Scand J Infect Dis 30: 115118, 1998

ORIGINAL ARTICLE

Immune Thrombocytopenic Purpura after

Recombinant Hepatitis B Vaccine: Retrospective
Study of Seven Cases
DIDIER NEAU1, FABRICE BONNET1, MAGGY MICHAUD2, YVES PEREL3,
MAI8 TE LONGY-BOURSIER4, JEAN-MARIE RAGNAUD1 and
JEAN-MICHEL GUILLARD3
From the 1Departement de Maladies Infectieuses et Medecine Interne, 2Laboratoire dHematologie, 3Ser6ice de Pediatrie,
Hopital Pellegrin, and 4Ser6ice de Medecine Interne, Hopital Saint-Andre, Bordeaux, France

Recombinant hepatitis B vaccine is usually well tolerated. Clinical and laboratory test manifestations with immunologic
mechanisms have nonetheless been described following use of this vaccine. We retrospectively report 7 cases of thrombocy-
topenia occurring within 3 months (7 weeks on the average) of 1 or following injections of recombinant hepatitis B vaccine.
Four boys and 3 girls, average age 12 y, were involved. Three had a history of immune thrombocytopenic purpura. Four had
haemorrhagic manifestations. The haemogram showed thrombocytopenia (24 109/l on the average) without alterations of
the other lines. Infectious and immune aetiologies were excluded in all cases. The course varied after treatment by
corticosteroids, high-dose intravenous immunoglobulin, or both. After describing the different manifestations subsequent to
recombinant hepatitis B vaccination, we discuss post-vaccinal thrombocytopenias (vaccines in question, mechanisms) and the
reality of this entity.
D. Neau, MD, Departement de Maladies Infectieuses et Medecine Interne (Ser7ice du Professeur Ragnaud), Hopital
Pellegrin, Place Amelie Raba-Leon, F-33076 Bordeaux Cedex, France

INTRODUCTION
Vaccination against hepatitis B is now widely used in the
world (1). The growing use of recombinant hepatitis B
vaccine has been accompanied by the publication of numer-
ous reports, isolated in most cases, of clinical and labora-
tory anomalies following this vaccination. Interpreting such
incidents is problematic, a causal relationship always being
difficult to formally establish. They do, however, raise the
issue of tolerance to the vaccine. Recently over a period of
several months, we observed 7 cases of thrombocytopenia
in the aftermath of the administration of a recombinant
vaccine against hepatitis B.
PATIENTS AND METHODS
We retrospectively studied the charts of 7 patients who had
had thrombocytopenic purpura after 1 or several injections
of a recombinant vaccine against hepatitis B.
The vaccines used were Genhevac (Laboratoire Pasteur),
expressed from recombinant DNA in mammalian cells, or
Engerix (SmithKline Beecham Pharmaceuticals) from re-
combinant DNA in the yeast Saccharomyces cerevisiae.
The vaccine was considered to be a possible source of the
disorder if thrombocytopenia occurred within 3 months of
the last injection. The work-up of these patients included a
search for a pharmacological, infectious, or immune
aetiology.
RESULTS
Patient characteristics
Four boys and 3 girls, with an average age of 12 y (range
4 15 y), had thrombocytopenic purpura after vaccination
with a recombinant vaccine against hepatitis B between
October 1994 and February 1996 (Table I).
Three had a history of immune thrombocytopenic pur-
pura of 9, 19 and 26 months, respectively, before the
vaccination. Before the first administration of the vaccine,
all had a normal platelet count.
Clinical history
The patients received an injection of recombinant vaccine
against hepatitis B an average of 7 weeks (range 2 weeks3
months) before thrombocytopenia was discovered. This
occurred most often after 2 injections of the vaccine in 5 of
the patients, after 1 injection in 1 of the patients, and after
3 injections in the other patient. The initial clinical toler-
ance of the vaccination had been excellent in every case.
Four of the patients had haemorrhagic manifestations in
the form of purpuric lesions or ecchymosis (n= 4), epistaxis
(n= 1) or subarachnoid haemorrhage (n= 1).
Upon the basis of questioning of the children and their
parents, the previous use of medication was excluded. None
had noted any symptom that might suggest a recent or
developing infectious process or underlying autoimmune
disorder. Clinical examination was normal, aside from the
haemorrhagic manifestations previously mentioned.

1998 Scandinavian University Press. ISSN 0036-5548

116 D. Neau et al. Scand J Infect Dis 30

Table I. Patient characteristics, biological data, treatment and outcome

Year of Medical Date of Date of Clinical Platelets Aetiologic

Patient Sex birth history vaccine Vaccine discovery manifestations (109/l) work-up Management Course

1 M 1980 no 16/09/1995 GENHEVAC 29/12/1995 diffuse 3 marrow smear high-dose i.v. favourable
purpura g-globulins
2 F 1985 no December Not specified February epistaxis 20 marrow smear steroid favourable
1995 1996 resistant,
haematomas ANAB high-dose i.v.
g-globulins
serologic
tests: EBV+
(IgG), HIV,
HCV,
HVA,
CMV,
HBs AB+
3 M 1979 no 20/05/1994 GENHEVAC 15/10/1994 None 42 marrow steroids steroid
smear dependence
17/06/1994 ANAB
13/07/1994 serologic
tests: EBV,
HIV,
HCV
HAV,
CMV,
rubella+
(IgG),
HBs AB+
anti-platelet
AB+
4 M 1982 no January Not specified 1/04/1995 diffuse 4 marrow smear high-dose i.v. favourable
1995 purpura g-globulins,
9/03/1995 Subarachnoid ANAB then steroids
hemorrhage
serologic
tests: EBV,
HIV,
rubella
5 M 1979 ITP September ENGERIX December None 6 ANAB high-dose i.v. not
1994 1994 g-globulins, recorded
October serologic then steroids
1994 tests: EBV,
HIV,
HAV,
HCV,
HBs AB+
6 F 1983 ITP September Not specified January None 70 ANAB: high-dose i.v. steroid de-
1995 1996 g-globulins, pendence
18/12/1995 serologic then steroids
tests: HIV,
CMV,
HAV,
HBs AB+
7 F 1991 ITP 28/01/1995 GENHEVAC 25/03/1995 Multiple 27 ANAB: high-dose i.v. favourable
ecchymoses g-globulins,
22/02/1995 serologic then steroids then
tests: HCV, recurrence
HIV

ANAB, antinuclear antibodies; EBV, Epstein Barr virus; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HAV, hepatitis A
virus; AB, antibodies; ITP, immune thrombocytopenic purpura.
Scand J Infect Dis 30 Immune thrombocytopenic purpura after recombinant Hepatitis B 6accine
Laboratory results and etiological work-up
Thrombocytopenia was found in all 7 subjects (average
24 109/l; range, 370109/l). There was no abnormality immune disease in the aftermath of various vaccinations
of the other blood cell lines. The other routine laboratory
tests were normal (electrolyte concentrations, renal func-
tion, liver tests) in all cases.
A marrow smear was not repeated in the 3 patients with
a history of thrombocytopenic purpura. In the 4 others, it
showed morphologically normal bone marrow with normal
to increased numbers of megakaryocytes.
An aetiological work-up was performed for all 7 patients.
An immunological assessment was included (search for
antinuclear antibodies) looking for a connective tissue dis-
ease. Serologic testing was also performed to detect a
possible concomitant infection.
Treatment and course
The treatment of the 7 children is detailed in Table I. The
course of the disorder was favourable in 3 cases permitting
the discontinuation of treatment in 3 months. Two patients
were steroid-dependent, thrombocytopenia recurring when
steroids were discontinued. The course of 1 patient was
initially favourable, but the disorder recurred during a bout
of chickenpox. One patient was lost to follow-up.
DISCUSSION
The incidence of severe side effects after recombinant vac-
cine against hepatitis B is estimated to be 1 case for 100,000
doses administered (2). According to Carmeli et al., most
such cases involve an immune mechanism. The introduc-
tion of antigens of the vaccine is thought to cause the
formation of circulating immune complexes, deposits of
which in the kidney, joints, eyes and other organs trigger
different manifestations in the systems involved (3). Various
immunologic incidents after recombinant hepatitis B have
been reported in the literature, including erythema nodo-
sum with or without joint pain (4, 5), necrotizing vasculitis
with or without cryoglobulins (2, 6), as well as eye (uveitis,
acute posterior multifocal placoid pigment epitheliopathy,
bilateral optic neuritis and papillitis) (79), neurological
(1014) and nephrological involvement (15, 16).
The occurrence of a thrombocytopenia with an immune
mechanism revealed by blood tests has been reported fol-
lowing other types of vaccinations. The most frequently
incriminated vaccine is the measles/mumps/rubella vaccine
(1719). Rare cases have also been described after diphthe-
ria/tetanus/pertussis (20) or smallpox (21) vaccines. Post-
vaccinal thrombocytopenias are interpreted in 2 ways. They
may be likened to post-infectious thrombocytopenia, the
vaccine antigen itself being of infectious origin (18). Re-
garding hepatitis B, one should not, however, lose sight of
the rarity of associated thrombocytopenia (22). The vacci-
nation might also be an inductor or exposer of an immune
disorder. Reports have been published of induction of an
117
immune disease by an infectious process. Moreover, there
also exist in the literature cases of patients developing an
(23).
To our knowledge, a case of thrombocytopenia after a
plasma-derived hepatitis B vaccine has never been reported.
In contrast, several cases have been described after recom-
binant vaccines. Poullin et al. reported the development of
thrombocytopenia in 2 patients vaccinated 3 and 4 weeks
earlier, respectively (24). Meyboon et al. pooled 28 cases
from several centres of pharmaceutical monitoring, but the
data that they collected was very sparse (25). Lastly, Mar-
tinez et al. noted the occurrence of thrombocytopenia
associated with haemolytic anaemia in a patient who had
Evans syndrome (26).
However, a critical evaluation of these various reports
appears to be in order, as is the case when analysing any
post-vaccinal clinical event or blood testing abnormality.
The observation of a rare clinical event after administration
of a vaccine that is extremely widespread in the population
is in no way convincing evidence of causality (25). Accord-
ing to Wiersbitzky et al., a chronological link between a
vaccination and thrombocytopenia is insufficient in itself to
establish a causal relationship (27). In the different studies
reported, the aetiological work-ups are rarely mentioned or
complete. Such data collection is often difficult because of
its retrospective character. Wiersbitzky et al. even doubt the
existence of a post-vaccinal thrombocytopenia entity (27).
Just as in the previously published cases, our 7 records
incite a certain degree of prudence, some of the thrombocy-
topenias being severe, symptomatic and potentially life
threatening. Lastly, as illustrated by 3 of our observations,
a history of immune thrombocytopenic purpura probably
contraindicates the use of recombinant hepatitis B vaccine
in the absence of a particular exposition or factor of risk
(28).
Vaccination against hepatitis B has now proven its effi-
cacy. The description of different adverse side effects does
not call its usefulness into question. The induction of
thrombocytopenia by such a vaccine appears plausible, but
a fortuitous association cannot be formally ruled out. Post-
vaccinal thrombocytopenia remains a diagnosis of exclu-
sion. Only the previous performance of thorough
aetiological work-ups and their negativity will permit the
establishment of the reality of this entity (27).
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Submitted October 20, 1997; accepted January 30, 1998
.
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