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Splenectomy I s S a f e and Effective in Human Immunodeficiency Virus-Related
Immune Thrombocytopenia
By Eric Oksenhendler, Philippe Bierling, Sylvie Chevret, Jean-Franqois Delfraissy, Yves Laurian,
Jean-Pierre Clauvel, and Maxime Seligmann
Sixty-eight patients, followed in a prospective cohort study
of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets <
5 0 X 109/L), underwent splenectomy, 2 to 4 1 months
(median: 1 0 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 1 8 X 1 09/L to 2 2 3 X 1 09/L with a persistent increase in 5 6 (82%). It also led to a significant
increase of the mean CD4 cell count from 4 7 5 X 106/L to
725 X 106/L within a mean delay of 1 0 months. In the
whole cohort, with a mean follow-up of 63 months (range,
6 to 126), the 5-year estimated rate for progression to acquired immunodeficiencysyndrome (AIDS) was 23% (95%
confidence interval [CI], 15% to 3 1 %) and the AIDS-free
survival was 69% (95%CI, 6 1 % t o 77%).To investigate the
potential impact of splenectomy, a Cox‘s multiple regression model was used; as splenectomy was not randomly
assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the
splenectomized and the nonsplenectomized patients:
AIDS progression rate (P = 0,23), survival (P = 0.64) and
AIDS-free survival (P = 0.72) were not influenced by
splenectomy. Splenectomy is both effective and safe in the
treatment of severe, refractory ITP associated with HIV
infection.
0 1993 by The American Society of Hematology.
I
indirect immunofluorescence assay, serum platelet-reactive IgG
were detectable in 36 of 60 sera (60%).In 65 cases, splenectomy was
proposed to patients who had failed to achieve a persistent response
with previous therapy; some of them had experienced a transient
response with corticosteroids ( 19/35), danazol(2/15), high-dose intravenous (IV) polyvalent IgG (36/44), anti-Rh IgG (8/13), or with
zidovudine (6/21). For three patients, splenectomy was the first
therapy used. Most ofthe patients received antipneumococcal vaccination and high-dose IV polyvalent IgG in preparation for surgery.
Lymphocyte subset coimts. Lymphocyte subsets reacting to
anti-CD4 and antLCD8 monoclonal antibodies (MoAbs) were analyzed by flow cytometry.
HIVp24 antigenemia. Serum was assayed for HIV p24 antigen
with an enzyme-linked immunosorbent assay (ELISA) (Abbott,
North Chicago, IL).
Response to therapy. Response was classified as complete if the
platelet count increased above 100 X 109/L and partial if above 50
X 109/Lwith a twofold increase in the initial count. Persistence of
the response was evaluated after 6 months.
Statistics. Survival analysis was based on the Kaplan-Meier estimate’ and the logrank test was used for comparisons between the
splenectomized and the nonsplenectomized patients. The survival
time was calculated from the date of ITP diagnosis. To investigate
the potential effect of splenectomy on AIDS-free survival, a Cox’s
multiple regression model was used.’ As splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate.
MMUNE thrombocytopenic purpura (ITP) is known to
be a frequent complication of human immunodeficiency virus (HIV) infection.’ The mechanisms responsible
for platelet destruction are not yet well characterized. HIV
itself, some of its antigenic structures, or antibodies to HIV
may be directly or indirectly involved. This condition
usually occurs at a relatively early stage of HIV infection.
Treatments used in autoimmune thrombocytopenia give
poor or transient re~ponse.’.~
Zidovudine was shown to be
effective in more than half of the patient^.^-^ However,
splenectomy is still warranted in patients with persistent,
severe, and symptomatic thrombocytopenia. The potential
hazards of splenectomy in HIV-infected patients require a
long-term follow-up of large series of patients.
Since January 1982, 185 patients with HIV-related severe
immune thrombocytopenia were followed in four institutions. Clinical and biologic evaluation were scheduled every
6 months. Long-term follow-up of this cohort study allows
evaluation of the possible influence of splenectomy on acquired immunodeficiency syndrome (AIDS) progression
rate and survival.
PATIENTS AND METHODS
Patients. The 68 patients who underwent splenectomy belonged to a prospective cohort study in which 185 patients were
enrolled from January 1982 to April 1991. They included 57 males
and I I females (Table 1). Initially, the patients were included on the
basis of ITP occumng in patients belonging to AIDS risk groups.
Retrospective analysis of stored sera confirmed HIV infection in all.
None of these patients had full-blown AIDS at inclusion. However,
1 1 (16%) had symptomatic disease and belonged to Centers for
Disease Control (CDC) group IV, 16 patients had persistent generalized lymphadenopathy, and I O had splenomegaly. Most of the patients had mild immune deficiency status as only five (7%) had a
CD4 cell count below 200 X 106/L. The mean CD8 cell count was
68 1 X 106/L.Serum p24 antigen was detectable in 9 of 53 (17%).
At inclusion, all patients had a platelet count below 50 x 109/L
and a normal or increased number of megakaryocytes in an otherwise normal bone marrow (BM) aspiration. Mild hemorrhagic
symptoms were observed in the 43 patients with a platelet count
below 20 X 109/L.Using a direct immunofluorescence assay, platelet IgG were detected in 44 of 58 patients tested (76%) and with an
Blood, VOI 82,NO 1 (July I ) , 1993:pp 29-32
From the Department of Immunopathology and Hematology and
the Department of Biostatistics, H6pital St Louis, Paris; the Department of Immunology and Blood Bank, H6pital Henri Mondor,
Crkteil; the Department of Hematology and Hemophilia Center,
H6pital Kremlin-Bicttre; and the Department ofhternal Medicine,
H6pital Antoine Beclere. Clamart, France.
Submitted November 2, 1992; accepted February 10, 1993.
Address reprint requests to Eric Oksenhendler, MD, Service d’lmmunopathologie et d’ Hkmatologie, HGpital Saint Louis, I , Ave
Claude Vellefazcx, 75010 Paris, France.
The publication costs ofthis article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
0 1993 by The American Society of Hematology.
0006-4971/93/8201-0022U.00/0
29
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OKSENHENDLER ET AL
30
Table 1. Patient Characteristics at ITP Diagnosis
IV drug users
Homosexual men
Hemophiliacs
Heterosexual
contacts
Blood recipients
Unknown risk
factor
CDC group IV'
Baseline CD4
cell count
Mean k SD
(X 1os/ L)t
n <200 x 106/L
Positive p24 Ag
Platelets
<20 x 1 0 9 1 ~
Splenectomized
(n = 68)
Nonsplenectomized
(n = 117)
All Patients
(n = 185)
34
19
10
49
33
15
83
52
25
2
2
8
8
10
10
1
11
4
20
5
31
527 k 2 6 4
5
9/53
4 0 0 2 274
27
12/95
4 4 5 i- 2 7 6
32
211148
43
46
89
* Symptomatic HIV infection.
t Statistically significant difference between the splenectomized and
the nonsplenectomized patients (P = ,004; Student's r-test).
To test the prognostic significance of splenectomy, a likelihood ratio test was used after adjustment on the major baseline prognostic
variable (CD4 cell count).
RESULTS
Splenectomy was performed with a mean delay of 13
months (range, 2 to 41) from the diagnosis of ITP. After 2
years, the cumulative probability of splenectomy was 32%
(95% CI, 24% to 40%). This population has not been randomly selected and at inclusion in the cohort study, the
mean kSD CD4 cell count was higher (527 f 264 X 106/L)
in the 68 patients that were proposed for surgery than in the
1 17 patients that did not undergo splenectomy (400 f 274
X 106/L), (P< .01; Student's t-test).
Response to splenectomy. The mean platelet count before splenectomy was 18 f 16 X 109/L. The mean peak
value of the platelet count after splenectomy was 223 2 15 1
X 109/L(range, 6 to 776). The initial response was complete
in 58 patients and partial in four. At 6 months, six patients
had relapsed and the overall persistent response rate was
82%. Late relapses were observed in three patients, 47, 57,
and 67 months after surgery. At last evaluation, the mean
platelet count was 219 f 124 X 109/L(range, 6 to 669) and
eight patients had less than 50 X 109/L.
The mean CD4 cell count before splenectomy was 475 2
301 X 106/Land it increased up to 725 f 612 X 106/Lafter
surgery. This significant increment (P= .002, paired Student's t-test) was caused by a twofold increase in the total
lymphocyte count, from 1651 X 106/L to 3425 X 106/L,
whereas the proportion of CD4 cells decreased significantly
from 28% f 1 1 % to 2 I % t 10% (P = .04, paired Student's
t-test) within a mean interval of 10 months between the two
evaluations. At last evaluation, after a mean delay of 57
months, the mean CD4 cell count had decreased to 55 1 +57 I X 106/L,and the proportion of CD4 cells to 16%i 8%.
Complications. One patient had postoperative portal
vein thrombosis. Two patients presented with Streptococcus
pneiimoniae meningitis, respectively, 27 and 4 1 months
after splenectomy. They had not been vaccinated against S
pneumoniae and they did not take any antibioprophylaxis;
both of them recovered. Two other patients died of fulminant septic shock, 23 and 26 months after surgery; in one
case, Hemophilus influenzae septicemia was documented.
Follow-up and HIV diseuse progression. In the whole
cohort, the mean follow-up from the diagnosis of ITP was
63 months (range, 6 to 126), 70 months for the 68 splenectomized and 57 for the 1 17 nonsplenectomized patients (Table 2). At the time of analysis, 16 patients were lost for
follow-up (>12 months); 7 of them had been splenectomized. Thirty-six patients of the cohort developed CDC-defined AIDS. The AIDS progression rate from ITP was 23%
at 5 years (95% C1, 15%to 31%). Thirty-nine patients have
died. In 4, death was related to ITP ( 2 cases of fatal visceral
bleeding in nonsplenectomized patients) or to its therapy (2
cases of fulminant septic shock in splenectomized patients).
Twenty-two patients died because of AIDS progression and
in 13 other cases, death was not HIV-related. At 5 years, the
overall survival was 77% (95% CI, 70% to 84%) and the
AIDS-free survival 69% (95% CI, 6 1 % to 77%). A CD4 cell
count below 200 X 106/L at time of ITP diagnosis appears as
the best prognostic indicator for progression to AIDS or
death (P < .OOOl and P < .0001, respectively).
Survival was then analyzed according to splenectomy, as
this treatment might have influenced the natural history of
HIV infection. Among the 68 splenectomized patients, 8
developed AIDS and 14 died (Table 2 and Fig I). Using a
time-dependent Cox's model, splenectomy was associated
with a reduction of the AIDS progression rate (P = .01,
relative risk: .35) and did not affect survival (P= .41) or
AIDS-free survival (P = .46) (Fig 1). However, this apparent
favorable predictive value of splenectomy on the AIDS progression rate was explained by the higher initial CD4 cell
count in the patients that had been proposed for surgery;
indeed, after adjustment on this covariate, splenectomy was
no more predictive of reduced AIDS progression rate (P =
.23). This adjusted analysis confirmed the absence of influence of splenectomy on survival (P = .64) or AIDS-free
survival (P = .72).
Table 2. Patients' Follow-Up From ITP Diagnosis
Baseline CD4
cell count
Mean f SD
(XlOS/L)
Mean follow-up
(mas)
AIDS
Deaths
Splenectomized
(n = 68)
Nonsplenectomized
(n = 117)
All Patients
(n = 185)
5 2 7 i- 2 6 4
400 k 274
445 ? 2 7 6
70
8
14
57
28
25
63
36
39
Using a time-dependent Cox's model, and after adjustment on the
baseline CD4 cell count, splenectomy had no influence on AIDS progression rate (P = ,231. survival (P = ,641. or AIDS-free survival (P = .72).
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SPLENECTOMY FOR HIV-RELATED ITP
0
0
.
I .
10
, .
20
,
30
.
,
40
.
,
31
.
50
,
60
.
,
70
.
,
80
.
,
90
.
/
100
Months
Fig 1. AIDS-free survival from splenectomy (Kaplan-Meier estimate) in 68 patients splenectomizedfor HIV-related thrombocytopenic purpura.
both presplenectomy vaccination and postoperative oral
antibioprophylaxis.
Splenectomy led to a twofold increment of the lymphocyte count and to a significant increase in the absolute CD4
cell count; however, the percentage of CD4 cells still continued to decrease. In these patients, the decisions regarding
antiretroviral therapy and especially prophylaxis of opportunistic infections should take these constatations into account and focus on the percentage of CD4 cells.
Therapy is warranted for patients with severe or symptomatic HIV-related ITP. In the cases who fail to respond to
medical treatment, splenectomy can be proposed. It is effective in most cases and it does not seem to affect the natural
history of HIV infection.
ACKNOWLEDGMENT
DISCUSSION
We thank Dr M.P. Archambeaud, Dr J. Peynet, Dr J.P. Farcet, F.
Rocher, M. Legrand, M. Bergere, P. Gallula, M.T. Rannou, and L.
Gtrard for their support in collecting data, V. Barateau and Dr F.
Ferchal for the virological study, and Dr C. Rahian-Herzog for the
immunologic study.
Therapy of HIV-related ITP remains controversial. The
disappointing response pattern, poor tolerance and potential risk of increased immune deficiency led us to avoid
steroids as initial therapy.' IV polyvalent high dose Ig is
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
1993 82: 29-32
Splenectomy is safe and effective in human immunodeficiency virusrelated immune thrombocytopenia [see comments]
E Oksenhendler, P Bierling, S Chevret, JF Delfraissy, Y Laurian, JP Clauvel and M Seligmann
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