Guideline

Transcription

Guideline

British Journal of Haematology, 2003, 120, 574–596
Guideline
GUIDELINES FOR THE INVESTIGATION AND MANAGEMENT OF IDIOPATHIC
THROMBOCYTOPENIC PURPURA IN ADULTS, CHILDREN AND IN PREGNANCY
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia (peripheral blood platelet count < 150 · 109 ⁄ l) due to
autoantibody binding to platelet antigen(s) causing their
premature destruction by the reticuloendothelial system,
and in particular the spleen (Woods et al, 1984a,b).
Although the basic underlying pathophysiology of ITP
has been known for 50 years (Harrington et al, 1951), the
literature shows that the investigation and management of
patients with thrombocytopenia vary widely, and is not
evidence-based, due to a lack of clinical trials and quality
research. Despite major advances in our understanding of
the molecular basis of many blood disorders, the diagnosis
of ITP remains one of exclusion; there are currently no
robust clinical or laboratory parameters that are able to
establish the diagnosis of ITP with accuracy. This guideline
aims to assess available diagnostic tests and therapies, and
attempts to provide a rational approach to the diagnosis and
treatment in adults, children and in pregnancy. Although
natural history data are becoming available (Cohen et al,
2000; Djulbegovic & Cohen, 2001; Portielje et al, 2001),
there are few randomized trials in ITP and many of the
recommendations, like those of the American Society of
Hematology (ASH) Panel (George et al, 1996), are based on
expert opinion.
thrombocytopenic purpura¢, ‘ITP’, ‘thrombocytopenia +
randomized’, ‘thrombocytopenia + randomised’, ‘thrombocytopenic + randomized’, ‘thrombocytopenic + randomised’, ‘thrombocytopenia + trial’, ‘thrombocytopenic +
trial’, ‘thrombocytopenic + therapy’, ‘thrombocytopenia +
therapy’. The search excluded ‘thrombotic’, ‘neonatal
alloimmune’ and ‘drug-induced thrombocytopenia’. For
paediatric reports the previous search terms were combined
with ‘child’ and ‘children’.
DESCRIPTION AND EPIDEMIOLOGY
The purpose of this guideline is to provide a rational
approach to the laboratory investigation and management
of patients with ITP, including pregnant and non-pregnant
adults and children, and patients with refractory disease.
The Guideline development group includes individuals from
relevant professional groups, and we have sought the views
of patients, through The ITP Support Association. Target
users of the Guideline include clinical haematologists
involved in the care of adults and children with ITP,
obstetricians and anaesthetists involved in the care of ITP in
pregnancy, paediatricians and physicians.
Immune-mediated thrombocytopenias comprise, among
others: drug-induced thrombocytopenia, neonatal alloimmune thrombocytopenia, post-transfusion purpura, ITP,
acute ITP and secondary ITP. This guideline aims to deal
with ITP in children, adults and pregnancy. Previous
guidelines for the management of thrombocytopenia in
pregnancy have been published (Greaves & Letsky, 1997).
Adult chronic ITP has an incidence of 58–66 new cases
per million population per year (5.8–6.6 per 100 000) in
the US (McMillan, 1997) with a similar incidence in the UK.
This form of ITP affects mainly women of childbearing age
(Female:Male, 3:1) (Waters, 1992). Childhood ITP has an
incidence of between 4.0 and 5.3 per 100 000 (Lilleyman,
1999; Zeller et al, 2000).
Acute abrupt onset ITP is seen mainly in childhood, and
often follows a viral illness or immunization. The majority of
children require no treatment and in 80–85% of cases the
disorder resolves within 6 months. Some 15–20% of children develop a chronic form of ITP, which, in some cases,
resembles the more typical adult disease. Chronic ITP in
childhood has an estimated incidence of 0.46 per 100 000
children per year (Reid, 1995) and prevalence of 4.6 per
100 000 children at any one time (Hedman et al, 1997).
Secondary immune thrombocytopenias occur in patients
with other underlying autoimmune disorders (e.g. systemic
lupus erythematosus), or malignant disease (e.g. chronic
lymphocytic leukaemia).
METHODS
ADULT ITP
MedLine was searched via PubMed using the following criteria: ‘thrombocytopenia’, ‘platelet count’, autoimmune
Clinical features
ITP in adults is quite distinct from the typically acute
disorder seen in childhood. In adults, ITP typically has an
insidious onset, with no preceding viral or other illness.
Symptoms and signs are highly variable and range from the
fairly common asymptomatic patient with mild bruising,
mucosal bleeding (e.g. oral or gastrointestinal tract)
AIMS OF THE GUIDELINE
Correspondence: The Secretary, BCSH, British Society for Haematology, 2 Carlton House Terrace, London SW1Y 5AF, UK. E-mail:
[email protected]
574
2003 Blackwell Publishing Ltd
Guideline
through to frank haemorrhage from any site, the most
serious of which is intracranial. Overall, bleeding symptoms
are uncommon unless the ITP is severe (platelet count
< 30 · 109 ⁄ l) (George & Raskob, 1998). ITP in adults is a
disease predominantly of women of childbearing age. The
natural history is poorly defined but studies are being
conducted, looking at the long-term outcome in terms of
morbidity and mortality in patients with ITP (Portielje et al,
2001).
Diagnostic approach for adults
Clinical history
The patient’s history is used to:
• Determine the type of bleeding and to distinguish ‘platelet-type’ mucocutaneous bleeding from ‘coagulation-type’
haematomas
• Assess the severity, extent and duration of bleeding. A
history of bleeding with previous surgery, dentistry and
trauma may be useful in determining the duration of
chronic thrombocytopenia in the absence of blood counts
• Determine the presence of other medical disorders which
may be responsible for thrombocytopenia by:
i) immune mechanisms, e.g. is there a recent history of
transfusion raising the possibility of post-transfusion
purpura?
ii) non-immune mechanisms, e.g. is there a history of
excess alcohol consumption or a family history of
thrombocytopenia suggesting an inherited nonimmune thrombocytopenia?
iii) Evolving aplastic anaemia, particularly relevant in
children
iv) Marrow infiltration with acute leukaemia
v) Type IIB von Willebrand’s disease
• Determine the presence of medical conditions which may
be associated with autoimmune thrombocytopenia, e.g.
drugs, human immunodeficiency virus (HIV) infection,
other autoimmune disorders, malignancy (e.g. lymphoproliferative disorders)
• Conditions which may increase the risk of bleeding, e.g.
local abnormalities in the gastrointestinal, genitourinary
or central nervous systems
Physical examination
The physical examination is used to:
• Assess the type, severity and extent of bleeding
• Exclude conditions that might cause non-immune
thrombocytopenia, e.g. severe infection, acute thrombocytopenia with neurological signs which may indicate a
diagnosis of thrombotic thrombocytopenic purpura (TTP),
skeletal and other abnormalities associated with congenital thrombocytopenias, lymphadenopathy, which may
suggest the presence of a lymphoproliferative disease, and
splenomegaly. It should be noted that splenomegaly has
been reported to occur in less than 3% of adult patients
with ITP (Doan et al, 1960) and its presence should
prompt a search for an alternative diagnosis
• Determine the presence of medical conditions that may be
associated with autoimmune thrombocytopenia, e.g. HIV
infection, other autoimmune disorders, malignancy
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Laboratory investigations
The finding of thrombocytopenia on a routine blood
count may be the first indication of autoimmune
thrombocytopenia. Thrombocytopenia should be confirmed
by examination of the blood film to exclude pseudothrombocytopenia due to EDTA-dependent platelet agglutination as the cause of the spuriously low platelet count;
this condition occurs in about 0.1% of adults, and is easily
confirmed by the finding of a normal platelet count using a
sample taken into citrate rather than EDTA anticoagulant
(Pegels et al, 1982).
The blood film should also be examined to exclude nonimmune thrombocytopenias such as those associated with
acute or chronic leukaemia, myelodysplasia, megaloblastic
anaemia, microangiopathic anaemia, inherited thrombocytopenias and pseudothrombocytopenia. An autoimmune
profile ⁄ screen should be carried out to exclude other
underlying autoimmune diseases.
If the history, physical examination, blood count and
blood film examination are consistent with the diagnosis of
ITP with no atypical findings, it can be argued that
additional investigations such as bone marrow examination
and assays for platelet antibodies are unnecessary. If
atypical findings are present, particularly those suggesting
alternative haematological diagnoses, additional investigations including bone marrow examination should be carried
out (Evidence level IV).
Bone Marrow Examination in adults
This is a contentious issue, and one where there was no
agreed consensus reached by the ASH panel, apart from
suggesting this investigation for patients older than
60 years or where splenectomy was being considered
(George et al, 1996). In a study of adults with suspected
ITP, 61 of 66 patients had bone marrow findings consistent
with ITP; four had mild hypocellularity and one had
neutrophil hypersegmentation and giant metamyelocytes,
but all five had a subsequent clinical course consistent with
chronic ITP (Westerman & Grigg, 1999). More recently, a
retrospective Chinese study evaluated 83 patients (aged
between 16 and 60 years) with suspected ITP, all of whom
underwent bone marrow examination. Apart from 11 cases
in which marrow iron was reduced or absent, the marrows were otherwise normal. Their recommendations were
that bone marrow sampling should be reserved for patients
who are older than 60 years, or have atypical features, or
have a poor response to first line (e.g. prednisolone)
treatment or in whom splenectomy is being considered
(Mak et al, 2000).
SPECIALIZED LABORATORY ASSAYS
IN THE DIAGNOSIS OF ITP
Assays for anti-platelet antibodies
The direct platelet immunofluorescence test (PIFT) is used to
investigate referred samples for the presence of plateletassociated immunoglobulin (PAIg); indirect testing of the
patient’s plasma against donor platelets is of little value in
the investigation of suspected ITP because the sensitivity
2003 Blackwell Publishing Ltd, British Journal of Haematology 120: 574–596
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Guideline
and specificity is even lower than for direct testing (see
below).
Increased levels of platelet-associated IgG (PAIgG) can be
detected in most patients with ITP, but the results are not
sufficiently sensitive or specific (patients with non-immune
thrombocytopenias, e.g. septicaemia, frequently have positive results) to justify the routine use of these assays in
patients with suspected ITP (Mueller-Eckhardt et al, 1980;
von dem Borne et al, 1986; Kelton et al, 1989).
Assays for antibodies to specific platelet membrane
glycoproteins (GP) IIb ⁄ IIIa and Ib ⁄ IX are less sensitive
(50–65%) but more specific (90%) in ITP (Berchtold &
Wenger, 1993; Brighton et al, 1996; Warner et al, 1999).
Although they may be useful in distinguishing between
immune and non-immune thrombocytopenia in complex
cases, their routine use in the diagnosis of ITP is not
considered to be justified.
Investigation of platelet autoantibodies may be of value
in adults with
• Combination of bone marrow failure associated with
immune-mediated thrombocytopenia
• ITP patients refractory to first and second line treatment
• Drug-dependent immune thrombocytopenia (DDITP)
• Miscellaneous disorders (rare), e.g. monoclonal gammopathies and acquired autoantibody-mediated thrombasthenia
Bone marrow failure and immune-mediated thrombocytopenia. Antibody-mediated platelet destruction may aggravate
thrombocytopenia in some patients with thrombocytopenia in whom there is inadequate thrombopoiesis, e.g.
patents with disorders such as chronic lymphocytic leukaemia (CLL) or bone marrow transplant recipients. Reactive megakaryocytopoiesis is often a feature of ITP, and
there may be doubt as to whether there is platelet
autoimmunity in addition to bone marrow infiltration or
failure; a PAIg test with determination of antibody specificity may be of use.
ITP patients refractory to first and second line treatment. For
ITP patients for whom third line treatment is considered,
measuring the autoantibody titre in addition to the platelet
count and clinical signs of bleeding can be used to monitor
the effect of treatment. A PAIg test and determination of
antibody specificity is recommended.
Drug-dependent immune thrombocytopenia (DDITP). Many
drugs are associated with thrombocytopenia. For some
drugs there is firm evidence that the thrombocytopenia is
antibody-mediated. Serological investigations to determine
whether the drug is the causative factor in the thrombocytopenia are important in clinical management. Testing for
DDITP is of value for the following drugs: heparin,
quin(id)ine, and teicoplanin (Terol et al, 1993; Veldman
et al, 1996).
Thrombopoietin (TPO) assays
Measurement of the TPO level may be informative in
complex cases of thrombocytopenia, and is particularly
useful in distinguishing between reduced production of
platelets (high TPO level) and increased destruction of
platelets (normal level) (Porcelijn et al, 1998). However,
this assay is not available in routine practice, and is
not recommended as part of the routine investigation of
ITP.
Reticulated platelets
Measurement of platelet RNA by flow cytometry using
thiazole orange staining can be used to assess platelet
maturity. Reticulated platelets are significantly increased in
children with ITP, reflecting increased platelet production,
compared with normal children and other causes of
thrombocytopenia, e.g. acute leukaemia, aplastic anaemia
(Saxon et al, 1998). The precise role for the reticulated
platelet assay has not been established and its use is not
currently recommended.
Helicobacter pylori infection
A number of studies have reported the presence of H. pylori
in patients with autoimmune disease, particularly ITP. In
some series antibiotic therapy aimed at eradication of
H. pylori has ameliorated ITP in patients resistant to other
therapies (Gasbarrini et al, 1998; Emilia et al, 2001; Kohda
et al, 2002) although other studies have generated conflicting data (Jarque et al, 2001). Despite this, in patients
refractory to therapy it is worthwhile performing serological
assays and breath tests aimed at detecting the microorganism (Evidence level III).
Recommendation for adults:
The diagnosis of ITP is based principally on the exclusion
of other causes of thrombocytopenia using the history,
physical examination, blood count, peripheral blood film,
autoimmune profile and other investigations. Further
investigations are not indicated in the routine work-up of
patients with suspected ITP if the history, examination,
blood count and film are typical of the diagnosis of ITP
and do not include unusual features that are uncommon
in ITP, or suggestive of other causes (Evidence IIb–IV;
Grade B, C).
A bone marrow examination is unnecessary in adults
unless there are atypical features, or the patient is over
the age of 60 years, or the patient relapses following
complete remission, on or off therapy, or splenectomy is
being considered (Evidence Level III).
PAIg is elevated in both immune and non-immune
thrombocytopenia and therefore has no role in the
diagnosis of uncomplicated ITP (Evidence level III).
It is worth determining the presence of H. pylori in
patients refractory to therapy since some patients have
shown improvement in platelet counts following eradication therapy (Evidence level III, Grade B recommendation).
MANAGEMENT OF ADULT ITP
General note: to date there have been few randomized
controlled trials conducted in ITP. Treatment should be
tailored to the individual patient.
Guideline
Natural history of adult ITP and the requirement
for medical or surgical treatment
The requirement for treatment varies from patient to patient,
and is dictated by factors such as clinical status (asymptomatic, bruising, bleeding or planned intervention likely to
induce bleeding in a patient with ITP who is thrombocytopenic). Haemorrhagic death is a major concern in thrombocytopenic patients, but recent data from 17 case series have
been reviewed and show that the rate of fatal haemorrhage is
between 0.0162 and 0.0389 cases per patient-year at risk
(the time at risk was defined as the time when the platelet
count is < 30 · 109 ⁄ l) (Cohen et al, 2000). A recent review
by Portielje et al (2001) found that more patients died of
infection than of bleeding. In this same review the authors
studied the natural history of 152 adult patients with ITP
that were consistently managed and followed up over a
10 year period, and showed that 93% of patients ultimately
achieving a platelet count of > 30 · 109 ⁄ l did so within
2 years. Some 85% achieved platelet counts above
30 · 109 ⁄ l off treatment and had a long-term mortality
identical to that of the general population; 9% of patients with
severe ITP (platelets < 30 · 109 ⁄ l) had refractory ITP with
an associated mortality risk of 4.2 (bleeding and infection
contributing equally). Six per cent of patients had platelets
> 30 · 109 ⁄ l while on maintenance therapy; the mortality in
this group was only slightly above that of the general
population. The study concludes that most adults with ITP
have a good outcome with few in-patient admissions and no
excess mortality. These findings would tend to favour a policy
of using therapy only when absolutely required, thereby
minimizing the risks of infection through immunosuppression, and reserving treatment for those who actually require
it, for example patients with severe symptomatic ITP.
First line therapy
Standard ﬁrst line therapy
In general, patients with platelet counts exceeding
30 · 109 ⁄ l require no treatment unless they are undergoing any procedure likely to induce blood loss including
surgery, dental extraction or delivery (Yang & Zhong, 2000)
(Grade C recommendation).
Recommendation for ‘‘safe’’ platelet counts in adults
Dentistry ‡ 10 · 109 ⁄ l
Extractions ‡ 30 · 109 ⁄ l
Regional dental block ‡ 30 · 109 ⁄ l
Minor surgery ‡ 50 · 109 ⁄ l
Major surgery ‡ 80 · 109 ⁄ l
Obstetrics see Thrombocytopenia in pregnancy
Evidence Level IV
First line therapy comprises oral corticosteroids and
intravenous immunoglobulin (IVIg). Splenectomy is often
cited as first line therapy but this mode of treatment is
seldom used as first line, and rather should be considered as
second line therapy.
Prednisolone. Prednisolone (or prednisone) is the initial
therapy for most patients with ITP who require treatment
(McMillan, 1981; Bussel, 1990; Warkentin & Kelton, 1990).
577
Some two-thirds of patients will respond to prednisolone at
1 mg ⁄ kg body weight per day for 2–4 weeks, tapering off
over several weeks (Ben-Yehuda et al, 1994; George et al,
1994; Stasi et al, 1995). Reported response rates vary widely
(from 3% to 50%) (George et al, 1996). A single randomized
trial showed no difference in response to low dose
0.25 mg ⁄ kg ⁄ d vs 1 mg ⁄ kg ⁄ d in 160 children and 223
adults (Bellucci et al, 1988). Relapse of thrombocytopenia is
common when the dose is reduced. Around one-third of
patients can expect a long-term response (Berchtold &
McMillan, 1989; George et al, 1996; Manoharan, 1991;
Blanchette et al, 1998). Corticosteroids should be rapidly
tapered and stopped in patients who fail to respond to oral
prednisolone after 4 weeks (Pizzuto & Ambriz, 1984; BenYehuda et al, 1994). Long-term remission is seen in only
10–20% of patients following cessation of prednisolone
therapy (Ben-Yehuda et al, 1994; Stasi et al, 1995). Patients
who fail to respond to treatment with corticosteroids or
require unacceptably high doses of corticosteroid in order to
maintain a safe platelet count should be considered for
splenectomy (Ben-Yehuda et al, 1994; George et al, 1994).
IVIg. Pooled normal human immunoglobulin is effective
in elevating the platelet count in 75% of patients, of which
50% will achieve normal platelet counts. However, responses are transient and 3–4 weeks following IVIg treatment platelet counts drift back to pre-treatment levels
(Dwyer, 1992; George et al, 1996), and there is little
evidence of a lasting effect. A prospective randomized trial
involving 30 adult patients with chronic ITP (comparing
IVIg, prednisolone or combination of the two) with a
minimum follow-up of 2 years showed quite clearly that the
response rates, duration of response and requirement for
splenectomy were the same in all arms (Jacobs et al, 1994)
(Evidence level Ib, Grade B). A single randomized study
showed no difference in efficacy between the two dosing
schedules 0.4 g ⁄ kg ⁄ d for 5 d and 1 g ⁄ kg ⁄ d as a single
infusion (Godeau et al, 1993). The mechanism of action of
IVIg in ITP remains largely unknown but is believed to
involve the blockade of Fc receptors on macrophages and
other effectors of antibody-dependent cytotoxicity (Geha &
Rosen, 1996), the presence of anti-idiotype antibodies in
IVIg which block autoantibody binding to circulating
platelets and immune suppression (Godeau et al, 1993;
Chong, 1995). While IVIg is a pooled blood product, it
has an excellent safety record although renal impairment
or failure has been reported with some preparations
(Schiavotto et al, 1993; Cayco et al, 1997).
Recommendations for first line therapy in adults:
There are no randomized studies comparing no treatment vs. therapy with corticosteroids or IVIg. There is no
indication for therapy in adults in whom there are no
symptoms or signs, or in whom the platelet count is
greater than 30 · 109 ⁄ l (Grade C recommendation).
IVIg is useful in 75% of patients in whom the platelet
count has to be raised either due to symptoms or signs,
or where there is predictable bleeding (e.g. surgery,
pregnancy ⁄ labour or operative dentistry).
578
Guideline
Second line therapy
Splenectomy
Splenectomy has been used for many years, before steroid
therapy was introduced in 1950 (Chong, 1995; George
et al, 1996), as a means of prolonging the survival of
antibody-coated platelets. The procedure is not strictly
‘curative’ since opsonization still takes place but the
effector of platelet destruction is removed. Two-thirds of
patients with ITP who undergo splenectomy will achieve a
normal platelet count, which is often sustained with no
additional therapy. Patients who do not have a complete
response can still expect some improvement in counts (e.g.
partial response) or transient increases in platelet count
(George et al, 1996).
Intraoperative platelet support. There is a suggestion, with
little evidence, that if random donor platelets are deemed
necessary to cover the surgery, these should be given once
the splenic artery has been clamped. Physiologically this
would appear logical but has never been subjected to
rigorous study (Level IV evidence).
Post-operative complications of splenectomy. Early studies
reported complication rates of around 22% and two series
from New Zealand and France showed no mortality and
morbidity of only 7% in 48 and 72 patients respectively
(Shaw, 1966; Naouri et al, 1993). In the study by
Portielje et al (2001), two deaths occurred (out of 78
patients undergoing splenectomy) and 26% had early
post-operative complications (pulmonary embolism, intraabdominal bleeding, abdominal abscess, abdominal wall
haematoma, gram negative sepsis, and others). Some 5%
of patients suffered late complications. Overall, the complication rate was higher in patients greater than 65 years
of age.
Platelet count pre-splenectomy. Stasi et al (1995) recommended a platelet count of 30 · 109 ⁄ l; this may require
treatment with oral corticosteroids or IVIg pre-operatively
if the platelets are below 30 · 109 ⁄ l. Others have used
oral dexamethasone (40 mg ⁄ d for 4 d) to prepare
13 patients for splenectomy, 11 of whom had sufficient
rise in the platelet count for surgery (Gillis & Eldor,
1998).
Predicting response to splenectomy. Various indicators of
the likely response to splenectomy have been reviewed
including response to oral steroids, which has a low
predictive value, response to high dose IVIg which, in two
small series, correlated well with response to splenectomy
(Chirletti et al, 1992; Law et al, 1997), and indium-labelled
autologous platelet scanning which appears to be the most
sensitive predictor of response to splenectomy, to date
(Najean et al, 1997). Recent work using indium-labelled
autologous platelets in 528 patients, has shown that when
platelet destruction was splenic, then 96% of patients
between the age of 5–30 years and 91% of those above
the age of 30 years could expect to obtain a remission.
However, where the platelet destruction was hepatic or
diffuse (mixed splenic and hepatic) 92% of patients failed to
normalize their platelet counts or had incomplete responses
to splenectomy (Najean et al, 1997; Evidence level III). The
indium-labelled autologous platelet scan appears to offer
objective evidence of likely response to splenectomy and
is recommended, where available, prior to splenectomy.
(Evidence level III.)
Accessory splenic tissue. The presence of an accessory
spleen (or spleens) should be considered in patients who fail
to respond to splenectomy or relapse following an initial
response (George et al, 1994). Imaging techniques have
shown the presence of accessory splenic tissue in up to 12%
of such patients (Facon et al, 1992).
Prevention of infection post-splenectomy. Patients should be
given prophylactic polyvalent pneumococcal vaccine (Pneumovax II), Haemophilus influenzae b (Hib) and meningococcal C conjugate vaccinations at least 2 weeks prior to
splenectomy (Centers for Disease Control (CDC), 1993;
British Committee for Standards in Haematology (BCSH),
1996). Revaccination with pneumococcal vaccine should
be offered every 5 years but is not currently recommended
for Hib. The recommendation for booster doses of meningococcal C conjugate virus may be introduced in the future.
Annual influenza vaccine is recommended in asplenic
patients. The patients’ vaccination status should be recorded in the case notes. Following splenectomy patients
should be offered phenoxymethylpenicillin 250–500 mg
twice daily, or equivalent, or erythromycin (500 mg bd)
possibly for life, in order to reduce the incidence of postsplenectomy pneumococcal infection (McMullin & Johnston,
1993; Reid, 1994) (Grade C recommendation). The efficacy
of such a regimen remains unproven (Makris et al, 1994).
Some authorities would suggest antibiotic prophylaxis for
3 years post-splenectomy. Patients should have a supply of
broad-spectrum antibiotics at home for use if fever develops.
In addition there are cards available that should be carried
by patients, to alert physicians that the patient is asplenic.
Some patients may wish to purchase alert bracelets or
pendants.
ADULT PATIENTS FAILING FIRST AND SECOND
LINE THERAPIES – CHRONIC REFRACTORY ITP
This defines patients who fail to respond to first line
treatment or require unacceptably high doses of corticosteroids to maintain a safe platelet count. The actual
percentage of patients defined as having refractory ITP
varies from 11% (Portielje et al, 2001) to 35% (George et al,
1994). A large number of drugs have been used as second
line therapy for ITP with variable success. The therapy used
will depend on the age of the patient, the severity of the
presentation, the level of the platelet count, whether the
disease is primary refractory or relapsed, and the length of
time prior to relapse.
When considering second line therapy the original first
line therapies (corticosteroids, IVIg or splenectomy) should
be reconsidered and implemented if possible (George et al,
1996), although the doses may have to be altered compared
with those used in first line therapy. Additional supportive
therapy may need to be considered to allow their chronic
use. For example, there is a small but significant risk of
osteoporosis and avascular necrosis in patients on long-term
corticosteroids and they should be assessed for this and
Guideline
treated accordingly with bisphosphonates or hormonal
replacement if indicated.
The actual necessity for treatment should always be
considered, weighing up the risks and side effects of
treatment, against the risks of no treatment. In some
patients symptomatic therapy such as fibrinolytic inhibitors
may be used, particularly if there is only mucous membrane
bleeding, and in severe bleeding, such as gastrointestinal
haemorrhage, then platelets may be transfused. Although
these are rapidly cleared from the circulation and have a
severely shortened half-life they are often effective in
stopping bleeding (Carr et al, 1986).
Conventional second-line treatment approaches
For the patient in whom further conventional treatment
with standard dose corticosteroids is inappropriate there
are a wide variety of therapeutic options (Collins &
Newland, 1992). These include: (i) high dose steroids, (ii)
high dose IVIg, (iii) intravenous anti-D, (iv) vinca alkaloids,
(v) danazol, (vi) immunosuppressive agents including
azathioprine and cyclophosphamide, (vii) combination
chemotherapy, and (viii) dapsone. The wide variety of
treatments available for second line therapy reflects their
relative lack of efficacy, and treatment should be tailored to
suit the individual.
High dose corticosteroids. As an alternative to prednisolone, Andersen (1994) reported favourable responses in
refractory patients using an oral high dose dexamethasone
regimen, comprising 40 mg of dexamethasone daily for 4 d,
repeated every 28 d for six cycles. Ten patients were treated
in this small study with favourable responses in all patients
(all had platelet counts exceeding 100 · 109 ⁄ l), sustained
for at least 6 months. At this dose, side effects are common
and subsequent studies conducted by other groups have not
met with such success (Caulier et al, 1995; Arruda &
Annichino-Bizzacchi, 1996; Demiroglu & Dundar, 1997;
Kuhne et al, 1997).
Methylprednisolone. Parenteral steroids such as methylprednisolone have been used as second and third line
treatments for patients with refractory ITP. One study
reported the results of nine adult patients with platelets
< 50 · 109 ⁄ l, all of whom were treated initially with oral
corticosteroids (prednisolone ⁄ prednisone at 1 mg ⁄ kg ⁄ d).
Methylprednisolone was given at 30 mg ⁄ kg ⁄ d for 3 d,
20 mg ⁄ kg ⁄ d for 4 d then 5, 2 and 1 mg ⁄ kg ⁄ d each for
1 week. The platelet count became normal within 3–5 d
in all patients, although in seven of nine the response
lasted only a few weeks before dropping to pre-treatment
levels (Akoglu et al, 1991). von dem Borne et al, 1988)
compared the effect of methylprednisolone with IVIg in
22 adult patients with a control series (17 patients
treated with standard oral corticosteroids). The methylprednisolone was found to be as effective as IVIg in terms
of the frequency of response, with no reported side effects.
The major difference noted between the modalities was
that the response to oral steroids was slower than that to
intravenous methylprednisolone (von dem Borne et al,
1988). Again, the response to intravenous steroids was
transient in all patients and maintenance with oral
579
steroids was required to achieve an adequate platelet
count.
High dose IVIg. High dose intravenous immunoglobulin
at a dose of 1 g ⁄ kg per day for two consecutive days, often
in combination with corticosteroids, will raise the platelet
count rapidly in a proportion of patients (Bussel &
Hilgartner, 1984; Imbach et al, 1985). Side effects,
particularly headaches, may occur, but if successful can
be given on an intermittent basis or substituted with
intravenous anti-D (Blanchette et al, 1993). Godeau et al
(1993) reported good responses, including sustained complete response (CR), in some patients with refractory ITP
treated with IVIg (1–2 g ⁄ kg) repeated every 2–3 weeks. In
general, however, the platelet response to IVIg is transient
with rare durable remissions (Schiavotto et al, 1995). IVIg
is usually reserved for patients with symptomatic ITP in
whom a rapid increase in platelet count is required, prior
to operative procedures likely to cause blood loss, or in
pregnancy.
Intravenous anti-D. Intravenous anti-D has been shown to
elevate the platelet count in 79–90% of adults (Scaradavou
et al, 1997). The mechanism of action is believed to be
mediated through the destruction of Rh (D) positive red cells
which are preferentially removed by the reticuloendothelial
system, particularly the spleen, thus sparing autoantibodycoated platelets through Fc receptor blockade (Bussel et al,
1991a).
In a single arm, open-label study of anti-D in 261 nonsplenectomized and 11 splenectomized patients, 72% of
patients showed an increase in platelet count of greater than
20 · 109 ⁄ l, and in 46% of patients the platelet count rose by
more than 50 · 109 ⁄ l. The improvement lasted for more
than 3 weeks in 50% of patients who responded (Scaradavou et al, 1997). Anti-D treatment is suitable for Rh (D)
positive patients who are not splenectomized, and is not
recommended for refractory patients following splenectomy.
Vinca alkaloids. This group of drugs may cause a
transient increase in the platelet count lasting between 1
and 3 weeks in two-thirds of patients treated. Around 50%
of splenectomized patients will respond, but sustained
responses are observed in less than 10% of patients
(Berchtold & McMillan, 1989; Manoharan, 1991; George
et al, 1996; Blanchette et al, 1998). Available drugs include
vincristine 1 mg (occasionally 2 mg) intravenously (IV), or
vinblastine 5–10 mg IV weekly for 4–6 weeks.
Danazol. Danazol, an attenuated androgen, appears to be
especially effective in patients with overlap syndromes
between ITP and lupus and can often be used as a
corticosteroid-sparing agent in responsive patients who
require longer term unacceptably high doses. Ahn et al
(1989) reported the outcome of 22 patients, of which 15
had undergone splenectomy, treated with danazol at a dose
of 200 mg 2–4 times daily for more than 2 months.
Around 60% showed elevation of the platelet count
above 50 · 109 ⁄ l that was sustained for more than
2 months. Older females and those who have undergone
splenectomy appeared to have the best response (Ahn et al,
1989). Danazol, when given for longer than a year, induced
remissions lasting for years even after its discontinuation,
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Guideline
but early relapses were frequent when it was administered
for less than 6 months (Ahn et al, 1989). The mechanism of
action of danazol is unknown but it is postulated to
downregulate the number of Fc receptors on splenic
macrophages (Schneider et al, 1997).
Immunosuppressive agents. Immunosuppression may be
required in patients who fail to respond to alternative
therapies. Treatment with azathioprine (2 mg ⁄ kg, usually
up to a maximum of 150 mg ⁄ d) or cyclophosphamide as
single agents may be considered and up to 25% of patients
may have a sustained response.
Bouroncle & Doan (1969) used azathioprine in 17 patients
and reported excellent responses in 23.5% and good responses in 41% after treatment for an average of 10 months (a
good response was one in which the normal platelet count
was sustained only with continued use of azathioprine).
Another review of the use of azathioprine (Quiquandon et al,
1990) reported 53 patients with chronic ITP who were
treated with azathioprine at 150 mg per day for a median of
18 months; 40 of the 53 patients had previously undergone splenectomy. Platelet responses were documented in
64% of patients and were complete in 45% of these.
Azathioprine is slow-acting, and should be continued for
up to 6 months before being deemed a failure. When a
platelet response occurs the dose should be reduced, while
maintaining a safe platelet count (Blanchette et al, 1998).
Cyclosporin A has been shown to increase the platelet
count when given either alone or with prednisolone but its
side effects make it unlikely to be of widespread practical
use. It may, however, sustain the patient over a difficult
period. Emilia et al. (1996) reported eight patients treated
over a 13–62 month period with cyclosporin A (three
patients had autoimmune haemolytic anaemia (AIHA), four
ITP and one Evans’ syndrome). Responses were seen in all
patients (six CR and two partial responses). Side effects were
moderate but transient. In most cases cyclosporin A had to
be continued in order to maintain an adequate platelet
count (Emilia et al, 1996). In a recent study (KappersKlunne & van’t Veer, 2001), 20 patients with ITP all of
whom were refractory to corticosteroids and half of whom
had undergone splenectomy, were treated with cyclosporin
A for at least 4 weeks. The dose was reduced by 50 mg ⁄ d
every 2 weeks in those showing responses. Five patients
remained in complete remission for at least 2 years after
discontinuing cyclosporin A, and a further six patients
showed partial responses. Cyclosporin A was discontinued
in six patients due to side effects.
Dapsone. In a series of 66 adults with chronic ITP and
platelet counts < 50 · 109 ⁄ l treated with dapsone at
75–100 mg orally, responses were observed in 33 of 66
patients (50%), with a median duration of treatment
required to achieve a response of 21 d. Sustained responses
were observed in 19 patients (Godeau et al, 1997).
Dapsone’s mechanism of action is unknown but may be
due to reticuloendothelial blockade through increased red
cell destruction (Godeau et al, 1997; Radaelli et al, 1999).
Half of all patients with chronic ITP treated with dapsone
will show some response within 3 weeks, but it appears to be
less effective in severe cases of ITP. The response rate to
dapsone is low in patients who have undergone splenectomy
(Hernandez et al, 1995).
Recommendation for second line therapy in adults:
Methylprednisolone is a useful second line treatment
especially where there is a need to elevate the platelet
count quickly, in combination with IV cyclophosphamide and ⁄ or IVIg. Evidence level IIa. Because of the
relatively frequent incidence of accessory splenic tissue,
this should be sought in those failing to respond to
splenectomy. Agents such as high dose IVIg, vinca
alkaloids, anti-D, danazol, azathioprine and cyclosporine
are worth considering in non-urgent or ‘semi-urgent’
cases where there is a need to elevate the platelet count.
Patients failing first and second line therapies
Fortunately, most adult patients with chronic refractory ITP
are able to tolerate marked thrombocytopenia relatively well
(Blanchette et al, 1998), and are able to have a normal or
near normal quality of life. For those who fail to respond to
standard first and second line therapy and who require
treatment the options are limited and include: (i) interferon-a
(IFN-a), (ii) anti-CD20, (iii) Campath 1H, (iv) mycophenolate
mofetil, (v) protein A columns, and (vi) other treatments.
IFN-a. There are several case series that report on the
use of IFN-a in refractory ITP, and have shown that 25% of
patients can achieve a platelet count of over 100 · 109 ⁄ l
for between 1 week and 7 months after the IFN-a treatment
(George et al, 1996). The mechanism of action is unknown
but may be due to modulation of effector B lymphocytes
involved in the autoimmune process. Because available data
suggest that IFN-a appears most effective in less severe ITP
(Proctor et al, 1989), and previous reports of exacerbation of
ITP while receiving IFN-a, with a fatal outcome in one
patient (Matthey et al, 1990), IFN-a does not have a current
role in the management of ITP.
Anti-CD20 antibody. Rituximab (chimaeric anti-CD20
monoclonal antibody) has been evaluated in a single study
(Stasi et al, 2001) in which 25 patients with ITP resistant to
2–5 therapeutic options were treated with 375 mg ⁄ m2
rituximab weekly for 4 weeks. Five patients showed a
complete response and a partial response was seen in a
further five. In seven patients the responses were sustained
for over 6 months. There was a suggestion that younger
patients showed better response rates.
Campath-1H. Lim et al (1993) treated six patients with
refractory ITP (three patients had underlying CLL ⁄ nonHodgkin’s lymphoma and one had Hodgkin’s disease). A
response was seen in four of five evaluable patients, and in
three of these the response lasted more than 4–9 months. In
most cases it took between 4 and 6 weeks for a response to
occur. Side effects were significant and included rigors and
fever during the infusion, and marked lymphopenia
(< 0.1 · 109 ⁄ l) in all patients treated. Worsening of
thrombocytopenia was noted in two patients during therapy.
A more recent study of the use of Campath-1H in patients
with a variety of cytopenias has shown that it was well
tolerated with encouraging responses (Willis et al, 2001).
Guideline
Mycophenolate mofetil. This antiproliferative immunosuppressant, licensed for the prophylaxis of acute renal, cardiac
or liver transplant rejection, has been shown to be of value
in some patients with autoimmune cytopenias including
refractory ITP (Evidence Level IV). However, the numbers of
patients treated to date are small and larger studies are
required (Zimmer-Molsberger et al, 1997; Allison & Eugui,
2000; Howard et al, 2002).
Protein A immunoadsorption column. Snyder et al (1992)
reported on the use of protein A columns in 72 patients with
refractory ITP, 49 of whom had undergone splenectomy. All
72 patients were given six immunoadsorption treatments
for 2–3 weeks. Twenty nine of the 72 (40%) were continued
on low dose steroid (prednisone <30 mg ⁄ d). Some 25% of
patients had good responses (platelets exceeding
100 · 109 ⁄ l, while 21% had fair responses (platelets
between 50 and 100 · 109 ⁄ l). Over half the patients
(54%) had poor responses (Snyder et al, 1992). The
mechanism of action of the protein A columns may involve
reducing platelet activation (Cahill et al, 1998). The use of
protein A columns requires good venous access, is cumbersome and relatively expensive (Karpatkin, 1997).
For patients who fail to respond to these therapies
there are limited data on the use of ascorbic acid (Brox
et al, 1988), chlorodeoxyadenosine, colchicine (Strother et al,
1984; Jim, 1986), liposomal doxorubicin, and peripheral
blood stem cell transplantation (Lim et al, 1997; Skoda et al,
1997).
Plasmapheresis. This treatment has been used in order to
remove antiplatelet antibodies and immune complexes.
There are several reports, the largest of which documented
the treatment of 14 patients, some of whom had acute ITP
(Marder et al, 1981). Five of nine with acute ITP responded
to plasmapheresis. Bussel et al (1988) have reported success
using a combination of plasmapheresis and IVIg for patients
with chronic refractory ITP. The general consensus is that
plasmapheresis is not a useful therapeutic manoeuvre in the
treatment of chronic ITP.
Liposomal doxorubicin. This has been used in the context
of small non-randomized studies only, with variable success
(Cosgriff et al, 1998).
Recommendation for therapy in adults failing first and
second line therapies:
Campath-1H and rituximab are agents that may be of
value for patients in whom there is no response to other
therapies and in whom there is a definite requirement to
elevate the platelet count (e.g. active bleeding). Mycophenolate mofetil appears to be effective in some patients
with severe refractory ITP but larger studies are required
to confirm its efficacy and safety. In terms of the risk:
benefit ratio, treatments with interferon-a, protein A
columns, plasmapheresis and liposomal doxorubicin are
not recommended.
Emergency treatment in adult patients
Urgent treatment is required for adults with severe
thrombocytopenia (e.g. platelets < 30 · 109 ⁄ l) and who
581
have active bleeding from the gastrointestinal (GI) or
genitourinary tracts, into the central nervous system or
other sites. In this situation, treatment is aimed at elevating
the platelet count to a ‘‘safe’’ level quickly (i.e. in less than
24 h). Clearly, many of the treatments discussed earlier
take much longer to achieve this effect, and therapies that
work almost immediately include platelet transfusion,
intravenous methylprednisolone and IVIg.
Combination chemotherapy. This mode of therapy may be
useful for patients who have failed other therapies but in
whom the need to elevate the platelet count is less urgent,
e.g. patients who are not actively bleeding. There is a risk of
second malignancies, including acute leukaemia, in patients
treated with these medications and the use of cytotoxic
agents, especially in younger patients, should be carefully
considered. In those patients with severe, symptomatic
chronic ITP refractory to multiple previous treatments the
use of cyclophosphamide, vincristine and prednisolone
combined in regimens such as those used in the lymphomas
have been shown to be effective. Figueroa et al (1993)
reported their results in 10 patients with refractory ITP.
Two patients had underlying malignant disease (Hodgkin’s
disease and CLL). All 10 had been treated previously with
steroids and had undergone splenectomy. The platelet count
was less than 5 · 109 ⁄ l in all patients. A complete response
was seen in six patients (durable in four); a partial response
was observed in two (one durable) and two died of
intracerebral haemorrhage.
Recommendations for emergency treatment in adults:
For rapid elevation of the platelet count in extreme
emergencies transfusion of random donor platelets is
appropriate. When a higher platelet count is required but
there is less urgency, IVIg and ⁄ or IV methylprednisolone
and ⁄ or IV cyclophosphamide may be useful. Evidence
Level IV.
INVESTIGATION AND MANAGEMENT
OF ITP IN CHILDREN
ITP in children is uncommon. It is usually a benign disorder
that requires no active management other than careful
explanation and counselling. This is because serious bleeding is rare, and about 80% of children with ITP will recover
spontaneously within 6–8 weeks. Children and their parents may benefit from the contacts and literature available
from ITP support groups such as The ITP Support Association (http://www.itpsupport.org.uk).
Diagnosis
The diagnosis of childhood ITP is by exclusion. It can occur
at any time of childhood, but in the neonatal period must be
distinguished from maternal ITP or alloimmune thrombocytopenia. In children older than 10 years a chronic course
may be more common. In acute ITP, the history is short
with the appearance of purpura and bruising over a
24–48 h period. The platelet count is usually less than
10–20 · 109 ⁄ l. Children with higher platelet counts rarely
show any symptoms. The presenting platelet count may be
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Guideline
unrecordable in the face of few symptoms and signs. The
illness may follow an acute viral infection or immunisation.
ITP associated with varicella needs special caution as
occasional cases have more complex coagulation disorders
with antibodies directed against proteins S and ⁄ or C
(Ganesan & Kirkham, 1997). ITP may be provoked by the
measles, mumps and rubella (MMR) vaccine, with an
estimated risk of 1 in 24 000 doses (Farrington et al, 1995),
usually occurring within 6 weeks of vaccination. There is
no evidence of a vaccine-associated recurrence in children
who developed ITP independently of and before MMR
vaccination (Miller et al, 2001). The Committee on the
Safety of Medicines (CSM) recommend that children who
develop ITP within 6 weeks of the first dose of MMR should
have their serological status for the three viruses evaluated
before the second dose is due. If serology suggests that a
child is not fully immune to measles, mumps and rubella,
then a second dose of MMR is recommended. The Public
Health laboratory Service is offering a free serological
testing service for children developing ITP within 6 weeks
of the first dose of MMR. Those not protected against
rubella by MMR are at risk of developing ITP from infection
with rubella itself when the risk is 1 in 3000 (data from the
Department of Health Education Authority, http://
www.immunisation.org.uk). The MMR vaccine package
inserts are being upgraded to reflect the CSM’s advice.
Differential diagnosis
The history of bruising and purpura is sometimes more
chronic, with symptoms developing more slowly over weeks
or months. In these children caution should be exercised
and particular attention paid to the possibility of a congenital disorder. These are most often missed because they are
uncommon and are therefore not considered.
Congenital disorders that may resemble ITP
(a) In a young child (within a few weeks or months of birth)
Wiskott Aldrich syndrome
Bernard Soulier syndrome
Other occasional families with isolated congenital or
hereditary thrombocytopenias of unspecified type
(b) In older children
Evolving Fanconi anaemia
von Willebrand’s disease type IIB (Donner et al, 1987)
Serious marrow disorders
Acute leukaemia (NB especially Down syndrome)
Aplastic anaemia
Special diagnostic considerations in older children
Children over the age of about 10 years may be more
likely to have a chronic course (Walker & Walker, 1984;
Reid, 1995). Other autoimmune diseases associated with
thrombocytopenia should be considered, particularly systemic lupus erythematosus (SLE) and antiphospholipid
syndrome. Older children should have additional investigations performed (see below). Thrombocytopenia has not
commonly been reported as the initial presentation of HIV
infection in children, but can occur during the course of
the disease.
Special diagnostic considerations in the
Accident & Emergency (A & E) Department
The possibility of non-accidental injury (NAI) and meningococcal disease must be considered by A & E staff when
dealing with a young child presenting with bruising and
purpura for the first time. Children with infection usually
have other features and non-accidental injury does not
present with generalized purpura.
Investigations
Full blood count and careful film examination by an
experienced morphologist. If a low platelet count does not fit
the clinical picture the count should be repeated to exclude
a spurious result.
Coagulation screening. Only necessary if there is a possibility of meningococcal infection, features to suggest an
inherited bleeding disorder in addition, or a suspicion of
NAI.
Antiplatelet antibodies. Measurement of antiplatelet antibodies does not assist in the diagnosis (Taub et al, 1995;
George et al, 1998).
H. pylori infection. This is discussed above. There is no
information about this infection as a precipitating cause of
ITP in children, although H. pylori infection does occur in
childhood. There is therefore no indication to screen
children with ITP unless there are other clinical indicators
to suggest infection (Sherman & Macarthur, 2001).
Bone marrow aspiration. Bone marrow examination
excludes some causes of thrombocytopenia but can only confirm that the picture is consistent with peripheral destruction.
Although it is argued that if a child has a sinister underlying
disorder there will be other clues in the blood picture or
the clinical examination (Halperin & Doyle, 1988; Calpin
et al, 1998) this is not always reliable (Reid, 1992).
Recommendation for investigation of suspected childhood ITP:
In a child with typical clinical and laboratory features
who needs no treatment, a bone marrow examination is
not required (Grade B recommendation). If therapy is
considered, it must be recognised that occasionally the
diagnosis of ITP will be incorrect. Bone marrow examination will usually reveal this. Marrow examination is
necessary in the presence of atypical clinical features or if
there is no response to treatment. It is also recommended
that the bone marrow be examined before steroid
therapy is given (Evidence Level IV). Marrow aspiration
should ideally be accompanied by a trephine biopsy
because this gives a better estimate of megakaryopoiesis
(Beardsley & Nathan, 1998). Marrow examination is
painful and is more acceptable when performed under
general anaesthesia (Evidence levels: IIb, III).
Management of ITP in childhood: general measures
It is essential that children are classified clinically and not
by platelet count, because children with severe thrombocytopenia (less than 10 · 109 ⁄ l) have usually ‘‘mild’’
clinical symptoms. Pronounced skin purpura and bruising,
Guideline
however, extensive, do not indicate a serious bleeding risk
on their own. To date there has been a universal
tendency to treat the count alone rather than the child’s
symptoms. Two UK national surveys of children with ITP
have demonstrated that only 4% of children with ITP
have serious symptoms such as severe epistaxis or GI
bleeding (Bolton-Maggs & Moon, 1997; Bolton-Maggs &
Moon, 2001). Similar data are available from Germany
(Sutor et al, 2001) and Norway (Zeller et al, 2000).
Several studies have confirmed that the incidence of
intracranial haemorrhage (ICH) is much less than the 1–
3% widely quoted, and is closer to 0.1–0.5% (Lilleyman,
1994). In the two UK national surveys there were two
ICH in 703 cases (0.3%), with complete recovery in both
cases, similar to the incidence derived from a retrospective
national survey (Lilleyman, 1994, 1997). Similarly, a
recent Japanese study found an incidence of 4 in 772
(0.52%) children, with no deaths (Iyori et al, 2000). It is
impossible to predict which children will develop an ICH,
and it may be that there are other predisposing factors
that contribute to this for example an underlying vascular
anomaly.
ICH has occurred in children who have been treated and
in one study this was the case in a third of children reviewed
(Lee & Kim, 1998). It is worth noting that in the first
randomized study of IVIg the only child to have ICH did so
early, was on IVIg and died 6 d after presentation (Imbach
et al, 1985). As discussed earlier, the need for treatment in
children with acute ITP should not be driven by the platelet
count alone, but mainly by symptoms. Children who
continue to be severely thrombocytopenic with significant
bleeding symptoms are very rare indeed, and should be
referred to a specialist centre for management (Lilleyman,
1999).
Clinical classifications
Two clinical scoring systems have been used, the first in
the two UK national surveys for analysis of 703 newly
diagnosed children (Bolton-Maggs & Moon, 1997, 2001),
and the second was reported from a single centre in Texas
where it has been analysed on 109 occasions in 54
patients, both at diagnosis and in established ITP (Buchanan & Adix, 2001). Both of these confirm that the
majority of children do not have serious bleeding problems
despite very low platelet counts. The severity of bleeding at
any given time, especially at presentation does not predict
the risk of subsequent episodes of serious bleeding.
Children should not be treated on the basis of cutaneous
signs alone, however, dramatic and widespread the
purpura.
Recommendation:
Clinical severity, in addition to platelet count, should be
used to define the severity of acute ITP in children.
Treatment should be considered on the basis of other
clinical symptoms in addition to cutaneous signs, and
not the platelet count alone (Level IIb evidence, Grade B
recommendation).
583
Treatment: Expectant ‘Watch and Wait’ policy
More than 80% of children with acute ITP do not have
significant bleeding symptoms and can be managed without
specific therapy directed at raising the platelet count
(Buchanan et al, 1997; Baronci et al, 1998; Dickerhoff &
von Ruecker, 2000; Bolton-Maggs et al, 2001; Bolton-Maggs
& Moon, 1997, 2001; Sutor et al, 2001) (Evidence levels III
and IV). It is essential that the parents, and child where able,
have an explanation that this is usually a self-limiting benign
disorder (Dickerhoff & von Ruecker, 2000). Most children
can be managed well at home, and do not require hospital
admission, which should be reserved for children with
clinically important bleeding (severe epistaxis, i.e. lasting
more than 30 min with heavy bleeding, GI bleeding, etc.).
Parents should be advised to watch for other signs of bleeding
and be given a contact name and 24 h telephone number;
similar advice as that given to families with a child with
severe haemophilia is often the most appropriate, with, as far
as possible, avoidance of formal contact sports or activities
with high risk of trauma or head injury. Other activities can
be continued as normal, and the child should be encouraged
to continue schooling on the basis that ITP is a disorder that
may last some weeks or months (Evidence levels: III and IV,
Grade B and C recommendation).
Most children with mild or moderate symptoms only (the
majority) can be safely managed as outpatients with weekly
or less frequent visits (level III evidence) (Dickerhoff & von
Ruecker, 2000; Bolton-Maggs et al, 2001). A repeat platelet
count is not necessary while a child still has purpura as this
symptom is an indication that the count is likely to be less
than 20 · 109 ⁄ l; however, a repeat count should be performed within the first 7–10 d to check that there is no
evidence of a serious marrow disorder emerging, particularly
aplasia. Otherwise the count can be performed when clinically indicated by a change of symptoms, or if the family feel
more at ease knowing the result. However, too close a focus
on numbers is not helpful. When the thrombocytopenia
persists but the child remains well, the intervals between visits
can be stretched out in order to minimise interference with
schooling. With increasing duration of a very low platelet
count and limitation of some sporting activities, lifestyle
issues become relatively more important and should be
sympathetically discussed. These issues may influence decisions about treatment. ‘Most parents and patients can live quite
comfortably with petechiae and low platelets awaiting spontaneous
remission providing their physician can’ (Dickerhoff, 1994).
Recommendation:
Children with acute ITP and mild clinical disease may be
managed expectantly with supportive advice and a 24 h
contact point, irrespective of platelet count (Grade B
recommendation). The full blood count should be repeated within 10 d of diagnosis to ensure there is no
evidence of evolution to a serious marrow disorder;
thereafter the count need not be monitored until
resolution of clinical symptoms suggests the onset of
remission or there are other clinical indicators suggesting
the need.
584
Guideline
Specific treatment to raise the platelet count
Several therapies raise the count faster than no treatment
(Ib evidence). However, all have significant side effects and
none alters the underlying pathology nor increases the
chance of complete remission. These strategies are appropriate for children with severe bleeding symptoms.
Corticosteroids
Prednisolone. Conventional doses of 1–2 mg ⁄ kg ⁄ d for a
maximum of 14 d may be effective in raising the count but
perhaps is little faster than no therapy (Buchanan &
Holtkamp, 1984) (Level 1b evidence). Prednisolone should
be discontinued after a maximum of 2–3 weeks irrespective
of platelet count because of the serious side effects
associated with prolonged treatment. There is evidence
that smaller doses (0.25 mg ⁄ kg ⁄ d for 21 d) may produce a
rise in count (Bellucci et al, 1988). A high dose regimen
(prednisolone 4 mg ⁄ kg ⁄ d) has been compared in two
randomized controlled trials and been shown to be more
effective (Level Ib evidence). Fifty three children were
randomized between IVIg, high dose (4 mg ⁄ kg ⁄ d) oral
prednisolone with tapering and cessation by 21 d and no
therapy in one study (Blanchette et al, 1993). The median
time to reach a count of > 50 · 109 ⁄ l was 4 d in the
prednisolone group compared with 16 d in the ‘no
treatment group, and 2 d in those given IVIg. The same
regimen was used in a later study of 146 children which
included a treatment arm with anti-D (Blanchette et al,
1994). In the latter study 28 ⁄ 39 (72%) of children in the
high dose steroid arm achieved a count > 50 · 109 ⁄ l
within 72 h.
The disadvantage of this steroid regimen is the duration
at high dose. A short course may be sufficient. A pilot study
of 25 children given 4 mg ⁄ kg for 4 d (Carcao et al, 1998)
demonstrated that 22 children achieved a count of
> 20 · 109 ⁄ l within a week with minimal side effects (Level
III evidence). If a child requires treatment for symptoms, an
early effect on count is reassuring. It is essential that
steroids are not continued for longer than 2 to 3 weeks or
titrated against the platelet count as this may lead to
inappropriate doses and duration, with very significant
long-term side effects.
Other steroid regimens
High dose methyl prednisolone (HDMP). This has been
used as an alternative to IVIg because it is cheaper and
effective. A small study of 22 children given an oral 7 d
course (30 mg ⁄ kg ⁄ d for 3 d followed by 20 mg ⁄ kg ⁄ d for
4 d) demonstrated that all patients achieved platelet
counts > 50 · 109 ⁄ l by d 7. Courses were repeated
monthly if the count was less than 20 · 109 ⁄ l on d 30,
for up to six courses (Ozer et al, 2000). Other small studies
have demonstrated HDMP to be as effective as IVIg in
raising the platelet count (Ozsoylu et al, 1989, 1993).
Two studies demonstrated the efficiency of a combined
approach using HDMP with IVIg but these were small
uncontrolled studies (Barrios et al, 1993; Gereige &
Barrios, 2000).
Pulsed high dose dexamethasone. This treatment appears
to be less effective in children than in adults in producing
long-term remission, but may be useful as a temporary
measure. There is no evidence that this treatment, or any
of the treatments that can produce an increase in the
platelet count, increases the chance of complete remission.
Three small studies of 11 (Kuhne et al, 1997), 17 (BorgnaPignatti et al, 1997) and seven children (Chen et al, 1997)
demonstrated some benefit in some children – 78%
children achieved a platelet count > 100 · 109 ⁄ l within
72 h in 41 cycles of treatment given to 11 children with
chronic ITP (Kuhne et al, 1997). However, side effects
were unacceptable in 3 ⁄ 11 children. This treatment
cannot be recommended as first line therapy in symptomatic children.
Recommendation:
If a child has mucous membrane bleeding and more
extensive cutaneous symptoms, high dose prednisolone
4 mg ⁄ kg ⁄ d is effective (Grade A recommendation, Level
Ib evidence). It can be given as a very short course
(maximum 4 d). There are no direct comparisons of low
dose (1–2 mg ⁄ kg ⁄ d) with high dose therapy. If lower
doses of 1–2 mg ⁄ kg ⁄ d are used the treatment should be
given for no longer than 14 days, irrespective of
response.
Intravenous immunoglobulin
Intravenous immunoglobulin is effective in raising the
platelet count in more than 80% of children, and does so
more rapidly than steroids or no therapy (Blanchette et al,
1994) (Level 1b evidence). It is expensive and invasive,
and should be reserved for emergency treatment of patients
who do not remit or respond to steroids and who have
active bleeding. It is an appropriate treatment to enable
essential surgery or dental extractions. It should not be
used to raise the platelet count in children with cutaneous
symptoms alone. IVIg is a pooled blood product, the risks
of which must be explained to patients. It has significant
side effects, noted in 75% of children treated in a recent
trial (Blanchette et al, 1993). Severe headache can be
troublesome (Kattamis et al, 1997). In addition, IVIg has
transmitted hepatitis C, a life-threatening infection (Duhem
et al, 1994). Its use in children with trivial symptoms is
not justified.
Dose regimen. The traditional dose is 0.4 g ⁄ kg daily for
5 d. This has now been superseded by short course high
dose treatment either with a single dose of 0.8 g ⁄ kg or
1 g ⁄ kg given on 1 or 2 d (Blanchette et al, 1994;
Tarantino et al, 1999). These larger doses may be
associated with a higher risk of side effects. Another
small, randomized multicentre study demonstrated lower
doses of 250, 400 or 500 mg ⁄ kg ⁄ d for 2 d to be
effective (count increasing by more than 30 · 109 ⁄ l) in
16 ⁄ 17 (94%) children aged 5–12 years (Warrier et al,
1997). The product chosen should be one with at least
two viral inactivation steps included in the manufacturing
process.
Guideline
Recommendation:
IVIg can raise the platelet count rapidly, but should be
reserved for emergency treatment of serious bleeding
symptoms or in children undergoing procedures likely to
induce blood loss. It is effective given as a single dose of
0.8 g ⁄ kg (Evidence level Ib, Grade A recommendation).
Lower doses are also effective, and fewer side effects are
seen, in younger children.
Other therapies
Anti-D immunoglobulin. This is less expensive than IVIg
and can be given to Rh (D) positive individuals as a short
infusion, and is therefore amenable to outpatient therapy. It
is effective in children (Scaradavou et al, 1997), but the
mechanism of action is not fully understood. Like IVIg,
anti-D has the disadvantage of being a pooled blood product,
but produces a rise in platelet count as rapidly as IVIg when
given at sufficient dosage (45–50 lg ⁄ kg) (Tarantino et al,
1999). Some degree of haemolysis is quite commonly seen,
which can occasionally be severe and is associated with
renal failure (Gaines, 2000). Lower dose treatment is less
effective at raising the platelet count than IVIg (Blanchette
et al, 1994).
Other treatments
As with adult ITP, a variety of other drugs have been tried in
patients with persistent thrombocytopenia and bleeding.
There is insufficient information concerning their use in
children to make specific recommendations concerning what
should be used or in which order. Cytotoxic drugs should
be used with extreme caution in children, with appropriate consideration given to infertility and carcinogenesis.
Use of blood products – platelet transfusions
Life-threatening haemorrhage is the only indication for
platelet transfusion in ITP, a destructive platelet disorder
where transfusions of normal doses are unlikely to be
effective. National surveys have demonstrated that platelet
transfusions are sometimes given for simple thrombocytopenia. This is never justified. In a life-threatening situation
(such as the rare ICH) larger than normal doses are required
with monitoring of the increment as a guide, and other
modalities such as high dose IV steroids and IVIg should be
given at the same time to maximise the chances of raising
the count and stopping the haemorrhage.
Recommendation:
Platelet transfusions should only be given for ICH or
other life-threatening bleeding, and then in much larger
doses than for marrow failure. At the same time,
immunomodulatory treatment should be given with
high dose intravenous steroids or IVIg (Grade C recommendation).
Chronic ITP in childhood
Most children with ITP will remit within 6 months. The
management of children with continuing thrombocytopenia
is essentially the same as for acute ITP. Many children settle
585
with an adequate platelet count (i.e. more than 20 · 109 ⁄ l)
and have no symptoms unless injured. In children under
10 years of age at diagnosis spontaneous remission is likely
to occur eventually; expectant management can continue.
Children more than 10 years of age at diagnosis, and in
particular adolescent females, are more likely to sustain a
chronic course and management considerations are much
as for adults. Most children need no specific therapy to raise
the count unless injured or requiring surgery or dental
extraction. Particular problems may arise for girls at the
onset of menstruation. Children and parents should not
forget the vulnerability to excessive bleeding following
serious accidents and it is advisable for the family to carry
a card or letter with details of the disorder in case of
emergency. A medical bracelet or pendant may be helpful.
Children with counts persistently below 10 · 109 ⁄ l are
likely to have some symptoms, e.g. easy bruising or odd
petechiae. Such children have been described as having
chronic severe ITP (CSITP), are very rare (estimated annual
incidence of perhaps 1 in 2 500 000; Lilleyman, 1999) and
are the most difficult to manage (Lilleyman, 2000). There is
a strong case for these children to be referred to paediatric
haematologists with a special interest. Occasionally, girls
carry ITP into adulthood, but it tends to attenuate over time
(anecdotal reports). There are no data on boys with
persistent ITP beyond their teens.
The risk of serious bleeding is a function of the duration of
time with a low count and has been estimated at 0.5% at
12 months in those with a count less than 20 · 109 ⁄ l
(Lilleyman, 1999). There is insufficient evidence in the
literature to determine the best course of management for
these patients (George et al, 1996; Lilleyman, 2000).
Treatment must be tailored to the child and situation,
based on three criteria: the therapy should be effective, it
should not carry more risk than the untreated condition,
and it should make the child feel better (George et al, 1996;
Lilleyman, 2000).
A significant group of children with ITP have counts of
10–30 · 109 ⁄ l, and although they have no serious bleeding,
are nevertheless troubled by purpura. Children, particularly
once at secondary school, become very conscious of their
appearance and need sympathetic support. Lifestyle issues
and restrictions on sporting activities become more important and should be taken into account in considering therapy.
Intermittent treatment with IVIg can be given to cover
activity holidays after appropriate discussion of the risks.
However, it should be noted that this might cause additional
problems with insurance cover when a child has been in
hospital within 6 months of going on holiday. There is no
evidence that air travel predisposes to bleeding in patients
with ITP; there is no indication to treat the count prior to
holidays other than to cover activities. Parents should
always declare the illness to their insurance company before
travelling in case treatment is required while on holiday.
Bleeding complications must be managed according to
severity and circumstances; there is no straightforward
strategy for these young people. Splenectomy is often
considered, but it is ineffective in around 25% of cases,
and with longer follow-up it is clear that the relapse rate is
586
Guideline
high, although often the platelet count runs at a more
acceptable level with fewer symptoms.
Recommendations:
1. Children with chronic ITP usually do not need
active therapy but should be followed up regularly
and reminded to report to hospital after injuries.
They should have a designated contact person and
number.
2. Children with chronic severe ITP should be referred
to a paediatric haematologist for management and
long term follow-up.
Splenectomy
Splenectomy is rarely indicated in children with ITP. Longterm follow-up demonstrates that spontaneous remissions
continue to occur at least up to 15 years from diagnosis
(Reid, 1995), so the persistence of a low count beyond 6 or
12 months is therefore not on its own an indication for
surgery. Given that the risk of dying from ITP in childhood
is extremely low (less than 1 in 500), that the mortality
associated with splenectomy is 1.4 (Najean et al, 1997) to
2.7% (Eraklis & Filler, 1972) and that the risk of overwhelming sepsis probably persists for life, splenectomy is
only justified in exceptional circumstances (Eden & Lilleyman, 1992). Severe lifestyle restrictions, crippling menorrhagia or life threatening haemorrhage may give good
reason for the procedure, but only 70–75% will respond
(George et al, 1996), and full precautions against sepsis
should be undertaken (BCSH, 1996).
Recommendation:
Splenectomy is rarely indicated in childhood ITP. It is
occasionally justified for life-threatening bleeding and for
children with chronic unremitting and severe ITP whose
disease has been present for more than 12–24 months
with demonstrable impairment of their quality of life, but
these children are rare, and should be referred to a
specialist paediatric haematologist for individual consideration (Grade C recommendation).
THROMBOCYTOPENIA IN PREGNANCY
Incidence of ITP in pregnancy
The advent of routine platelet counting using automated
blood cell counters highlighted the fact that mild to
moderate thrombocytopenia is common in healthy women
with an apparently normal pregnancy. Excluding those
cases with spurious counts due to EDTA-induced in vitro
platelet aggregation, the large majority of these women
have ‘gestational thrombocytopenia’ (GT), a benign selflimiting phenomenon with no significant bleeding-risk to
mother or infant. However, it may be difficult or
impossible to distinguish GT from idiopathic (autoimmune) thrombocytopenia (ITP) in which the transmission
of platelet antibodies across the placenta has the potential
to cause fetal or neonatal thrombocytopenia and haemorrhage. Maternal thrombocytopenia may also be an
Table I. The major causes of maternal thrombocytopenia in pregnancy.
Spurious – EDTA-induced platelet aggregation
Gestational thrombocytopenia
Pre-eclampsia and HELLP* syndrome
Autoimmune thrombocytopenia
– idiopathic
– drug-related
– SLE
– antiphospholipid syndrome
– HIV-related
Disseminated intravascular coagulation
Haemolytic uraemic syndrome ⁄ thrombotic thrombocytopenic
purpura
Folate deficiency
Congenital platelet disorders
Coincidental marrow disease
Hypersplenism
*Haemolysis, elevated liver enzymes and low platelets.
indicator of significant complications of pregnancy such
as pre-eclampsia or disseminated intravascular coagulation (DIC) in addition to a range of less common acquired
or congenital disorders (Table I). Thus, the assessment
of individual cases of thrombocytopenia in pregnancy
focuses on excluding important secondary causes and
weighing the risks of bleeding in mother and infant
against the hazards of diagnostic and therapeutic interventions.
Normal platelet count in pregnancy
Most pregnant women have platelet counts within the nonpregnant reference range. However, large prospective studies (level III evidence) have confirmed that platelet counts
tend to fall during pregnancy and levels of 120–
150 · 109 ⁄ l are not uncommon in the third trimester (Sill
et al, 1985; Burrows & Kelton, 1988). A single-institutional
study (Burrows & Kelton, 1988) of 1357 women with
normal pregnancy, delivering at term, showed a mean
platelet count of 225 · 10 ⁄ l with 95% confidence intervals
of 109–341 · 109 ⁄ l.
PRESENTATION AND DIAGNOSIS
Gestational thrombocytopenia (incidental thrombocytopenia
of pregnancy)
The best evidence for the natural history of this phenomenon comes from a sequence of prospective studies reported
by the McMaster group in Ontario (Burrows & Kelton,
1988, 1990, 1993) (Level III evidence). At term, thrombocytopenia was present in 5.4–8.3% of healthy mothers.
Platelet counts were only mildly reduced in most patients
(mean 135 · 109 ⁄ l) and were between 100 and
150 · 109 ⁄ l in 95% of cases. It is exceptional for the
platelet count to fall below 80 · 109 ⁄ l but rare cases,
subsequently confirmed as GT, had counts as low as
50 · 109 ⁄ l.
Guideline
The incidence of thrombocytopenia in cord blood samples
taken from the infants of women with GT and women with
normal platelet counts was identical at 4%.
Hence, GT is characterized by:
• Mild thrombocytopenia (rarely < 80 · 109 ⁄ l)
• Occurrence in healthy women with otherwise normal
blood counts
• Most commonly occurs in the third trimester of pregnancy
• Normal platelet counts before and after pregnancy
• No association with maternal haemorrhage
• No association with fetal or neonatal thrombocytopenia
GT is difficult to distinguish from ITP when thrombocytopenia is identified for the first time during pregnancy and
no previous counts have been documented.
Idiopathic (autoimmune) thrombocytopenia (ITP)
Chronic ITP is most common in women of reproductive age
and is therefore encountered in pregnancy. The estimated
prevalence is 1–5 cases per 10,000 pregnancies (Kessler
et al, 1982), i.e. around 100 times less common than GT.
Patients occasionally present for the first time with severe
thrombocytopenia in pregnancy and women with previously diagnosed ITP may experience an exacerbation in
pregnancy, the nadir platelet count usually occurring in the
third trimester (Burrows & Kelton, 1992). However, the
most common presentation is the finding of asymptomatic
thrombocytopenia on routine laboratory testing, when the
distinction from GT may be difficult.
As in the non-pregnant patient, the diagnosis of ITP is
largely one of exclusion as there is no confirmatory
laboratory test (Burrows & Kelton, 1992). Documentation
of a low platelet count outside pregnancy is invaluable. It is
important to exclude pre-eclamptic syndromes, DIC or
autoimmune disorders such as SLE and the antiphospholipid syndrome, which carry significant prognostic
and therapeutic implications (Table II). Patients should be
carefully examined for hepatosplenomegaly and lymphadenopathy or features of pre-eclampsia (hypertension,
proteinuria, intrauterine growth restriction).
If there are no additional clinical features and the blood
count and film are otherwise normal, bone marrow
examination is not recommended (Letsky & Greaves, 1996).
As with non-pregnant adults and paediatric ITP, plateletassociated IgG is of no diagnostic value. Despite recent
Table II. Recommended laboratory investigations of thrombocytopenia in pregnancy (Grade C recommendation)
Blood film (to exclude spurious thrombocytopenia, red cell
fragments, other haematological disorders)
Coagulation screen (PT, APTT, fibrinogen, D-dimer)
Liver function tests
Anticardiolipin antibodies ⁄ lupus anticoagulant
SLE serology
PT, prothrombin time; APTT, activated partial thromboplastin
time; DRVVT, dilute Russell’s viper venom time.
587
innovative methodologies, measurement of serum platelet
autoantibodies are not clearly diagnostic of ITP in individual
patients and do not predict the likelihood of neonatal
thrombocytopenia (Burrows & Kelton, 1992; Letsky &
Greaves, 1996; Sainio et al, 1998; Boehlen et al, 1999).
Recommendation for investigation of suspected ITP in
pregnancy:
As in non-pregnant patients, the diagnosis of ITP is one
of exclusion. Benign gestational thrombocytopenia is
100 times more common but, as there are no definitive
diagnostic tests, it may be impossible to distinguish these
conditions until a non-pregnant platelet count is available. All women with platelet counts < 100 · 109 ⁄ l
should be screened for clinical or laboratory evidence of
pre-eclampsia, coagulopathy or autoimmune disease.
Bone marrow examination is unnecessary unless there is
suspicion of leukaemia or lymphoma. The routine
measurement of PAIg or platelet antibodies is not
recommended (Evidence Levels III ⁄ IV, Grade C recommendations).
OPTIONS FOR TREATMENT
Optimum management of ITP in pregnancy requires close
collaboration between the obstetrician, haematologist and
paediatrician. There are no high quality prospective studies
or randomized clinical trials to inform management of the
mother, delivery or the neonate. Recommendations are
based on clinical experience and expert consensus (Grade C
recommendation).
Management of the pregnant woman with ITP
The decision to treat the pregnant woman with ITP is based
on assessment of the risk of significant haemorrhage. The
count usually falls as pregnancy progresses, the greatest
rate of decline and nadir occurring in the third trimester
(Burrows & Kelton, 1992). Therefore, careful planning is
required to ensure a ‘safe’ platelet count at the time of
delivery. Frequency of monitoring depends on the individual
case, taking into account the absolute platelet count, rate of
change and proximity of delivery.
Targets for treatment
Asymptomatic patients with platelet counts > 20 · 109 ⁄ l
do not require treatment until delivery is imminent but
should be carefully monitored, both clinically and haematologically (Letsky & Greaves, 1996). Platelet counts of
> 50 · 109 ⁄ l are regarded as safe for normal vaginal
delivery (Letsky & Greaves, 1996) and some experts extend
this to levels of 30–50 · 109 ⁄ l (Lichtin, 1996). A platelet
count of > 50 · 109 ⁄ l is also safe for Caesarian section but
would preclude the use of epidural anaesthesia for which
the platelet count should be > 80 · 109 ⁄ l. Because of the
theoretical risk of haematoma formation and neurological
damage, spinal or epidural anaesthesia is not recommended
if the platelet count is < 80> 50 · 109 ⁄ l (Letsky & Greaves,
1996). There is no evidence that the template bleeding time
predicts the risk of haemorrhage in this situation.
588
Guideline
Treatment options
The major treatment options for maternal ITP are
corticosteroids or IVIg. Vinca alkaloids, androgens and
most immunosuppressive drugs should not be used in
pregnancy although azathioprine has been used safely in
transplant patients.
If the duration of treatment is likely to be short, i.e.
starting in the third trimester, corticosteroids are a costeffective option. An initial dose of 1 mg ⁄ kg (based on prepregnancy weight) is recommended (Burrows & Kelton,
1992; Letsky & Greaves, 1996), subsequently tapered to the
minimum haemostatically effective dose. Patients must be
carefully monitored for significant side effects such as
hypertension, hyperglycaemia, osteoporosis, excessive
weight gain and psychosis. As 90% of the administered
dose of prednisolone is metabolised in the placenta (Smith &
Torday, 1982), serious fetal side effects such as adrenal
suppression are unlikely. The only systematic study showed
no beneficial effect of low dose maternal steroids on the fetal
platelet count (Christiaens et al, 1990).
If steroid therapy is likely to be prolonged, significant side
effects occur or an unacceptably high maintenance dose is
required (perhaps > 7.5 mg prednisolone daily) IVIg therapy should be considered. There are no published comparative trials of steroids and IVIg in pregnancy. The
conventional dose of IVIg is 0.4 g ⁄ kg ⁄ d for 5 d although
1 g ⁄ kg for 2 d has been used successfully and may be more
convenient (Burrows & Kelton, 1992). The response rate
(80%) and duration of response (2–3 weeks) is similar to
non-pregnant patients. After an initial response, repeat
single infusions can be used to prevent haemorrhagic
symptoms and ensure an adequate platelet count for
delivery. The ability of maternal IVIg therapy to improve
fetal platelet counts remains controversial (Nicolini et al,
1990). IVIg carries the same potential risks and side effects
as in the non-pregnant patient and the financial cost is
much higher than corticosteroids.
Therapeutic options for those women with severely symptomatic ITP refractory to oral steroids or IVIg include high
dose intravenous methyl prednisolone (1000 mg), perhaps
combined with IVIg, or azathioprine (Letsky & Greaves,
1996). From available data, the latter appears to cause no
significant problems to either mother or fetus (Erkman &
Blythe, 1972; Price et al, 1976; Alstead et al, 1990). Splenectomy in pregnancy is now rarely performed. If essential, it
is best carried out in the second trimester and may be
successfully performed by the laparoscopic route, although
this may be technically difficult beyond 20 weeks gestation.
Recommendation: (All Grade C)
• Asymptomatic women with platelet counts > 20 ·
109 ⁄ l do not need treatment until delivery is imminent
• Platelet counts > 50 · 109 ⁄ l are safe for normal
vaginal delivery in patients with otherwise normal
coagulation
• Platelet counts > 80 · 109 ⁄ l are safe for caesarean
section, spinal or epidural anaesthesia in patients with
otherwise normal coagulation
• In women who need treatment, both oral corticosteroids and IVIg appear to have a similar response rate to
the use of these agents in the non-pregnant patient
Although many clinicians now favour the use of IVIg
in pregnancy there are no good comparative studies
and the decision must take into account maternal
clinical factors and preference in addition to the
expense, availability and (remote) risks of microbial
transmission by IVIg.
• There are no convincing data on the effect (beneficial
or otherwise) of corticosteroids or IVIg on the
fetal ⁄ neonatal platelet count.
• Severe refractory ITP may respond to high dose IV
methyl prednisolone ± IVIg or azathioprine. If essential, splenectomy may be performed (ideally in the
second trimester) and the laparoscopic route may have
clinical advantages similar to those seen in nonpregnant patients.
Management of delivery and the newborn infant
Historically, management of the delivery in mothers with
ITP was dominated by concerns over the risk of severe
neonatal thrombocytopenia and haemorrhage. In 1976,
caesarean section was recommended for all patients based
on a reported perinatal mortality of 12–21%, largely due to
birth trauma and ICH (Murray & Harris, 1976). These data
were clearly selective and excessively pessimistic; more
recent reviews suggesting a neonatal mortality of around
0.6% (Burrows & Kelton, 1992). Large prospective studies
published in the 1990s show an incidence of severe
neonatal thrombocytopenia (< 50 · 109 ⁄ l) of 8.9–14.7%
with ICH occurring in 0–1.5% of infants (Bussel et al,
1991b; Burrows & Kelton, 1993). There is no evidence that
caesarean section is safer for the thrombocytopenic neonate
than uncomplicated vaginal delivery (which is unequivocally safer for the mother). In any event, most haemorrhagic events in neonates occurred 24–48 h after delivery
at the nadir of the platelet count.
Attempts have been made to predict which neonates will
have severe thrombocytopenia to inform management
decisions. It is reported (evidence level III) that the fetal or
neonatal platelet count cannot be reliably predicted from
the maternal platelet count, maternal platelet antibody
levels (by a variety of techniques) or a history of maternal
splenectomy for ITP (Samuels et al, 1990; Burrows &
Kelton, 1992; Letsky & Greaves, 1996; Sainio et al, 1998;
Boehlen et al, 1999). Fetal blood sampling by cordocentesis
has been explored (Scioscia et al, 1988) but this procedure
carries a mortality of 1–2%, which is at least as high as the
risk of ICH. Scalp blood sampling in early labour to
measure the fetal platelet count has also been advocated
(Scott et al, 1980). This procedure is technically difficult,
commonly produces artefactually low results because
of clotting due to exposure to vernix or amniotic fluid
and can cause significant haemorrhage. For these reasons,
both cordocentesis and fetal scalp blood sampling have now
been largely abandoned in the management of ITP in
pregnancy.
Guideline
In view of the difficulty in predicting those few neonates
with severe thrombocytopenia and the very low risk of
serious haemorrhage, it is now generally agreed (Level III
evidence, Grade B recommendation) that the mode of
delivery in ITP should be determined by purely obstetric
indications (Bussel et al, 1991c; Burrows & Kelton, 1992;
Letsky & Greaves, 1996).
Following delivery, a cord blood platelet count should
be determined in all cases (Level III evidence, Grade C
recommendation). Those infants with subnormal counts
should be closely observed clinically and haematologically
as the platelet count tends to fall further to a nadir
between d 2 and 5 after birth (Burrows & Kelton, 1992).
Treatment of the neonate is rarely required. In those with
clinical haemorrhage or platelet counts < 20 · 109 ⁄ l
treatment with IVIg 1 g ⁄ kg produces a rapid response.
Life-threatening haemorrhage should be treated by platelet
transfusion combined with IVIg (Burrows & Kelton,
1992).
Severe thrombocytopenia and clinical haemorrhage in
neonates are sufficiently unusual in association with
maternal ITP that where they occur, neonatal alloimmune
thrombocytopenia should be excluded by laboratory testing.
This is important not only for the appropriate management
of the neonate, but also in relation to the antenatal
management of subsequent pregnancies.
OBSTETRIC ANAESTHETICS
Anaesthetic management options
The obstetric anaesthetist is often called upon to make a
decision regarding the advisability of regional analgesia and
anaesthesia in these cases. Several textbooks and articles
offer guidance on this subject, and the general trend in
recent years has been to lower the ‘cut-off point’ from a
platelet count of 80–100 · 109 ⁄ l (Beilin et al, 1997). In
fact, there is no evidence to support this sort of ‘‘allor-nothing’’ approach, and every case must therefore be
considered on its own merits, with the risk of the procedure
(epidural ⁄ spinal haematoma) balanced against the benefits
(pain relief, better blood pressure control, avoidance of
general anaesthesia).
When monitoring platelet levels, the trend as well as the
absolute value is important, and the mother with a rapidly
falling count should be regarded with more suspicion than
the one with a low, but stable, platelet level (Greaves &
Letsky, 1997). At the same time, the cause of the
thrombocytopenia must be taken into account since
different pathologies have different effects upon the haemostatic mechanism for a given platelet count. In general,
patients with a platelet count of > 80 · 109 ⁄ l in the absence
of pre-eclampsia are unlikely to have significantly altered
platelet function. Tests of platelet function, such as bleeding
time, are operator-dependent and therefore of limited
predictive value. Thromboelastography is a promising
development in this field, but its place in clinical practice
has yet to be determined, and will require further clinical
trials (Gorton & Lyons, 1999). Routine coagulation studies
are usually indicated in thrombocytopenia in case any other
589
defect should be present. The mother should always be
questioned about excessive bruising or bleeding since the
presence of these may signify impaired platelet function in
borderline cases.
The use of powerful non-steroidal anti-inflammatory
drugs for post-partum or post-operative analgesia should
be avoided in women with platelet counts less than
100 · 109 ⁄ l because of their anti-platelet activity which
may increase the risk of haemorrhage (Level IV Evidence,
Grade C Recommendation).
Venous thromboembolism (VTE) is the commonest cause
of maternal mortality in the UK and all women with ITP
should be considered for thromboprophylaxis if they are
undergoing surgical delivery, are immobilized by other
medical complications, have a congenital or acquired
thrombophilia (especially the antiphospholipid syndrome)
or recent venous thrombosis. In each case an individual
risk assessment must be made about the desirability and
safety of anticoagulant therapy taking into account factors
such as age, obesity and personal and family history.
Although there are no published data to guide clinical
practice, treatment or prophylaxis with standard doses of
unfractionated heparin (UFH) or low-molecular-weight
heparin (LMWH) should be used in women with platelet
counts > 50 · 109 ⁄ l (Level IV Evidence, Grade C Recommendation) in whom the risk of haemorrhage is very low.
In women regarded at especially high risk of VTE (e.g.
antiphospholipid syndrome, antithrombin deficiency) the
balance of risks would probably favour thromboprophylaxis
at platelet counts down to 50 · 109 ⁄ l, especially if LMWH
with its more favourable ‘therapeutic window’ is used. All
at-risk patients should use appropriate graduated compression hosiery and be considered for intermittent mechanical
pneumocompression of the calves during surgery (Level IV
Evidence, Grade C Recommendation).
Recommendation:
• The mode of delivery in women with ITP should be
decided by primarily obstetric indications. There is no
evidence to support the routine use of caesarean
section (Grade B)
• Platelet counts > 50 · 109 ⁄ l are safe for normal
vaginal delivery if coagulation is otherwise normal
• Platelet counts > 80 · 109 ⁄ l are safe for spinal ⁄ epidural anaesthesia or caesarean section if coagulation is
otherwise normal
• Women undergoing operative delivery should be
considered for thromboprophylaxis according to their
individual clinical risk factors. Standard prophylactic
doses of UFH or LMW heparin should be used if the
maternal platelet count is > 100 · 109 ⁄ l (Grade C)
• Non-steroidal anti-inflammatory drugs should be avoided for post-partum or post-operative analgesia in
women with platelet counts < 100 · 109 ⁄ l (Grade C)
• The risk of clinically dangerous thrombocytopenia in
the neonate is very low but cannot be predicted by
clinical or laboratory parameters in the mother.
Attempts to measure the fetal platelet count by
590
Guideline
cordocentesis or fetal scalp blood sampling are not
recommended as they carry more risks than potential
clinical benefits (Grade B)
• Because of the risk of haemorrhagic complications in
the neonate the application of scalp electrodes for
monitoring in labour and fetal blood sampling should
be avoided. The use of vacuum extraction (ventouse) is
contraindicated and complicated instrumental delivery
(e.g. rotational forceps) should be avoided if possible
(Grade C)
• Cord platelet counts should be measured in all
neonates of mothers with ITP and those with subnormal levels monitored clinically and with daily counts
until after the nadir which usually occurs on d 2–5
after delivery (Grade C)
• Treatment of the thrombocytopenic neonate should be
reserved for those with clinical evidence of haemorrhage or a platelet count < 20 · 109 ⁄ l when there is
usually a prompt response to IVIg (1 g ⁄ kg). Lifethreatening haemorrhage should be treated with
immediate platelet transfusion and IVIg (Grade C).
MANAGEMENT OF MENORRHAGIA
For patients with ITP in whom heavy menstrual bleeding
occurs, symptom control may be achieved using tranexamic
acid and ⁄ or oral contraceptives. The Mirena coil is a
progestogen-loaded intrauterine contraceptive that induces
endometrial atrophy, and is effective in controlling menorrhagia.
PATIENT SUPPORT
The ITP Support Association was formed in 1995 to offer
support to those with adult, childhood and maternal ITP.
Assisted by its medical advisors the Association publishes a
quarterly newsletter and a wealth of reader friendly booklets
and factsheets on ITP and its associated concerns, including
guidelines for schools, protocol for dentists of affected
patients, splenectomy patient’s guide and holiday guidelines. ITP HealthCare cards are supplied for a small fee,
giving personal details on a wallet-size laminated card in
case of emergency.
Annual national conventions featuring ITP specialists
from the UK and USA allow patients to overcome their
feelings of isolation by meeting fellow sufferers. The
Association has funded research and part funded the
National Register of Patients and the first ITP Specialist
Nurse. By sending an A5 SAE with 2x 1st class stamps to
The ITP Support Association, Synehurste, Kimbolton Road,
Bolnhurst, Bedfordshire, MK44 2EW, UK, ITP sufferers ⁄ families can receive a free information pack. There is
no membership fee, the ITP Support Association is run by
volunteers and relies mainly on voluntary donations to fund
its operation. Further information can be found on http://
www.itpsupport.org.uk and Where to Get Help patient
leaflets can be ordered free of charge by e-mailing shirley@
itpsupport.org.uk.
ACKNOWLEDGMENTS
The section on paediatric ITP is based on an article by Dr
Bolton-Maggs (2002), written for Current Paediatrics and is
reproduced with permission by Elsevier Science Ltd.
DISCLAIMER
Although the advice and information contained in these
guidelines is believed to be true and accurate at the time of
going to press, neither the authors nor the publishers can
accept any legal responsibility for any errors or omissions
that may have been made.
British Committee for Standards in
Haematology General Haematology Task Force
WORKING PARTY
Dr Drew Provan, Bart’s & The London, Queen Mary’s School
of Medicine and Dentistry, London, UK
Professor Adrian Newland, Bart’s & The London, Queen
Mary’s School of Medicine and Dentistry, London UK
Dr Derek Norfolk, Department of Haematology, General
Infirmary at Leeds, Leeds, UK
Dr Paula Bolton-Maggs, Department of Haematology,
Alder Hey Children’s Hospital, Liverpool, UK
Professor John Lilleyman, Bart’s & The London, Queen
Mary’s School of Medicine and Dentistry, London, UK
Professor Ian Greer, Department of Obstetrics, University
of Glasgow, Glasgow Royal Infirmary, Glasgow, UK
Dr Anne May, Department of Anaesthetics, Leicester
Royal Infirmary, Leicester, UK
Dr Mike Murphy, National Blood Service, Department of
Haematology, Oxford Radcliffe Hospitals, and University of
Oxford, UK
Dr Willem Ouwehand, Department of Transfusion Medicine, Cambridge and NBS Cambridge
Mrs Shirley Watson, ITP Support Association, Bedford,
UK
Classification of Evidence Levels
Ia
Ib
IIa
IIb
III
IV
Evidence obtained from meta-analysis of randomized
controlled trials
Evidence obtained from at least one randomized
controlled trial
Evidence obtained from at least one well-designed
controlled study without randomization
Evidence obtained from at least one other type of
well-designed quasi-experimental study*
Evidence obtained from well-designed non-experimental
descriptive studies, such as comparative studies,
correlated studies and case studies
Evidence obtained from expert committee reports or
opinions and ⁄ or clinical experience of respected authorities
*Refers to a situation in which implementation of an intervention
is outwith the control of the investigators, but an opportunity exists
to evaluate its effect.
Guideline
Classification of Grades of Recommendations
A
B
C
Requires at least one
randomized controlled trial
as part of a body of literature
of overall good quality and
consistency addressing specific
recommendation
Requires the availability of
well-conducted clinical
studies but no randomized
clinical trials on the topic
of recommendation
Requires evidence obtained
from expert committee reports
or opinions and ⁄ or clinical
experiences of respected
authorities. Indicates an
absence of directly applicable
clinical studies of good quality
Evidence
levels Ia, Ib
Evidence levels
IIa, IIb, III
Evidence
level IV
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Keywords: thrombocytopenia, investigation, management,
adults, paediatrics, pregnancy.

Guideline

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