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Paediatric Haematology
Table 1: Staging and Management of Patients with Immune
Table 2: Summary of Immunomodulation
Thrombocytopenic Purpura
Immunomodulation Examples References
Stages/Bleeding Platelet (x10
9
/l) Management Antigen suppression Fcr on Antibiotics, virostatics, IVIG 11, 56, 57, 58,
1. Minor/mild bleeding, >10–20 Consent for observation dentritic cells activation 59, 60, 61, 62
normal lifestyle Toll like receptor
2. Moderate bleeding, <10–20 Punctual intervention Inhibition of T cells Cyclosporin A, 63, 64, 65, 66,
troublesome lifestyle to reach stage 1 and signalling tacrolimus, IVIG 67, 68
3. Severe, life-threatening Mostly <10 Intervention Regulation of autoreacitve B cells Anti-CD20/-CD52 42, 44, 45, 69,
bleeding and anti-idiotype network Antiidiotypic antibodies, IVIG 70, 71, 72, 73
Modulation of: Anti-D IgG, IVIG 9, 34, 74, 75,
Figure 1: ICIS Registry 1 – Follow-up of 308/2,031 Children with
• phagocytosis 76, 77, 78
Ongoing Immune Thrombocytopenic Purpura Six to 12 Months • complement
After Diagnosis – Platelet Count (x10
9
/l)
• apoptosis
100
Figure 2: Cascade of Immune Response
90
31.3%
25.7%
80
Antigen
Antigen-
70
presenting
cells
60
Ag
HLA
23.0%
82.5% ligands
IL-10
c
hildren
50
T cells
63.0%
Signalling
% of 40
>150
B cells/antibodies
30
20–150
FcR
45.7%
20
FcR
Complement
n
7.7%
>10–19 Phagocyte
Apoptosis
10 4.2%
9.8%
7.1% <10
0
Table 3: Routine Testing in Addition to Initial Laboratory
Initially 6 months 12 months
Analysis in Children with Persistent Immune Thrombocytopenic
Purpura of Three to Six Months’ Duration
Source: Pediatr Blood Cancer, 2006;46:351.
Bone marrow analysis, endocrine function, urine analysis, abdominal ultrasound
was the first targeted immunomodulation, which today is used in a
Antinuclear antibody, direct antiglobin, lupus anticoagulant, platelet antigen-specific
broad field of chronic inflammatory and autoimmune diseases.
6–9
In
antibodies, serum immunoglobulins with lgG subclasses, platelet function test,
1980, 300kg of IVIG was produced worldwide, which increased to
coagulation studies
over 60 tons until 2007 (personal communication by CSL Behring). Viral serology (HIV, CMV, EBV, VZV, rubeola, parvovirus B19 and others)
In 1994, thrombopoietic growth factor has been developed and its fearful of bleeding and tyrannised by low platelet counts. The outcome of
administration increased platelet counts in volunteers.
19
This first the individual patient cannot be predicted, although most children and
generation of thrombopoietic growth factor as recombinant human some adults show spontaneous resolvement or improvement of ITP.
thrombopoietin (rhTPO) and as pegylated human recombinant
megakaryocyte growth and development factor PEG rHu MGDF had to In two prospective Intercontintental Childhood ITP (ICIS) registries with
be stopped in clinical trials when autoantibodies against the newly diagnosed children (n=2,031 and 1,015, respectively) two-thirds of
administered factor (PEG rHu MGDF) were detected in healthy human patients initially had platelet counts below 20x10
9
/l.
2
In Registry II 20 of 629
subjects. A second generation of thrombopoietin-receptor agonists patients (3.2%) had severe bleeding, 150 (23.6%) showed moderate
(AMG 531 for subcutaneous use, eltrombopag and AKR 501 for oral bleeding and 459 (73%) showed mild or no bleeding initially.
21
This is in
use and others) stimulate growth of thrombopoietin-dependent cell accordance with the British assessment
22
and a single-centre analysis in the
lines and increase platelet counts. Within the last five years these US.
23
Intracranial bleeding occurs in about 1:500–700 children, and is fatal
second-generation thrombopoietic factors have demonstrated safety, in one-third.
24
The initial management (mean platelet counts) in ICIS registry
tolerability and efficacy in patients with ITP.
19
Further studies (long-term I was as follows: about one-third of children received IVIG (8.1x10
9
/l) and
application, activation of platelet function etc.) have to be concluded one-third corticosteroids (13.3x10
9
/l), and the remaining one-third were
before approval for clinical use of these agent will be released. observed (28.6x10
9
/l).
2
In children with persistent ITP of three to six months
in duration, additional laboratory tests are recommended (see Table 1).
Although the serum level of thrombopoietin of patients with ITP is
normal or slightly increased, recent in vitro studies showed reduced Unlike ITP in adults, persistent thrombocytopenia is observed in 20–30% of
megakaryocyte production and impaired maturation in the presence of children and the rate of severe ITP is decreasing with duration of ITP (see
ITP plasma-containing autoantibodies against platelets
20
– apparently a Figure 1). In the above-mentioned registry I, follow-up data 12 months after
reason for efficacy in patients with ITP. diagnosis was evaluable for 308 children with persistent ITP at six months.
25
Between six and 12 months from diagnosis, 79 of the 308 children (25.6%)
Clinical Manifestation of Immune recovered with platelet counts above 150x10
9
/l, while 229 (74.4%) still had
Thrombocytopenic Purpura persistent ITP. The distribution of platelet counts at diagnosis at six and 12
The clinical manifestation, severity of bleeding and platelet count and the months showed that the number of children with platelet counts below 10
natural history of ITP are heterogenous. Child patients and their parents are and 20x10
9
/l markedly decreased within the first 12 months of diagnosis.
90 EUROPEAN HAEMATOLOGY
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