV, all patients had a resolution of their bleeding by day 8. The median
maximum platelet count achieved with the IGlV was 220,000/mm3 (range 76-426,000/
mm3). No patient achieved either a sustained complete or partial remission after the
conclusion of the IVlG therapy. Toxicities were minimal with the majority being headache
and nausea. In conclusion, patients with sexually transmitted HIV infection and immune
thrombocytopenia respond favorably to WIG. This treatment should be considered as
first-line therapy for patients with HIV-related immune thrombocytopenia who require
immediate but temporary increase in their platelet count, attributable to symptoms or
signs of clinical bleeding or because of the need for an invasive procedure.
Key words: thrombocytopenia, HIV infection, intravenous gammaglobulin
INTRODUCTION
Infection by the human immunodeficiency virus (HIV)
is manifest by a spectrum of clinical diseases. Hematologic abnormalities include anemia, leukopenia, thrombocytopenia, and coagulation abnormalities [ 1-71.
Thrombocytopenia may be the initial manifestation of
HIV disease in up to 1 1 % of infected patients [8]. The
etiology of thrombocytopenia is multifactorial, including
immune-mediated peripheral destruction, splenic sequestration, decreased megakaryocytopoiesis, and in some
instances, drug-related causes as well [9-141. Most
patients may be asymptomatic or may present with only
minor manifestations of bleeding. Only rarely do patients
exhibit severe bleeding, but cranial hemmorhage or
symptomatic gastrointestinal bleeding can be seen
"7 ,9,141.
The treatment of immune associated HIV thrombocytopenia is not well established. Corticosteroids will
produce a rise in platelet count in most patients [15,16]
but rarely produce a sustained remission; furthermore,
long-term use of steroids may complicate the underlying
HIV-induced immunodeficiency. Splenectomy may also
0 1991 Wiley-Liss, Inc.
induce short-term remissions in up to 90% of the patients
[17], but late relapses may occur 1181. A more rapid
progression of the HIV infection in splenectomized
patients has been seen by some investigators [ 191 but not
by others [20]. The use of vincristine results in a minor
response rate but the neuropathic toxicity may limit its
clinical value 1211. Danazol has had only minor activity
in patients with HIV-related thrombocytopenia [22]. The
protein A immunoadsorption column 1231 and anti-Rh
antibodies [24] have also been used to treat patients with
HIV-related thrombocytopenia, although data are rather
limited. Recently, zidovudine (ZDV) has been shown to
improve the thrombocytopenia in up to 90% of HIVinfected patients [25-301.
Intravenous gammaglobulin (IVIG) has been used
widely in patients with classic autoimmune thrombocy-
Received for publication January 2, 1991; accepted May 16, 1991.
Address reprint requests to Dr. Mark U. Rarick, USC School of
Medicine, Norris Cancer Hospital, 1441 Eastlake Ave., Rrn. 162, Los
Angeles, CA 90033.
262
Rarick et al.
topenia. Most patients will respond to gammaglobulin,
and long-term remissions occasionally can be seen [31341. IVIG has also been used successfully in patients with
HIV-related thrombocytopenia [35,36]. These reports
have included patients with thrombocytopenia who consist of a spectrum of groups at risk of HIV infection,
including homosexual and bisexual men, hemophiliacs,
and IV drug users. Since preliminary evidence suggests
that the mechanism of HIV-thrombocytopenia may differ
depending on the risk factor for HIV infection, it is
possible that response rates to IVIG in these groups may
also differ [ 141. In the current study, a uniform group of
patients with sexually transmitted HIV infection and
severe thrombocytopenia (<30,000/mm3) were treated
with IVIG in order to ascertain the response rate,
toxicities, and long-term efficacy in this subgroup of
patients.
MATERIAL AND METHODS
Patients
For the purpose of this study, patients were included if
they had documented HIV infection via sexual transmission and severe thrombocytopenia, as defined by a
platelet count of <30,000/mm3 on two occasions at least
1 week apart. All patients underwent bone marrow
aspirate and biopsy, the results of which were required to
be consistent with immune thrombocytopenia, without
evidence of other underlying pathologic process. Patients
with vitamin deficiencies (B 12 and folate) were excluded,
as were those with opportunistic infections or neoplasms
requiring cytotoxic drug therapy. Patients were required
to have received no therapy for thrombocytopenia for at
least 4 weeks. At the time of the study, the effect of ZDV
on thrombocytopenia was unknown. Therefore, patients
who met the licensed indicators for ZDV at the time of the
study (previous episode of Pneumocystis carinii pneumonia or CD4+ lymphocyte count of <200/mm3) and
met the above entrance criteria were eligible for study
inclusion.
Drug Regimen and Definition of Response
A treatment cycle of intravenous gammaglobulin
(IVIG), (Gamimune-N, 5 % , Cutter Biologic, pH 4.25)
was defined as 1 g/kg IVIG administered intravenously
on day 1 and day 2, followed by 1 g/kg on day 15.
Maintenance therapy followed, consisting of 1 g/kg IVIG
every 3 weeks for three additional treatments. The
infusion rate of IVIG did not exceed 0.4 ml/kg/min.
A complete remission was defined as development of
a platelet count of >150,000/mm3, sustained for 1
month. Partial remission was defined as a rise in platelet
count to >50,000, but <150,000, sustained for 1 month.
A relapse of thrombocytopenia was defined as development of a platelet count of <50,000/mm3 at any time.
Since the initial seven patients had all relapsed by the
time of the first 3-week maintenance dose, the schedule
of IVIG was changed for the subsequent seven patieqts to
1 g/kg IVIG on the first and second day of their treatment,
followed by 1 g/kg every 2 weeks for four doses (total of
six doses of IVIG). Patients were then followed once a
month for 3 months and assessed for sustained response
and toxicity.
Laboratory Monitoring
Platelet counts were obtained at baseline and prior to
each dose of IVIG. Platelet bound IgG and IgM were
measured by direct immunofluorescence [37]. Serum
anti-platelet IgG was measured by indirect immunofluorescence. The number of peripheral blood CD4+ lymphocytes was analyzed by flow cytometry . Quantitative
IgG, IgA, and IgM were measured at baseline and prior
to each treatment cycle, as were circulating immune
complexes, determined by the pethyethylene glycol
(PEG) method [38].
Statistical Methods
The response variable was the platelet count at day 15,
maximum value over baseline, and day of last follow-up.
The explanatory variables were baseline platelet count,
CD4+ lymphocyte count at baseline and D15, platelet
antibody titers at baseline and D15, and quantitative
immunoglobulins also at baseline and D15. Platelet
counts were plotted as a function of time. Scatter plots
were drawn to display any possible associations between
the response and the explanatory variables.
To evaluate quantitatively the association of the explanatory variables with the response, the WilcoxonMann-Whitney test was used [39]. All P values were
two-sided.
RESULTS
Fourteen patients with HIV infection were enrolled and
received a total of 104 doses of IVIG. Patient characteristics are demonstrated in Table I. There were 13 males
and 1 female, with a median age of 27 years (range 23-37
years). The risk factor for HIV infection was through
sexual transmission in all cases. The majority of the
patients had a history of relatively minor bleeding,
consisting of petechiae in 64%, spontaneous ecchymoses
in 29%, traumatic ecchymoses in 7 I %, gum bleeding in
64%, and epistaxis in 36%. One patient had history of
headaches; a computed tomographic (CT) scan revealed
a possible intracranial bleed, although a magnetic resonance imaging (MRI) scan was normal. One patient had
no bleeding history.
Ten of the patients (72%) had received no prior therapy
for immune thrombocytopenia. Three patients (21%) had
received IVIG in the past for thrombocytopenia, and one
lGlV Use in HIV-Related Immune Thrombocytopenia
263
TABLE 1. Patient Characteristics*
Patient
Prior TCP
treatment
HIV
stage
5
Mild headache
1
31
M
Danazol
[I1
1.
2.
3.
4.
2
26
M
IVIG 3 months prior
I11
1. Petechiae
2. Gum bleeding
PGL
11
Mild diarrhea
for 24 hr after
infusion
3
21
M
IVIG 4 months prior
111
Nausea, mild
headache
25
M
None
111
PGL
Petechiae
Ecchymoses
PGL
13
4
1.
2.
3.
1.
2.
3.
5
26
M
None
IVA
1. Petechiae
2. Spontaneous ecchymoses
3. Gum bleeding
PGL
Hairy
leukoplakia
10
6
25
M
IVIG 2 months prior
I11
6
Headache
33
None
PGL
6
None
None
I 11
111
Petechiae
Post-traumatic ecchymoses
Gum bleeding
Post-traumatic ecchymoses
PGL
Ecchymoses
I
1.
2.
3.
I.
I.
2.
1.
2.
Post-traumatic ecchymoses
Epistaxis
PGL
9
None
PGL
6
Mild phlebitis
PGL
6
None
8
31
9
33
M
None
111
10
26
F
None
I11
Petechiae
Traumatic ecchymoses
Gum bleeding
Epistaxis
Petechiae
Traumatic ecchymoses
Gum bleeding
Petechiae
Post-traumatic bruises
Headache with questionable
intracranial hemorrhage by CT
scan; MRI negative
Petechiae
Post-traumatic
ecchymoses
3. Gum bleeding
+ spontaneous
1 . Ecchymoses: spontaneous,
P.E.
Toxicity
Sex
M
M
Bleeding
# Doses
( I g/kg)
Age
PGL
Petechiae
6
None
Nausea
traumatic
2. Epistaxis
IVA
1. Petechiae
2. Post-traumatic ecchymoses
3. Gum bleeding
PGL
Petechiae, gum
bleeding
6
None
M
AZT stopped prior to
Rx 1 wk restarted
D43 of protocol
None
111
1. Petechiae
2. Ecchymoses, post-traumatic,
spontaneous
3. Gum bleeding
4. Epistaxis
PGL
Petechiae,
ecchymoses
6
Pruritis X5 min
mild headache
23
M
None
I11
None
PGL
9
Mild swelling
at injection
site
Transient
disorientation
Mild headache
<24 hr
32
M
None
111
1. Gum bleeding
2. Epistaxis
PGL
9
Headache X2
11
26
M
12
36
13
14
* TCP, thrombocytopenia; PGL, persistent generalized lymphadenopathy.
Rarick et al.
264
P
L
A
1
E
L
E
T
C
0
U
n
T
X
1
0
0
0
-
l
i
5
8
*MEDIAN
29
36
CYCS DAY
f
MAX
+ MIN
Fig. 1. Median platelet count cycle 1. Days 1, 2, 5,8,15,29,
and 36.
patient (7%) had received Danazol. There was only one
patient who had received ZDV. This patient had stage
IVA HIV infection with T4 cells <200/mm3. He had
discontinued the ZDV one week prior to study entry
because of symptomatic ZDV toxicity consisting of
nausea and headache.
On physical examination, generalized lymphadenopathy was seen in all (100%) patients. The only other HIV
related abnormality was hairy leukoplakia in one patient.
Other abnormalities on exam consisted of petechiae in
four patients (29%), mild ecchymoses in three patients
(21%), and active gum bleeding in one patient (7%)).
Figure 1 demonstrates the median platelet count at
baseline and throughout the first two treatment cycles. As
shown, the median baseline platelet count was 17,000/
mm3 (range 3-61 ,000/mm3), the median maximum
platelet count achieved was 220,000/mm3 (range 7 6
426,000/mm3), at a median time of day 8 (range D3D29). Although none of the patients achieved a formal
complete or partial remission, all patients experienced a
platelet count rise of 55 ,00W07,000/mm3 (median rise
of 158,000/mm3).Clinical bleeding present at baseline
resolved in all patients by day 8. One patient underwent
extraction of two wisdom teeth while on therapy, with no
bleeding complications from the surgical procedure. No
patient achieved a sustained complete or partial remission
of thrombocytopenia after 1 month off therapy.
Toxicities experienced from the IVIG were minima1
and consisted of headache during the infusion in five
(36%), nausea in two (14%),and one episode each of
diarrhea, phlebitis, pruritis, swelling at the injection site,
and mild disorientation. Five patients (36%) experienced
no toxicity whatsoever.
In comparison to baseline, there was no statistical
change in CD4+ lymphocyte count, platelet antibody
titers, or quantitative immunoglobulins, as shown in
Table 11, although there was a tendency toward a greater
rise in platelet count in patients who had lower baseline
levels of platelet bound antibody and immunoglobulins
( P = 0.09).
TABLE 11. Clinical Values of Study Patients
Median platelet count (/mm3) X lo3
(range)
CD4 lymphocyte count (/mm3)
(range)
Platelet-bound IgG (RF)"
(range)
Platelet-bound IgM (RF)"
(range)
Serum antiplatelet ATB (RF)a
(range)
PEG immune complexb (/*g/ml)
IgG' (mg/dl)
Range
IgA' (mg/dl)
Range
lgMC(mg/dl)
Range
Baseline
Dav 15
17
(3-61)
377
(154-909)
2.7
(1.5-13.9)
3.35
(0.8-14.8)
1.2
(0.7-5.4)
40
(19-217)
105
(30-470)
2,120
(1 ,460-5,270)
2.50
(14 1-694)
207
( I 14-634)
"RF, reference range; normal <1.5.
bNormal <30 pg/ml.
'Normal IgG, 600-2,000 mg/dl; IgM, 50-400 mg/dl; IgA, 40-250 mg/dl.
3.5
(1.3-22.7)
4.8
(1.3-19.5)
1 .o
(0.4-5.3)
56
(30-980)
2,890
(2.330-4,690)
275
(1 19-675)
219
(95-676)
IGlV Use in HIV-Related Immune Thrombocytopenia
DISCUSSION
The optimal therapy for thrombocytopenia in an HIVinfected patient must incorporate the state of underlying
immunodeficiency. Previously, corticosteroids were often used in this setting. However, with the known
immunosuppressive effects of corticosteroids, and the
recent evidence indicating an association of Kaposi’s
sarcoma with glucocorticoids [40], the use of this modality may not be optimal. Short-term follow-up of
patients undergoing splenectomy for HIV-related immune thrombocytopenia has shown a response rate of
90% [17]. However, long-term study is needed to
understand fully the impact of splenectomy on the
subsequent course of these immunocompromised patients, since earlier development to acquired immunodeficiency syndrome (AIDS) has been reported after splenectomy.
In the present study, all patients with sexually transmitted HIV-related thrombocytopenia responded within 8
days to IVIG infusion. Although the response was
short-lived, it is apparent that patients requiring an
immediate increase in platelet count may be well managed with IVIG infusion. The long-term response rate of
IVIG is disappointing, however. Interestingly, patients
with non-HIV-related immune thrombocytopenia may
achieve long-term remissions with the use of IVIG
infusions. The reason that patients with HIV immunothrombocytopenia relapse quickly after IVIG is unknown
but may include the severity of persistent immunodeficiency, sustained elevated levels of circulating immune
complexes, and/or persistent B-cell dysregulation with
production of high titers of antiplatelet antibodies.
The mechanism of action of IVIG in each of the
immune-related thrombocytopenias may include interference with the reticuloendothelial system or macrophage
Fc receptor, inactivation of antiplatelet antibodies, decrease in natural killer (NK) cell activity, and decrease in
platelet antibody synthesis [4147]. In our study, we did
not observe changes in platelet bound antibodies or
circulating immune complexes.
Recent reports indicating the efficacy of ZDV [24-291
and interferon-y (IFN-a) [48,49] in patients with HIVrelated immune thrombocytopenia are encouraging.
Combined therapy using IVIG with ZDV or IFN-a may
ameliorate the early relapse seen in patients treated with
IVIG alone. Trials of combined therapy with ZDV and
IVIG for HIV-related thrombocytopenia are currently
under way, and results are awaited with interest.
ACKNOWLEDGMENTS
This study was presented in part at the Fourth International Conference on AIDS, Stockholm, Sweden, June
12-16, 1988. We would like to thank Laurie Hornor for
265
her diligence and expertise in preparation of this manuscript. This work was supported in part by a clinical grant
from the Cutter Biologic Corporation.
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Теги
treatment, immunodeficiency, intravenous, immunoglobulin, virus, thrombocytopenic, related, human
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