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‫‪dr2003eg@hotmail.com‬‬
‫(البقرة‪)32:‬‬
INTRODUCTION
dr2003eg@hotmail.com
Immune thrombocytopenic purpura (ITP) is an
acquired disease in which autoantibodies to
platelets cause their sequestration and destruction
by mononuclear macrophages, principally in the
spleen.
the number of circulating platelets decreases
(thrombocytopenia), resulting in a characteristic
bleeding tendency (purpura) .
Immune thrombocytopenic purpura (ITP) is
traditionally divided in acute and chronic forms
based on the duration of the disease.
A minority of children with idiopathic or immune
thrombocytopenic purpura (ITP) have the
refractory chronic form with bleeding problems
(stage III or IV).
• Characters:
• Immune
(idiopathic)
thrombocytopenic
purpura (ITP) is a syndrome characterized by:
• 1: Thrombocytopenia (platelet count less than
100 x 109 /L).
• 2: Shortened platelet survival.(chromium -51
labeled platelets have
a life span of a few
minutes to 1-4 hours).
• 3: Presence of antiplatelet antibody in the
plasma.
• 4: Increased megakaryocytes in the bone
marrow.
Classification:
This condition may be acute, chronic or recurrent.
1. Acute form, the platelet count return to normal (>150 x
109/L) within 6 months after diagnosis and relapse does
not occur.
2. Chronic form, the platelet count remains low after 6
months.
3. Recurrent form, the platelet count decreases after having
returned to normal levels. In adults, the chronic form is
more common, whereas in children, the acute form is
more common.
●A minority of children with idiopathic or immune
thrombocytopenic purpura (ITP) have the refractory
chronic form with bleeding problems (stage III or IV).
Chronic refractory idiopathic thrombocytopenic
purpura (ITP) is defined as ITP with persistent
thrombocytopenia despite conventional initial
management with Prednisone and splenectomy
Pathophysiology
•
Recent articles have revealed the dominance of a proinflammatory state in ITP following a relatively
benign viral or environmental trigger
•
In addition, several articles have documented the
persistence of inflammatory cytokines. and disturbed
T cell apoptosis in childhood ITP. every child and
adult has the potential to form autoantibodies to
platelets. For unclear reasons, these self-reactive
antiplatelet clones are not deleted during fetal
development and persist in the antibody repertoire of
the mature individual
Pathogenesis can be summarized in
three steps:
1:Platelet Autoantibodies and Antigens:
There are two types of mechanisms for the role of
auto antibodies in ITP:
A: Autoantibodies against Platelets:
B: Autoantibodies against Megakaryocytes:
2: Platelets Clearance:
3: Infections
Diagnosis of ITP
A. clinical Findings
Typically, children with acute ITP appear healthy and the physical
examination is unremarkable except for
Skin Ecchymoses and petechiae
Mucous membranes
A small number of patients have ‘wet purpura’ with oral blood
blisters or mucocutaneous or subconjunctival Bleeding from the nose
gums, Mucous membranes, gastrointestinal tract, or kidneys is not
uncommon, Menorrhagia may occur and may be severe.
Hematemesis and melena are infrequent.
Internal organs
Bleeding may occur into the following organs:
1. Central nervous system a serious complication
2. Retinal hemorrhage
3. Middle ear: uncommon leading to hear impairment
4. Deep muscle hematoma and hemarthrosis: rare.
Signs
With exception of hemorrhagic manifestation, the
physical examination is not significant
Usually, there is neither pallor nor hepatosplenomegaly.
A palpable spleen is usually suggestive of a secondary
cause (leukaemia, systemic lupus erythematosus,
infectious mononucleosis, or hypersplenism) but the
splenic tip may be palpable in 5–10% of patients with
acute ITP.
Cervical lymphadenopathy is not present unless the
precipitating factor is viral illness
B. Laboratory Findings
A complete blood count (CBC) and peripheral blood
smear examination remain the most important
laboratory tests
The CBC should be within normal limits for age
(normal hemoglobin levels, red blood cell count
indices, and total and differential white blood cell
counts) except for the low platelet count and mildly
elevated platelet size.
A peripheral smear should demonstrate normal
morphology of all cell lines with a few large
platelets.
Tests to consider when a patient does not meet the criteria
forchildhood immune thrombocytopenic purpura or has
persistent thrombocytopenia
---------------------------------------------------------------------------------Bone marrow aspiration
Coagulation profile: prothrombin time, partial thromboplastin
time
Specific serum antibody assays for glycoprotein IIb/IIIa
Viral serology (HIV, EBV, CMV, parvovirus B19, VZV, hepatitis
A, B, C, roseola)
Antinuclear antibodies, lupus anticoagulant
Direct antiglobulin test
Thyroid function studies
Quantitative serum immunoglobulins with IgG subclasses
Reticulated platelet count
Platelet function tests
----------------------------------------------------------------------------------
Common laboratory tests obtained in the thrombocytopenic patient at presentation.
Complete blood count and differential review Rule out: Multilineage involvement leukemia or
aplastic/myelodysplasia
smear
Evaluate platelet size (giant or "dust-like")
Reticulocyte count
Hemolytic anemia or chronic blood loss
Blood type, Rh, antibody screen
Possible anti-D antibody treatment Autoimmune
hemolytic disease
Chemistry panel
Eliminate systemic disease, i.e., hemolytic
uremic syndrome, hepatitis, hemolysis, occult
malignancy with elevated LDH or uric acid
DIC screen
Sepsis, Kasabach-Merritt syndrome
Quantitative immunoglobulin levels
Rule out: common variable immune deficiency,
Wiscott-Aldrich
Viral titers/PCR
Cytomegalovirus, Epstein-Barr virus, human
immundeficiency virus
Collagen vascular panel (ANA, anti-DNA)
Older patients, especially those with more
chronic onset
History and physical findings not consistent with (ITP) of childhood.
History/Findings
Alternative Diagnosis
Thrombocytopenia present from birth
Amegakaryocytosis
Primary thrombocytopenia
Giant platelet syndromes
Weight loss and recurrent fevers
Malignancy, immune deficiencies
Bloody diarrhea
Wiskott Aldrich Hemolytic uremic syndrome
Recurrent infections or failure to thrive
Primary immune disorder, HIV
History or presence of jaundice
Autoimmune hemolytic disease
Hepatitis, cirrhosis with splenomegaly
Splenomegaly,lymphadenopathy
Autoimmune lymphoproliferative syndrome
(ALPS), primary immune disorders, Gauchers
malignancies, hypersplenism syndromes
Forearm or hand anomalies
Thrombocytopenia absent radii (TAR)
Fanconi’s syndrome
Malar rash, dermatomyocytis,
polymyocytis, eczema
Collagen vascular disease, Wiskott Aldrich
Cardiac malformation with or without DiGeorge Chromosome 22 microdeletions with large
syndrome
platelets, with or without Evans syndrome
C.Other Laboratory Tests
Additional tests should be considered in children
with persistent ITP of 3–6 months’ duration or in
whom secondary thrombocytopenia is suspected .
A-Specific
serum
antibody
assays
for
glycoprotein IIb/IIIa have a role in distinguishing
immune from non-immune thrombocytopenia in
adults with ITP; their value in pediatric patients
is limited ,
B- Assessment of platelet maturity by measuring
reticulated platelets may be helpful in the
diagnosis of ITP in children with atypical
presentations. Elevated reticulated platelet
counts are indicative of increased production.
Differential diagnosis of childhood immune
thrombocytopenic Purpura
Congenital syndromes
Fanconi anemia, thrombocytopenia-absent radii, Wiskott-Aldrich,
Alport, and Bernard Soulier syndromes, May-Hegglin anomaly, gray
platelet syndrome
Decreased platelet production
Acute leukemia, lymphoma, aplastic anemia, amegakaryocytic
thrombocytopenia, myelodysplastic syndrome, metastatic infiltration
Of bone marrow
Increased platelet destruction
Disseminated intravascular coagulation, thrombotic
thrombocytopenic
Purpura, hemolytic uremic syndrome, Evans syndrome.
• Criteria for the diagnosis :
1. Clinical examination: purpura with an otherwise
essentially normal physical examination, with no significant
splenomegaly and no lymphadenopathy
2. Platelet count and blood smears: thrombocytopenia only,
with no evidence of red cell or white blood cell abnormalities
3.
Bone
marrow:
normal to increased number of
megakaryocytes with normal myeloid and erythroid elements
4. Exclusion of secondary causes of thrombocytopenia,
such as hypersplenism, microangiopathic hemolytic anaemia,
disseminated intravascular coagulation, drug- induced
thrombocytopenia, SLE, infections such as EBV, HIV, and
parvovirus
Prognosis
1. Excellent; 50% recover usually within 1 month
and 70-80% recover Within 6 months.
2. Spontaneous remission after 1 year is uncommon,
although may occur even after several years.
3. When a demonstrable underlying cause of ITP
exists, the prognosis is related to cause.
4. Age older than 10 years, insidious onset, and
female gender are associated with the development
of chronic ITP.
5. Of all chronic patients, 50-60% eventually
stabilize without any therapy and without recourse to
splenectomy
Khalid @Show
• the recently published BSH (the British Committee for
Standards in Hematology, 2003) practice guidelines for
ITP in children clearly recommend that treatment be
considered on the basis of clinical symptoms and
cutaneous signs and not just platelet count alone.
• The ASH (the American Society of Hematology )
practice guidelines published in 1996 differ from those
of the BSH in that the triggers for initiating treatment
for children with ITP are based on a low platelet count
and the very small but definite risk of ICH, rather than
symptoms. (George et al, 1996) and minor purpura do
not require treatment or hospitalization. Children with
platelet counts of <20 000/uL and significant mucous
membrane bleeding, or children with platelet counts of
<10 000/uL and minor purpura, should receive
treatment with IVIG, IV RhIG, or corticosteroids to
increase the platelet count .
• Firstly, the severity and bleeding risk of
the patient have to be considered. A
patient with stage I or II will only be
actively
treated
in
special
circumstances. In patients with stage III
or IV, the aim of treatment is to reach
stage II or stage I.
Staging of immune thrombocytopenic purpura (ITP)
Stage
I
II
Symptoms/platelet count
No bleeding; mean platelet
Count above 30 x109/L
Mild skin bleeding; mean
platelet count above 30
x
strategy of
III
IV
Moderate skin and/or
mucosal bleeding; mean
platelet count 10–30 x 109/L
Severe bleeding with drop in
hemoglobin/hematocrit level;
platelet count below 10 x109/L
Recommendation
No drug intervention
Reach individual consensus
109/L
parents/patient fo
watchful observation
Aim: normal lifestyle without drug
treatment, appropriate intervention
with regard to sport, special
events, surgery etc
Drug treatment in the presence of
active bleeding
Aim: reach stage II or stage I
Intervention, including drug
treatment and eventually
substitution of
thrombocytes and/or
A: Pharmacologic Therapy
Comparison of acute (ITP) treatment regimens in children.
Treatment Response
IV Immunoglobulin
(1-2 g/kg)
Anti-D
Immunoglobulin (75 µg/kg)
Response > 20,000 at 60-70% of patients
48 hours
70–80% of patients
77% of patients
Common side effects
Post-infusion
headache, vomiting,
allergic reactions,
fever, chills
Hemolysis,
headache
Rare
but
reactions
Prednisone
(4 mg/k/day 1-7, max
60 mg)
Weight gain,
irritability,
hypertension, stomach
pain,
hyperglycemia
chills,
fever,
severe Gastic ulcer, reflux,
bleeding,
hypertensioninduced ICH
Anaphylaxis, aseptic
Massive hemolysis with
meningitis,
renal associated back
failure
Pain myalgia, anemia
Duration of initial Wide range of
response (days)
response
after 30 days of
weaning from initial
dose to 0
21-72
days
with 21–48 days based on the75
platelet count greater µg/kg dose
than 20,000/mm3
Figure 2. Mechanisms of Action of Therapies for Immune Thrombocytopenic Purpura.
1. Corticosteroids
Corticosteroids block the destruction of antibodycoated platelets by the reticuloendothelial system,
reduce bleeding by stabilization of capillaries, and
decrease the synthesis of antiplatelet antibodies
●Oral prednisone in a dose of 1–4 mg/kg (usually 2
mg/kg/day or 60 mg/m2/day continued until platelet
recovery and for 3–4 weeks) has been the gold
standard for treating ITP in children for several
decades.
•For more urgent treatment of acute severe
thrombocytopenia (platelet counts of <10 000/UL)
with mucosal or other acute bleeding, intravenous
methyl prednisolone (30 mg/kg/day for 3 days or
500mg/m 2/day; maximum 1g /day is the drug of
choice.
Recently, The ASH guidelines endorse the use of :
A - Prednisone: 4 mg/kg/day on days 1–7, 2 mg/kg/day on days
8–12, 1 mg/kg/day on days 13–17, tapered on days 18–20 with
discontinuation at day 21 or prednisone 4 mg/kg/day for 4 days
B - Dexamethasone: 20 mg/m2/day for 4 days every 28 days for
six courses, but it appears to be effective and well tolerated if
given in newly diagnosed patients daily for 4 days as a single
treatment.
Most pediatricians in the UK prefer to use corticosteroids as
first-line treatment for ITP in children.
The BSH guidelines endorse the use of high-dose prednisolone
4 mg/kg/day as a very short course (4 days) or low- dose
prednisolone (1–2 mg/kg/day) for no more than 14 days,
regardless of response, for children with mucous membrane and
significant cutaneous bleeding.
• Continuing prednisone treatment beyond 2–3
weeks (even at minimal doses), or titrating it
against the platelet count is not recommended as
it is likely to induce additional adverse effects
of hypercortisolism, including facial swelling
(moon facies), weight gain, growth retardation,
cataracts, osteopenia, hypertension, and
increased susceptibility to infections. For these
reasons, prednisone is recommended for acute,
short-term (induction) treatment of ITP in
children,
but
long-term
(maintenance)
treatment is strongly discouraged, particularly
since less toxic alternative treatments are now
available.
2. Intravenous Immunoglobulin
Mechanisms of action of high-dose IVGG include:
A. Reticuloendothelial Fc-receptor blockade.
B. Activation of inhibitory pathways.
C. Decrease in autoantibody synthesis.
Indications of IVGG in acute ITP
A. Neonatal symptomatic immune thrombocytopenia and
infants less than 2 years of age who are generally more
refractory to steroid treatment
B. Alternative therapy to corticosteroid therapy but is much
more expensive, has significant side effect, is not
significantly clinically better than steroid therapy to
justify expense and side effect of its use.
Dosage
A. Acute ITP: a total dose of 2g/kg body weight given as
follow:
(1)0.4g/kg IVGG per day for 5days OR
(2)1g/kg per day for 2 days.
Lower doses of 800mg/kg/day as a single dose or 250
mg/kg/day for 2 days have been used with success, and
fewer side effects are seen, in younger children.
B. chronic ITP:
(1) Initial IVGG dose of 1g/kg body weight daily for 2
days, followed by periodic single infusions (0.4-1g/kg
depending on response) to
maintain platelet count at a safe level (<20,000/mm2)
(2) alternate-day corticosteroids is useful adjunctive
therapy when IVGG is used
3. Intravenous Anti-D Rhesus (Rh) 0
Immunoglobulin
• Compared with IVIG, IV RhIG has the advantages
of ease of administration and lower treatmentrelated costs .
• increasing the dose of IV RhIG from the
standard 50 µg/kg to an off-label dose of 75
µg/kg, administered as an infusion, may
increase efficacy without increasing adverse
effects.
• The principal disadvantages of IV RhIG are its
lack of efficacy for Rh (D)-negative patients and
for patients who have undergone a
splenectomy. The principal adverse effect of IV
RhIG is anemia due to anti-D-mediated immune
hemolysis.
• Rarely, patients have experienced acute
hemoglobinemia, hemoglobinuria, or acute renal
failure after an infusion of IV RhIG. To avoid the
possibility of symptomatic anemia associated
with excessive hemolysis, IV RhIG should not be
infused in a patient whose hemoglobin is <10
g/dL.
• B: Surgical Interventions
●Splenectomy
• Splenectomy was the only reliable treatment for
ITP. Response rates as high as 92% following
splenectomy have been reported in surgical
journals
• However, these optimistic assessments were based
on relatively short-term, post-surgical follow-up
and a general lack of understanding of the
importance of the spleen in limiting bacterial
infections. A current assessment of the relatively
few reports of long-term, follow-up of children
who have had splenectomies for ITP revealed
remission rates of 70–80% .
Short-term morbidity and mortality associated with
splenectomy have been reduced by the use of less
invasive laparoscopic techniques.
Post-splenectomy mortality due to bacterial sepsis,
which carried a fatality rate as high as 15 %,has been
dramatically reduced by immunizing children against
encapsulated organisms prior to splenectomy followed
by prophylactic penicillin for at least 1 year after
splenectomy.
However, a splenectomy is rarely indicated today in
children with ITP as spontaneous remissions continue to
occur up to at least 15 years from diagnosis, Several
relatively new effective non surgical treatments are
available, and all patients following splenectomy
continue to have a small, but life-long, potentially fatal
risk of bacterial sepsis. However, splenectomy should be
considered in children with chronic, persistent, and
severe ITP that has been present for more than 12–24
months and is having a significant impact on their
quality of life .
All children scheduled for a splenectomy require a
review of their immunization status. At least 2 weeks
prior to undergoing asplenectomy, children aged ≥
2years should be immunized with 23-valent
pneumococcal polysaccharide vaccine.
Haemophilus influenzae type b vaccine and
heptavalent pneumococcal conjugate vaccine should
also be provided depending on the patient’s age and
immunization history. The meningococcal vaccine is
also used for children aged ≥ 2 years. Daily penicillin
prophylaxis is recommended for children aged ≤ 5
years and should be continued for at least 1 year after
a splenectomy.
Treatment of children with life
threatening hemorrhage:
1: platelet transfusion
2: methylprednisolone 500mg/m2 IV per
day for 3day
3: IVGG 2g/kg
4: emergency splenectomy.
These measures can be used singly or in
combination, depending on severity and
response to treatment.
Management of Children with
Refractory ITP:
1 .Vinca Alkaloids
• An IV dosage of vincristine 1.5 mg/m2,
maximum 2mg, or vinblastine 0.1 mg/kg
bodyweight is given every 7 days for 4–6 weeks.
2. Azathioprine
• Azathioprine is given in a dosage of 1–4 mg/kg
bodyweight per day orally.
• Azathioprine should be given for at least 4
months, but no longer than 12 months.
3. Cyclophosphamide
• Cyclophosphamide is effective in 30–40% of
patients and is given orally at 1–2 mg/kg
bodyweight per day. If a response occurs
within 2 months, the treatment should be
continued for a total of 3 months and then
stopped.
4. Cyclic High-Dose Methylprednisolone
• Cyclic high-dose methylprednisolone (IV 20–
30 mg/kg bodyweight) or dexamethasone
(oral 1 mg/kg bodyweight) can be given on 3–
4 consecutive days every 4 weeks for 4
months.
5. Splenectomy
6. Plasmapheresis
Immunoadsorption
or
Protein
A
• Plasmapheresis
or
protein
A
immunoadsorption transiently reduces (auto)
antibodies and platelet activation.
• The response rate is low and the costs are high.
In children, this procedure is indicated in those
with high platelet-associated antibody levels
and severe bleeding.
Possible Future Treatment Options for
Refractory ITP
1-Treatment influencing antigenemia:
Platelet counts were improved after antibacterial
eradication of Helicobacter pylori
2-Treatment
response:
influencing
the
T-cell
immune
A-Cyclosporine.
B-CTLA-4-Ig
3-Treatment influencing the B-cell immune
response:
A- anti-CD20monoclonal antibody (rituximab): Within
three to four courses of rituximab (IV 375 mg/m2/week
X four weeks), approximately two-thirds of patients
had an increase in platelet count and some had longlasting responses (>6 months).
B-Anti-CD52 Monoclonal Antibody (Alemtuzumab
C- interferon-
4-Other options:
A- thrombopoietin.
B-autologous hematologic stem celltransplantation
Future Therapies for ITP
A-Thrombopoietin (TPO) Agents
AMG 531 and eltrombopag are the second-generation
TPO receptor agonists that share no sequence
homology with native TPO.
B-Specific Inhibitors of PhagocyteMediated Consumption of Platelets
A humanized antibody, GMA-161, has been developed
and used in 2 low-dose cohorts of 8 adults with chronic,
refractory ITP.
Mervat hesham